Restenosis: A Guide to Therapy

RESTENOSIS: A GUIDE TO THERAPY Dedicated to my wife, Monica, and to my children, Nathaniel and Kimberly, for all of t...

Author: David Faxon

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RESTENOSIS: A GUIDE TO THERAPY

Dedicated to my wife, Monica, and to my children, Nathaniel and Kimberly, for all of their support

RESTENOSIS: A GUIDE TO THERAPY Edited by

David P Faxon MD Chief Section of Cardiology The University of Chicago Chicago IL USA

MARTIN DUNITZ

© 2001 Martin Dunitz Ltd, a member of the Taylor & Francis Group First published in the United Kingdom in 2001 by Martin Dunitz Ltd, The Livery House, 7–9 Pratt Street, London NW1 0AE This edition published in the Taylor & Francis e-Library, 2003.

Tel.: Fax.: E-mail: Website:

+44 (0) 20 7482-2202 +44 (0) 20 7267-0159 [email protected] http://www.dunitz.co.uk

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. A CIP record for this book is available from the British Library. ISBN 0-203-21303-3 Master e-book ISBN

ISBN 0-203-27013-4 (Adobe eReader Format) ISBN 1 85317 897 7 (Print Edition)

Composition by Wearset, Boldon, Tyne and Wear

iv

Contents

Preface Contributors

vii ix

8

Drug-coated stent for restenosis Marco A Costa

9

Gene transfer for coronary restenosis 129 Ripudamanjit Singh and Robert D Simari

1

Defining the clinical problem Thomas Feeney and David P Faxon

1

2

Pathophysiology of restenosis John D Altman, Antoni Bayes-Genis and Robert S Schwartz

9

3

4

5

6

7

Clinical presentations and noninvasive assessment of restenosis 21 Joel W Heger and Sanjeev D Ravipudi Clinical, biochemical, angiographic and intravascular ultrasound predictors of restenosis 39 Stefan Verheye and Glenn Van Langenhove Importance of physiologic assessment pre- and post intervention Michael D Eisenhauer and Morton J Kern

113

10 Stenting to prevent restenosis J Aaron Grantham and David R Holmes, Jr

145

11 Debulk/ stenting Antonio Colombo and Evangelia Karvouni

159

12 Management of in-stent restenosis 179 Richard A Howard and Alice K Jacobs 13 Management of restenosis through radiation therapy Ron Waksman

203

55

The role of intravascular ultrasound in the prevention and treatment of restenosis 77 Shinichi Shimodozono, Yasuhiro Honda, Heidi N Bonneau and Peter J Fitzgerald Pharmacological approaches to prevent restenosis 97 Vatsal H Mody, Alex Durairaj and Anil O Mehra

14 Radiation for restenosis Paul S Teirstein

221

15 Radioisotope stents Tim A Fischell

241

16 Restenosis in the peripheral vasculature Manu Rajachandran and Robert Schainfeld Index

251

273

v

vi

Preface

When Dr Andreas Grüntzig initially performed coronary angioplasty more than twenty years ago, it was estimated that no more than five percent of patients would be suitable for the procedure. Clearly, this has not been the case, with more than one and a half million patients undergoing the procedure each year in the United States. Despite enormous advances in technology that have resulted in increased success and reduced complications, restenosis has remained the Achilles’ heel of angioplasty. Over the past twenty years, there have been major advances in our understanding of the pathophysiology of restenosis that have allowed new and effective treatments for restenosis. This book addresses the major issues of restenosis, from clinical presentation and pathophysiology to current therapy. Specifically, the role of stents and

new interventional devices in the treatment of restenosis are discussed. In addition, several chapters have been devoted to the emerging technologies of intravascular radiation therapy and drug eluding stents, as both have shown considerable promise in reducing the incidence of restenosis. The chapters in this book are written by internationally recognized authorities in each of their respective areas of expertise. We have attempted to provide not only a thorough review of the topic, but also the most current information relative to it. We hope you find this book of value in understanding this rapidly advancing field and that this knowledge will be a foundation for future research that ultimately leads to an effective treatment for restenosis. David P Faxon

vii

viii

Contributors

John D Altman, MD

Michael D Eisenhauer, MD

Center for Applied Vascular Biology Mayo Clinic ROCHESTER MN 55905-0001 USA

Chief, Cardiology Service William Beaumont Army Medical Center El Paso TX 79920 USA

Antoni Bayes-Genis, MD

David P Faxon, MD

Mayo Clinic ROCHESTER MN 55905-0001 USA

Chief, Section of Cardiology University of Chicago Chicago IL 60637 USA

Heidi N Bonneau, MS, RN Stanford University Medical Center Stanford CA 94305-5637 USA

Marco A Costa, MD, PhD Department of Interventional Cardiology Institute Dante Pazzanese of Cardiology Ibirapuera Sao Paulo Brazil

Antonio Colombo, MD Director, Cardiac Catheterization Laboratory EMO Centro Cuore Columbus 20145 Milano Italy

Alex Durairaj, MD Medical Center Division of Cardiology Los Angeles CA 90033 USA

Thomas Feeney, MD Pasadena CA 91107 USA

Tim A Fischell, MD, FACC Director of Cardiovascular Research Heart Institute at Borgess Medical Center Kalamazoo MI 49001 USA

Peter J Fitzgerald, MD, PhD Associate Professor of Medicine Stanford University Medical Center Stanford CA 94305-5637 USA

J Aaron Grantham, MD, FACC Division of Cardiovascular Disease and Cardiac Catheterization Laboratory Mayo Clinic Rochester MN 55905 USA

ix

CONTRIBUTORS

Joel W Heger, MD

Morton J Kern, MD, FACC

Division of Cardiology University of Southern California School of Medicine Los Angeles CA 90033 USA

Director, JG Mudd Cardiac Catheterization Laboratory St Louis University School of Medicine St Louis MO 63110 USA

David R Holmes, Jr, MD

Anil O Mehra, MD

Consultant in Cardiovascular Diseases and Internal Medicine Mayo Clinic Rochester MN 55905 USA

Yasuhiro Honda, MD Assistant Director, Cardiovascular Care Analysis Laboratory Stanford University Medical Center Stanford CA 94305-5637 USA

Richard A Howard, MD Senior Fellow in Cardiology Section of Cardiology Boston Medical Center Boston MA 02118 USA

Alice K Jacobs, MD Professor of Medicine, Director, Cardiac Catheterization Laboratory and Interventional Cardiology Section of Cardiology Boston Medical Center Boston MA 02118 USA

Evangelia Karvouni, MD Columbus Hospital 20145 Milano Italy

x

Medical Center Division of Cardiology Los Angeles CA 90033 USA

Vatsal H Mody, MD Medical Center Division of Cardiology Los Angeles CA 90033 USA

Manu Rajachandran, MD Medical Director, Comprehensive Vascular program, Deborah Heart and Lung Center Assistant Professor of Medicine Division of Vascular Medicine SMC4DVM St Elizabeth’s Medical Center Boston MA 02135-2997 USA

Sanjeev D Ravipudi, MD Division of Cardiology University of Southern California School of Medicine Los Angeles CA 90033 USA

CONTRIBUTORS

Robert Schainfeld, MD

Paul S Teirstein, MD

Assistant Professor of Medicine, Tufts University School of Medicine and Director, Noninvasive Vascular Laboratory Division of Vascular Medicine St Elizabeth’s Medical Center Boston MA 02135-2997 USA

Director, Interventional Cardiology Scripps Clinic and Research Foundation La Jolla CA 92307-1027 USA

Robert S Schwartz, MD Consultant in Cardiovascular Diseases and Internal Medicine Mayo Clinic Rochester MN 55905-0001 USA

Stefan Verheye, MD Cardiovascular Translational Research Institute, Middelheim, Antwerp, Belgium and Interventional Cardiology Middelheim Hospital 2020 Antwerp Belgium

Glenn Van Langenhove, MD, PhD Shinichi Shimodozono, MD Stanford University Medical Center Stanford CA 94305-5637 USA

Middelheim Hospital 2020 Antwerp Belgium

Ron Waksman, MD, FACC Robert D Simari, MD Associate Professor of Medicine Mayo Clinic Rochester MN 55905-0001 USA

Ripudamanjit Singh, MD

Professor of Medicine (Cardiology), Georgetown University Director of Experimental Angioplasty Cardiology Research Foundation Washington Hospital Center Washington DC 20010 USA

Department of Cardiology Mayo Clinic Rochester MN 55905-0001 USA

xi

1 Defining the clinical problem Thomas Feeney and David P Faxon

Introduction Andreas Grüntzig first introduced percutaneous transluminal coronary angioplasty (PTCA) in 1977, however, 15 years earlier Charles Dotter conceived the idea of angioplasty and performed the initial clinical studies in peripheral vessels.1 Since its inception, the technique has become the most commonly performed coronary revascularization procedure in the world, with an estimated one million procedures per year. While the technique initially used only balloon catheters to enlarge the vessel lumen, today, atherectomy, laser, and stents complement the technique, with nearly 70% of procedures utilizing stents.2 Accordingly, the technique is more commonly referred to today as percutaneous coronary intervention or PCI to reflect these changes. Although major advances in equipment, pharmacology and techniques have led to wider application and improved success with reduced complications, restenosis remains the primary limiting factor in long term vessel patency (Table 1.1). Restenosis, or renarrowing of the treated vessel segment, occurs in approximately 30% of patients within 9 months of the procedure and accounts for significant morbidity and health care expenditures. Numerous clinical and experimental trials have studied mechanical and pharmacological approaches to the problem, but nearly all have been unsuccess-

ful. Pharmacological trials have evaluated platelet inhibitors, thrombin inhibitors, lipid lowering, fish oil, steroids, angiotensin converting enzyme (ACE) inhibitors, antiinflammatories and gene therapy to inhibit smooth muscle cell proliferation, antioxidants, and antiproliferative agents.3 Despite the advances in interventional techniques and pharmacotherapy, restenosis remains the Achilles heel of angioplasty. The formidable challenge ahead is to better understand restenosis and develop a mechanistic approach to its treatment.

Mechanism of angioplasty In an effort to gain further insight into the restenotic process, the mechanism of percutaneous coronary intervention (PCI) must be understood.4 At the time of PCI, the balloon stretches the arterial wall and produces tears in the atherosclerotic plaques in order to produce a larger luminal area. The vessel then progresses through a complex process consisting of initial elastic recoil, subsequent thrombosis and later, intimal thickening and vascular remodeling. Elastic recoil is defined as the difference between inflated balloon diameter and minimal lumen diameter upon balloon deflation. The degree of elastic recoil depends on the viscoelastic properties in the atherosclerotic plaque and the arterial wall. Most of the elastic recoil occurs within 30

1

DEFINING THE CLINICAL PROBLEM

Variable Years No. of patients New devices % MVD Angiographic success Clinical success In hospital Death (%) MI (%) CABG (%) Restenosis TVR

Grüntzig 1977–80 169 No 42 79 – 0 7 2.9 30 16

NHLBI-I 1977–81 1156 No 25 68 61 1.2 4.9 5.8 32 21

NHLBI-II 1985–86 1802 No 53 91 78 1.0 4.3 3.4 – 30

MCD 1990–94 3787 Yes 51 89 86 0.4 5.2 2.7 – 23

NHLBI-III 1997–98 2700 69% 66 93 93 0.6 2.5 0.7 – 20.3

PCI, percutaneous coronary intervention; NHLBI, National Heart, Lung and Blood Institute; MCD, multivessel coronary disease; MVD, mitral valve disease; MI, myocardial infarction; CABG, coronary artery bypass graft; TVR, target vessel revascularization.

Table 1.1 Changes in PCI practice and outcomes.

minutes after balloon deflation but may also occur up to 24 hours after the procedure. This elastic recoil can result in as much as a 50% decrease in cross-sectional area. This recoil is more common after PCI, especially when performing interventions on eccentric and ostial lesions. In terms of device predilection, elastic recoil is greatest after PCI, intermediate after directional coronary atherectomy (DCA) and does not significantly occur after stenting. Angiographic analysis suggests that the early recoil is associated with a greater incidence of restenosis. A partial explanation for the benefits of stenting in reducing restenosis may relate to the elimination of this elastic recoil. PCI works by stretching and thus, injuring the vessel wall. In the process of injuring the wall, the endothelial lining is completely removed. Almost immediately following an intervention, with any device, the subendothelial structures are exposed to circulating blood elements. Platelets are immediately laid down

2

through adhesion of the platelet glycoprotein (GP)-1a receptor to collagen and von Willebrand’s factor. Aggregation ensues and can in some cases lead to thrombotic occlusion or abrupt closure of the vessel. Over the next few days, a significant inflammatory response leads to infiltration of polymorphonuclear cells initially, and subsequently, monocytes and macrophages. These blood elements (including platelets), as well as injury to the smooth muscle cells, result in release of a number of growth factors and cytokines that stimulate smooth muscle cell migration and proliferation into the injured area. The fibroblast within the adventitia is felt by many to be an important component of this cellular proliferation process, as well. Finally, the late stages of healing involve remodeling of the extracellular matrix with the production of collagen and this process may lead to generalized geometrical remodeling of the vessel, with either enlargement or constriction. This further

CLINICAL COURSE

aggravates the restenosis process. Clinical studies have supported the concept that remodeling is the most dominant factor in restenosis, accounting for ⬎ 60% of ultimate lumen loss.

Definition of restenosis Initially the field was hampered by a wide variety of angiographic and clinical definitions that led to widely disparate incidences of the problem (Table 1.2).5 Grüntzig proposed that restenosis be defined as the loss of 50% of the gain in initial lumen diameter. The National Heart Lung and Blood Institute (NHLBI) proposed four definitions, which included Grüntzig’s initial definition. The Thorax Center proposed a loss of more than 0.72 mm in lumen diameter, measured by quantitative methods, at follow-up. However, Dr Grüntzig subsequently proposed that restenosis be defined as more than a 50% stenosis at the time of follow-up angiography, a definition that is now widely accepted as the angiographic definition of restenosis. While this definition is practical and easy to use, it does not accurately reflect the biological process that results in restenosis. It has been demonstrated by Serruys et al that when restenosis is defined as the absolute decrease in lumen diameter, the majority of patients show as least some degree of restenosis and the distribution follows a Gaussian curve.6 In addition, it was shown by Kuntz and Baim that the absolute loss in lumen diameter (late loss) was inversely related to the acute gain in lumen diameter.7 It was also demonstrated that the ratio of late loss to acute gain approximated 50% with nearly all interventional techniques. Late loss ratio is therefore, a much better index of the biological process, since it takes into account the degree of initial

change in lumen diameter, presumably a measure of the damage to the vessel wall. Clinical restenosis has also been defined in various ways. Currently, the most accepted definition of clinical restenosis is target vessel or target lesion revascularization, defined as the recurrence of symptoms with angiographic evidence of restenosis in the same vessel or in the same lesion and a subsequent PCI or surgery of that lesion. Earlier definitions had not required a revascularization and therefore, a large number of patients who had medically managed borderline lesions were also defined as having restenosis. Defining restenosis as target vessel revascularization (TVR) is most relevant to the patient, since it accurately reflects his or her risk of needing another procedure as a result of restenosis. The incidence of TVR or target lesion revascularization (TLR) is approximately half that for angiographic restenosis. However, because TVR closely parallels angiographic restenosis, it is commonly used as a surrogate endpoint in clinic trials.

Clinical course The time course of restenosis is variable, but usually occurs within the first 9 months, with the median time at 3 months. It had been previously felt that restenosis occurred within the first 6 months of the procedure based on angiographic studies. However, since early angiographic restenosis is often silent, clinical restenosis or TVR occurs later, but usually before 9 months. Also, it rarely, if ever, occurs in the first month and recurrence of symptoms in this time period usually reflects either late subacute thrombosis or as a result of disease in other vessels that were not dilated. Restenosis can occur after 9 months and has been reported to occur up to 7 years after the procedure at a rate of 1–2% per year, the same as for progression of disease. It is doubtful that

3


Associated Clinical Diabetes Unstable angina Variant angina Dialysis Tobacco use Primary PCI Hypercholesterolemia Male gender Previous MI Hypertension Age Previous restenosis Long lesion (⬎ 20 mm) Multivessel Multilesion SVG (prox & body) Chronic total occlusion Collaterals to dilated vessel Ostial stenosis Angulation (⬎ 45°) Eccentricity Calcification Bifurcation lesion Thrombus Proximal location LIMA SVG (distal lesion) Procedural Pressure gradient ⬎ 20 mmHg Residual stenosis ⬎ 30% Balloon inflation variables Number of inflations Inflation time Balloon material Maximum inflation Inflation technique

Possibly associated

No association

x x x x x x x x x x x x x x x x x x x x x x x x x x x x x

x x x x x

PCI, percutaneous coronary intervention; MI, myocardial infarction; SVG, saphenous vein graft; LIMA, left internal mammary artery.

Table 1.2 Clinical, angiographic, and procedural variables identified as risk factors for restenosis.

4

STENTS AND RESTENOSIS

the biological process resulting in this late recurrence is the same as that responsible for restenosis and is more likely due to progression of atherosclerosis.

Predictors of restenosis A number of clinical studies have identified clinical and angiographic predictors of restenosis (Table 1.2).3 Clinical factors have included male gender, diabetes, unstable angina, variant angina, prior myocardial infarction (MI), dialysis, and prior restenosis. Angiographic variables have included long lesions, multivessel procedures, saphenous vein graft angioplasty, chronic total occlusion, ostial lesions, and bifurcation lesions. Procedural variables have included acute gain, final minimal lumen diameter (MLD), final percent stenosis, absence of a dissection, and thrombus. In large data banks, multivariate analysis has identified only a few of these variables to have independent influence.8 By far, the most potent predictor is the final MLD or percent stenosis. Other variables include lesion length, saphenous vein graft (SVG) lesions, instent restenosis, and unstable angina. However, these variables only explain 20–30% of restenosis, underscoring the poor understanding of the cause of restenosis.

Stents and restenosis In order to understand the process of restenosis, the trends in coronary intervention over the last 23 years should be analysed. One report from the Society of Cardiac Angiography and Interventions examined contemporary trends in percutaneous coronary procedures performed from 1996 to 1998.9 Nineteen thousand, five hundred and ten coronary procedures were performed during this time in 33 separate institutions. The most striking feature

is the dramatic increase in coronary stent implantation and a decrease in the use of balloon angioplasty. The overall use of ablative devices in general practice remained modest, with rotational atherectomy use increasing and directional atherectomy use decreasing. The use of platelet receptor antagonists remained modest, at 13% overall. In terms of the frequency of device selection, by 1998, stents were used 71% of the time. Other databases, such as the NHLBI PTCA Registry, also support these observations.10 Stent implantation has been shown to improve both short and long term results of coronary interventions.11 The use of these endoluminal scaffolds has dramatically increased since their introduction, as indicated above. One of the most compelling reasons for their widespread use is the favorable acute angiographic and clinical outcomes that result from their use. A comparison of overall hospital outcomes between balloon angioplasty and stent use from the NHBLI PTCA Registry showed a reduction in the frequency of emergency bypass surgery and the combined rates of death and emergent bypass surgery in the stent population. Two clinical trials, STRESS and BENESTENT, were instrumental in demonstrating the benefits of stenting in reducing restenosis and were largely responsible for the tremendous growth in their use. The mechanism for the reduction of restenosis by stents is the prevention of recoil and remodeling rather than a reduction in intimal hyperplasia. In fact, stents increase the amount of intimal hyperplasia due to the larger lumens achieved by the procedure. Despite the success of stents in preventing restenosis, recurrence following stenting occurs in approximately 15–20% of patients.12 The rates of restenosis are significantly higher in subgroups of patients with less favorable anatomy, ranging from 30% to 50%. Once

5


restenosis has occurred within the stent, treatment is difficult and re-restenosis is very high, ranging from 40% to 60%. Angiographic patterns of in-stent restenosis range from focal to diffuse (⬎ 10 mm) and may be only within the stent or on the edges (within 5 mm). The angiographic predictors of in-stent restenosis are prior restenosis, long lesion, multiple stents, small vessels, and high-pressure inflation (⬎ 16 atm).13 Patients with diabetes have a significantly higher restenosis rate independent of the device used, but within the diabetic subgroup, stents reduce the rate of restenosis.14 The mechanism of in-stent restenosis is entirely due to intimal hyperplasia, as remodeling is prevented by the stent. The treatment of in-stent restenosis is difficult, as nearly all devices are ineffective in reducing its incidence.15 The greatest potential treatment appears to be intravascular radiation. Recently, several devices have been approved for use. Although recent advances in stent deployment techniques and the use of aspirin and anti-platelet medications have improved the safety and reduced the length of stay and vascular complication rates, studies performed during the era of reduced anticoagulation suggest that the economic impact of stenting is not substantially different from earlier data obtained from the STRESS trial. It is likely

6

that the overall 1-year costs of stent deployment will remain $500 to $1000 higher compared with balloon angioplasty.16 Whether the issue of ‘routine’ vs ‘provisional’ stenting becomes a cost-effective strategy remains in question. Eventually, however, the in-hospital costs of stenting may decrease sufficiently to the point where the long-term costs of stenting are similar to balloon angioplasty. This, of course, will be dependent on the degree of reduction in restenosis.

Conclusion The field of interventional cardiology has made enormous advances over the past 20 years. However, to be able to provide an effective and long lasting treatment to patients with symptomatic coronary disease, it will be essential that the problem of restenosis be solved. This book, written by authoritative leaders in the field, addresses the current status of restenosis and the means to prevent it. New therapies, including pharmacological, gene, mechanical, and radiation, now offer considerable hope of reducing restenosis below 10% and perhaps even to the 5% range. Achieving this would provide a durable revascularization procedure that would have an early failure rate equal to coronary bypass surgery.

REFERENCES

References

1. 2. 3.

4. 5.

6.

7. 8.

9.

Grüntzig AR, Senning Å, Siegenthaler WE. Nonoperative dilation of coronary-artery stenosis. N Eng J Med 1979; 301:61–68. Topol EJ, Serruys PW. Frontiers in interventional cardiology. Circulation 1998; 98:1802–1820. Hillegass WB, Ohman ME, Califf RM. Restenosis: the clinical issues. In: Topol EJ, ed. Textbook of Interventional Cardiology, 2nd edn. Philadelphia: WB Saunders Company, 1993, 415–435. Schwarz RS. Pathophysiology of restenosis: interaction of thrombosis, hyperplasia, and/or remodeling. Am J Cardiol 1998; 81:14E–17E. Beatt KJ, Serruys PW, Renseing BJ, Hagennoltz PR. Restenosis after coronary angioplasty: new standards for clinical studies. J Am Coll Cardiol 1990; 15:491–498. Serruys PW, Luitjen HE, Beatt KJ et al. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. Circulation 1988; 77:361–371. Kuntz RE, Baim DS. Defining coronary restenosis: newer clinical and angiographic paradigms. Circulation 1993; 88:1310–1323. Rensing BJ, Hermans WR, Vos J et al. Luminal narrowing after percutaneous transluminal coronary angioplasty. A study of clinical, procedural, and lesional factors related to long-term angiographic outcome. Coronary Artery Restenosis Prevention on Repeated Thromboxane Antagonism (CARPORT) Study Group. Circulation 1993; 88:975–985. Laskey WK, Kimmel S, Krone RJ. Contemporary trends in coronary intervention: a report

10.

11.

12.

13.

14.

15. 16.

from the registry of the Society for Cardiac Angiography and Interventions. Catheter Cardiovasc Interv 2000; 49:19–22. Cohen HA, Jacobs AK, Yeh W et al. Does therapy with GP IIb/IIIa receptor antagonists improve late clinical outcome following percutaneous coronary intervention? A report from the NHLBI PTCA Dynamic Registry. J Am Coll Cardiol 2000; 35:31A (abst). Kimura T, Yokai H, Tamara T et al. Three years clinical and quantitative angiographic follow-up after the Palmaz–Schatz coronary stent implantation. J Am Coll Cardiol 1995; 25:375A (abst). Holmes DR Jr, Hirshfeld J Jr, Faxon D et al. ACC Expert Consensus document on coronary artery stents. Document of the American College of Cardiology. J Am Coll Cardiol 1998; 32:1471–1482. Klugherz BD, Meneveau NF, Kolansky DM. Predictors of clinical outcome following percutaneous intervention for in-stent restenosis. Am J Cardiol 2000; 85:1427–1431. Van Belle E, Bauters C, Hubert E et al. Restenosis rates in diabetic patients. A comparison of coronary stenting and balloon angioplasty in native coronary vessels. Circulation 1997; 96:1454–1460. Mintz GS, Mehran R, Waksman R et al. Treatment of in-stent restenosis. Semin Interv Cardiol 1998 Jun; 3:117–121. Cohen DJ, Breall JA, Ho KKL et al. The economics of elective coronary revascularization: a comparison of costs and charges for conventional angioplasty, directional atherectomy, stenting, and bypass surgery. J Am Coll Cardiol 1993; 22:1052–1059.

7

2 Pathophysiology of restenosis John D Altman, Antoni Bayes-Genis, Robert S Schwartz

Introduction In 1999, more than 400 000 coronary angioplasties were performed in the United States and more than 1 000 000 world wide. In the treatment of flow-limiting stenosis, a high pressure angioplasty balloon is inflated within the lesion causing fractures in the plaque, the internal elastic membrane, media, and adventitial structures. The subsequent arterial healing response begins immediately, and eventually is essential for restoring normal arterial function. However, in 30–40% of patients this normal response is exaggerated, resulting in restenosis. The process of restenosis is complex, involving many separate mechanisms including elastic recoil, mural thrombus, neointimal formation, and arterial remodeling.

Elastic recoil and thrombus Elastic recoil is defined as the difference in vessel cross-sectional area during and shortly after balloon inflation. Elastic recoil is an acute event impacting procedural success rate rather than long-term restenosis rate. The most potent predictor of long-term lumen diameter is post procedural lumen diameter. The elastic components of the arterial wall, the media, adventitia, and internal and external elastic membranes, have memory and can cause significant acute recoil after balloon

deflation. Debulking with the removal of medial and adventitial tissue reduces elastic recoil and results in larger post procedural luminal areas compared to angioplasty alone. However, debulking does not improve longterm clinical event rates except to the extent that carefully performed atherectomy results in a larger lumen.1 The use of intravascular stents has dramatically increased procedural success rates by limiting elastic recoil. However, acute stent recoil of 15–30% is routinely observed, especially in calcific and densely fibrotic lesions. Thrombus formation is common following angioplasty but rarely causes clinical symptoms of abrupt vessel closure. The extent of nonocclusive mural thrombus is proportional to the degree of vessel injury and occurs despite the aggressive use of antiplatelet and antithrombin agents. In a healthy artery, the endothelial lining regulates platelet activation and thrombus formation through the release of nitric oxide, prostacyclin, and antithrombin III. Disruption of the endothelial lining is the first sign of injury following angioplasty and results in the acute loss of these inhibitory functions. Similarly, denudation exposes the highly thrombogenic subendothelial matrix and collagen. Tissue factor, known as thromboplastin, binds factor VII/VIIa and leads to thrombin activation and fibrin deposition. Platelets are recruited to the injured vessel through interactions with collagen and the

9

PATHOPHYSIOLOGY OF RESTENOSIS

platelet glycoprotein lalla complex. This interaction is strengthened by subendothelial von Willebrand factor binding. Adherent platelets are activated by thrombin and release alpha granule contents including serotonin, thromboxane A2 and platelet-derived growth factor (PDGF). Activation also leads to conformational changes in the platelet glycoprotein IIb/IIIa receptor, allowing for fibrin crosslinking to occur. The resulting fibrin-platelet rich thrombus is a potent stimulus for neointimal formation (Fig. 2.1). Thrombin, fibrin degradation products, platelet substances including PDGF and cytokines released from recruited inflammatory cells can cause the migration and proliferation of neointimal cells. The fate of the mural thrombus in humans is that it most likely organizes into neointima. In porcine coronary arteries, a layer of endothelium covers the mural thrombus 4 days after injury. A mononuclear inflammatory infiltrate occurs and by 21 days has actively resorbed the thrombus material. In the meantime, ␣-actin positive cells migrate into

the thrombus using it as scaffolding for neointimal formation.

Neointimal formation The intima is the region of the artery bordered by the luminal surface and the internal elastic membrane. At birth the intima consists of only endothelial cells sitting on the internal elastic membrane. With increasing age, smooth muscle cells begin to appear within the intima. Their longitudinal orientation, compared to the circular orientation in the media, suggests a response to changes in wall stress. In atherosclerotic heart disease, lipid rich deposits accumulate at these sites, accelerating the intimal thickening process. Stenosed arteries are routinely treated with angioplasty and the healing response that follows can be dramatic with further intimal thickening, called neointima (Fig. 2.2). The process of neointima formation includes mural thrombus formation and the proliferation and migration of myofibroblasts and smooth muscle cells. Endothelial, inflam-

Neointima Chronic Thrombus Lumen Acute Thrombus

Plaque

10

Figure 2.1 Thrombus formation is common following angioplasty and is proportional to the degree of vessel injury. The artery shown is from a patient that died in a motor vehicle accident 10 months after balloon angioplasty. The insert identifies acute and chronic thrombus formation. Inflammatory cells are seen infiltrating the chronic thrombus and beneath, neointimal formation is apparent.

NEOINTIMAL FORMATION

Neo intima Lumen

Figure 2.2 Restenosis of the left anterior descending artery 3 years post percutaneous transluminal coronary angioplasty in a 70-year-old male. Neointimal hyperplasia is found overlying the areas of medial tear (arrows) and also covering the atherosclerotic plaque.

Plaque

matory and smooth muscle-like cells are the key players in these processes.

Endothelial cells Disruption of the endothelial lining is the first stage of arterial injury following balloon angioplasty. Endothelial cells rapidly enter the replication cycle to restore endothelial continuity, a process of 1–2 weeks. Even after complete reendothelialization, endothelial function may not be restored for many months. Acute loss of the endothelial barrier exposes subendothelial collagen to circulating thrombin and platelets. Small amounts of mural thrombus form and although not occlusive, are a potent stimulus for neointima formation. In addition to its well known role in regulating vessel tone and platelet aggregation, the endothelium appears to directly modulate

the proliferative activity of the underlying smooth muscle cells (SMCs). Nitric oxide is a potent inhibitor of SMC proliferation and migration in cell culture.3,4 Nitric oxide also balances the biological effects of endothelin-1. Endothelin-1, released by the endothelium in response to many stimuli including mechanical injury, is a potent vasoconstrictor and mitogen for SMCs. These effects are mediated by endothelin-1 receptor A (ETA) located on SMCs.3 In healthy endothelium, the effects of endothelin-1 are balanced by endothelin-1 receptor B (ETB) mediated increases in nitric oxide and prostacyclin release. Angioplasty disrupts this balance. Following angioplasty, coronary sinus endothelin-1 levels are elevated and ETA expression is increased within the neointima while nitric oxide release remains depressed for many weeks. The role of endothelin-1 is validated in animal models by

11


demonstrating the efficacy of endothelin-1 antagonists in reducing neointimal thickening.5 Previous investigations have underscored the principle of cross-talk between endothelial cells and SMCs.4 Neointimal thickness is closely related to the presence of a regenerated endothelium, although the extent of medial injury plays a greater role in determining the magnitude of neointimal formation. Large areas of endothelial denudation without trauma to the media lead to mild neointimal thickening.6 In contrast, focal endothelial denudation with substantial medial trauma, including rupture of the internal elastic lamina and/or external elastic lamina, is associated with marked neointimal thickening, despite prompt endothelial regeneration.7 This latter type of injury is induced in animals by placing a soft silicone catheter around the artery. A significant neointimal response occurs with minimal endothelial disruption indicating that endothelial injury alone is not sufficient to produce significant neointimal thickening.

Smooth muscle-like cells Since the introduction of coronary angioplasty over two decades ago, most of the hypotheses of the mechanisms of restenosis had a similar life cycle: initial enthusiasm followed by subsequent revision. The current understanding is that SMCs are activated after balloon injury and shift from contractile to synthetic phenotype that leads to proliferation, migration, and extracellular matrix formation.8 The importance of SMC proliferation is still controversial in human neointimal hyperplasia. Two studies of human restenotic lesions using directional atherectomy showed conflicting results. Pickering et al9 found cellular proliferation rates of about 20%, while O’Brien et al4 reported less than 1%.9,5 As a result, cell

12

migration through the internal elastic membrane has emerged as a distinct and active mechanism in the genesis of neointimal hyperplasia. There are multiple ways to explain the complexity of neointimal formation after balloon injury. this overview attempts to simplify the issue, by discussing three different perspectives of neointimal growth according to the origin of the cells: medial, adventitial, and luminal. Although the animal models and the methodology used are different, taken together they provide a reasonable understanding of cell kinetics in neointima formation. The medial origin of neointimal cells was suggested by experiments performed in the rat and rabbit peripheral arteries.4 Fogarty catheters were used to gently rub the endothelial cells off the surface of the artery with minimal medial damage. In this model, a first wave of cell proliferation begins in the media within 24 hours after injury and is mediated by basic fibroblast growth factor (bFGF).10,11 Administration of a bFGF neutralizing antibody limits early medial SMC replication after injury but has no effect on the resulting neointimal thickening.12 This study also questions the significance of SMC proliferation in neointimal formation. Hormonal factors released at the site of injury also play a role in the response of SMCs to balloon injury. Infusion of angiotensin II in rats is followed by marked SMC proliferation in the intima.13 Powell et al reported that inhibitors of angiotensin converting enzyme (ACE) suppress myointimal proliferation after vascular injury.14 The actions of ACE inhibitors are probably not solely related to an effect on angiotensin II levels, but may be caused in part by an effect on bradykinin metabolism or by effects mediated by aldosterone. Nonetheless, two large placebo-controlled trials showed no benefit of ACE inhibitors in human restenosis rates.15,16 The second wave of the response to injury in

NEOINTIMAL FORMATION

rat arteries involves migration of SMCs from their normal position in the tunica media to the intimal layer. PDGF is a critical signal for this migration.17 Although PDGF is a potent mitogen for SMCs in cell culture, its action in injured rat arteries appears to be chemoattraction. Most studies in injured porcine coronary arteries are consistent with the medial origin of neointimal cells. Porcine coronary arteries are injured with rigid, non-compliant angioplasty balloons that cause breaks in the medial wall exposing the outer elastic. Neointimal formation occurs in the region between the broken ends of the media and is thought to consist of SMCs migrating from the injured medial segment. Similarly, porcine and human post angioplasty restenosis lesions are thought to consist of SMCs originating from the media, since the majority of neointimal cells are ␣-smooth muscle actin positive by immunostaining (Fig. 2.3).18,19 However, there is evidence that non-muscle cells may express ␣-smooth muscle actin with the appropriate stimulation.20 Myofibroblasts are specialized

fibroblast-like cells that show induced expression of ␣-smooth muscle actin.21 These cells have the ultrastructural features intermediate between a fibroblast and a SMC. Myofibroblasts typically lack markers of highly differentiated SMCs such as desmin, h-caldesmon, and smooth muscle myosin, but show induced expression of ␣-smooth muscle actin.22 Recent work by Wilcox suggests that myofibroblasts in the adventitia proliferate after angioplasty and migrate into the neointima where they appear as smooth muscle ␣-actin containing cells.23,24 Three days after injury of the porcine coronary artery the highest cellular proliferation is observed in the adventitia near the site of medial tear. Two weeks later these cells are found within the neointima. Additional work must be done in order to establish the exact percentage of neointimal cells with adventitial origin. Schwartz et al suggest that blood borne cells capable of ␣-smooth muscle actin expression play a significant role in neointimal formation.25 Deposition of nonocclusive mural thrombus following angioplasty is a potent chemoattractant for inflammatory cells. Three

Lumen

Neointima

Media Adventitia

Figure 2.3 Neointimal hyperplasia observed 28 days after radio frequency-induced injury in a pig coronary artery. This model of vessel injury is characterized by medial necrosis and voluminous neointimal hyperplasia. Note the thick neointima made of actin-positive cells and extracellular matrix. Left panel: elastic von-Gieson stain. Middle panel: hematoxylin-eosin stain. Right panel: ␣-smooth muscle actin stain. Magnification 25⫻.

13


to 8 days after porcine coronary artery injury an intense cellular infiltration is evident. The infiltrate consists of monocytes transitioning to macrophages, neutrophills, and lymphocytes. The inflammatory infiltrate develops from the luminal side of the injured artery, with cells migrating progressively deeper into the mural thrombus. Inflammatory cells release cytokines and growth factor and 8 days after injury actin-positive cells are observed forming a ‘cap’ across the top of the mural thrombus. The observation that smooth muscle-like cells are first seen at the luminal surface suggests a blood origin. The SMC migration and proliferation into the degenerated thrombus creates substantially increased neointimal volume, much greater than that of the thrombus alone. The influence of elastin on migration and proliferation of SMCs in the restenosis process is under intense investigation since it appears that elastin degradation facilitates SMC migration. Oho et al26 showed that following arterial injury, elastase activity is increased and associated temporally with the development of neointima. They suggest that this may be prevented with the administration of serine proteinase inhibitors, thereby reducing elastase activity. Similarly, the dramatic neointimal formation associated with closure of the ductus arteriosus is initiated by internal elastic membrane digestion with subsequent SMC migration. Lastly, studies in mice where the elastin gene was deleted indicated the key role elastin plays in maintaining normal artery architecture.

Extracellular matrix Two observations indicate that the production of extracellular matrix (ECM) proteins by activated neointimal cells significantly contributes to the development of restenosis.27

14

First, the time course of restenosis does not correlate with cellular proliferation. The restenotic process appears to plateau at 3–6 months while cellular proliferation rapidly declines after a few weeks. Secondly, only 11% of the neointima consists of cellular material; the vast majority is myxoid tissue.25 the major ECM components include fibrous proteins of two functional types (structural collagens and elastin) and cell adhesive or antiadhesive molecules such as fibronectin, vitronectin, laminin; and proteoglycans hyaluran. In a rabbit model of restenosis, the synthesis and net content of collagen, elastin and proteoglycans were significantly increased at 1, 2 and 4 weeks after angioplasty in iliac arteries.28 Increased synthesis of proteoglycans (biglycan and decorin) and collagen types I, III and IV has also been described in primary atherosclerotic and restenotic human coronary arteries.29 Moreover, hyaluronan along with its receptor CD44 is upregulated in the neointima.30 CD44 has also been shown to play a role in migration of cells into fibrin or osteopontin.31 Rasmussen et al32 found that administration of neutralizing anti-transforming growth factor (TGF)-␤1 antibody to cultured rat SMC from injured arteries inhibited the production of proteoglycan synthesis. The direct transfer of TGF-␤1 gene into porcine arteries is associated with increase of collagen and proteoglycan synthesis accompanied by intimal and medial hyperplasia.33 Together, these findings suggest that TGF-␤1 may be a major mediator of abnormal ECM protein expression in the pathology of vascular restenosis. Little has been done to identify the matrix proteins involved in SMC migration into the intima. Osteopontin is of special interest because it is characteristically expressed in sites where tissues are undergoing marked remodeling. Cells can attach to osteopontin

REMODELING

via ␣V␤3, which appears to be the major migration promoting receptor in vitro.34 this may be true in vivo as well since antagonists directed at the ␣V␤3 inhibit formation of the intima after balloon injury.35 Another integrin seen in the vascular tissue in vivo is ␣1␤1, which may be the major integrin involved in SMC migration on collagen. The influence of ECM proteins on SMC migration in the onset of restenosis is not clear, although degradation of matrix protein by proteases may facilitate SMC migration.36 This hypothesis is supported by the observation that administration of a protease inhibitor significantly inhibited SMC migration in the rat. Given the abundance of ECM in restenotic lesions, one alternative ‘antirestenosis’ strategy would be to directly reduce the matrix volume surrounding each cell, either by reducing synthesis or by increasing proteolysis.

Remodeling Remodeling is defined as a change in artery size over time, as measured in area of the internal or external elastic membrane.37 Favorable or adaptive remodeling is the outward expansion and unfavorable or pathological remodeling is the inward shrinkage of an artery. Adaptive remodeling is observed in early coronary artery disease. Vessel enlargement keeps pace with the increases in plaque burden thereby preventing luminal stenosis. However, in many individuals, plaque volume outpaces the remodeling capacity of the artery and stenosis ensues. This occurs after the plaque volume occupies greater than 40% of the vessel although animal studies do not indicate a limit to the amount of favorable remodeling that can occur. Autopsies performed in marathon runners and African Masai tribesmen have shown coronary arteries 2–3 times the normal size indicating a great capacity of the artery to expand.38,39

Remodeling following balloon angioplasty can be favorable or unfavorable (Fig. 2.4). In the setting of restenosis, artery shrinkage is often to blame and may account for up to 805 of lumen loss. Artery shrinkage in response to injury was first hypothesized in animal models as an explanation of the discrepancy between large lumen loss and the small amount of neointima formed. Autopsy studies, in patients whom had undergone angioplasty at some time point in life, illustrate the importance of remodeling in the restenosis process. Artery size, measured as the area of the external elastic membrane, was decreased in restenotic lesions and increased in lesions without significant luminal narrowing. Neointimal thickness in restenotic and nonrestenotic lesions was nearly identical (1.74 ⫾ 1.0 mm2 vs 1.70 ⫾ 0.9 mm2) confirming the pivotal role of remodeling in restenosis. Utilizing serial intravascular ultrasound after angioplasty, Mintz et al40 identified two groups of patients at 6 months. One group showed compensatory enlargement while the second group showed shrinkage of the treated segment. Favorable remodeling was associated with a much lower 6-month restenosis rate (28% vs 60%). Surprisingly, 87% of the lumen loss between 1 and 6 months was owing to artery shrinkage. The only predictor or unfavorable remodeling was the arc of calcium within the vessel. Unfavorable remodeling occurs after balloon angioplasty and with other coronary devices including rotational atherectomy and eximer laser angioplasty. Controversy exists regarding the role of artery shrinkage in restenosis following directional coronary atherectomy (DCA).41 Nearly 80% of all percutaneous coronary interventions involve coronary artery stenting. Coronary stents limit acute recoil, improve procedural success rates, increase post procedural lumen diameter, and decrease overall

15


Normal

No remodeling

Favorable remodeling

Unfavorable remodeling

Figure 2.4 Favorable or adaptive remodeling is the outward expansion and unfavorable or pathological remodeling is the inward shrinkage of an artery. Favorable remodeling is observed in early coronary artery disease and can keep pace with the increases in plaque burden to prevent luminal narrowing. Remodeling following balloon angioplasty is often unfavorable, accounting for up to 80% of late lumen loss.

incidence of restenosis. The stent crosssectional area does not change significantly over time. Remodeling, both favorable and unfavorable, does not occur within the stent. However, at stent borders and articulation sites remodeling does occur. Unfavorable remodeling at these sites accounts for up to 88% of the lumen loss being greatest at the articulation sites.43 The mechanisms responsible for favorable remodeling in response to increases in plaque burden are markedly different than those for unfavorable remodeling following angioplasty. Blood flow and shear stress are powerful stimuli for artery enlargement. Dramatic increases in arterial size occur after the cre-

16

ation of an atriovenous fistula or use of the internal mammary artery as an arterial bypass conduit. Increases in blood flow are also cited as the mechanism of coronary collateral maturation. In coronary artery disease, positive remodeling occurs to normalize luminal shear. Arterial mechano-receptors in the endothelium sense changes in shear with increases in blood flow. The signal generated by the endothelium must then be transferred to the adventitia where lumen enlargement occurs. Possible mediators include nitric oxide, prostacyclin, endothelial hyperpolarizing factor, adenosine S⬘-triphosphate ATP, and substance P, all increased by shear. The mechanisms responsible for artery con-

CONCLUSION

traction following angioplasty are unknown but may be analogous to wound contraction. Adventitia myofibroblast are likely to be involved in unfavorable remodeling as these cells are found encircling the artery. Three days after angioplasty, adventitial myofibroblasts show the highest rate of proliferation, nearly 30%.23,24 Proliferation is concentrated at the site of injury and circumferential even at sites without medial injury. PDGF and its receptor are increased in the adventitia after injury and may mediate this proliferative response. Injured myofibroblasts also change phenotypes and begin expressing smooth muscle ␣-actin, a protein usually confined to SMCs. A similar phenotype change is observed in cutaneous wound healing and in response to the cytokines TGF-␤ and ␥-interferon.

Conclusion More than 20 years after Andreas Grüntzig performed the first angioplasty, restenosis following coronary intervention continues to be problematic. Restenosis involves acute recoil, mural thrombus, neointimal formation, and unfavorable remodeling. The mediators are the endothelial, smooth muscle-like, and inflammatory cells. The role of adventitial myofibroblast is currently under investigation. Unfavorable remodeling is the main component in restenosis following balloon angioplasty, rotational atherectomy, and laser angioplasty. Its role in DCA is controversial. Intravascular stents reduce restenosis by limiting acute recoil and preventing unfavorable remodeling. However, in-stent restenosis is commonly 15–30%, attributable solely to neointimal formation.

17


References

1.

Tsuchikane E, Sumitsuji S, Awata N et al. Final results of the stent versus directional coronary atherectomy randomized trial. J Am Coll Cardiol 1999; 34:1050–1057. 2. Schwartz RS. Pathophysiology of restenosis: interaction of thrombosis, hyperplasia, and/or remodeling. Am J Cardiol 1998; 81:14E–17E. 3. McKenna CJ, Burke S, Opgenroth TJ et al. Selective ET-A receptor antagonism reduces neointimal hyperplasia in a porcine coronary stent model. Circulation 1998; 97:2551–2556. 4. Reidy MA. Endothelial regeneration VII. Interaction of smooth muscle cells with endothelial regrowth. Lab Invest 1988; 59:36–43. 5. O’Brien ER, Alpers CE, Stewart DK et al. Proliferation in primary and restenotic coronary atherectomy tissue: implications for antiproliferative therapy. Circ Res 1993; 73:223–231. 6. Fingerle J, Tina AUYP, Clowes AW et al. Intimal lesion formation in rat carotid arteries after endothelial denudation in absence of medial injury. Arteriosclerosis 1990; 10:1082–1087. 7. Walker LN, Ramsay MM, Bowyer DE. Endothelial healing following defined injury to rabbit aorta: depth of injury and mode of repair. Arteriosclerosis 1983; 47:123–130. 8. Schwartz SM, Campbell CR, Campbell JH. Replication of smooth muscle cells in vascular disease. Circ Res 1986; 58:427–444. 9. Pickering JG, Weir L, Jekanowski J et al. Proliferative activity in peripheral and coronary atherosclerotic plaque among patients undergoing percutaneous revascularization. J Clin Invest 1993; 91:1469–1480. 10. Reidy MA, Fingerle J, Lindner V. Factors controlling the development of arterial lesions after injury. Circulation 1992; 86:III43–III46. 11. Lindner V, Lappi DA, Baird A et al. Role of basic fibroblast growth factor in vascular lesion formation. Circ Res 1991; 68:106–113. 12. Lindner V, Reidy MA. Proliferation of smooth muscle cells after vascular injury is inhibited by

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an antibody against basic fibroblast growth factor. Proc Natl Acad Sci USA 1991; 88:3739–3743. Dzau VJ. Vascular renin-angiotensin: a possible autocrine or paracrine system in control of vascular function. J Cardiovasc Pharmacol 1984; 6 Suppl 2:S377–S382. Powell JS, Muller RKM, Kuhn H et al. Inhibitors of angiotensin-converting enzyme prevents myointimal proliferation after vascular injury. Science 1989; 245:186–188. Does the new angiotensin-converting enzyme inhibitor, cilazapril, prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind placebo-controlled trial. Circulation 1992; 86:100–110. Faxon DP. Effect of high dose angiotensinconverting enzyme inhibition on restenosis: final results of the MARCATOR study, a multicenter, double blind, placebo-controlled trial of cilazapril. the Multicenter American Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Occlusion and Restenosis (MARCATOR) Study group. J Am Coll Cardiol 1995; 25:362–369. Fingerle J, Johnson R, Clowes AW et al. Rose of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery. Proc Natl Acad Sci USA 1989; 86:8412–8416. Schwartz RS, Murphy JG, Edwards WD et al. Restenosis after balloon angioplasty, a practical proliferative model in porcine coronary arteries. Circulation 1990; 82:2190–2200. Karas SP, Gravanis MB, Santoian EC et al. Coronary intimal proliferation after balloon injury and stenting in swine: an animal model of restenosis. J Am Coll Cardiol 1992; 20:467–474. Leslie KO, Taatjes DJ, Schwartz J et al. Cardiac myofibroblasts express alpha smooth

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muscle actin during right ventricular pressure overload in the rabbit. Am J Pathol 1991; 139:207–216. Skalli O, Schurch W, Seemayer T et al. Myofibroblast from diverse pathologic settings are heterogeneous in their content of actin isoforms and intermediate filament proteins. Lab Invest 1989; 60:275–285. Lazard D, Sastre X, Frid MG et al. Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl Acad Sci USA 1993; 90:999–1003. Scott NA, Martin F, Simonet L et al. Contribution of adventitial myofibroblasts to vascular remodeling and lesion formation after experimental angioplasty in pig coronary arteries. FASEB J 1995; 9:A845. Scott NA, Ross CE, Dunn B et al. Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury in porcine coronary arteries. Circulation 1996; 93:2178–2187. Schwartz RS, Holmes Dr Jr, Topol E. The restenosis paradigm revisited: an alternative proposal for cellular mechanisms. J Am Coll Cardiol 1992; 20:1284–1293. Oho S, Koo E, Gotlieb A, Rabinovitch M. Increased elastolytic activity associated with intimal proliferation in the porcine aortic organ culture. FASEB J 1993; 7:A491. Macleod DC, Struss BH, deJong M et al. Proliferation and extracellular matrix synthesis of smooth muscle cells cultured from human coronary atherosclerotic and restenotic lesions. J Am Coll Cardiol 1994; 23:59–65. Strauss BH, Chisholm RJ, Keeley FW et al. Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis. Circ Res 1994; 75:650–658. Riessen R, Isner JM, Blessing E et al. Regional differences in the distribution of the proteoglycans biglycan and decorin in the extracellular matrix of atherosclerotic and restenotic human coronary arteries. Am J Pathol 1994; 144:962–974. Jain M, He Q, Lee WS et al. Role of CD44 in the reaction of vascular smooth muscle cells to arterial wall injury. J Clin Invest 1996; 97:596–603.

31. Weber GF, Ashakar S, Glimcher MJ, Cantor H. Receptor-ligand interaction between CD44 and osteopontin. Science 1996; 271:509–512. 32. Rasmussen LM, Wolf YG, Ruoslahti E. Vascular smooth muscle cells from injured rat aortas display elevated matrix production associated with transforming growth factor-␤ activity. Am J Pathol 1995; 147:1041–1048. 33. Nabel EG, Shum L, Pompili VJ et al. Direct transfer of transforming growth factor ␤1 gene into arteries stimulates fibrocellular hyperplasia. Proc Natl Acad Sci USA 1993; 90:10759–10763. 34. Hoshiga M, Alpers CE, Smith LL et al. ␣V␤3 integrin expression in normal and atherosclerotic artery. Circ Res 1995; 77:1129–1135. 35. Matsuno H, Stassen JM, Vermylen J, Deckmyn H. Inhibition of integrin function by a cyclic RGD-containing peptide prevents neointima formation. Circulation 1994; 90:2203–2206. 36. Dollery CM, McEwan JR, Henney AM. Matrix metalloprotinase and cardiovascular disease. Circ Res 1995; 77:863–868. 37. Schwartz RS, Topol EJ, Serruys PW et al. Artery size, neointima, and remodeling. Time for some standards. J Am Coll Cardiol 1998; 32:2087–2094. 38. Mann G, Spoerry A, Gray M, Jarashow D. Atherosclerosis in the Masai. Am J Epidemiol 1972; 95:26–37. 39. Glagov S, Weisnberg G, Zarins C et al. Compensatory enlargement of artery segments in response to enlarging atherosclerotic plaques. N Engl J Med 1987; 316:1371–1375. 40. Mintz GS, Popma J, Pichard A et al. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation 1996; 94:35–43. 41. Birnbaum Y, Fishbein MC, Luo H et al. Regional remodeling of atherosclerotic arteries: a major determinant of clinical manifestations of disease. J Am Coll Cardiol 1997; 30:1149–1164. 42. Degwa T, Mitsuo K, Tsunoda T et al. Differential mechanisms of late lumen loss after Palmaz-Schatz stenting; evaluation by serial intravascular ultrasound study. Circulation 1996; 94 suppl 1:1–200.

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3 Clinical presentations and noninvasive assessment of restenosis Joel W Heger and Sanjeev D Ravipudi

Introduction Restenosis has been recognized as the Achilles’ heel of coronary angioplasty.1 It is a limiting factor that occurs in 12–48% of patients who undergo a successful percutaneous coronary intervention.2 The scope of this vexing problem is staggering; of the 500 000 coronary interventions performed in the United States each year, more than 150 000 patients develop restenosis (based on 1997 American Heart Association statistics).

Mechanisms of restenosis Much has been learned about the mechanism of restenosis with the advent of new intracoronary devices (such as stents and atherectomy) and with new intracoronary imaging modalities (such as intravascular ultrasound (IVUS) and angioscopy). Elastic recoil usually occurs within minutes to hours of an intervention and is usually asymptomatic. Approximately 15% of successful percutaneous transluminal coronary angioplasty (PTCA) develop a ⬎ 0.5 mm luminal loss at 24 hours due to recoil and thrombus.3 One-half of these will proceed to restenosis.4 Most of the time there is little lumen change between day 1 and 1 month. The vast majority of cases occur between 1 and 3 months owing to neointimal hyperplasia and negative remodeling. Recur-

rence of clinical or angiographic restenosis after 6 months is rare.2,3,5–7

Clinical restenosis Reported ranges of chest pain recurrence within 6 months are as low as 25% to as high as 93%. The average rate is approximately 50%. It is estimated that the positive predictive value of symptoms alone is 60%.6,7 It is difficult to establish a clinical definition of restenosis given the limitations of symptoms and stress testing. Estimating the incidence of clinical restenosis by composite endpoints of target vessel revascularization, myocardial infarction (MI), and death has some clinical relevance. Patients with restenotic lesions rarely present with acute MI (⬍ 2%) or death (⬍ 1%) presumably due to the soft fibromuscular process that rarely ruptures.5,8–10 Estimating restenosis by target vessel revascularization in studies with longer follow-up is confounded by disease progression and incomplete revascularization. Combining data from the large randomized trials of PTCA vs coronary artery bypass graft (CABG), the rate of repeat revascularization among the PTCA group averages approximately 40% over 2 years.11 The main clinical predictors of restenosis include diabetes, chronic dialysis, variant angina, and unstable angina.6,7

21

CLINICAL PRESENTATIONS AND NONINVASIVE ASSESSMENT OF RESTENOSIS

Angiographic restenosis Numerous definitions of restenosis have been reported. The most commonly accepted angiographic definition is a ⱖ 50% luminal diameter stenosis at 6-month follow-up.5 Differing methods of assessment (visual, calipers, computer-assisted edge detection) account for considerable reporting variability. Despite these issues, angiographic restenosis rates vary from 30–50%. IVUS has proven valuable, but still has limitations because the ‘reference site’ for comparison is often diffusely diseased.3,7 Angiographic assessment still remains the standard for most clinical trials of restenosis. A number of indices have been measured and described with regard to the mechanics of angiographic restenosis. Acute gain is the change in minimal luminal diameter (MLD) from baseline to immediately after PTCA. The late loss is the difference between the immediate post procedure MLD to that measured at 6 months. The net gain is the difference between follow-up MLD from baseline (acute gain-late loss). The loss index refers to the percentage of early gain which is ultimately lost (late loss/acute gain). These indices vary depending on what devices are used for intervention. The acute gain is greatest with stenting as is the net gain. In aggressive directional atherectomy, the net gain may approach that of stenting. Balloon angioplasty, laser atherectomy, and rotational atherectomy usually have only moderate net gain. The major angiographic predictors of restenosis are long lesions, chronic total occlusions, ostial lesions, angulated lesions (⬎ 45°), and saphenous vein graft proximal and body lesions.6,7 Asymptomatic angiographic stenosis occurs in upwards of 15% of angioplasty patients. The significance of ‘silent restenosis’ is

22

unknown. Limited data suggests a favorable outlook for patients with silent restenosis regardless of inducible ischemia.

Clinical presentation Owing to the myriad of clinical, histologic, and angiographic variables involved in restenosis, the timing and presentation of symptoms can vary. Clinical restenosis refers to the incidence of clinical events that ultimately lead to repeat revascularization of the index lesion. Studies of restenosis have used a composite endpoint of death, MI, and target vessel revascularization to assess clinical outcomes from coronary interventions.12 Retrospective analysis of Emory University data showed that restenotic patients, when compared to patients without restenosis, had a higher incidence of angina (71% vs 39%) and target vessel reintervention (at 6 months, 56% vs 4%), a lower freedom from MI (at 6 months, 0.88 vs 0.97 and at 6 years, 0.85 vs 0.93) and coronary artery bypass surgery (at 6 months, 0.94 vs 0.99 and at 6 years, 0.78 vs 0.91), and a poorer survival rate (at 6 years, 0.93 vs 0.95).13 Highlighting the unfavorable outcomes associated with restenosis has led to the importance of recognition, appropriate diagnosis, and treatment.

Timing Analysis of data from early registries investigating restenosis suggested a strong relationship existed between the incidence of restenosis and the timing of occurrence after angioplasty. Holmes et al5 reported from the PTCA registry of the National Heart, Lung, and Blood Institute (NHLBI) on the prevalence of restenosis in 557 patients who underwent follow-up angiography after successful angioplasty. With a definition of restenosis

CLINICAL PRESENTATION

being a loss of at least 50% of the gain achieved at PTCA, restenosis was documented in 32.8% of the patients. A definite relationship existed between the timing of follow-up angiography and the occurrence of restenosis, with the highest incidence during the first 5 months. Restenosis was rarely observed at 9–12 months or beyond 12 months.5 Nobuyoshi et al3 confirmed an associated ‘time course’ with restenosis in a prospective study of 546 patients undergoing successful PTCA. Follow-up angiography in 229 patients was performed at day 1, 1 month, 3 months, 6 months, and 1 year. As early as 24 hours post procedure, an appreciable loss in lumen diameter of ⬎ 0.5 mm was detected in 16% of the patients, thought to be consistent with lesion recoil or thrombus formation. Using a definition of restenosis as ⱖ 50% loss of the gain in the absolute stenotic diameter, actuarial restenosis rates at 1, 3, 6, and 12 months were 12.7%, 43%, 49.4%, and 52% respectively (Fig. 3.1). The greatest change occurred between 1 and 3 months with a modest increase observed from 3 to 6 months. No significant increase in actuarial restenosis rate or decrease in stenosis diameter was observed from 6 months to 1 year.3 There has been widespread agreement that restenosis is a relatively early phenomenon that presents within 6 months of angioplasty, and is extremely rare after 12 months.2,3,5 In an angiographic follow-up study 5 years after PTCA Ormiston et al14 confirmed a lack of late progression involving index lesion restenosis and also demonstrated that vascular remodeling might even result in late lesion regression. Studies performed using various percutaneous coronary revascularization devices have observed an alike ‘time course’.15 Given the available data, it is evident that the majority of restenoses occurs during the first 3 months

following angioplasty, and that occurrence after 6 months is rare; patients who are free of restenosis at 6 months will likely continue to observe success of their index lesion angioplasty.6

Symptomatic restenosis Following successful angioplasty, clinicians are watchful of signs and symptoms associated with abrupt vessel closure, restenosis, and other possible complications of PTCA. In this setting, chest pain is the most sensitive clinical finding. Unfortunately, this symptom has considerable overlap with multiple pathologic processes that can occur during the post angioplasty setting. Local coronary artery trauma can cause chest pain minutes to hours following PTCA.16 Elastic recoil, also occurring minutes to hours following PTCA, can lead to restenosis and its associated symptoms.17 Additionally, platelet deposition at the site of endothelial denudation early after angioplasty (minutes to days) can induce spasm and the formation of a mural thrombus, which may cause acute chest pain, induce abrupt vessel closure, or subsequently organize and lead to restenosis.2 Abrupt vessel closure occurs minutes to weeks following angioplasty in 1–8% of patients and produces symptoms of acute infarction.5,8 Thus, from a practical standpoint, a clinician cannot rely solely on symptoms to direct appropriate therapy. The restenotic process has been described as a ‘healing’ response to vascular injury with lesion development occurring gradually over a period of weeks to months.18 Events late after angioplasty (7–150 days) include the release of platelet-derived growth factor and other humoral and hemostatic factors. In the setting of restenosis, these factors induce an excessive intimal fibroproliferative response comprised

23


100 90 80 70 60 49.4

50

52

43

40 30 20 12.7

10 0 1

3

6

12

Months after PTCA

Figure 3.1 Actuarial restenosis rate following successful PTCA: In a prospective study of 546 patients undergoing successful PTCA, follow-up angiography was performed in 229 patients at day 1, 1 month, 3 months, 6 months, and 1 year. 219 patients completed follow-up angiography for ⱖ 3 months. Mean stenosis diameter was 1.91 ⫾ 0.53 mm immediately after coronary angioplasty, 1.72 ⫾ 0.52 mm on day 1, 1.86 ⫾ 0.58 mm at 1 month, and 1.43 ⫾ 0.67 mm at 3 months. 149 patients completed follow up angiography for ⱖ 6 months with a mean stenosis diameter of 1.66 ⫾ 0.58 mm at 3 months and 1.66 ⫾ 0.62 mm at 6 months. 73 patients went on to complete follow-up with a mean stenosis diameter of 1.65 ⫾ 0.56 mm at 6 months and 1.66 ⫾ 0.57 mm at 1 year. Actuarial restenosis rates at 1, 3, 6, and 12 months were 12.7%, 43%, 49.4%, and 52% respectively. The greatest change occurred between 1 and 3 months with a modest increase observed from 3 to 6 months. No significant increase in actuarial restenosis rate or decrease in stenosis diameter was observed from 6 months to 1 year. Data from Nobuyoshi M, Kimura T, Nosaka H et al. Restenosis after successful percutaneous transluminal coronary angioplasty: Serial angiographic follow-up of 229 patients. J Am Coll Cardiol 1988; 12:616–623. PTCA, percutaneous transluminal coronary angioplasty.

mostly of smooth muscle cells. Progressing over a period of weeks to months, the fibromuscular overgrowth histologically comprises the majority of the restenotic lesion, unlike the typical lipid laden coronary plaque.2,18 As a result, the majority of patients who develop symptomatic restenosis experience a

24

gradual return of their typical anginal symptoms. In the NHLBI registry, 56% of patients with definite or probable angina had angiographic restenosis.5 In general, it is observed that two-thirds of patients who present with angiographic restenosis complain of anginal symptoms. It is also important to realize that

CLINICAL PRESENTATION

14% of patients in the registry who were asymptomatic also had evidence of angiographic restenosis (Fig. 3.2).5 Thus, the ability to utilize recurrent symptoms alone to detect restenosis is not reliable. Miller et al7 pooled data from several trials evaluating restenosis and found that symptoms alone had a positive predictive value of only 60% and a negative predictive value of 85%. Joelson et al19 evaluated the angiographic findings of 102 patients who underwent coronary angiography for recurrent angina. The mean interval from PTCA to recurrent chest pain was 5.3 months and the mean interval from PTCA to follow-up angiography was 6.9 months. Sixty-three percent of the patients were classified as having angiographic restenosis, 15% had new coronary narrowings, 9% had incomplete revascularization, and 15% had no significant angiographic stenosis. Univariate analysis revealed that chest pain prior to 1

month after angioplasty was associated with incomplete revascularization in six of 12 patients (50%). Restenosis was present in only one of 12 patients (8%). Restenosis was the most common finding for recurrent angina 1 to 6 months after PTCA, present in 60 of 69 patients (87%). In patients with recurrent angina more than 6 months after PTCA, new coronary disease was most often responsible and restenosis was found only in two of 21 patients (10%) (Fig. 3.3).19 Referencing recurrent symptoms with the timing of occurrence after angioplasty improves the utility of clinical symptoms to identify those patients with restenosis. In general, patients with typical symptom recurrence 1 to 6 months after angioplasty are more likely to have restenosis of the index lesion. These patients warrant further studies to define the presence of significant restenosis. Development of anginal symptoms prior to 1 month is more commonly associated with

100% 80%

44

60%

86

40% 56 20% 14

0% Symptomatic

Asymptomatic Restenosis

No restenosis

Figure 3.2 Correlation between angiographic restenosis and recurrence of anginal symptoms. Data from Holmes Jr DR, Vlietstra RE, Smith HC et al. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): A report from the PTCA registry of the National Heart, Lung, and Blood Institute. Am J Cardiol 1984; 53:77C–81C.

25


100% 90% 80% 70%

New coronary disease

60%

Restenosis

50%

Incomplete revascularization

40%

Normal

30% 20% 10% 0% ⬍1

1 to 6

⬎6

Months after successful PTCA

Figure 3.3 Relationship of angiographic findings with the timing of recurrent angina. [⬍ 1 month n ⫽ 12, 1 re, 0 new, 6 ir, 5 nl; 1 to 6 months n ⫽ 69, 60 re, 2 new, 2 ir, 5 nl; ⬎ 6 months n ⫽ 21, 2 re, 13 new, 1 ir, 5 nl]. (re – restenosis, new – new significant coronary lesions, ir – incomplete revascularization, nl – no significant lesions at the time of follow-up). Data from Joelson JM, Most AS, Williams DO. Angiographic findings when chest pain recurs after successful percutaneous transluminal angioplasty. Am J Cardiol 1987; 60:792–795.

incomplete revascularization or abrupt vessel closure. Symptom occurrence beyond 6 months is likely a result of disease progression involving a different stenosis.19 Patients who present with symptoms atypical of those prior to angioplasty infrequently have restenosis.20

Asymptomatic or silent restenosis Even though the presence of angiographic restenosis is commonly associated with a return of pre-angioplasty symptoms, anywhere from 2% to 50% of these patients remain

26

asymptomatic.5,13,21–23 With such a wide range of reported rates for silent restenosis, several explanations have been proposed to explain the disparity. Amongst the landmark trials, factors influencing the rate of silent restenosis include variable definitions of angiographic restenosis, differing methods of analysing angiographic data, timing of follow-up angiography, rates of late angiographic examination, presence of collaterals, degree of antianginal therapy, and differing baseline patient characteristics including history of infarction and diabetes. Using pooled data

NON-INVASIVE EVALUATION OF RESTENOSIS

from several small and large trials, Moliterno and Topol6 calculated that silent restenosis occurs in approximately 12% of the post PTCA population. Asymptomatic or silent restenosis has been commonly defined as angiographically observed ⱖ 50% diameter stenosis in the absence of anginal symptoms up to 6 months after angioplasty. Several hypotheses have been proposed to explain the occurrence of silent restenosis. Popma et al21 and Hernandez et al22 found that up to 50% of patients with silent restenosis at 6 months went on to develop symptoms in later months. These patients may represent a subset who are characterized as silent restenosis early after angioplasty but eventually progress to develop restenosis later on. There also exists evidence that patients with asymptomatic restenosis may actually have less severe coronary obstruction. Other theories claim that the formation of collateral vessels may protect against ischemia despite a progressive reduction in index lesion diameter. It has also been suggested that if infarction is present in the vascular territory supplied by the index vessel, reduced metabolic requirements may accommodate the reduction in flow imposed by restenosis. These theories bring into question whether the angiographic definition of restenosis is adequate. As part of its imperfection, the definition does not reflect the physiologic significance of the lesion.21,22 The long-term significance of silent restenosis has yet to be determined. However, data exist to suggest that the clinical outcome of these patients is favorable.6,7,24 In evaluating thallium for detecting restenosis, Pfisterer et al24 found that 60% of 405 patients with nuclear evidence of ischemia were asymptomatic. Compared to those with symptomatic ischemia, the asymptomatic population was less likely to undergo repeat

revascularization.24 Other studies followed similar patients for a mean period of three years and discovered that the majority of patients (about 80%) remained symptom free.6,7,25,26 Of the 20% who experienced a cardiac event, three-quarters suffered from recurrent angina and one-quarter suffered a non-fatal myocardial infarction.26 Weintraub et al13 followed 1 500 patients with restenosis for 6 years; the symptomatic group had a higher incidence of MI, CABG, and PTCA when compared to the asymptomatic group. There are no prospective trials looking at the need for intervention in patients with silent restenosis. Adding to the difficulty in defining the long-term significance of silent restenosis is the fact that any long term study would be confounded by the natural progression of coronary artery disease (CAD). With the available data, it appears that this patient population possesses a good prognosis. Any repeat interventions in these patients should be guided by the emergence of symptoms or significant ischemia.

Non-invasive evaluation of restenosis The use of non-invasive testing for evaluating restenosis has become increasingly popular. Although very attractive as a mode of evaluation in this setting, it is still important to note that the American College of Cardiology/American Heart Association (ACC/AHA) do not recommend the universal use of noninvasive testing in every post PTCA patient.27 If widespread testing was implemented, analysis estimates that it would cost around $10 000 to $20 000 to identify an asymptomatic patient with restenosis.28 The wide availability and safety of non-invasive testing is no substitute for an educated approach towards

27


risk stratification and management of these patients.

Exercise electrocardiography Exercise testing can be a valuable tool in evaluating patients with coronary heart disease. Duration of exercise, increase in heart rate, blood pressure response, and reproduction of symptoms represent complementary functional data that can be incorporated in the evaluation and management of these patients. Additionally, exercise has the unique advantage of providing a powerful physiologic stress by which to evaluate endothelial vasodilatory capacity, a major contributor to myocardial ischemia. Pharmacologic stress suffers from the disadvantage of not producing a physiologic stress on the cardiovascular system. It is therefore recommended that exercise stress should be performed whenever possible.29 Since the presence of chest pain after PTCA does not signify restenosis with certainty, there exists a need for a noninvasive technique that can accurately predict and identify restenosis, reducing the need for unnecessary coronary angiography. The use of exercise electrocardiographic testing in this setting has been widely studied. Some of the limitations encountered with exercise testing after PTCA include the presence of multivessel disease, previous myocardial infarction, baseline electrocardiographic abnormalities, and the significant number of uninterpretable tests. Exercise testing soon after successful angioplasty for predicting restenosis Early exercise testing after PTCA is reliably utilized to establish a new functional baseline, increase patient confidence in resuming early activity or return to work, and aid in establishing guidelines for cardiac rehabilitation counseling.30,31 Evaluation of early exercise

28

treadmill testing (ETT) in the prediction of restenosis has alternatively produced variable results and has significant limitations. Exercise testing in this setting has been evaluated by a number of groups; Deligonul et al32 performed testing a mean of 9 days after successful PTCA, Balady et al32 at 1–3 days, and Korzick et al31 at 1–4 days. None of these authors could support any prognostic value of early exercise in predicting future cardiac events or restenosis. For example, the values observed by Korzick et al31 were as poor as 35.3% sensitivity, 52.5% specificity, 39.6% positive predictive value, and 48% negative predictive value. Thus, a positive ETT early after successful angioplasty is of no value to the clinician. It is postulated that early after angioplasty the presence of vasoconstriction, smooth muscle cell migration and proliferation, and platelet adhesion and aggregation may play a role in producing a misleading early positive exercise test despite the absence of true anatomic restenosis. Furthermore, several reports have questioned the safety of high workload and symptom limited exercise testing soon after angioplasty.30,33 Incidence of acute ischemic complications associated with post PTCA exercise testing range from 0.8% to 1.4%.30,31 Subgroup analysis by Sionis et al found that patients with an angioplasty complicated by intimal dissection had early exercise complication rates as high as 5%.30 Early exercise testing after successful angioplasty for predicting restenosis not only is limited in its prognostic value but also is not without risk. The ACC/AHA have concluded that exercise testing following PTCA may be performed on patients after discharge for activity counseling and/or exercise training as part of cardiac rehabilitation in patients who have undergone coronary revascularization. Based on the above data, early exercise testing after revas-


cularization for the purpose of predicting restenosis is not recommended.27 Exercise testing 1–12 months after successful angioplasty for the assessment of restenosis Considerable efforts have also focused on analysing the utility of ETT to detect restenosis. One to 8 months after successful PTCA, Wijns et al34 and Ernst et al35 performed exercise tests on patients prior to repeat angiography. The positive predictive value of exercise induced angina or horizontal ST segment depression ⱖ 1 mm to detect restenosis was only 50%.34,35 In a larger study involving 854 patients, Hillegass et al36 found the sensitivity and specificity of ETT for detecting restenosis to be a disappointing 58% and 62–64% respectively. Additionally important was the fact that 29% of the studies were uninterpretable. Miller et al7 pooled data from 15 studies that examined the predictive value of ETT in the post PTCA setting. This included 2249 patients with angiographic follow-up. Statistical analysis revealed a 55% positive predictive value and a 76% negative predictive value, results that are no better than those of recurrent angina in predicting restenosis.7 The ACC/AHA concur that a Class I indication for performing ETT is for the evaluation of restenosis in patients with recurrent symptoms 1–6 months after catheter-based revascularization.33 For the detection of silent restenosis, some have advocated the use of routine exercise testing in all patients after PTCA. The ACC/AHA favors an alternative approach. Routine exercise testing should be reserved for a select group of asymptomatic patients considered to be higher risk. This includes those with decreased left ventricular function, multivessel CAD, proximal left anterior descending disease, family history of sudden death, diabetes mellitus, hazardous occupations, and suboptimal PTCA results.33

Regardless of the strategy used, clinicians should realize that exercise ECG is an insensitive detector of restenosis. Use of adjunctive data obtained from exercise testing for the assessment of restenosis Adjunctive data obtained from exercise testing has been looked at to possibly improve the predictive value of ETT in detecting restenosis. Michaelides et al37 compared ST segment changes in exercise testing before and after angioplasty and asked whether changes observed in the same leads or different leads were more closely related to restenosis. They found that restenosis was more commonly associated with ST segment depression in the same leads (48%) and that ST segment depression observed in different leads was only associated with restenosis 12% of the time.37 Investigations using other measurable values such as Delta ST, Sigma ST, Delta ST/Delta heart rate index, or QT dispersion measurements, resulted in only modest improvements of the predictive values of treadmill testing to detect restenosis and have not found their way into regular clinical use.38–43 A more hopeful finding came from a study evaluating exercise capacity measurements to detect restenosis. A group of 395 patients underwent bicycle exercise testing 2 weeks before and 2 and 20 weeks after PTCA, as well as repeat angiography 20 weeks after angioplasty. Exercise capacity was defined as work performed by body weight ((watts ⫻ minutes)/kg). Both exercise capacity and MLD increased after PTCA and then decreased at 20-week follow-up, correlating with a statistical significance of p ⱕ 0.0001. Multivariate logistic regression analysis revealed that a late decrease in exercise capacity was independently predictive of both angiographic restenosis (⫺5.3 vs 0.4 W ⫻ minutes/kg, p ⬍ 0.0001) and clinical

29


restenosis (⫺6.3 vs 0.09 W ⫻ minutes/kg, p ⬍ 0.0001).44 Although exercise electrocardiographic stress testing is an insensitive predictor of restenosis, utilizing adjunctive data produced by stress testing shows promise in complementing clinical and non-invasive efforts to detect restenosis.

Nuclear imaging Combining stress testing with nuclear imaging has become one of the most popular and reliable non-invasive techniques for identifying and excluding restenosis.6,7,34,35,45–50 Additionally, SPECT imaging has exhibited an added ability to localize ischemic coronary vascular territories when evaluating restenosis. Limitations of nuclear imaging to detect restenosis have included multivessel disease, previous myocardial infarction, incomplete revascularization, and the presence of collaterals.48,51–53 Nuclear testing early after successful angioplasty for predicting restenosis Studies of stress nuclear imaging early after successful PTCA have evaluated the potential for predicting restenosis, assessing adequacy of revascularization, and detecting complications of angioplasty.34,45,51,54,55 Observations noted an improvement in regional myocardial perfusion in the distribution of the dilated coronary artery and that the degree of improvement tended to correlate with the change in luminal diameter achieved. However, when nuclear measurements of perfusion were compared with invasive measurements of coronary perfusion early after PTCA a discrepancy was observed. A similar discrepancy was also seen by Johnson et al who measured coronary vasodilator reserve early after PTCA and found that it correlated poorly with angiographically measured lumen patency.56 Powelson et al57 sought to evaluate this

30

prospectively in 46 patients by performing thallium SPECT and repeat angiography 1–2 days after successful angioplasty. Thallium perfusion defects were present in 13 vascular territories of which only four had evidence of early restenosis. Investigators observed an increased rate of false positive thallium scans soon after successful coronary intervention and found that the presence of perfusion abnormalities soon after PTCA was not a strong predictor for restenosis.48,57 This discordance is thought to be related to a temporary impairment of regional blood flow related to local trauma or sustained abnormalities in myocardial cell uptake (stunned or hibernating myocardium).57 In an effort to characterize the changes of myocardial perfusion observed in patients after complete revascularization, Manyari et al58 evaluated 43 patients who underwent successful PTCA for single vessel CAD, had no previous MI, and no evidence of restenosis on follow-up. Serial exercise thallium scintigraphy was performed before PTCA and at 9 days, 3 months, and 6 months after PTCA. Abnormal scans were observed in 28% of patients after PTCA with a significant increase in myocardial perfusion at 9 days and 3 months. No significant changes were seen at 6 months. Thus, abnormalities of myocardial perfusion observed with nuclear imaging early after PTCA progressively improve and usually normalize by 3 months. Based on the available data, performing exercise nuclear imaging for the prediction or detection of restenosis early after PTCA is not recommended. 48 Nuclear testing 1–12 months after successful angioplasty for the assessment of restenosis Stress nuclear imaging 1–12 months after successful angioplasty is clinically useful in detecting and localizing ischemia related to


restenosis. Hecht et al performed thallium SPECT imaging in 116 patients before undergoing repeat angiography for suspected restenosis.51 SPECT imaging accurately identified restenosis in 86% of sites with similar results for patients with partial or complete revascularization.6,51 The negative predictive value of thallium SPECT has also proven to be of significant clinical importance. Breisblatt et al56 performed three sequential follow-up thallium SPECT studies in each of 121 patients after successful PTCA. Of the 104 patients who remained asymptomatic at the time of imaging 4–6 weeks after PTCA, regional perfusion abnormalities in the target vessel were demonstrated in 25%. Of these patients, restenosis was demonstrated in 85% at 6 months and 96% at 1 year. Patients with normal scans at 3–6 months had a very low likelihood of developing recurrent symptoms or angiographic restenosis.48,56 Pooling data amongst four benchmark studies of thallium SPECT to detect restenosis revealed a sensitivity of 91%, specificity of 87%, positive predictive value of 83%, and negative predictive value of 93%.6,7,51,56,57,59 Comparable results have also been observed with the use of sestamibi SPECT.60,61 In those patients who are unable to exercise, the use of pharmacological stress with dipyridamole or dobutamine has yielded similar results also.59,62 The improved positive predictive value, as well as the significant negative predictive value, makes thallium SPECT a valuable noninvasive tool in evaluating patients for restenosis.6,7,48 Detection of silent restenosis by nuclear testing The value of SPECT imaging to detect silent restenosis has also been looked at. Hecht et al63 performed thallium SPECT imaging and repeat coronary angiography on 116 patients

after PTCA, 41 of which were asymptomatic. SPECT imaging had a sensitivity of 96% and specificity of 75% for detecting restenosis in the asymptomatic group. The ischemia associated with restenotic lesions among symptomatic and asymptomatic patients was equal in amount and degree of severity.63 A similar study by Marie et al confirmed that thallium SPECT efficiently detected patients with asymptomatic restenosis.57 Regardless of its ability to detect silent restenosis, routine use of SPECT imaging in all patients who have undergone successful PTCA is not recommended. The prognosis of this subset of patients without intervention appears to be favorable and with no prospective trials looking at the need for repeat intervention in patients with silent restenosis routine SPECT after PTCA should be reserved for a select group of asymptomatic patients who are considered to be higher risk.

Stress echocardiography Performing supine bicycle exercise echocardiography early after angioplasty to predict restenosis was recently re-evaluated by Dagianti et al.64 Seventy-six patients with exercise-induced wallmotion abnormalities underwent elective PTCA and repeat exercise echocardiography 2–3 days after successful angioplasty. Congruent with prior studies, wall motion abnormalities and exercise performance improved after successful PTCA. However, 29% of the patients continued to exhibit exercise-induced wall motion abnormalities despite successful angioplasty. In their analysis, this was a predictor of restenosis with an odds ratio of 3.08.64 For predicting restenosis, stress echo initially appears to be promising. However, owing to its low sensitivity, early exercise echocardiography after successful angioplasty to predict restenosis is not universally recommended.

31


Stress echocardiography for non-invasive detection of restenosis 1–12 months after successful angioplasty has been found to be an equivalent alternative to nuclear testing. Stress echo can detect and locate transient stressinduced regional LV wall motion abnormalities and correlate them to perfusion territories of individual coronary arteries, similar to SPECT.28 An advantage of stress echo is the ability to evaluate exercise effects on LV systolic function, which is a strong indicator of true myocardial ischemia. Limitations of stress echocardiography include the incidence of technically difficult imaging that is unsuitable for interpretation, as well as the subjectivity involved with the interpretation of studies. Crouse et al65 and Hecht et al66 looked at using exercise echo in patients with suspected restenosis as much as a year after successful angioplasty. Results for detecting restenosis were as impressive as a sensitivity of 87–95% and specificity of 82–95%.65,66 Using pharmacologic stress with echocardiographic imaging to detect restenosis has also been studied. Heinle et al67 looked at dobutamine stress echocardiography (DSE) and Takeuchi et al68 compared DSE with thallium stress. DSE was comparable in diagnostic accuracy to SPECT for detecting restenosis in patients after PTCA.67,68 A similar comparison by Pirelli et al using dipyridamole echocardiography and exercise thallium yielded similar findings.69 In experienced hands, stress echo has a diagnostic accuracy equal to that of nuclear imaging. Thus, preferential use of either noninvasive modality to detect restenosis would be largely institutionally dependant.

Positron emission tomography (PET) Using different isotopes, PET studies can quantitate regional myocardial metabolism

32

and perfusion as well as evaluate wall motion with diagnostic accuracy equal to or possibly better than sestamibi. The potential for use of PET in evaluating restenosis exists but has not been specifically evaluated at this time.70,71

Effect of stenting on non-invasive evaluation of restenosis Delay of restoration of coronary flow reserve has been documented in vascular territories that have undergone coronary angioplasty. This phenomenon has been postulated to be directly related to the high incidence of false positive noninvasive tests observed early after angioplasty. Mechanisms of this phenomenon are unclear. Release of vasoactive agents at the site of intervention related to mechanical trauma as well as local spasm or dynamic recoil might play an integral role. Those who hypothesize that the mechanical instability of the coronary wall after PTCA is a major determining factor believe that implantation of stents should stabilize the artery wall and may reduce the observed phenomenon. Early investigations with invasive and noninvasive measurements of coronary flow suggest that early normalization does occur in arteries dilated by stents compared to those dilated by balloon angioplasty.72–74 At this time, it is unknown how stenting has influenced the non-invasive evaluation of restenosis.

A practical approach After a successful percutaneous intervention the clinician should have thorough knowledge and documentation of the clinical, angiographic, and procedural risk factors for restenosis. The clinician should follow the patient closely during the ‘vulnerable period’ (day 1 to 3 months). For patients in whom typical symptoms recur or those with atypical

A PRACTICAL APPROACH

symptoms and abnormal non-invasive testing after complete revascularization at the index procedure, it is our practice to go directly to the cardiac catheterization laboratory for confirmation of restenosis. We tend to avoid exercise imaging for the first 3–4 weeks because a substantial percentage (28%) of patients with single vessel disease and a successful procedure will have abnormal scans with no clinical or angiographic evidence of restenosis (i.e. false positive). Possible explanations for this phenomenon include impaired vasodilator reserve distal to the intervention site, stunned myocardium, or hibernating myocardium. One to 12 months after successful intervention, our choice is to use stress nuclear or echo to stratify patients with atypical symptoms. Patients with normal studies are likely to remain free of significant restenosis and can be followed clinically. Substantial clinical judgment is required on how to handle asymptomatic patients with positive exercise imaging at 2–3 months. The clinical setting, angiographic factors, the

degree of ischemia, and the patient’s desires should all be carefully weighed. At the time of repeat study for suspected restenosis, it is our custom to discuss the potential solutions with the patient and family as is appropriate. Just as the oncologist has the difficult task of approaching the cancer patient with the various approaches of chemotherapy, radiation, and surgery; the cardiologist needs to have an eclectic, multi-pronged, ‘cancer-like’ approach while we await more discoveries. It is reasonable to use debulking and stenting as our ‘first surgical’ approach and the advent of radiation therapy appears extremely promising. It is likely that some ongoing chemotherapy will involve antiplatelet, antiproliferative, or genetically directed agents. One can speculate that this intensive multi-tiered approach will markedly reduce the incidence of restenosis, but there are probably a certain percentage of cases that will be refractory to treatment until new concepts and research find the missing pieces of the puzzle.

33


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36

after percutaneous transluminal angioplasty. Clin Cardiol 1999; 22:639–648. Hamasaki S, Arima S, Tahara M et al. Increase in the delta ST/delta heart rate index: a new predictor of restenosis after successful percutaneous transluminal angioplasty. Am J Cardiol 1996; 78:990–995. Hamasaki S, Abematsu H, Arima S et al. A new predictor of restenosis after successful percutaneous transluminal coronary angioplasty in patients with multivessel coronary artery disease. Am J Cardiol 1997; 80:411–415. Aytemir K, Ozer N, Aksoyek S et al. QT dispersion plus ST-segment depression: a new predictor of restenosis after successful percutaneous transluminal coronary angioplasty. Clin Cardiol 1999; 22:409–412. Jorgensen B, Simonsen S, Endresen K et al. Physiologic response to gain and loss in coronary minimal luminal diameter in patients treated with coronary angioplasty: prediction of restenosis on the basis of exercise capacity. Am Heart J 2000; 139:482–490. O’Keefe JH, Lapeyre AC, Holmes DR et al. Usefulness of early radionuclide angiography for identifying low-risk patients for late restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1988; 61:51–54. DePuey EG, Boskovic D, Krajcer Z et al. Exercise radionuclide ventriculography in evaluating successful transluminal coronary angioplasty. Cathet Cardiovasc Diagn 1983; 9:153–166. DePuey EG, Leatherman RD, Dear WE et al. Restenosis after transluminal coronary angioplasty detected with exercise-gated radionuclide ventriculography. J Am Coll Cardiol 1984; 3:1103–1113. DePuey, Gordon E. Radionuclide methods to evaluate percutaneous transluminal coronary angioplasty. In: Seminars in Nuclear Medicine, vol XXI, no 2. WB Saunders Company, 1991; 102–115. Hardoff R, Shefer A, Gips S et al. Predicting late restenosis after coronary angioplasty by very early (12 to 24 h) thallium-201 scintigraphy: implications with regard to mechanisms of late coronary restenosis. J Am Coll Cardiol 1990; 15:1486–1492.

50. Scholl JM, Chaitman BR, David PR et al. Exercise electrocardiography and myocardial scintigraphy in the serial evaluation of the results of percutaneous transluminal coronary angioplasty. Circulation 1982; 66:380–390. 51. Hecht HS, Shaw RE, Bruce TR et al. Usefulness of tomographic thallium-201 imaging for detection of restenosis after percutaneous transluminal coronary angioplasty. Am Heart J 1993; 126:571–577. 52. Breisblatt WM, Barnes JV, Weiland F et al. Incomplete revascularization in multivessel percutaneous transluminal coronary angioplasty: the role for stress thallium-201 imaging. J Am Coll Cardiol 1988; 11:1183–1190. 53. Marie PY, Canchin N, Karcher G et al. Usefulness of exercise SPECT-thallium to detect asymptomatic restenosis in patients who had angina before coronary angioplasty. Am Heart J 1993; 126:571–577. 54. Lewis BS, Hardoff R, Merdler A et al. Importance of immediate and very early post procedural angiographic and thallium-201 single photon emission computed tomographic perfusion measurements in predicting late results after coronary intervention. Am Heart J 1995; 130:425–432. 55. Miller DD, Liu P, Strauss W et al. Prognostic value of computer-quantitated exercise thallium imaging early after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1987; 10:275–283. 56. Johnson MR, Wilson RF, Skorton DJ et al. Coronary lumen area immediately after angioplasty does not correlate with coronary vasodilator reserve: a videodensitometric study. Circulation 1986; 74(Suppl II):II-193 (abst). 57. Powelson SW, DePuey EG, Roubin GS et al. Discordance of coronary angiography and thallium tomography early after transluminal coronary angioplasty. J Nucl Med 1986; 27:6. (abst) 58. Manyari DE, Knudtson M, Kloiber R et al. Sequential thallium-201 myocardial perfusion studies after successful percutaneous transluminal coronary angioplasty: delayed resolution of exercise-induced scintigraphic abnormalities. Circulation 1988; 77:86–95. 59. Jain SP, Jain A, Collins TJ et al. Predictors of

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restenosis: a morphometric and quantitative evaluation by intravascular ultrasound. Am Heart J 1994; 128:664–673. Georgaoulias P, Demakopoulos N, Kontos A et al. Tc-99 tetrofosmin myocardial perfusion imaging before and six months after percutaneous transluminal coronary angioplasty. Clin Nucl Med 1998; 23:678–682. Milan E, Zoccarato O, Terzi A et al. Technetium-99m-sestamibi SPECT to detect restenosis after successful percutaneous coronary angioplasty. J Nucl Med 1996; 37:1300–1305. Elhendy A, Geleijnse ML, Roelandt JR et al. Dobutamine TC-99m-mibi SPET myocardial perfusion scintigraphy in the prediction of restenosis after percutaneous transluminal coronary angioplasty in patients unable to perform an exercise test. Nucl Med Comm 1996; 18:122–128. Hecht HS, Shaw RE, Chin HL et al. Silent ischemia after coronary angioplasty: evaluation of restenosis and extent of ischemia in asymptomatic patients by tomographic thallium-201 exercise imaging and comparison with symptomatic patients. J Am Coll Cardiol 1991; 17:670–677. Dagianti A, Rosanio S, Penco M et al. Clinical and prognostic usefulness of supine bicycle exercise echocardiography in the functional evaluation of patients undergoing elective percutaneous transluminal coronary angioplasty. Circulation 1997; 95:1176–1184. Crouse L, Vacek J, Beauchamp G et al. Use of exercise echocardiography to evaluate patients after coronary angioplasty. Am J Cardiol 1996; 78:1163–1166. Hecht H, DeBord L, Shaw R et al. Usefulness of supine bicycle stress echocardiography for detection of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1993; 71:293–296.

67. Heinle S, Lieberman E, Ancukiewicz M et al. Usefulness of dobutamine echocardiography for detecting restenosis after percutaneous transluminal angioplasty. Am J Cardiol 1993; 72:1220–1225. 68. Takeuchi M, Miura Y, Toyokawa T et al. The comparative diagnostic value of dobutamine stress echocardiography and thallium stress tomography for detecting restenosis after coronary angioplasty. J Am Soc Echocardiography 1995; 8:696–702. 69. Pirelli S, Danzi G, Massa D et al. Exercise thallium scintigraphy versus high-dose dipyridamole echocardiography testing for detection of asymptomatic restenosis in patients with positive exercise tests after coronary angioplasty. Am J Cardiol 1993; 71:1052–1056. 70. Bergman SR, Cardiac Positron Emission Tomography. Seminars in Nuclear Medicine 1998; vol XXVIII: 320–340. 71. Ronnow Sand NP, Bottcher M, Madsen MM et al. Evaluation of regional myocardial perfusion in patients with severe left ventricular dysfunction: comparison of 13N-ammonia PET and 99mTC sestamibi SPECT. J Nucl Cardiol 1998; 5:4–13. 72. Kern MJ, Aguirre FV, Donohue TJ et al. Impact of residual lumen narrowing on coronary flow after angioplasty and stent: intravascular ultrasound Doppler and imaging data in support of physiologically-guided coronary angioplasty. Circulation 1995; 92 (Suppl I): I-263 (abst). 73. Bowers TR, Safian RD, Stewart RE et al. Normalization of coronary flow reserve immediately after stenting but not after PTCA. J Am Coll Cardiol 1996; 27:19A (abst). 74. Kosa I, Blasini R, Schneider-Eicke J et al. Early recovery of coronary flow reserve after stent implantation as assessed by positron emission tomography. J Am Coll Cardiol 1999; 34:1036–1041.

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4 Clinical, biochemical, angiographic and intravascular ultrasound predictors of restenosis Stefan Verheye and Glenn Van Langenhove

Introduction Restenosis after percutaneous intervention has plagued interventional cardiology since its inception. Multiple techniques have been tried without success to eliminate this problem. One of the main reasons for this failure is the lack of knowledge regarding the mechanism of restenosis. It is crucial, therefore, that other factors, which may help in assessing the risk of restenosis, be determined. Indeed, the assessment of clinical risk factors for coronary heart disease is now commonplace in clinical cardiology; the prevention and treatment of these risks have been a major step forward in cardiology, and many patients have benefited from it. In a similar way, knowledge of a variety of factors with a predictive value may help in the selection and treatment of patients who are at increased risk of restenosis and therefore reduce the rate of restenosis. The focus of this chapter is to give an overview of predictors of restenosis after any percutaneous intervention – clinically, biochemically, angiographically as well as by using intravascular ultrasound (IVUS) – that have been proposed in the recent literature.

Clinical predictors Clinical parameters of restenosis with varying predictive value after conventional balloon

angioplasty have been considered for more than two decades. Other interventional techniques have been introduced and along with that, clinical predictors have changed and others have been added. However, a clinical predictor is defined as a clinical marker with a (low or high) value in predicting restenosis, regardless of interventional technique. The determination of predictors is based on statistical analyses of uni- and multivariate regression models that rely on groups of patients with different characteristics. Published reports usually differ from each other with regard to patient characteristics and in addition, differences between prospective studies and retrospective database analyses may account for differences in predictive markers. Furthermore, one has to bear in mind that many reports are related to a specific indication for percutaneous revascularization and therefore predictors must be judged in relation to the situation the cardiologist is dealing with, i.e. restenosis after balloon angioplasty differs from in-stent restenosis. As a consequence, contradictory findings in the literature are not uncommon. The importance of defining the problem is illustrated by the following two observations. Analyses of earlier studies evaluating the effect of an angiotensin-converting enzyme (ACE)inhibitor after conventional balloon angioplasty on restenosis at 6 months showed that

39

CLINICAL, BIOCHEMICAL, ANGIOGRAPHIC AND INTRAVASCULAR ULTRASOUND

the restenosis phenomenon could not be predicted accurately by any patient variables.1 On the other hand, Gershlick et al2 found positive clinical parameters in patients undergoing balloon angioplasty with 6-month follow-up and reported that early recurrent symptoms were the best predictors of angiographic restenosis, whereas history of recurrent angina or positive exercise testing alone at follow-up were poor predictors. The predictive value even increased when exercise testing was positive in patients complaining of angina.2 The first study tried to predict restenosis based on clinical variables prior to the procedure, whereas the second study tried to determine predictors that are partially post procedural. ‘Classical’ clinical factors such as age and male gender have been proposed as independent predictors for restenosis after angioplasty.3,4 Although a significantly increased risk of acute complications could be documented only in women undergoing percutaneous transluminal coronary angioplasty (PTCA) for stable angina pectoris and not in acute coronary syndrome, Heidland et al reported that gender was not a predictor since the long-term outcome was similar between the two sexes.5 The same group also concluded that age and cardiovascular risk factors were not predictors for restenosis. Gurlek et al also showed that age and sex were not associated with risk of restenosis.6 However in another study reporting long-term results of patients who underwent a first stent implantation, multivariable analysis showed that female sex was an independent predictor of increased mortality after stenting.7 Many reports concluded that the restenosis risk could not be predicted from clinical variables known at the time of the procedure (directional atherectomy or stent implantation).8–11 However, a history of unstable angina12 as well as duration of angina less

40

than 6 months13 were both found to be independent predictors for restenosis although Mittal et al found that rather the presence of angina at the time of follow-up was significantly associated with restenosis.8 On the other hand, in the EPIC trial, absence of rest angina was also independently associated with an increased rate of clinical events.14 Traditional risk factors for atherosclerosis are generally not related to increased restenosis and are therefore poor predictors.13 However, several authors have reported on some well known risk factors for atherosclerosis that may function as good predictors for restenosis. Smoking is an important risk factor and is found to be an independent predictor not only for in-stent restenosis, but also for target vessel revascularization.15–18 However, Gurlek et al reported that smoking was not a predictor for restenosis,6,19 which was confirmed by another group.20 Similarly, diabetes mellitus is a traditional risk factor that has been associated with restenosis as an independent predictor more than any other risk factor.21–27 According to Kastrati et al, diabetes increased the risk of binary restenosis with an odds ratio (OR) (95% confidence interval [CI]) of 1.86 and the risk of target lesion revascularization with an OR of 1.45.22 Furthermore, in a report published by Lee et al, diabetes was associated with diffuse in-stent restenosis after coronary stent placement that may reflect an enhanced rate of neointimal formation within the stent in diabetic patients.24 Van Belle et al go further and report that treatment with insulin is an independent predictor for vessel occlusion in the same patient population.27 Again, conflicting results have been reported regarding the predictive value of the presence of diabetes mellitus after angioplasty6,28 and stent implantation29 being negative in both situations. Other clinical predictors have been

BIOCHEMICAL AND GENETIC PREDICTORS

Clinical predictors

Relative importance

Age Male gender Smoking Diabetes mellitus Hypertension Previous myocardial infarction Peripheral vascular disease Prior restenosis Presence of organ failure Hypercholesterolemia Statin therapy

+ – ± +++ + + + + + ± ±

Table 4.1. Clinical predictors of restenosis (relative importance graded from – to +++ with ± meaning that conflicting results were reported).

described and include the presence of a previous myocardial infarction, a history of peripheral vascular disease, prior restenosis, and the presence of organ failure.13,14,26,27,30 In a recent report, multivariate analysis identified statin therapy as an independent predictor for reduced subsequent restenosis development. Statin therapy may be associated with reduced recurrence rates and improved clinical outcome after coronary stent implantation,31 although randomized trials of statins have failed to show benefit. Finally, hypertension has also been associated with increased risk of restenosis after percutaneous intervention.6 An overview of clinical predictors is presented in Table 4.1.

Biochemical and genetic predictors A whole variety of serum markers have been proposed as possible predictors for restenosis. However, the mechanism of restenosis between the two types of intervention (balloon

angioplasty and stenting) differs, resulting in up- or down-regulation of several proteins and genes that can be detected and, therefore, the prediction of restenosis in both situations may require separate screening methods.32 An analysis of the available literature discussing these predictors is presented below.

Serum lipid concentration Serum cholesterol is a well known risk factor for atherosclerosis, however, its role in the prediction of restenosis after percutaneous intervention is unknown. In a mega-analysis based on four major restenosis trials in patients undergoing coronary balloon angioplasty, Violaris et al found that there was no association between cholesterol and 33 restenosis. Even subgroup analysis based on HDL and LDL cholesterol levels revealed no differences in the categorical restenosis rate, suggesting no influence of these cholesterol subfractions on restenosis. It was suggested, therefore, that reduction of total cholesterol

41


would not result in reduction of restenosis. This suggestion was evaluated in the PREDICT trial in which it was shown that cholesterol lowering had no effect on angiographic outcome at the target site 6 months after coronary angioplasty.34 This finding is in contrast with other reports demonstrating that high levels of serum cholesterol are associated with a higher restenosis rate.6,30,35

C-reactive protein The preprocedural C-reactive protein (CRP) level, a marker of acute phase response that can be easily measured, is a powerful predictor of both early and late outcome in patients undergoing single vessel balloon angioplasty, suggesting that early complications and clinical restenosis are markedly influenced by the preprocedural degree of inflammatory cell activation.36 Using multivariate analysis, Heeschen et al found that both CRP and troponin T emerged as independent predictors of mortality and myocardial infarction at 6-month follow-up. On the other hand, the incidence of coronary restenosis during 6-month follow-up was not related to Troponin T status (3% vs 4.5%; p=0.49) but was significantly related to CRP status (7% vs 2.3%; p=0.03). These authors concluded that CRP was an independent predictor of both cardiac risk and repeated coronary revascularization (coronary artery bypass graft surgery and PCTA) during 6-month follow-up.36 Other markers of inflammation, such as IL6, have also been shown to be related to restenosis.38 Conflicting results were provided by Zhou et al, who demonstrated that although both Chlamydia infection and elevated CRP levels are associated with coronary artery disease and coronary artery disease events, neither appears to play a role in the development of restenosis in human subjects.39

42

Fibrinogen Tschopl et al40 showed comprehensively that baseline plasma fibrinogen, CRP concentration, and the severity of the arterial disease were significantly predictive of coronary restenosis. Their results indicate that high procoagulant factors and persistent thrombin generation of the haemostatic system might promote restenosis, particularly in patients with extended atherosclerosis.40 A high plasma fibrinogen level also seems to play a role in the development of restenosis after renal artery intervention.41 Schoebel et al found that the high rate of angiographic restenosis in patients with end stage renal disease seems to be related to the size of the vessel dilated and to an increased prothrombotic risk, as indicated by higher fibrinogen concentrations.42 Others, however, have contradicted the importance of fibrinogen as a predictor for restenosis.43

Lipoprotein (a) Serum lipoprotein (a) [Lp(a)] level is a known risk factor for arteriosclerotic coronary artery disease, but its association with restenosis after balloon angioplasty in coronary arteries is controversial. It was hypothesized that through a pathophysiological mechanism leading to excess thrombin generation or inhibition of fibrinolysis, the risk for restenosis would be increased. However, several groups found no correlation between restenosis after balloon angioplasty and levels of Lp(a),28,44,45 while others have found conflicting results. Balloon angioplasty and Japanese origin in combination with an increased Lp(a) level seems to constitute a risk factor for restenosis.46–49 In a study analysing the predictive role of plasma Lp(a) for restenosis after elective coro-

ANGIOGRAPHIC PREDICTORS

nary stenting, Ribichini et al50 found that multiple stents were associated with a higher incidence of restenosis (p = 0.006), but biochemical data in these patients were similar to those treated with single stents. They concluded that the basal plasma level of Lp(a) measured before the procedure is not a predictor for restenosis after elective high-pressure coronary stenting.50 Wehinger et al confirmed these results at 1-year follow-up.51

Serum amyloid A A somewhat unusual predictive factor was described by Blum et al.52 Patients who had an increase in their serum amyloid type A level of > 100% in the first 24 hours after balloon angioplasty and also developed a positive antibody result (antinuclear factor or anticardiolipin), had a relative risk of 10.6 for developing restenosis in the first year after the initial revascularization.

after conventional balloon angioplasty.53–55 Hamon et al took it a step further and concluded that genotyping of ACE and angiotensin I-receptor polymorphisms before conventional balloon angioplasty is not clinically useful.56 More encouraging results between restenosis and ACE I/D polymorphism were found in patients undergoing coronary artery stent implantation.57,58 Analysis of these studies showed that the I/D polymorphism was significantly associated with the occurrence of in-stent restenosis, suggesting that ACE may indeed play an important part in the formation of neointimal tissue after stent implantation. However, another group looking at a similar patient population recently could not confirm these results.59

Other Several other parameters have been described and are referred to in Table 4.2.

Angiotensin-converting enzyme

Angiographic Predictors

The angiotensin-converting enzyme (ACE) is an important molecule that is involved in the conversion of angiotensin I to angiotensin II and the inhibition of bradykinin. The plasma and cellular levels of ACE in humans are associated with an I (insertion)/D (deletion) genetic polymorphism in the ACE gene. Patients with DD have higher levels of ACE. It has been suggested that polymorphisms of this system are involved in neointimal formation after arterial injury. Since neointimal formation plays an important role in renarrowing after balloon angioplasty and a predominant role after coronary artery stenting, the ACE I/D polymorphism has been thoroughly evaluated as a predictive marker for restenosis. Several groups agreed on the lack of correlation between ACE polymorphism and restenosis

Numerous angiographic studies have evaluated the effects of balloon angioplasty, stent implantation, directional coronary atherectomy, rotational atherectomy, laser angioplasty, intracoronary brachytherapy, systemic pharmacological treatment, local drug delivery, and stent coating on angiographic restenosis. The majority of them have tried to determine specific variables after different and complex analyses that would help in predicting the risk of restenosis after a given percutaneous coronary intervention. It is apparent from several studies that these so-called predictive factors differ, depending on the technique, the number of patients, the nature of the trial, the selection bias, the angiographic endpoints, the percentage follow-up and last, but not least, the definition of restenosis itself.

43


Factor

Correlation

Reference

CD64 CD66 IL-1 beta Plasma uPA antigen levels PAI-1 antigen levels high plasma activity of ACE intracoronary SMMHC Serum levels of soluble Fas ligand Mac-1 (CD11b/CD18) on the surface of the neutrophils increased sICAM-1 levels homozygosity for apolipoprotein epsilon 4 high endothelin levels von Willebrand factor

– – + + + + + + + + + + +

18 18 18 Strauss 99 Strauss 99 Ribichini 97 Tsuchio 2000 Hara 2000 Inoue 98 Inoue 98 Van Bokxmeer 94 20 Montalescot 95

IL, interleukin; ACE, angiotensin-converting enzyme; PAI, plasminogen activator inhibitor; SMMHC, serum smooth muscle; PA, plasminogen activator Strauss BH, Lau HK, Bowman KA, et al. Plasma urokinase antigen and plasminogen activator inhibitor-1 antigen levels predict angiographic coronary restenosis. Circulation 1999; 100:1616–1622. Ribichini F, Steffenino G, Dellavalle A, et al. Plasma activity and insertion/deletion polymorphism of angiotensin I-converting enzyme: a major risk factor and a marker of risk for coronary stent restenosis. Circulation 1998; 97:147–154. Tsuchio Y, Naito S, Nogami A, et al. Intracoronary serum smooth muscle myosin heavy chain levels following PTCA may predict restenosis. Japanese Heart Journal 2000; 41:131–140. Hara H, Sato R, Katagiri T, Hasegawa M. Evaluation of restenosis by serum levels of soluble Fas, Fas ligand and nuclear matrix protein before and after coronary intervention. Journal of Cardiology 2000; 35:89–93. Inoue T, Sakai Y, Hoshi K, Yaguchi I, Fujito T, Morooka S. Lower expression of neutrophil adhesion molecule indicates less vessel wall injury and might explain lower restenosis rate after cutting balloon angioplasty. Circulation 1998; 97:2511–2518. van Bockxmeer FM, Mamotte CD, Gibbons FR, Taylor RR. Apolipoprotein epsilon 4 homozygosity–a determinant of restenosis after coronary angioplasty. Atherosclerosis 1994; 110, 195, 202. Montalescot G, Ankri A, Vicaut E, Drobinski G, Grosgogeat Y, Thomas D. Fibrinogen after coronary angioplasty as a risk factor for restenosis. Circulation 1995; 92:91–98.

Table 4.2. Other biochemical and genetic predictors for restenosis. Correlation is + when predictive of restenosis, and – if protective.

Defining restenosis is of the utmost importance, as it must correlate well with clinical end points and it determines the success of a treatment modality. Several definitions have been proposed and each of them must be seen in relation to the purpose of each individual study. The traditional definition is a dichotomous definition in which restenosis is defined as a > 50% renarrowing at follow-up. This definition relates to a late failure of an initial successful intervention. However, since restenosis is a continuous phenomenon and

44

parametric statistical tests are more powerful, it might be preferable to use late percentage diameter stenosis or absolute late minimal lumen diameter (MLD) rather than any binary restenosis definition.60 The absolute late loss itself is an even better measure, however, since late loss is highly related to the acute gain produced by the intervention, it is common to define restenosis as the ratio of late loss to acute gain or “loss index.” Based on several analyses, this index has also been found to be relatively insensitive to the device used. It has

ULTRASOUND PREDICTORS

correctly identified a number of biological variables (left anterior descending LAD artery, location, diabetes) that increase restenosis. These considerations should be taken into account when analysing the predictive angiographic parameters for restenosis. A common finding in nearly all of the angiographic studies evaluating predictive factors for restenosis is the MLD after the intervention.3,13,21–24,30,31,61–64 The magnitude of the predictive value of the post intervention MLD varies among several reports and is often related to the technique used to treat the lesion. In a multivariable modeling for restenosis after balloon angioplasty, Carozza et al showed that a post procedure lumen diameter < 2.80 mm was one of the only independent predictors of restenosis among diabetes mellitus, and prior restenosis.61 Using univariate analysis, Moscucci et al demonstrated that a post procedure luminal diameter < 3.1 mm was a strong predictor for binary restenosis.26 In relation to directional coronary atherectomy, Fishman et al found that a post procedure lumen diameter > 3 mm was a predictor of a lower restenosis rate.30 Using rotational atherectomy, the burr-to-artery ratio (< 0.6) was found to be a univariate predictor of repeat restenosis.65 In another study by Rau et al, a post stenting MLD of ≤ 2.54 mm was also found to adversely influence the angiographic outcome.66 Kastrati et al reported that a MLD < 3 mm at the end of the procedure augmented the risk of binary restenosis with an OR of 1.81.22 A second well known predictor for restenosis is the reference vessel diameter. Small vessels are invariably found to be associated with an increased risk of restenosis.13,21,24,62,63,67,68 The length of the lesion or the stented vessel segment length is another common and good predictor for restenosis.15,23,62,69,70 Popma et al

found that a lesion length of more than 10 mm was associated with an increased risk of restenosis after directional coronary atherectomy.3 According to Rau et al, a stent length > 16 mm has a high chance of restenosis.66 Increasing the number of stents also negatively influences the long-term angiographic outcome,7,22,25 as does multivessel stenting.7,24 The location of the lesion is another important predictor. Very often, the risk for restenosis is increased when the LAD artery is involved,13,26 the lesion is ostial or at the proximal segment of an artery,13,65,71 the stenosis is within a saphenous vein graft,3,17,20,21,26,27 or it involves a bifurcation.27 Other factors with a predictive value for restenosis after balloon angioplasty and/or stent implantation have been reported and include percentage diameter stenosis after the procedure63 and at follow-up,71 a balloon/ vessel diameter ratio for final stent expansion ≤ 1.00,65 the presence of a dissection after balloon angioplasty,65 lesion symmetry,15,67 the angiographic pattern of in-stent restenosis,25,64 bailout stenting,7 acute neointimal recoil,72 stenting without debulking,70 high-pressure balloon inflation (>16 atm),70 prestenting vessel angulation,73 and the changes in vessel angulation after stent implantation.73 Very recently, the placement of a new stent in conjunction with intravascular brachytherapy has been found to be associated with a high predictive value of late total occlusion in patients with in-stent restenosis.74

Ultrasound predictors The abundance of trials on angiographic prediction of restenosis stands in sharp contrast to the paucity of strong data concerning the ultrasound predictors of restenosis. To our knowledge, no well-conducted trial has investigated the possibility of IVUS as a predictor

45


of restenosis in a non-biased way. Later in this chapter we will describe two trials that used ultrasound guidance; although the pharmacological agents used in these trials did not show any benefit in reducing in-stent restenosis, the data that arose from these trials were very useful in constructing an IVUS-guided prediction model for in-stent restenosis. 75 In a small study of IVUS-guided balloon angioplasty, Jain et al76 found that of the various parameters analysed, the absence of plaque fracture, the existence of a major dissection, and greater plaque burden were associated with increased incidence of restenosis 6 months after the index balloon angioplasty. They indicated that IVUS can identify a subset of patients in whom restenosis is likely to develop, and that the information about the morphological features of the atheroma and its composition may be used to modify the interventional strategy and thus optimize lumen size and possibly reduce the chance of restenosis. Mintz et al found that reference vessel size, the preintervention quantitative coronary angiographic (QCA) assessment of lesion severity and the postintervention IVUS crosssectional measurements predicted the late angiographic results in a study of 350 patients following balloon angioplasty.77 In particular, the IVUS postintervention cross-sectional narrowing (plaque plus media cross-sectional area (CSA) divided by external elastic membrane CSA) predicted the primary end point (restenosis) as well as two of the three secondary end points (follow-up diameter stenosis and late lumen loss) and was therefore the most consistent predictor of restenosis. In a study of 70 patients where 40 were treated by balloon angioplasty alone, and 30 by combination of rotational atherectomy plus balloon angioplasty, Schiele et al found that the only independent predictor of late clinical

46

outcome after percutaneous re-intervention for in-stent restenosis was final lumen size, no matter which means were used to achieve it.78 In a study of 164 patients, Peters et al stated that qualitative IVUS parameters after balloon angioplasty did not predict restenosis.79 A larger lumen and vessel area and a smaller plaque area by IVUS were associated with a larger angiographic MLD at follow-up, but these parameters were not significantly related to categorical restenosis. Moreover, plaque morphology data did not seem to correlate to restenosis rate. This study may have been biased by its retrospective design. In two landmark studies, Albiero et al80 and de Jaegere et al81 both demonstrated the added benefit of performing IVUS during stent implantation to reduce the 6-month restenosis rate. Albiero et al showed that the dichotomous restenosis rate was lower in the IVUS group than in the angiographic group (9.2% vs 22.3%; p = 0.04).80 The authors concluded that in matched lesions treated with high-pressure stenting, IVUS guidance achieved a larger MLD than angiographic guidance. In the MUSIC trial, which was originally set up to validate the safety and feasibility of IVUSguided stenting without subsequent anticoagulation, and its impact on the 6-month restenosis rate, de Jaegere et al found that in selected patients, stents can be implanted safely without the use of systemic anticoagulation, provided optimal stent expansion is achieved.81 Based on these initial findings, de Feyter et al created a reference chart to predict the expected in-stent restenosis rate based on operator-dependent IVUS parameters.75 IVUSdetermined post-stent-implantation predictors of 6-month in-stent restenosis on QCA were identified by logistic regression analysis. These predictors were used to construct a reference chart that predicts the expected 6-month QCA restenosis rate. IVUS and QCA data were

ULTRASOUND PREDICTORS

obtained from three registries (MUSIC [Multicenter Ultrasound Stenting in Coronaries study], WEST-II [West European Stent Trial II], and ESSEX [European Scimed Stent EXperience]) and two randomized in-stent restenosis trials (ERASER [Evaluation of ReoPro And Stenting to Eliminate Restenosis] and TRAPIST [TRApidil vs placebo to Prevent In-STent intimal hyperplasia]), as neither abciximab nor trapidil resulted in a reduction of instent restenosis. IVUS predictors were minimum and mean in-stent area, stent length, and instent diameter. Multiple models were constructed with multivariate logistic regression analysis. The model containing minimum instent area and stent length best fit the Hosmer–Lemeshow goodness-of-fit test. Thus, the expected 6-month in-stent restenosis rate after stent implantation for short lesions in relatively large vessels can be predicted by considering the in-stent minimal area (which is inversely related to restenosis) and stent length (which is directly related to restenosis; Fig. 4.1). Hong et al confirmed the findings of the MUSIC trial.82 In 285 consecutive patients

Restenosis

1.00

0.67

0.33 60

0.00 3.0

35

7.5 Minimum in-stent area

12.0 10

Stent length

Figure 4.1 Three-dimensional representation of restenosis rate (y-axis) in relation to minimum in-stent area (x-axis) and stent length (z-axis).

with 304 native coronary lesions, the investigators evaluated the predictors of angiographic restenosis and compared them with stent lumen CSA and stent length between short stent length (< 20 mm) and long (≥ 20 mm) coronary stenting. The overall angiographic restenosis rate in this group was 22.8% (56 of 246 lesions) (short stent 17.6% vs long stent 32.2%, p = 0.009). Using multivariate logistic regression analysis, the independent predictors of angiographic restenosis were the IVUS stent lumen CSA (OR 1.51, 95% CI 1.18–1.92, p = 0.001 for overall comparison among groups) and stent length (OR 0.95, 95% CI 0.91–1.00, p = 0.039). The angiographic restenosis rate was 54.8% for stent lumen CSA of < 5.0 mm2 (short stent 37.5% vs long stent 73.3%, p = 0.049), 27.4% for CSA between 5.0 and 7.0 mm2 (short stent 24.1% vs long stent 31.7%, p = 0.409), 10.5% for CSA between 7.0 and 9.0 mm2 (short stent 10.0% vs long stent 12.5%, p = 0.772), and 11.4% for stent lumen CSA of ≥ 9.0 mm2 (short stent 10.4% vs long stent 13.3%, p = 0.767) (p = 0.001). Interestingly, long coronary stenting, as opposed to short coronary stenting, is an effective treatment modality to cover long lesions resulting in comparable long-term clinical outcomes providing that a stent lumen CSA of ≥ 7.0 mm2 is achieved. Therefore, the most important factor determining angiographic restenosis, regardless of the stent length, is the IVUS stent lumen CSA in relatively large coronary artery lesions. Hofmann et al found that ostial lesion location and IVUS preinterventional plaque burden (plaque/total arterial area) and postinterventional lumen dimensions were the most consistent predictors of angiographic in-stent restenosis in a study of 382 lesions in 291 patients treated with 476 Palmaz–Schatz stents.71

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In a large retrospective study of 1,706 patients with 2,343 lesions treated with intracoronary stenting, Kasaoka et al found instent restenosis was angiographically documented in 282 patients with 409 lesions (25%).62 The restenosis group had a significantly longer total stent length, smaller reference lumen diameter, smaller final MLD by angiography and smaller stent lumen CSA by IVUS. In lesions where IVUS guidance was used, the restenosis rate was 24% compared with 29% if IVUS was not used (p < 0.05). By multivariate logistic regression analysis, longer total stent length, smaller reference lumen diameter and smaller final MLD were strong predictors of in-stent restenosis. In lesions with IVUS guidance, IVUS stent lumen CSA was a better independent predictor than the angiographic measurements. The conclusions of the investigators were somewhat predictive of what was later to be found in randomized trials, namely that achieving an optimal stent lumen CSA by using IVUS guidance during the procedure and minimizing the total stent length may reduce in-stent restenosis.

Practical implications It is not an easy task to provide a straightforward list with actions to be undertaken to minimize the risk for restenosis. As has been mentioned previously, many conflicting results are provided in the literature. In Figure 4.2 we have tried to capture the most important risk factors. We have divided them into three categories: those that have arisen from non-confirmed circumstantial evidence (small circles), those that have provided conflicting results but provided positive evidence in most cases (medium-sized circles) and those that are based on solid evidence (large circles). The colour code further splits them into treatable (green) and non-treatable (red).

48

Fibrinogen

Smoking

Organ failure Lipoprotein (a)

Male

Cholesterol Unstable Old age

CRP

Hypertension

S Amyloid A

ACE I/D polym

Diabetes

Previous MI

Restenosis

Proximal segm

Ref vessel size IVUS Periph vasc dis Ostial lesion LAD involved

Small vessels

MLD post interv Radioact stent

Lesion length

High press PTCA

Diss PostPTCA Prior restenosis

Figure 4.2 Qualitative overview of the most important risk factors for restenosis. We divided them into three categories: those that have arisen from nonconfirmed circumstantial evidence (small circles), those that have provided conflicting results but provided positive evidence in most cases (medium-sized circles), and those that are based on solid evidence (large circles). The color code further splits them into treatable (green) and nontreatable (red). Unstable = Unstable angina at presentation; Previous MI = previous myocardial infarction; CRP = C-reactive protein; S Amyloid A = Serum Amyloid A; ACE I/D polym = Angiotensine-converting enzyme insertion deletion polymorphism; Proximal segm = Proximal segment; LAD = Left anterior descending artery; Radioact stent = Radioactive stent; Periph Vasc Dis = Peripheral vascular disease; High press percutaneous transluminal coronary angioplasty = High pressure PTCA; Diss PostPTCA = Dissection post PTCA; MLD post interv = Minimal luminal diameter post intervention; Ref vessel size IVUS = Reference vessel size using intravascular ultrasound.

CONCLUSIONS

Looking at this figure, it becomes obvious that restenosis is a complex, multi-tiered process that is not easy to tackle. It is probably safe to say that an old, smoking, hypertensive diabetic with hypercholesterolemia with a history of restenosis in a previously treated vessel, who is now treated with a radioactive stent after high-pressure PTCA for a 40 mm lesion in a 2.5 mm caliber LAD lesion is likely to develop restenosis. Caution should be exercised therefore, when patients with a ‘high-risk profile’ present with coronary lesions. Treatable risks should be taken care

of, and angiographic and ultrasound parameters should be optimized.

Conclusions Restenosis represents the last hurdle for the interventional cardiologist in overcoming their restraint in treating all coronary lesions percutaneously. In this chapter we represent an overview of how optimization of the patient’s clinical characteristics and of the periprocedural parameters can be modified so as to minimize this hazardous event.

49


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5 Importance of physiologic assessment pre- and post intervention* Michael D Eisenhauer and Morton J Kern

Introduction Coronary angiography is the principle tool for the evaluation of coronary stenoses, including those lesions recurring after percutaneous coronary intervention. In clinical terms, however, the use of angiography has significant limitations when assessing lesions of intermediate severity, and becomes even more problematic when evaluating the results following coronary interventions with the inherent and inconsistent luminal disruption. Because of the limitations of lumenography, the physiologic assessment of coronary stenoses, both before and after intervention, has emerged with an increasingly important role. It is generally appreciated that an assessment of coronary blood flow is important for decision-making in patients with coronary artery disease. Objective evidence of abnormal coronary blood flow by noninvasive stress testing is relied upon in every cardiology center worldwide. The American College of Cardiology/American Heart Association (AHA/ACC) guidelines for percutaneous transluminal coronary angioplasty (PTCA)

*The opinions or assertions contained herein reflect the views of the authors, and are not to be construed as official, or as representing the position of United States Army Medical Department, the Department of Defense, or the United States Federal Government.

recommend acquiring ‘. . . assurance that . . . symptoms are indeed due to the coronary lesion proposed for dilatation’, and discuss the importance of objective evidence of regional myocardial ischemia before proceeding with an intervention.1 Widely accepted indirect methods to detect regional abnormalities in coronary blood flow include inducible left ventricular contractile abnormalities during stress echocardiography, ischemic electrocardiographic changes on exercise or ambulatory monitoring, and abnormal stress radionuclide perfusion scintigraphy (Table 5.1). However, these indirect methods of coronary blood flow evaluation often require additional time and expense either before or after diagnostic catheterization. The direct influence of a coronary stenosis on physiology, evaluating the distal arterial pressure–flow relationship, can now be easily and safely measured with sensor-tipped angioplasty guidewires at the time of coronary angiography. The measurements of post stenotic absolute coronary flow velocity reserve (CVR), the relative CVR (rCVR), and the pressure-derived fractional flow reserve (FFR) of the myocardium have been identified, refined, simplified, and validated. Assessing coronary blood flow provides unique information that complements anatomic data obtained during diagnostic angiography and following an intervention.2–5 This chapter will review the

55

IMPORTANCE OF PHYSIOLOGIC ASSESSMENT PRE- AND POST INTERVENTION

Indirect methods Electrocardiographic stress or ambulatory ischemia monitoring Radionuclide scintigraphy/perfusion stress imaging Exercise stress Pharmacologic stress: adenosine, dipyridamole, dobutamine Two-dimensional echocardiographic left ventricular imaging Exercise stress Pharmacologic stress: dobutamine, dipyridamole Echocardiographic myocardial perfusion Contrast echocardiography Harmonic processing/tissue Doppler velocities Positron emission tomography Magnetic resonance imaging/angiography Direct methods Anatomic Coronary angiography Intravascular ultrasound Physiologic Intracoronary Doppler flow velocity and reserve (CVR) Intracoronary pressure gradients during hyperemia (FFR) Coronary sinus thermodilution

Table 5.1 Methods of coronary artery assessment.

fundamental assumptions, methodology, validation, and clinical applications for lesion assessment before and after coronary interventions.

Basic coronary physiology An epicardial stenosis produces an increased resistance to antegrade blood flow. In response to decreased epicardial flow, the distant microvascular resistance vessels dilate to maintain regional basal flow at a level appropriate for concurrent myocardial oxygen demand. Increasing the capacitance of the vascular bed reduces the potential maximal flow reserve available. The resting post stenotic epicardial blood flow is generally unchanged from its normal level until the stenosis becomes very

56

severe (usually ⬎ 90% narrowed), and usually is satisfactory to maintain myocardial systolic function, oxidative metabolism, and cellular viability. In the presence of a significant stenosis, any further increase in myocardial oxygen demand or other hyperemic stimuli will result in a reduced post stenotic hyperemia relative to the coronary flow increase that would occur in the same or another myocardial region without a stenosis. A blunted post stenotic hyperemia (reserve) can be easily identified in the catheterization laboratory using a pharmacologic hyperemic stimuli, such as intracoronary adenosine or papaverine, and measuring coronary flow velocity. As a companion to diminished flow, a significant stenosis also produces a loss of post stenotic arterial pressure because of a loss of

BASIC CORONARY PHYSIOLOGY

kinetic energy due to viscous friction, turbulence, and flow separation. The reduction of the distal distending arterial pressure results in a pressure differential (gradient) between the aortic and distal coronary pressure. The absolute distal pressure is directly related to the flow rate as described by the curvilinear pressure–flow relationship of stenosis resistance (Fig. 5.1).6

A

B ⌬P

Flow

Pd B

A

Figure 5.1 Coronary pressure–flow relationship for two stenoses of same angiographic severity (A and B), demonstrating a physiologic difference between lesions. Top: pressure gradient (⌬P) vs coronary flow. Bottom: absolute distal coronary pressure (Pd) versus flow. Increasing coronary flow produces a marked loss of Pd and an increase in ⌬P. Loss of Pd in absolute terms determines myocardial perfusion pressure (Pd – venous pressure) and potential for inducible ischemia. (Adapted from reference 3, with permission).

Until recently, the hemodynamic significance of a given stenosis as determined by the pressure–flow relationship has not been routinely incorporated into clinical practice. Earlier cumbersome techniques and conflicting results from validating studies7,8 raised adverse theoretical concerns regarding the translation of basic physiology from experimental animal models to patient care.9 Most, if not all objections have been overcome by employing sensor guidewires and validating a more thorough understanding of coronary physiology using distal flow and pressure measurements.

Coronary flow velocity reserve Intracoronary Doppler flow velocity can be measured using a Doppler-tipped angioplasty guidewire. This guidewire is a 175 cm long, 0.014–0.018 inch (0.035–0.046 cm) diameter, flexible, steerable wire with a piezoelectric ultrasound transducer integrated into the tip (FloWire; Endosonics, Inc., Rancho Cordova, CA, USA). The cross-sectional area of the wire itself is 0.164 mm2, only 21% of the crosssectional area of a 1 mm catheter. As a result, the guidewire induces very little flow disturbance, and like standard angioplasty guide wires, can be used as a primary angioplasty crossing wire with ⬎ 90% success for most coronary stenoses. The velocity signals are processed through a real-time spectrum analyser, continuously displayed on a video monitor, and recorded on videocassette or a thermal page printer. Reproducibility of the velocity signals is generally excellent with low interobserver (⬍ 12%) and intraobserver (9%) variability.10 Coronary flow velocity is calculated from the Doppler frequency shift defined as the difference between the transmitted and returning frequency: V ⫽ [(F1–F0)*C]/[(2F0)*(Cos ␾)]

57


where: V ⫽ velocity of blood flow F0 ⫽ transmitting (transducer) frequency F1 ⫽ returning frequency C ⫽ constant: speed of sound in blood ␾ ⫽ angle of incidence Volumetric blood flow is calculated as the product of vessel cross-sectional area (cm2) and flow velocity (cm/sec), yielding a value in cm3/sec. Doppler coronary flow velocities represent changes in absolute coronary flow only when the vessel cross-sectional area remains unchanged during measurements. The maximum velocity is most accurately recorded when the transducer beam is parallel to blood flow and ␾ is zero (Cos ␾ ⫽ 1).11 Assuming a constant vessel diameter and an interrogating Doppler angle of ⬍ 20°, the flow rate can be calculated from the velocity measurements within 5% of absolute values. The influence of a stenosis on coronary flow velocity produces characteristic alterations of phasic flow patterns, hyperemic capacity, and, relative distal flow compared to other unobstructed arterial branches. For normal coronary vessels with diameters ⬎ 2.0 mm, arterial flow velocity is nominally maintained within 15% from proximal to distal regions along the course of the artery.10,12 Normally, there is no significant decline in distal blood flow velocity, since the blood flow volume and epicardial conduit cross-sectional area are proportionately reduced over the course of the vessel. A proximal to distal velocity ratio of nearly 1 can then be assumed.12 A marked decrement in distal flow relative to proximal flow is seen with hemodynamically significant lesions and is predicated on a branched tube model, wherein flow is diverted away from the branch with a higher resistance (stenosis) to branches with lower resistance (normal, open segments). A proximal to distal

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blood flow velocity ratio (P/D) ⬎ 1.7 (i.e. distal velocity reduced) is associated with a resting translesional pressure gradient ⬎ 30 mmHg, usually warranting intervention.12 In a branching system, coronary flow or velocity measured proximal to a stenosis will differ from post stenotic flow or velocity, because of the lower prelesional branch resistance directing flow away or around the coronary stenosis.13 The proximal/distal flow ratio does not apply in conduits without branches, wherein the continuity equation mandates equality of flow at all points along the circuit. A proximal/distal flow velocity ratio is therefore not useful for left main stenosis, very proximal or ostial lesions, LIMA or saphenous vein graft conduits, diffusely diseased vessels, or those vessels with multiple sequential stenoses. Coronary flow velocity reserve (CVR) is computed as the ratio of maximal hyperemic/basal mean coronary flow velocities distal to the stenosis (Fig. 5.2). Coronary hyperemia is induced by intracoronary papaverine (10 mg) or adenosine (18–24 ␮g in the right coronary artery or 24–30 ␮g in the left coronary artery), or intravenous adenosine infusion 140 ␮g/kg/min.14,15 Although early studies suggested a CVR ratio of 3.5–5 in normal patients,16 lower values are more commonly observed in patients with chest pain undergoing cardiac catheterization with angiographically normal vessels, suggesting a degree of patient–patient variability and distal microvascular disease that is beyond the threshold of angiographic detection.17 A post stenotic CVR ⬎ 2.0 has a high correlation with normal myocardial perfusion stress imaging.18–21 High sensitivity, specificity, and predictive accuracy are reported in CVR correlation studies with both perfusion sestamibi and 201thallium imaging and contrast stress echocardiography.22 Most investigators


Figure 5.2 Coronary flow velocity signals obtained in a normal circumflex coronary artery (N.L., CFX). Left panel: The display screen is divided into top and bottom panels, and the bottom half is divided into left and right panels. The top half represents continuous flow velocity signals in real-time. The electrocardiogram, heart rate, aortic pressure, and spectral flow signals are provided in each window. The scale is 0–120 cm/s. S and D ⫽ systolic and diastolic flow periods demarcated by the electrocardiogram, respectively. The lower left panel demonstrates basal flow velocity, and the lower right panel demonstrates the peak hyperemic velocity after intracoronary adenosine administration. Right panel: The trend plot of the continuous flow velocity measurement (average peak velocity (APV)) is shown in the lower window. After intracoronary adenosine administration, APV increased from 11 to 29 cm/s, producing a coronary flow reserve (CFR) ratio of 2.6. The duration of hyperemia shown is 45 seconds in a 90-second display window. The scale is 0–40 cm/s. (Adapted from reference 2, with permission).

consider the post stenotic CVR ⬍ 2.0 to be abnormal.

Relative coronary flow velocity Because CVR is the summed response of a two-component system, there is some uncertainty in accepting an abnormal CVR as the sole indicator of lesion significance. Post stenotic coronary flow reserve is determined not only by epicardial stenosis severity but also by the structural and functional status of the microvasculature, as well as variations in heart rate, blood pressure, and myocardial contractile function.23,24 Factors such as hyper-

tension, diabetes, hypercholesterolemia, and smoking will affect both the microcirculation and macrocirculation, presumably in a uniform distribution. It may be impossible to differentiate which of these factors, if any, is responsible for a reduced CVR. Gould et al first introduced the concept of relative coronary flow (volume) reserve (rCVR), defined as maximal flow in the coronary with stenosis/maximal flow in a coronary without stenosis.25 His team demonstrated that rCVR is independent of the aortic pressure and rate–pressure product, and is particularly well suited to assess the physiologic significance of coronary stenoses when an

59


stenosis in the target vessel. Because of the necessity of instrumenting a normal reference vessel, the rCVR cannot be determined in patients with 3-vessel disease. FFR

rCVR

CVRTARGET

CVRREFERENCE

Figure 5.3 Anatomic representation comparing FFR, CVR, and rCVR. The fractional flow reserve (FFR) evaluates only the pressure gradient across the target stenosis, while the coronary flow velocity reserve (CVR) incorporates the resistance effect of the myocardium and distal microvascular disease (as well as the effect of the target stenosis) in the measurement of hyperemic coronary flow velocity. The relative CVR (rCVR) allows for comparison between target and reference vessels, thereby canceling the effect of distal microvascular and myocardial resistance.

adjacent non-diseased coronary artery is available. In the catheterization lab, it is believed that the ratio between measured CVR in a target and reference vessel reflects a similar physiology (Fig. 5.3). CVR measurements in normal vessels generally are similar (i.e. ⬍ 10% variance) among the perfusion territories of the three major coronary arteries.17,26 Baumgart et al,27 demonstrated that the relative difference in CVR between a target artery compared with a normal reference artery segment in another distribution does, indeed, correlate more strongly than CVR alone with the degree of

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Coronary pressure: basics of fractional flow reserve The concept of a pressure-derived index of coronary perfusion, the myocardial fractional flow reserve (FFR), has been developed as an invasively determined index of the functional severity of a stenosis.4,5,28 FFR, simply defined, is the ratio of maximal blood flow through the stenotic artery to the myocardium to the theoretical normal maximal flow through the artery in the absence of the stenosis. This index represents the fraction of the normal

s

n

FFR ⫽

Max Hyperemic Pressures Max Hyperemic Pressuren

Since n ⫽ aortic pressure if the proximal coronary is unobstructed, then FFR ⫽

Max Hyperemic Pressures Aortic Pressure

Figure 5.4 Fractional flow reserve (FFR) is the ratio between maximal hyperemic pressure beyond a target stenosis (s) and the maximal hyperemic pressure in the same vessel in the theoretical absence of the stenosis (n). Because pressure transmission along the course of the coronary artery is preserved, aortic pressure can be used for the pressure of the theoretical normal vessel.


FFR⫽ 105/133⫽0.78

adenosine

aortic

Pa

coronary Pd

CVR ⫽ 2.2 Coronary velocity

Figure 5.5 Case example of simultaneous aortic and coronary pressures following the hyperemic response after intracoronary adenosine administration. The pressure gradient (Pa–Pd) is greatest approximately 15–20 sec after the adenosine is given. Note that the resting gradient is small, but is exaggerated during the hyperemic state. FFR ⫽ Pa/Pd, or 0.78, a non-ischemia related value. Simultaneous coronary velocity as measured by Doppler, demonstrates a coronary flow velocity reserve (CVR) of 2.2, also a normal value. Pa ⫽ pressure, aortic; Pd ⫽ pressure, distal coronary.

maximal flow that can be achieved despite the coronary stenosis. It is derived from formulas equating pressure changes to measured flow when resistance is at an absolute minimum (Fig. 5.4). FFR is calculated as the ratio of the mean absolute distal coronary artery pressure to the mean aortic pressure measured during maximal vasodilatation as shown in Fig. 5.5.28 This index is independent of changes in systemic blood pressure and heart rate, and is unaffected by conditions known to increase the baseline myocardial flow.29 Unlike CVR or

rCVR, FFR takes into account the contribution of the collateral blood supply to maximal myocardial perfusion.28,30 The normal FFR is 1.0, regardless of the patient or the specific vessel studied.5 A threshold value of FFR ⬍ 0.75 has been identified, indicating a functionally significant epicardial stenosis that correlates with induced ischemia by stress testing in ⬎ 90% of patients.4 The correlation between rCVR and FFR appears to be strong (r ⫽ 0.91) when simultaneously compared in the same artery (Fig. 5.6).27 However, like CVR, FFR has potential

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4

1.0 0.9

rCVR

CVR

3

2

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y⫽ 0.01⫻ ⫹1.16 r⫽0.33 p⫽ 0.12

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y ⫽0.79⫻ ⫹17.7 r ⫽ 0.91 p ⬍ 0.0001

0.6 0.5 0.4

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0.8

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Figure 5.6 Left panel: Correlation between FFR and CVR. The correlation indicates no significant relation between the two variables. Right panel: Linear correlation between FFR and rCVR. The correlation is highly significant (r ⫽ ⫺0.91). (Adapted from reference 27, with permission).

limitations. Small-vessel disease, diffuse coronary artery disease, and left ventricular (LV) hypertrophy are conditions which restrict the increase in blood flow after pharmacologic vasodilatation, and potentially blunt the corresponding decrease in distal coronary artery pressure.4,5,28,30 Under these conditions, FFR may underestimate the severity of a stenosis because of a limited increase in flow. However, FFR still addresses the degree to which luminal enlargement may improve flow. Under conditions of microcirculatory abnormality, a normal FFR indicates that angioplasty alone would not likely augment coronary flow perfusion at the microvascular level. Intracoronary pressure measurements can be made with either of two commercially available devices, the Pressure Guide (Radi Medical Systems, Uppsala, Sweden) or the WaveWire (Endosonics, Inc., Rancho Cordova, CA, USA). Both sensor wires

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produce a high fidelity signal with phasic pressure waveforms equivalent to larger highfidelity catheters.

Preintervention physiologic assessment Validation with noninvasive testing Several single center studies18–20,22 and one multicenter trial,21 report strong correlations between post stenotic CVR and FFR with noninvasive stress echocardiography, electrocardiography, or perfusion scintigraphy. An abnormal distal hyperemic flow velocity reserve (CVR ⬍ 2.0) corresponds to abnormal myocardial perfusion scintigraphy defects with high sensitivity (86–92%), specificity (89–100%), predictive accuracy (89–96%), and positive and negative predictive values (94–100%, and 77–95%, respectively).

PREINTERVENTION PHYSIOLOGIC ASSESSMENT

Pijls et al4 documented a very strong correlation between FFR and four commonly used noninvasive tests to detect myocardial ischemia in patients with moderate coronary stenoses. In patients with an FFR of ⱖ 0.75, all tests for myocardial ischemia were negative (NPV ⫽ 88%). An FFR of ⬍ 0.75 identified physiologically significant stenoses associated with inducible myocardial scintigraphic ischemia, with high sensitivity (88%), specificity (100%), positive predicted value (100%), and overall accuracy (93%).4,31

Preintervention assessment: comparison to QCA and IVUS In a comparative preintervention study between intravascular ultrasound (IVUS), quantitative coronary analysis (QCA), and CVR in 73 patients, Abizaid et al32 reported that a minimum lumen cross-sectional area (CSA) of ⱖ 4.0 mm2 or mean lumen diameter (MLDIVUS) of ⱖ 2.0 mm has a diagnostic accuracy of 92% for identification of diseased vessels with a measured hyperemic CVR of ⱖ 2.0. QCA determinations of lesion length, but not lumen diameter, were also independent predictors of hyperemic CVR. A similar preintervention study comparing IVUS, QCA and FFR in 42 patients with 51 stenoses, also demonstrated that QCA alone was not effective in determining physiologic lesion significance assessed by either IVUS or FFR.33 There was, however, a strong correlation between MLDIVUS ⱕ 3.0 mm2 and CSAIVUS stenosis ⬎ 60% with a measured FFR ⬍ 0.75 (IVUS sensitivity 83%, specificity 92%), indicating abnormal flow physiology.

Deferring interventions Based on the results of several studies, a strategy of deferring interventions for intermediate

lesions with normal physiologic measurements can be strongly supported. The clinical outcomes of deferring coronary intervention for intermediate stenoses with normal physiology are remarkably consistent, with clinical event rates of ⬍ 10% over a 2-year follow-up period.4,34–37 Owing to clinical and ethical requirements, in these studies it was not feasible to defer treatment in symptomatic patients with abnormal translesional physiology. It is highly likely that those individuals would, at the least, continue to be as symptomatic or have even higher event rates. However, there remain some patients with deferred procedures who may still have recurrent angina, requiring continued medical therapy.35 Nonetheless, when physiologically normal, the functional and clinical impact of angiographically intermediate stenoses is associated with an excellent clinical outcome. In-laboratory translesional hemodynamics may not reflect the episodic ischemia-producing conditions of daily life; particularly those related to vasomotor changes during exercise or emotional stress.38 Fortunately, most dynamic conditions are often highly responsive to medical therapy. Criteria validated with ischemic stress testing appear to support decisions to defer intervention in such situations while continuing medical therapy for endothelial dysfunction, hypertension, hyperlipidemia, and episodic coronary vasoconstriction. Direct measurements of coronary blood flow prior to intervening may also prove helpful in selecting the hemodynamically significant lesions in patients with multivessel coronary disease. Because of the uncertainty regarding the physiologic impact of angiographically intermediate stenoses, the simple identification of restenosis by angiography should not drive the strategy towards repeat intervention with the attendant increased recurrence rates. This response, sometimes known as the ‘oculo-

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stenotic reflex’, can be overcome by measuring the physiologic significance of the stenosis when objective evidence of ischemia is lacking.

Predicting restenosis? Unfortunately, there is no data currently available to suggest that a preintervention physiologic measurement of coronary flow with CVR, rCVR, or FFR can predict which lesions will restenose following coronary intervention. From large percutaneous transluminal coronary angioplasty (PTCA) registries, clinical and anatomic variables such as vessel size and anatomy (i.e. branch points), lesion length and location (LAD), and the degree of calcification appear more predictive than current physiologic data.

Physiologic assessment post intervention Provisional stenting using physiologic guidance Angiography is an insufficient tool to determine a satisfactory PTCA result. QCA is limited in its ability to assess short and long term outcomes, because dissections induced by balloon inflation may fill with contrast medium, resulting in near-normal angiographic luminography. IVUS studies have shown that an almost normal angiographic luminogram after PTCA can still be accompanied by considerable residual stenosis.39 Moreover, during the initial years, first-generation stents were difficult to place, and limited by an uncertain future regarding acute thrombotic occlusion and/or delayed restenosis. In this setting, a concept of provisional stenting using balloon angioplasty, augmenting the angiographic endpoint with physiology to obviate

64

obligatory stenting, was tested and validated. In the contemporary era of third generation stents and potent anti-platelet pharmacotherapy, the concept of provisional stenting is rarely practiced although, as studies show, it remains valid.40 A multicenter prospective trial (DEBATE: Doppler End Point Balloon Angioplasty Trial Europe) demonstrated that the combination of optimal angiographic and functional results by coronary flow velocity measurements could identify a subset of patients in whom a clinical event rate was low at 6 months and comparable to results after coronary stenting. The Debate I study revealed that a combined endpoint of QCA residual stenosis ⬍ 35% and CVR ⬎ 2.5 immediately after PTCA is associated with reduced incidence of recurrent angina, need for repeat target lesion revascularization (TLR), and provided for angiographic restenosis rates of ⬍ 16%.40 These data support a physiologically guided intervention to facilitate achieving an optimal lumen and perhaps reduce unnecessary stent placement. Indeed, preliminary data from several other multicenter trials in progress (DEBATE II, Destini-CVR, and FROST) also demonstrate that a direct assessment of coronary flow (CVR) following angioplasty is predictive for recurrent ischemia, TLR, and restenosis.

Mechanisms of abnormal CVR after PTCA and stenting Because balloon angioplasty usually converts an angiographically severe stenosis into an angiographically acceptable but physiologically intermediate stenosis, intracoronary flow measurements can help determine the adequacy of restoration and stabilization of flow following PTCA. Early studies of impaired post angioplasty CVR were likely to be

PHYSIOLOGIC ASSESSMENT POST INTERVENTION

associated with residual lumen impairment undetected by satisfactory angiographic results. Sequential flow velocity data have confirmed that the normalization of CVR occurring in only 50% of patients after PTCA alone may be increased to 80% of patients after stenting (Fig. 5.7).41,42 The relationship between lumen area and coronary blood flow, examined by serial measurements of CVR, rCVR, QCA, and IVUS in a 55-patient study after PTCA alone and again after stent placement, emphasizes the physiologic importance of lumen enlargement.41 The percentage diameter stenosis decreased from 75 ⫾ 13% to 40 ⫾ 18% after PTCA, and to 10 ⫾ 9% after stent placement. CVR increased from 1.6 ⫾ 0.7 to 1.9 ⫾ 0.6 after PTCA, and to 2.5 ⫾ 0.8 after stenting, with normalization of rCVR (0.64 ⫾ 0.26 to 1.00 ⫾ 0.34). In a 15patient subset, IVUS cross-sectional area was significantly larger after stenting compared with PTCA alone (7.6 mm2 vs 4.5 mm2, p ⬍ 0.01), again demonstrating the relationship between lumen size and coronary flow.

CVR and rCVR post intervention Although a majority of patients after stenting have a normalized CVRTARGET, some patients may still have an abnormal CVRTARGET (⬍ 2.0). It has been suggested that in patients with a CVRTARGET ⬍ 2.0 after stenting, a normal calculated rCVR (CVRTARGET/CVRREFERENCE) supports the diagnosis of global microvascular disease.43 Theoretically, rCVR should normalize the abnormal absolute CVRTARGET for regional differences. The improvement in CVR in the myocardial region supplied by a stented coronary artery compared to an adjacent territory with no intervention has also been demonstrated indirectly by positron emission tomography (PET).44 Several studies also demonstrate a late

improvement of impaired CVR following PTCA without stenting, most likely owing to remodeling of the epicardial lesion44 and/or delayed recovery of autoregulation.45 Van Liebergen et al42 reported long-term changes in coronary blood flow in 54 patients with single-vessel disease and normal left ventricular function after PTCA alone (n ⫽ 34) compared with stenting (n ⫽ 20). Both CVR and rCVR were measured immediately after the intervention and again 6 months later. An improvement in CVR and rCVR towards normal values occurred immediately after PTCA alone (CVR, 1.6 ⫾ 0.7 to 3.1 ⫾ 1.0; rCVR, 0.50 ⫾ 0.22 to 0.96 ⫾ 0.32). Despite the additional lumen enlargement (determined angiographically) after stent implantation, there was no further improvement in either CVR (2.8 ⫾ 1.1) or rCVR (0.87 ⫾ 0.24) compared to PTCA alone (CVR 2.6 ⫾ 0.7, rCVR 0.84 ⫾ 0.22). Approximately 40% of patients had a persistently abnormal CVR (ⱕ 2.5) immediately post-PTCA or stenting, which was related to an increase in baseline blood flow velocity rather than blunted hyperemia. In both the PTCA-treated and stent-treated groups, the impaired CVR values following the intervention improved at 6-month followup, increasing toward the values of the reference vessel CVR in patients without restenosis (PTCA rCVR, 0.65 ⫾ 0.16 to 0.84 ⫾ 0.21; stent rCVR, 0.71 ⫾ 0.19 to 1.05 ⫾ 0.12). Post PTCA and post stent CVR and FFR measurements have revealed several mechanisms that may limit the immediate normalization of coronary blood flow. One major mechanism of persistently impaired coronary blood flow after PTCA is suboptimal lumen expansion that may not be identified by conventional angiography.43 In distinction from quantitative angiography or IVUS alone, an increased CVR after PTCA to normal ranges coupled with satisfactory anatomic results is

65


Figure 5.7 Angiographic and coronary flow velocity data before and after transluminal percutaneous coronary angioplasty (PTCA) and again after stent placement. Cineangiographic frames and coronary basal and hyperemic flow velocity are shown after each stage in the procedure. CVR is 1.0 before PTCA (top row), increasing to 2.0 after PTCA (middle row), and 2.7 after stenting (bottom row). Velocity scale is 0–120 cm/s. APV ⫽ average peak velocity; DSVR ⫽ diastolic/systolic velocity ratio; MPV ⫽ maximal peak velocity; ACC ⫽ acceleration index; S and D ⫽ systolic/diastolic phase markers based on electrocardiogram. (Adapted from reference 41, with permission).

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PHYSIOLOGIC ASSESSMENT POST INTERVENTION

associated with a reduced 30-day and 6-month ischemic event rate.

Predictors of acute occlusion Cyclical flow variations during PTCA are easily detected by the Doppler flow wire, and often precede angiographic signs of impending vessel failure such as no/slow reflow, thrombus embolization, progressive dissection, or vasospasm.46 Because of the early detection and improved ability to continuously monitor coronary flow, early precautionary actions can be initiated. If used for monitoring PTCA procedures, the Doppler wire assists by guiding therapy, and may reduce the volume of injected contrast needed for serial angiograms over a 15–30 minute monitoring period.

FFR after angioplasty or stenting Compared to CVR, FFR has emerged as a relatively easy and straightforward method to assess stenoses both pre- and post intervention. FFR measurements prior to interventional procedures can determine whether a particular stenosis is associated with inducible ischemia. After intervention, FFR provides important prognostic benefit as well. A hyperemic FFRSTENT ⬎ 0.90 is better than simple resting transstenotic gradients to predict the percent diameter restenosis at 6-month followup angiography.47 Bech et al47 reported 2-year clinical followup data for 60 patients after single vessel angioplasty compared with post-intervention FFR. In the 43% (26 of 60) of patients with optimal PTCA angiographic (QCA residual ⱕ 35%) and functional (FFR ⱖ 0.90) results, event-free survival rates were significantly better at 6 months (92% vs 72%, p ⫽ 0.047), 12 months (92% vs 69%, p ⫽ 0.028), and 24 months (88% vs 59%, p ⫽ 0.014) months

compared to those patients with at FFR ⬍ 0.90. No improvement in clinical outcome was gained by additional stenting. These data suggest that with an optimal functional and angiographic result after PTCA, the incidence of clinically significant restenosis is equal to that after stenting. Conversely, given the high event rate in study patients with a suboptimal functional PTCA reflected by an FFR ⬍ 0.90, further intervention to improve the result with stenting seems appropriate.

Relationship between IVUSSTENT and FFRSTENT Although IVUS is the present standard for the evaluation of optimum stent deployment, it is expensive and not routinely practiced in most catheterization laboratories. In an elegant study of 30 patients with staged stent deployment to increasing pressures, Hanekamp et al48 demonstrated that the coronary pressurederived FFR is a potentially inexpensive and rapid alternative to IVUS for that purpose. During serial increases in balloon implantation pressures within a Wiktor-i stent, a total of 81 paired IVUS and FFR measurements reaching the optimum threshold were obtained, with a 91% concordance in the ability to predict suboptimum stent deployment with either technique (p ⬍ 0.00001). On the contrary, QCA alone showed a low concordance rate with both IVUS and FFR (48% and 46%, respectively). The utility of FFR to identify the physiologic endpoint after coronary stenting is currently under evaluation in a US multicenter trial (FUSION study).

Alternative noninvasive methods post intervention Many catheterization laboratories do not have the hardware required to perform either FFR

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or CFR determinations following PTCA. A subjective TIMI (thrombolysis in myocardial infarction) flow-grading system may be used as a qualitative measure of coronary flow,49 and may be standardized by using the corrected TIMI frame count (CTFC) as a semiquantitative approach.50,51 Recently, Stankovic et al52 demonstrated that a new index comparing the corrected TIMI frame count against the mean luminal diameter (MLD, using electronic calipers) after PTCA, was predictive of both angiographic and clinical restenosis. The measured CTFC correlated well with post stenotic average peak velocity (APV) values (as measured with a Doppler guidewire) and volumetric flow both before and after PTCA (r ⫽ 0.82 and r ⫽ 0.80, respectively). The investigators demonstrated that the CTFC/MLD ratio, containing information on coronary flow normalized by the residual MLD was strongly predictive for both angiographic and clinical restenosis, with an odds ratio of 1.42 (1.13–1.79, p ⫽ 0.003). Although the number of patients evaluated in this retrospective study was relatively small, CTFC/MLD ratio cutoff values of ⬎ 7.88 and ⬎ 7.94 predicted angiographic and clinical restenosis with a sensitivity of 72–77%, specificity 64–68%, and negative predictive value of 81%, respectively. In the population studied, the ratio was more predictive than either measurement alone and better than measured CVR.53 Although not yet convincingly demonstrated in a post PTCA group, Doppler echocardiographic techniques appear to be of some value in determining CVR in the left anterior descending (LAD) coronary artery. Both transthoracic contrast-enhanced secondand transharmonic echo-Doppler,54 esophageal (TEE) pulsed-wave Doppler mapping55,56 correlate with intracoronary Doppler-guidewire measured flow velocity.

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Paraskevaidis et al57 demonstrated that TEEderived CVR (but not resting coronary velocity) could identify a residual proximal LAD stenosis 72 hours after PTCA. Other investigators report that an increase in diastolic flow measured by TEE may serve as an index of successful LAD PTCA.58 Although cumbersome and limited to the LAD, these evolving techniques may predict restenosis following a coronary intervention.

Coronary lesion assessment for patients with myocardial infarction The assessment of stenoses associated with acute myocardial infarction (AMI) represents the next frontier for coronary physiologic evaluation. AMI results in regional heterogeneity of the microcirculation, invalidating the use of both CVR and rCVR for lesion assessment. A large transmural infarction may alter the measured CVR in the infarcted vessel as well as in adjacent noninfarct related arteries, thus invalidating a primary assumption upon which rCVR is based. The applicability of FFR in this setting remains promising and is under investigation. Nonetheless, some studies suggest that physiologic measurements may be useful for viability assessments, and therefore, carry with it some prognostic information. Experimental animal reperfusion studies and recent clinical studies with perfusion imaging techniques have shown that the CVR is severely impaired after an infarct induced by transient occlusion of the target vessel.59 As might be anticipated, Claeys et al60 demonstrated that CVR was significantly lower in patients with a recent MI (13 ⫾ 7 days) than in those without prior MI, and that CVR remained impaired even after angiographically successful PTCA. Pre- and post PTCA CVR

CORONARY LESION ASSESSMENT FOR PATIENTS WITH MYOCARDIAL INFARCTION

values were lower in infarct-related vessels compared with noninfarct-related vessels over a wide range of stenosis severity: 1.22 ⫾ 0.26 vs 1.50 ⫾ 0.45 before PTCA (p ⬍ 0.05), and 1.72 ⫾ 0.43 vs 2.21 ⫾ 0.74 after PTCA, respectively (p ⬍ 0.01).

Coronary physiologic responses of no-reflow and viability Animal experiments61 and clinical studies62 suggest that the no-reflow phenomenon (reperfusion injury) following MI is the major reason that LV function cannot be salvaged, even after adequate recanalization. Prolonged ischemia resulting in cellular injury initiates a local inflammatory response, accumulation of neutrophils and production of leukotrienes, thereby increasing vascular permeability.63 Increasing vascular permeability completes a deleterious cycle exacerbating interstitial edema and extravascular resistance to blood flow. Beyond the microvascular injury, patients with a recent MI may also show an abnormal vasomotor response with inappropriate constriction of the small resistance vessels as a result of the platelet release and activation of vasoactive substances (thromboxane A2, serotonin, thrombin).63 Restoration of flow after stenting has been identified by both positron emission tomography (PET) and video densitometry, reflecting an impaired myocardial vasodilating response owing to reperfusion-related microvascular injury.59,64 Although some studies report a CVR ⬎ 1.3 to be associated with post infarction viability, Claeys et al60 found no relationship between CVR and residual viability (assessed scintigraphically), and CVR did not differentiate those patients with extensive versus small infarction. This suggests that the coronary vasodilating capacity is not totally affected by the gross amount of microvascular necrosis,

and further suggests that an impaired CVR is related to the degree of microcirculatory injury in the region adjacent to the infarct, and is mediated by a process of microvascular stunning that is partially reversible over time.65 Unlike CVR after PTCA, the lower CVR in patients with recent MI appears to be related to lower hyperemic APV values, suggesting an impaired flow resistance in the reperfused myocardium rather than a resetting of basal flow. Kawamoto et al65 measured APV as well as diastolic flow velocity deceleration time (DDT) in 23 patients with acute anterior MI, demonstrating that if the APV was ⬎ 6.5 cm/s or the DDT ⬎ 600 ms, the more myocardium within the infarcted region would recover with an improved regional wall motion assessed by echocardiography. Tsunoda et al66 evaluated 19 patients with acute anterior MI with continuous flow velocity measurements for 18 ⫾ 4 hours after successful PTCA. Two divergent groups were identified. Regional wall motion and overall LV systolic function were shown to improve in those patients in whom APV increased after only a transient decline (EF increased 17 ⫾ 9%), whereas LV systolic function did not improve if the APV progressively decreased throughout the next day (EF increased only 4 ⫾ 9%, p ⫽ 0.007). Evidence such as this indicates that a short course of hemodynamic support with an intraaortic balloon pump (IABP) might augment myocardial perfusion and result in improved myocardial salvage,67 or that vasodilators such as verapamil68 or adenosine69 might modulate reperfusion injury.

Recovery of LV function and microcirculatory regulation post infarction Neumann et al70 measured coronary flow, CVR, and regional LV function immediately

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after stenting and again 14 days later in two groups of acute infarction patients; a control group treated with standard heparin, and another group treated with glycoprotein (GP) IIb/IIIa inhibition with abciximab (ReoPro™). Improved recovery of coronary vascular function as well as regional systolic wall motion was observed in the abciximab group compared with heparin alone after intracoronary stenting (Fig. 5.8).70 The authors concluded that not only large-vessel patency but also improved microvascular perfusion is an achievable and rewarding goal for the treatment of AMI patients. GP IIb/IIIa antithrombotic therapy may limit the degree of

microvascular damage, and lead to improved LV function and long term outcomes.

The economics of lesion assessment In view of the clinical validation of physiologic assessments in the catheterization laboratory to accurately guide therapy, questions regarding economic feasibility should be addressed. Doppler and pressure guidewires in use today cost $350–450, with capital equipment expenses of $45 000 and $15 000 for Doppler and pressure signal analysers, respectively.

GP IIb/IIIa receptor blockade in AMI 40

0.8 heparin

abciximab p⫽ 0.024

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Figure 5.8 Left panel: Chart of differences between 14-day follow-up and initial post-interventional study in basal flow velocity and in papaverine-induced peak flow velocity at the treated lesion. Right panel: Chart of differences between 14-day follow-up and initial post-interventional study in wall motion index. Both panels: Columns represent mean difference; error bars indicate 95% CI. The p-values above each pair of columns refer to statistical differences between the two treatment groups (abciximab vs heparin). (Adapted from reference 70, with permission).

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SUMMARY

These expenses are offset by the costs of noninvasive stress testing and associated additional hospital time. To compare potential cost savings using inlaboratory physiologic assessment versus a strategy of out-of-laboratory thallium scintigraphy, the PEACH trial randomized 53 patients with intermediate coronary stenoses to CVR measurements in the lab or thallium stress testing in the days following angiography.71 A definitive diagnosis was made in 28 of 29 patients randomized to in-lab testing, with an average associated cost of $1914 ⫾ 55. Patients randomized to stress thallium testing required an additional 2.1 ⫾ 0.8 hospital days, with an average calculated cost of $2718 ⫾ 242. The investigators concluded that in-lab coronary lesion assessment is a cost-effective and clinically useful means for managing CAD patients with intermediate coronary stenoses. The current status of reimbursement does provide for a partial recovery of the expenses of ancillary device (IVUS, pressure, flow) use in the catheterization laboratory. Although HCFA reimburses for physician interpretation of results ($93 for first vessel, $72 for each additional vessel), the disposable and fixed

equipment expenses of non-angiographic methods for evaluating stenoses must be covered by the institution. The clinical benefit is provided to the patient, but the cost of the information translates into an operational expense for the laboratory budget, albeit at an overall savings to the health care delivery system.

Summary The direct physiologic influence of a coronary stenosis, prior to an intervention for either de novo or restenotic lesions, can be easily and safely determined with sensor-tipped angioplasty guidewires, employing post stenotic absolute coronary flow velocity reserve (CVR), relative CVR (rCVR), and the pressure-derived fractional flow reserve (FFR). This information supports decisions regarding planned interventions on restenotic or de novo lesions of intermediate angiographic severity. Following percutaneous interventions, these measurements provide prognostic information that may not only direct the need for repeat balloon dilatation, stent implantation or highpressure expansion, but also predict long term clinical outcome.

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6 The role of intravascular ultrasound in the prevention and treatment of restenosis Shinichi Shimodozono, Yasuhiro Honda, Heidi N Bonneau and Peter J Fitzgerald

Introduction Intravascular ultrasound (IVUS) represents a major development for the assessment of arterial disease. In addition to providing accurate on-line quantitative information regarding lumen size and residual plaque burden, IVUS has contributed to our understanding of plaque behavior and morphology. Although cineangiography remains an indispensable part of diagnosis and treatment for coronary artery disease, angiography provides only a two dimensional silhouette of the lumen. Furthermore, angiography cannot evaluate the mechanisms of various interventional procedures over time, with respect to disease progression/ regression and vessel morphology. IVUS can look beyond the lumen and assess plaque mass, thereby influencing clinical decision-making, initial device selection as well as optimizing the endpoint of various interventional strategies. This chapter will examine the role of IVUS in the prevention and treatment of restenosis. In particular, the importance of accurate knowledge regarding vessel architecture for diagnosis, device selection, endpoint analysis, and as a direct therapy will be addressed.

Practical catheterization lab uses Modalities for coronary endoluminal intervention have increased significantly since the birth of interventional cardiology, first performed by Andreas Grüntzig in September, 1977.1 Today the use of IVUS in the cardiac catheterization laboratory provides direct tomographic visualization of the extent of coronary artery disease. With the improved image quality and signal penetration of currently available systems, IVUS enables a view beyond the vessel surface and a spatial orientation based on veins, pericardium and often adventitial landmarks. In addition, recent advances in reduced IVUS catheter profiles permit the examination of serial changes during a particular intervention in vivo as well as the critical vessel morphologic parameters, including vessel size, length and plaque type. These IVUS-derived parameters contribute to the ‘road map’ of angiography in providing a unique lesion assessment of atherosclerotic coronary disease.

Vessel size Numerous studies have examined the accuracy and reproducibility of angiography. The

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THE ROLE OF INTRAVASCULAR ULTRASOUND

limitations of angiography include: 1. Planner silhouette imaging – Necropsy and IVUS studies have reported that coronary cross-sectional anatomy is frequently eccentric and complex. Angiographic images depict complex coronary lesions from a planner silhouette of the contrast-filled lumen. These complex coronary lesions often appear as unclear images, either slitlike or hazy. Thus, angiography is sometimes unable to reveal the exact degree of lesion complexity and severity. Coronary interventions such as balloon angioplasty often produce acute lumen gain by creating plaque fracture or dissection.2 Con-

sequently, the newly created lumen often seems extensively enlarged, often hazy in angiographic appearance. As a result, the angiographic silhouette may overestimate the actual gain in cross-sectional area (Fig. 6.1). 2. Indirect estimation of luminal narrowing (compared to reference) – To assess lesion severity, angiographic estimates are based on the comparison of minimum lumen dimensions at the lesion site with an adjacent, ‘normal looking’ reference. However, necropsy studies report that lesion characteristics emerge as diffuse in most circumstances rather than focal in nature.3,4 Diffuse atherosclerosis often appears as a

Post PTCA complex lesion

View B

True stenosis

View A

Figure 6.1 Limitation of angiography. Schematic demonstration of overestimation of newly created cross sectional lumen vs true luminal stenosis on the basis of viewing silhouette with multiple direction.

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small ‘normal looking’ vessel. Additionally, a positively remodeled lesion with large plaque burden can be seen angiographically as a ‘mild’ luminal irregularity. On the other hand, IVUS provides several advantages for the accurate assessment of luminal dimensions; first, IVUS produces a complete 360° tomographic view, allowing for the immediate on-line measurement of lumen, plaque, and vessel from a cross-sectional area. These IVUS indices have been validated in vivo and in vitro.5–7 Vessel features seen by IVUS are of great value for the interventional cardiologist in selecting treatment, whether or not to intervene at all, and device sizing. Although angiographers often encounter lesions of uncertain severity in the catheterization laboratory, especially as multiple vessel

disease is approached percutaneously, it is often difficult to decide whether to intervene without ‘on-line’ functional assessment. For intermediate lesions, direct tomographic visualization permits not only the morphologic assessment of atherosclerotic plaque but also an accurate quantitative measurement, independent of the radiographic projection, confirming its significance, thus providing the clue to avoiding unnecessary treatment (Fig. 6.2). A recent report comparing preinterventional IVUS measurements and stress myocardial perfusion SPECT in 70 de novo coronary lesions, in which a lesion lumen area ⱕ 4.0 mm2 visualized by IVUS was defined as significant coronary stenosis, demonstrated a sensitivity of 88% and a specificity of 90%.8 Regarding physiologic assessment by IVUS,

MLA : 3.2 mm2

Figure 6.2 Angiographic hazy appearance. Intravascular ultrasound (IVUS) revealed ambiguous degree of stenosis in complex calcified lesion which appeared to be hazy by angiographic silhouette. IVUS shows critical lumen compromise with minimum lumen area (MLA) ⫽ 3.2 mm2.

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other investigators have demonstrated a high diagnostic accuracy with the same criteria (lesion lumen area ⱕ 4.0 mm2) in comparison with an abnormal coronary flow reserve of 2.0 by Doppler technique.9 Abizaid et al9 reported long term results after deferred intervention on the basis of this IVUS criteria in 300 patients with 357 intermediate de novo native coronary lesions. At 12 months follow-up, clinical event rates were 4.4% with a target lesion revascularization (TLR) rate of 2.8% in 248 lesions with a lesion lumen area ⱖ 4.0 mm2. The long term follow-up after IVUS-guided deferred intervention was comparable to those after physiological assessment such as coronary flow reserve or FFRMYO in previous reports.10 The unique capability of IVUS to yield tomographic images also has a direct impact on device selection and sizing when used prior to or during coronary intervention. Numerous studies have documented that the major determinant of the late loss is the percentage diameter stenosis or minimum lumen diameter (MLD) achieved after intervention, leading to a ‘bigger is better’ approach. However, the use of balloons larger than the angiographic reference lumen diameter failed to improve the result of percutaneous transluminal coronary angioplasty (PTCA) and was associated with an unacceptably high rate of acute complications.11,12 With IVUS, the balloon size selection can be based on measurements of the total diameter of the vessel wall. The CLOUT (CLinical Outcome with Ultrasound Trial) investigators13 proposed increasing the diameter of the balloon based on the mean diameter of the lumen and vessel at the reference site. This IVUS-guided strategy produced favorable target lesion dimensions without increased rates of dissection or in-hospital ischemia. A single-center, nonrandomized study of 252 patients has demonstrated that

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long term outcome utilizing vessel size adapted PTCA, according to the external elastic membrane (EEM) diameter as measured by IVUS, resulted in a low restenosis rate (19%) after 1 year.14 This aggressive strategy of using a larger balloon has become an alternative in treating coronary artery stenosis in de novo lesions. In a subgroup analysis from the BENESTENT-1 trial, which revealed good long term results for stand alone balloon angioplasty when stent-like results (residual diameter stenosis ⱕ 30%) were obtained, this was especially true for the non-left anterior descending lesion group.15 The OCBAS (Optimal Coronary Balloon Angioplasty with provisional stenting vs primary Stent) trial provides support for provisional stenting with similar restenosis rates (19.2% vs 16.4%, p ⫽ NS) and TLR rates (17.5% vs 13.5%, p ⫽ NS) in agreement with the BENESTENT-1 trial.16 Appropriate sizing of the balloon to the arterial segment using IVUS may be a strategy for improving PTCA by creating a larger post procedural MLD, in particular, for angiographically appearing small vessels that actually might be larger vessels with diffuse atherosclerosis.17

Vessel length For appropriate device selection, vessel length is another important element to be determined. Actual lesion length is often underestimated following angiography because of a ‘normal looking’ reference vessel. Mintz et al systematically demonstrated that only 60 (6.8%) of 884 angiographically normal reference segments were normal by IVUS.18 In addition, angiographic lesion length measurements are limited by the difficulty in visualizing a foreshortened, tortuous, threedimensional vascular conduit in two dimensions.

VESSEL SIZE

IVUS utilizing the motorized pullback device throughout the length of distal to proximal reference sites enables axial length measurement, which has been validated in vivo.19 Rapid processing with IVUS machines capable of presenting longitudinal views facilitates spatial orientation of the vasculature, and allows lesion length quantitation with the ability to ‘truly’ match a single stent length to extent of disease.

Plaque type Another important feature which IVUS can provide for device selection is the detection and quantification of calcific patterns as well as the presence of remodeling. These IVUS findings prior to intervention appear to have an impact on both acute and long-term outcomes. Calcified plaque The presence of calcium within the vessel wall may have a critical impact on the diagnostic evaluation, treatment strategy and long term outcome. Calcium is commonly seen by IVUS as a bright echo reflection without ultrasound signal penetration through plaque substance (shadowing) and with reverberation within the distal shadowing. Heavily calcified lesions can often be misinterpreted as more severe stenotic lesions owing to an angiographic hazy appearance, produced by distortion of luminal geometry and shadow contrast filling. This misinterpretation, in fact, may have an influence on the decision to intervene on intermediate lesions based on angiography. Ultrasound is more sensitive than angiography in the detection of calcification, permitting identification of calcified atheroma without any apparent calcification on fluoroscopy. In comparison with ultrasound, fluoroscopy

detects calcium deposits which involve more than 180° of the vessel circumference with sensitivity (63%) but is less reliable with smaller calcium deposits.20,21 Mintz et al20 reported that in 1155 coronary lesions, IVUS detected calcium in 73% of the lesions (38% by angiography). In this study, overall sensitivity of angiography was 48% with specificity of 89% compared to IVUS.20 In the clinical setting, the presence of calcium was found to limit the vessel expansion, resulting in failure to achieve sufficient luminal gain after intervention,22,23 which has been considered the most critical factor in preserving luminal patency. Additionally, IVUS can clarify the location and extent of calcification; deep at the medial border, at the luminal surface, and/or within the plaque itself. Thus, lesion-specific treatment regarding the location and extent of calcium can be done when IVUS is used to interrogate the target lesion within the coronary artery. For heavily calcified lesions, highspeed rotational atherectomy (HSRA) has been found to be an alternative catheter-based treatment modality, owing to its ability to selectively ablate calcific plaque. Kovach et al reported the mechanism of HSRA and adjunct balloon angioplasty using IVUS in 48 lesions.24 Sequential IVUS images have revealed that HSRA produces lumen enlargement by selective ablation of calcified plaque with little tissue disruption and rare arterial expansion. Further increases in lumen cross-sectional area produced by adjunctive balloon angioplasty are a result of combined dissection and expansion of more compliant plaque elements. Although several studies have shown favorable acute results with HSRA, high restenosis rates of 37–51% remained after rotational atherectomy.25–27 To challenge heavily calcified lesions, stenting following HSRA has been shown to be a promising strategy for such lesions. Moussa et al28 found

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procedural success and angiographic restenosis rates at 4.6 ⫾ 1.9 months to be 93% and 23%, respectively. Recently, a nonrandomized, single-center analysis of 306 patients,29 comparing calcified lesions in large (ⱖ 3.0 mm) vessels treated with HSRA and stenting to those treated with either HSRA or stenting alone, demonstrated favorable acute and long term results among those patients treated with HSRA prior to stenting. Larger final MLDs were obtained after HSRA prior to stenting (3.21 ⫾ 0.49 mm) compared to stent alone (2.88 ⫾ 0.51 mm) or HSRA plus balloon angioplasty (2.29 ⫾ 0.55 mm). Ninemonth follow-up revealed higher event-free survival sustained in the HSRA prior to stent cohort vs either stent alone or HSRA cohorts. Remodeling As first described by Glagov et al,30 adaptive arterial remodeling early in coronary artery arteriosclerosis delays focal stenosis despite significant plaque accumulation. Lumen reduction may be induced either by tissue growth that has exceeded the vessel’s ability to remodel, or by failure to remodel in the presence of a small or moderate plaque burden. Pathological remodeling rather than intimal growth has been considered to be the predominant mechanism of the restenotic process following angioplasty.31–33 In recent studies, positive remodeling has been associated with unstable clinical syndromes, implying that this process may be indicative of biologically active or vulnerable plaques.34,35 The direction and extent of arterial remodeling and clinical presentations of patients with coronary artery disease were investigated extensively by Shoenhagen et al,34 showing that positive remodeling occurred in 52% of the unstable syndrome group and in only 20% of the stable angina group. In addition, other studies examining the extent and

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direction of remodeling in patients with stable coronary syndromes reported a high proportion of negative remodeling.36 Furthermore, in an analysis of 777 lesions treated with nonstent coronary intervention, Dangas et al showed that positive lesion-site remodeling was associated with a higher longterm TLR after the nonstent intervention.37 Pasterkamp et al reported in a necropsy study of femoral arteries that positive remodeling is associated with histologic markers for vulnerable plaque in both the cap and shoulder of the plaque, suggesting the enhancement of the risk of plaque rupture.38 Currently, only IVUS can detect these remodeling conditions in vivo (Figs 6.3, 6.4). Thus, with improved image quality in the future, IVUS may have potential as a diagnostic modality for predicting vulnerable plaque. With regard to device selection, stenoses due to negative (or pathologic) remodeling may require expansion of the total vessel area, possibly using a stent to prevent acute or chronic vessel recoil. For stenoses with larger plaque burden in positively remodeled vessels, atherectomy or other plaque removal catheters might be preferable as a suitable therapeutic device. Directional coronary atherectomy (DCA) is primarily used for debulking eccentric, noncalcified lesions in proximal, nontortuous vessels that are large enough to accommodate the DCA device. Without IVUS guidance, more than 50% of the DCA cuts collected the media and 30% reached the adventitia.39,40 Thus, the use of IVUS during DCA to appropriately direct debulking toward the maximal zone of plaque accumulation may minimize trauma and complications following DCA. The presence of a large plaque burden may limit complete stent expansions, in part accounting for suboptimal results in complex lesions. Accordingly, debulking the plaque prior to stent

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Figure 6.3 Positive remodeling. Intravascular ultrasound can reveal localized vessel enlargement with plaque accumulation (vessel area: proximal 17.1 mm2, lesion 19.7 mm2, distal 16.9 mm2, respectively).

deployment appears to provide the best anatomical conditions for optimal stent expansion. The Stenting after Optimal Lesion Debulking (SOLD) registry, which tested plaque removal using DCA prior to stent placement with 71 consecutive patients, showed a remarkably low angiographic restenosis rate of 11% at 6-month follow-up.41 Preliminary IVUS analysis from DESIRE (the DEbulking and Stenting In Restenosis Elimination), which is a randomized multicenter trial

comparing DCA prior to stent implantation to conventional stenting, demonstrated larger acute gain in patients who underwent DCA/stent compared to those who underwent stent alone (7.2 ⫾ 2.1 vs 5.7 ⫾ 1.5 mm2), resulting in a larger minimal lumen area after the procedure (8.6 ⫾ 2.3 vs 7.2 ⫾ 2.6 mm2, p ⫽ 0.03).42 This improved acute gain with DCA prior to stent implantation may translate into better long term results. Ongoing prospective multicenter trials of DESIRE and

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Figure 6.4 Negative remodeling. Vessel shrinkage with less plaque accumulation contributed to luminal stenosis (vessel area: proximal 17.6 mm2, lesion 8.5 mm2, distal 12.5 mm2, respectively).

AMIGO (Atherectomy before Multilink Improves lumen Gain and clinical Outcomes) may address the superiority of debulking plus stenting to stenting alone in a randomized manner.

Stent optimization Intracoronary stenting was initially limited to the treatment of acute closure complicating coronary angioplasty. At present it has been widely used for elective catheter treatment of obstructive coronary artery disease, reducing

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the incidence of clinical restenosis with mechanical scaffolding. Stents have reduced restenosis in both de novo and restenotic lesions, especially in vessels ⬎ 3.0 mm in size, and the left anterior descending (LAD) location.43–45 IVUS can detect vessel stent subtleties not apparent by angiographic features. Apart from assisting with selection of stent size, length, and post dilation balloon diameter, IVUS can be used to accomplish complete apposition and sufficient geometric expansion within the stented segment. IVUS had an essential role in the develop-

STENT OPTIMIZATION

ment of an optimal strategy for stent deployment. Early stent implantation utilized inflation pressures of 6–8 atm, with resultant unacceptable subacute stent thrombosis rates of 18–24%.46,47 IVUS observations demonstrated that incomplete apposition of the stent struts to the vessel wall, residual lumen narrowing or irregular eccentric lumen in the stented segment were still present in 88% of the cases despite having an optimal angiographic result.48 IVUS-guided high-pressure stent deployment coupled with specific antiplatelet regimens were shown to dramatically decrease subacute stent thrombosis rates.48,49 IVUS can detect morphologic and morphometric issues which are often silent by angiography, including incomplete apposition (struts separated from the vessel wall), incomplete expansion (MLD not achieving desired size), and edge dissections; these IVUS findings are illustrated in Fig. 6.5.

A. Incomplete apposition

Long term Because the vast majority of coronary interventions include stenting, rigid assessment of stent geometry following deployment is crucial. In the era of stent optimization, IVUS can be used as a reliable modality to evaluate the minimal stent area (MSA) immediately after stent deployment. Several single center studies have demonstrated significant negative correlation between MSA and subsequent restenosis.50–53 In addition, these studies have also reported an inverse relationship between clinical outcome and the IVUS-derived final MSA. Lessons from multicenter clinical trials In the MUSIC (Multicenter Ultrasound guidance of Stents In Coronaries) study, strict IVUS optimization criteria led to a very low restenosis rate (9.7%), and TLR rate during

B. Incomplete expansion

C. Edge dissection

Figure 6.5 Ultrasound findings after stenting. Incomplete apposition (A), incomplete expansion (B), and edge tear (C). Panel A shows a gap between the stent strut and the vessel wall. Panel B shows incomplete expansion of the stent relative to the vessel size. Panel C shows the edge tear at the stent margin (see arrow).

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follow-up was 4.5%.54 The RESIST (REStenosis after Ivus guide STenting) study group showed a 6.3% absolute reduction in the angiographic restenosis rate (22.5% vs 28.8%) and a 20% increase in late lumen cross-sectional area in the IVUS guidance group compared to angiography guidance alone.55 The recent report of the multicenter randomized CRUISE (Can Routine intravascular Ultrasound Influence Stent Expansion) study, an IVUS substudy of STARS (STent Antithrombotic Regimen Study), demonstrated the positive impact of IVUS on stent deployment in the high pressure era. A total of 525 patients were enrolled in this study, comparing IVUS-guided vs angiographic-guided stenting, which showed that ultrasound guidance resulted in a larger stent lumen area compared to angiographic guidance alone (7.78 ⫾ 1.72 vs 7.06 ⫾ 2.13 mm2, p ⬍ 0.001). Consequently, the IVUS-guided stenting cohort reported a decreased TLR rate (8.5% vs 15.3%, p ⬍ 0.05) with relative reduction of 44% at 9 months compared to angiographic guidance alone.56 The investigators suggest that ultrasound guidance of stent implantation may result in more effective stent expansion compared with angiographic guidance alone. Whether IVUS-guided stent deployment would offset initial catheter costs by a reduction in restenosis remains to be seen.

IVUS observations following brachytherapy Catheter-based intracoronary radiation therapy has been shown to favorably affect restenosis following angioplasty or stenting. IVUS plays a substantial role in elucidating responses, both favorable and unfavorable, following brachytherapy. In this section, the

86

current knowledge of brachytherapy from the imaging viewpoint will be reviewed, focusing on radiation dosimetry, specific findings after brachytherapy, and the role of IVUS in the field of catheter based brachytherapy.

Dosing (centered vs non-centered) In the animal model, follow-up results of irradiation were vascular positive remodeling and inhibition of neointimal formation.57,58 Similar results were obtained from IVUS analyses of human beta source studies.59,60 To optimize treatment, care must be given to insure accurate dose prescription via dosimetry. To date, beta and gamma emitters are the major classes of radioisotopes used for catheter-based brachytherapy. Beta source is characterized to attenuate much stronger than gamma source. Consequently, distance from the source to the target appears to be much more critical for beta than for gamma with respect to the actual dose on target vessel, particularly the adventitia. In this regard, IVUS can contribute to appropriate dose prescription with detailed quantitative dosimetric analysis. Two types of catheter-based brachytherapy devices, centering and non-centering, are presently in use in the clinical setting. One important question regarding local radiation delivery is whether centered delivery systems are needed for suitable dosing. Dose uniformity to the arterial wall depends on source positioning in the lumen and the cylindrical symmetry of the artery. Without centering, especially in a large artery, a non-centered position of the radiation source might cause overdosing on one side of the vessel wall and underdosing on the other side. In this regard, the use of a centering device would seem to have an advantage over the non-centering device. In earlier dosimetric reports, using

IVUS OBSERVATIONS FOLLOWING BRACHYTHERAPY

analytical calculations of dose distributions and dose rate,61 or measuring surface dose of different size balloons,62 centering devices produced good surface dose homogeneity. In most target lesions consisting of eccentric plaque, the centering device was limited in the delivery of a uniform dose to the vessel wall or adventitia, allowing centering only within the lumen but not within the vessel (Fig. 6.6). In light of this, one may question the effectiveness of the centering device in the clinical setting. Dose volume histogram (DVH) has been used to describe the cumulative distribution of dose over two specific volumes: at the level of the luminal surface, and the adventitia. Contours of the lumen and EEM that can be obtained from three-dimensional IVUS analy-

sis, are then entered into computer program to calculate DVH. DVH provides a tool for reporting the actual delivered dose at the site believed to be the target, the adventitia, and to detect excessive radiation which could lead to vascular complications. From a dosimetric study assessing the impact of centering on the distance from the source to the EEM and the longitudinal variations along the target vessel segment in the START (STents And Radiation Therapy) trial, Takagi et al63 demonstrated that the dose enhancement derived from centering at the EEM was only 11% (12.5–13.9 Gy) in the large vessel group, and 7% (11.1–11.9 Gy) in the small vessel group with 90Sr/Y source, despite the statistically significant decrease in the distance from source. They concluded that

Centering

Non-centering

Figure 6.6 Schematic demonstration of the position of centering and non-centering catheters within the vessel wall. Even the centering catheter is limited to the center of the lumen and not adventitia in eccentric plaque.

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centering did not impact on variation in dose as a function of distance along the longitudinal axis. Further investigation based on DVH using IVUS quantitative parameters will provide additional clues to better understand these issues.

Vascular remodeling after brachytherapy As mentioned above, vascular positive remodeling and inhibition of neointimal formation were considered to be an effect of irradiation at follow-up in animal models. Recently, serial three-dimensional IVUS observations in human studies have provided new insight regarding the mechanisms of brachytherapy. A three-dimensional IVUS study by Sabate et al,60 demonstrated that mean EEM volume and plaque volume in the beta-irradiated segment increased significantly, whereas luminal volume remained unchanged. The adaptive increase of EEM volume appears to be the major contributor to the luminal volume at follow-up. Furthermore, in another study with gamma irradiation (192Ir), even in the noninjured but irradiated reference segments, lumen area remains unchanged as a result of positive vessel remodeling despite the plaque growth.64

Delayed healing Intracoronary radiation may prevent normal healing processes after balloon injury, resulting in unhealed dissection (Fig. 6.7). According to reports by Kay et al, 16 of 22 nonstented patients from the BERT 1.5 cohort had dissection at initial procedure and dissection was still seen in six patients on angiography (38%) and eight patients (50%) on IVUS at 6 month follow-up.65 No relation was found between prescribed radiation dose and

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healing outcomes. Additional quantitative investigation by Meerkin et al66 showed all residual dissections were partially healed at follow-up. No change in clinical outcomes was seen between completely healed dissection groups and partially healed ones. Whether dose and healing processes are closely related remains to be investigated in larger population studies with individual calculated dose prescription.

Therapeutic catheter-based ultrasound Beyond the phase of diagnostic use for cardiovascular disease, ultrasound technology has advanced into the therapeutic phase. The biomechanical effect of ultrasound has been reported to inhibit the proliferation of cancer cells as well as migration and adhesion of smooth muscle cells (SMCs),67–69 suggesting the therapeutic potential of ultrasound therapy in vivo to limit neointimal growth following stenting. A recent animal study70 demonstrated the favorable effect of therapeutic ultrasound, or sonotherapy, on neointimal hyperplasia in vivo, using a swine stent injury model. An 8F, over-the-wire catheter system (URX™, PharmaSonics Inc.) was developed for intracoronary sonotherapy treatment, which incorporates an ultrasonic transducer 8 mm in length, exposing an average peak ultrasonic intensity of 100 W/cm2 at a center frequency of 700 kHz (Fig. 6.8, left). Target segments were exposed to intracoronary sonotherapy for 300 seconds for both the cell proliferation study and intimal-growth study. At 7 days, SMC proliferation assessed by bromodeoxyuridine histology preparation was significantly reduced in the sonotherapy group compared to the control group (24.1 ⫾ 7.0 vs 31.2 ⫾ 3.0%). At 28 days, area stenosis was

CONCLUSION

Baseline

Follow up

Figure 6.7 Unhealed dissection at 8-month follow-up following brachytherapy. Tracking vessel morphology following brachytherapy shows unhealed dissection at follow-up (see arrows), which may be due to delay by radiation.

significantly less in the sonotherapy group than in the control group (36 ⫾ 24 vs 44 ⫾ 27%, p ⬍ 0.05) (Fig. 6.8, right). This first feasibility study indicated the efficacy of in vivo intracoronary sonotherapy on intimal hyperplasia in a swine stent model (Fig. 6.9). If intracoronary sonotherapy were also effective in human coronary arteries, it would be a novel method of inhibiting restenosis, offering some potential benefits compared to intracoronary brachytherapy. First, the delivery of ultrasound energy does not require shielding in the catheterization laboratory. Second, it may be able to be utilized during de novo stenting rather than for in-stent restenosis indications. Finally, ultrasound has been shown to enhance drug delivery as well as gene transfection, suggesting that sonotherapy

may be augmented further with a pharmacological approach.71,72 Apart from conventional IVUS use, therapeutic catheter-based sonotherapy is currently under human clinical investigation as a tool to prevent restenosis.

Conclusion Since its introduction to the cardiac catheterization laboratory, IVUS has been established as a new standard for the visualization of coronary atherosclerosis through its unique capability of acquiring direct tomographic images in humans. This feature is valuable not only for the accurate analysis of luminal stenosis but also for elucidating the composition of the atherosclerotic plaque, in aiding the decision of which interventional tool to use,

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40

p ⬍0.05

% BrdU

35

30

25

20 SHT

IST

Figure 6.8 Left panel: Angiographic appearance of catheter-based intracoronary sonotherapy catheter: Right panel: Smooth muscle cell proliferation after intracoronary sonotherapy. Smooth muscle cell proliferation assessed using bromodeoxyuridine (BrdU) histology preparation at 7 days in a swine injury model following intracoronary sonotherapy was significantly reduced compared to the control group.

Sham (control)

Sonotherapy

Figure 6.9 Histopathological samples demonstrating the effect of intracoronary catheter-based sonotherapy on neointimal growth.

90

CONCLUSION

sizing, and even for avoiding unnecessary intervention. As a guide to the interventional procedure, operators can improve suboptimal results to further reduce the risk of restenosis in the long term. In addition, IVUS plays an indispensable role in dosimetry analysis for

suitable brachytherapy, and in revealing the mechanisms and favorable/unfavorable effects after brachytherapy. Finally, beyond the diagnostic use of IVUS, therapeutic catheter-based ultrasound is being evaluated in clinical studies as an alternative treatment for restenosis.

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7 Pharmacological approaches to prevent restenosis Vatsal H Mody, Alex Durairaj and Anil O Mehra

Introduction Since the introduction of percutaneous transluminal coronary angioplasty (PTCA) by Andreas Grüntzig in 1977, tremendous progress has been made in the technique, in understanding its mechanisms, and in its applications. The use of angioplasty has been expanded to include patients with unstable angina, myocardial infarction (MI), multivessel coronary artery disease and complex lesions. Despite the high rate of initial procedural success and marked reduction in acute complications, such as hospital deaths, MIs and emergency bypass surgery, the major limitation of angioplasty remains the high incidence of restenosis. Although the introduction of stents has brought some reduction in the rate of restenosis, in-stent restenosis often occurs after the procedure. The pathophysiology of restenosis begins with vascular and plaque injury and is related to the process of wound healing. During angioplasty, immediately after balloon inflation, platelets adhere to the injured intimal surface and release thromboxane A2 (TXA2) which is a powerful vasoconstrictor and a strong stimulus for platelet aggregation. Through a complex interaction between platelets, coronary endothelium, inflammatory cells and vascular smooth muscle, a host of cytokines is released.1 These include plateletderived growth factor (PDGF), endothelial

and fibroblast growth factors, tumor necrosis factor alpha, transforming growth factor beta, insulin-like growth factor, several interleukins, adenosine diphosphate (ADP), thrombin, epinephrine, angiotensin II, serotonin, thrombospondin, and free oxygen radicals. These mitogens, particularly PDGF, stimulate migration and proliferation of smooth muscle cells from the media into the intima, followed by the formation of fibrocellular tissue with an abundant proteoglycan matrix. This results in an enlarging mass of neointimal hyperplasia causing coronary luminal stenosis and ischemia. Arterial remodeling plays an important role in balloon angioplasty and atherectomy that has been modified by the use of stents.2 Considering the widespread use of stents in the current management of the majority of patients with coronary artery disease, efforts to reduce restenosis have been redirected towards reducing neointimal hyperplasia. Keeping in mind the pathophysiology of restenosis, numerous animal studies and clinical trials have been conducted in an attempt to reduce restenosis by intervening at various steps.

Antiplatelet and antithrombotic agents (Table 7.1) Platelet adhesion and aggregation is a key initial event after percutaneous coronary

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PHARMACOLOGICAL APPROACHES TO PREVENT RESTENOSIS

Aspirin Dipyridamole Thromboxane receptor antagonists – vapiprost, solutroban Prostacyclin analogs – epoprostanol, ciprostene Omega-3 fatty acids Ticlopidine Dextran Unfractionated heparin (UFH) Low molecular weight heparin (LMWH) Direct thrombin inhibitors – hirudin, hirulog Warfarin Glycoprotein IIb/IIIa inhibitors – abciximab, eptifibatide, tirofiban

Table 7.1 Antiplatelet and antithrombotic agents.

interventions, with subsequent thrombus formation and smooth muscle cell proliferation responsible for restenosis. TXA2, a product of arachidonic acid metabolism, is a powerful platelet aggregator and vasoconstrictor.3 Therefore, many investigators have directed the antiplatelet approaches toward various points in the arachidonic acid pathway (Fig. 7.1). Aspirin, one of the oldest antiplatelet agents, was initially studied in several restenosis trials. It irreversibly blocks the cyclooxygenase pathway in arachidonic acid metabolism and reduces the synthesis of TXA2 after vascular injury and reduces platelet activation and aggregation. However, a meta-analysis of four studies using aspirin for reducing restenosis showed a relative risk of restenosis of 0.932 with aspirin compared with placebo treatment.4 Aspirin, when compared to placebo did not significantly reduce restenosis, but was beneficial in reducing acute complications. Another meta-analysis of four dose finding

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studies with aspirin showed that higher doses of aspirin might even exert a detrimental effect, with a relative risk of restenosis of 1.2 when a daily dose of ⬎ 1000 mg is used compared with a dose of ⬍ 350 mg.4 Thus, aspirin has not been shown to reduce restenosis effectively. Dipyridamole is thought to affect vasodilation and platelet-antagonism by mechanisms such as potentiation of prostacyclin’s inhibition of platelets by blocking platelet phosphodiesterase and increasing cyclic adenosine monophosphate (cAMP), the direct stimulation of prostacyclin release from the vascular endothelium, and the inhibition of cellular uptake and metabolism of adenosine. The Antiplatelet Trialists Collaboration, in an analysis of various trials involving about 800 patients after coronary angioplasty, found that allocation to 6 months of antiplatelet therapy, usually consisting of aspirin and dipyridamole, reduced the occurrence of coronary occlusion by only 4% in patients (p ⫽ 0.02).5 Other clinical trials in the literature have not shown that the addition of dipyridamole to aspirin achieves any benefit in preventing restenosis. As a result of the failure of aspirin and dipyridamole to reduce restenosis rates, attention was directed to other mechanisms, such as the selective blockade of TXA2 receptors, inhibition of thromboxane synthetase and supplementation of prostacyclin. Selective blockade of the TXA2 receptor blunts the effects of TXA2 and also blocks some intermediaries, including prostaglandins G2 and H2, which also activate the TXA2 receptor. In the Coronary Artery Restenosis Prevention on Repeated Thromboxane-Antagonism (CARPORT) trial, 697 postPTCA patients were randomized to receive vapiprost (a thromboxane receptor antagonist) or placebo, both in combination with aspirin.6 It was a well-designed, multicenter, randomized, double-blind, placebo-controlled trial

ANTIPLATELET AND ANTITHROMBOTIC AGENTS

Arachidonic acid Cyclooxygenase

Aspirin NSAIDs

Prostaglandin G2 Peroxidase Thromboxane synthase inhibitors

Prostaglandin H2

Prostacyclin synthase

Thromboxane synthase

Thromboxane A2

TXA2 receptor

Prostacyclin

Prostacyclin analogs

TXA2 receptor blocker

Figure 7.1 Formation of thromboxane A2 (TXA2) from arachidonic acid metabolism and mechanism of action of various antiplatelet agents. Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) inhibit cyclooxygenase. Thromboxane synthase inhibitors block conversion of prostaglandin H2 to TXA2, leading to increased formation of prostacyclin which prevents platelet aggregation and is a vasodilator. TXA2 receptor blockers reduce platelet aggregation and also block effects of prostaglandin H2 on platelets. Prostacyclin analogs are vasodilators and inhibit platelet aggregation induced by thrombin, collagen, and platelet activation factor. Adapted from Oates JA, Fitzgerald GA, Branch RA et al. Clinical implications of prostaglandins and thromboxane A2 formation. N Engl J Med 1988; 319:689–698.2

with a 6-month follow-up, including clinical evaluation, exercise test and quantitative angiography. However, it failed to show any difference in restenosis or clinical outcome between the treatment groups. The GRASP (Glaxo Restenosis and Symptoms Project) study, using long-term vapiprost therapy in 1192 patients after PTCA, showed a 21% reduction in ischemic clinical events at 6

months, especially MI and the need for repeat PTCA (p ⫽ 0.02), but did not provide information regarding angiographic restenosis.7 The Multi-Hospital Eastern Atlantic Restenosis Trial (M-HEART II) sought to determine the effect of solutroban, a TXA2 receptor inhibitor, relative to aspirin and to placebo. Seven hundred and fifty-two patients were randomized and followed-up

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clinically and angiographically for 6 months. The results showed that neither aspirin nor solutroban differed from placebo in reducing the rate of angiographic restenosis.8 Thus, TXA2 receptor antagonists have not been conclusively shown to reduce angiographic restenosis. Prostacyclin is a vasodilator produced by endothelial cells. It has effects opposite to that of TXA2 and prevents platelet activation and aggregation. Some studies indicate that endothelial prostacyclin production may be deficient in cases of restenosis. Therefore, various investigators have considered pharmacologic supplementation of prostacyclin for restenosis prevention. Knudtson et al evaluated the short-term use of prostacyclin in a randomized clinical trial of 286 patients and failed to show a statistically significant difference between the drug and placebo in preventing angiographic restenosis.9 Similarly, Gershlick et al, in a randomized, placebo controlled trial of 135 patients, found that epoprostanol (prostacyclin PGI2), was unable to inhibit platelet aggregation or significantly reduce angiographic restenosis at 6-month follow-up after PTCA.10 In another randomized trial involving 311 patients, ciprostene, a stable analog of prostacyclin, was found to reduce clinical markers of restenosis (repeat PTCA, coronary bypass surgery, MI, or death) (p ⫽ 0.004). Angiograms of 86% of the patients who completed the protocol were retrospectively analysed, and confirmed reduction in angiographic restenosis (p ⫽ 0.025).11 However, larger trials with prospective angiographic follow-up are required to evaluate the efficacy of ciprostene. Omega-3 fatty acids, which have been extensively studied, act by inhibiting TXA2 production and inhibiting leukotriene formation by competitively interfering with arachidonic acid metabolism. They also have the

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beneficial effects of reduction of triglycerides and very low density lipoprotein (VLDL) cholesterol. Several trials have been performed to determine whether omega-3 fatty acids derived from fish oils prevent restenosis. One metaanalysis from seven studies concluded that a small beneficial effect existed, but confirmation is needed from larger randomized trials.12 Two large randomized trials, the Fish Oil Restenosis Trial (FORT) and the Enoxaparin and Maxepa for the Prevention of Angioplasty Restenosis (EMPAR), were subsequently done. The FORT investigators, randomized 551 patients to high-dose omega-3 fatty acids (8 g daily) or corn oil for 6 months. The angiographic restenosis rates, among analysable patients, were 46% for corn oil and 52% for fish oil (p ⫽ 0.37).13 EMPAR randomized 814 patients in four centers to receive 5.4 g of omega-3 polyunsaturated fatty acids or placebo daily, starting an average of 6 days before PTCA and continuing for 18 weeks post-angioplasty. Restenosis rates were 46.5% in the fish oil group and 44.7% in the placebo group.14 Thus, there was no reduction in restenosis with active treatment, even though the active treatment was started prior to angioplasty. The almost identical restenosis rates of these large and well-designed trials make it highly unlikely that omega-3 fatty acids have any benefit in reducing restenosis. Ticlopidine, a newer antiplatelet agent, is a thienopyridine drug that inhibits ADP receptors and also prevents transformation of the glycoprotein (GP) IIb-IIIa receptor into its high affinity stage. A randomized multicenter trial by White et al involving 236 patients did not find ticlopidine (750 mg/day) to reduce angiographic or clinical restenosis relative to aspirin (650 mg/day) or placebo.15 The Ticlopidine Angioplasty Coronary Trial (TACT) involving 266 patients showed no benefit of ticlopidine (500 mg/day) vs placebo for

ANTIPLATELET AND ANTITHROMBOTIC AGENTS

prevention of restenosis.16 These and other trials have shown ticlopidine to be ineffective in reducing restenosis. Dextran is an antiplatelet agent that appears to act by antagonizing the interaction of factor VII with von Willebrand’s factor. However, dextran has not been shown to reduce restenosis either.17 Unfractionated heparin (UFH), one of the initial antithrombotic agents, has been studied for prevention of coronary restenosis after coronary intervention. Apart from its antithrombotic effect, it also has a direct inhibitory effect on vascular smooth muscle cell proliferation. However, a large randomized trial comprising 416 patients, done to evaluate whether heparinization extended to 18–24 hours could reduce restenosis 6 months following PTCA, was unable to show any such benefit.18 The Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) trial, a multicenter randomized trial, investigated whether high dose subcutaneous heparin for 4 months could reduce restenosis and failed to show any reduction in restenosis.19 These studies show that the systemic administration of heparin does not prevent restenosis. Use of heparin coated stents such as Palmaz–Schatz stents and the Wiktor stents have also shown no benefit in reducing instent restenosis.20 However, local administration of heparin at the angioplasty site via local delivery catheters, such as the infusion sleeve or coil balloon, may have some benefit in reducing restenosis.21 Further studies to confirm this finding are needed. Low molecular weight heparins (LMWHs) have been considered for restenosis prophylaxis. The LMWHs are obtained by chemical or enzymatic depolymerization of the polysaccharide chains of heparin to provide chains with molecular weights ranging from 1000 to 10 000. Compared to UFH, LMWHs are more

selective in catalysing the inhibition of factor Xa by antithrombin III and less selective in inactivating thrombin. They also have an inhibitory effect on smooth muscle proliferation. In the multicenter, double-blind Enoxaparin Restenosis (ERA) trial, 458 patients were randomized to receive daily subcutaneous injections of 40 mg of enoxaparin or placebo, starting less than 24 hours after angioplasty and continuing for 28 days.22 No significant reduction in restenosis or adverse clinical events was noted with active treatment.23 The EMPAR study, an even larger multicenter trial, in which 653 patients were randomized to receive 30 mg of enoxaparin twice daily for 6 weeks or placebo, also showed no difference in restenosis.16 Similarly, the Reviparin in Percutaneous Transluminal Coronary Angioplasty (REDUCE) trial and the Fraxiparine Angioplastie Coronaire Transluminale (FACT) study, failed to show reduction in the rate of major clinical events or the incidence of restenosis.24,25 Thus, various studies with different LMWHs have failed to show any benefit in reducing restenosis. Local administration of LMWH by special delivery catheters has been evaluated in small trials with no significant benefit. However, future larger studies are needed to discover any beneficial role in reducing restenosis. Hirudin, a specific thrombin inhibitor, binds directly to and inactivates thrombin without the use of antithrombin III, making it more effective and potent than heparin in preventing coronary thrombus formation during PTCA. The Hirudin vs Heparin in the Prevention of Restenosis after PTCA (HELVETICA) trial randomized 1141 patients with unstable angina undergoing PTCA to 24-hour hirudin or heparin infusion for 24 hours with subcutaneous placebo. This trial showed that despite a significant reduction in early cardiac events with hirudin (relative risk 0.61; 95% CI,

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0.41–0.90, p ⫽ 0.023), there was no difference in the change in minimal lumen diameter (MLD) or in 7-month clinical restenosis.25 Similarly, hirulog was not effective in post-angioplasty patients for preventing restenosis.26 Warfarin, an anticoagulant, is an antagonist of vitamin K and reduces the formation of clotting factors II, VII, IX, and X. In a randomized study of 248 patients, warfarin was not found to yield any benefit on restenosis relative to 325 mg daily aspirin.27 The thrombolytic agent, tissue plasminogen activator, has been tested in animal models of restenosis. However, clinical trials with thrombolytic agents to reduce restenosis have yet to be done. Recently, attention has been directed to the platelet glycoprotein IIb/IIIa integrin receptor that is specific and abundant on the platelet surface. The platelet GP IIb/IIIa receptor antagonists act by occupying the receptor, preventing fibrinogen binding, and platelet aggregation. In the Evaluation of c7E3 (abciximab) for the Prevention of Ischemic Complications (EPIC) Trial, 2099 patients, who had evolving or recent myocardial infarction, unstable angina, or high-risk angiographic or clinical characteristics and needed balloon angioplasty or directional atherectomy, were randomized to receive c7E3 Fab or placebo in addition to aspirin and heparin.28 At 6 months, patients who had an initially successful angioplasty had a 26% reduction in target vessel revascularizations and a 23% reduction in all ischemic events with bolus and infusion c7E3 Fab therapy compared with placebo. Both abrupt closure and clinical restenosis were significantly reduced in the antibody-treated group, showing a clear benefit of the drug in high-risk angioplasty. This initial observation suggesting beneficial effect of abciximab on restenosis was not confirmed in subsequent

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trials, such as EPISTENT.29 The Evaluation of Reopro And Stenting to Eliminate Restenosis (ERASER) study investigators evaluated abciximab infusion for prevention of in-stent restenosis and concluded that it was ineffective in reducing in-stent restenosis by analysis of restenotic tissue volume on intravascular ultrasound.30 Trials involving smaller molecules, such as eptifibatide and tirofiban, have also been done. Eptifibatide (Integrelin™) is a cyclic heptapeptide and tirofiban is a nonpeptide. They have a half-life of 2–3 hours and are highly specific for the GPIIb-IIIa integrin. In the Integrelin to Minimize Platelet Aggregation and Prevent Coronary Thrombosis (IMPACT-II) angiographic substudy, there was no improvement in minimal luminal diameter or rate of restenosis compared with placebo at 6 months’ post angioplasty.31 The Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) trial enrolled 2139 patients undergoing balloon angioplasty or directional atherectomy within 72 hours of presentation of unstable angina or acute myocardial infarction and randomized them to tirofiban or placebo. Six-month angiographic and clinical follow-up showed that tirofiban did not decrease the incidence of coronary restenosis.32 In summary, platelet glycoprotein IIb/IIIa integrin receptor blocking agents have failed to show a definite reduction in coronary restenosis.

Anti-inflammatory drugs (Table 7.2) With the apparent correlations between restenosis and exaggerated wound healing in response to injury and the potential role played by inflammatory cells and the mitogens and chemoattractants they secrete, some investigators have considered the use of antiinflam-

ANTI-INFLAMMATORY DRUGS

Steroids – methylprednisolone, prednisone Nonsteroidal antiinflammatory drugs – ebselen Antiallergic agent – tranilast

Table 7.2 Anti-inflammatory agents.

matory drugs, in particular corticosteroids, for preventing restenosis. Two studies with small numbers of patients using steroids (methyl prednisolone and prednisone) failed to show a reduction of restenosis.33,34 To eliminate the effect of small sample size, a large multicenter study was undertaken by Pepine et al to see whether prophylactic corticosteroids could elicit a significant reduction in restenosis.35 Nine hundred and fifteen patients were randomized to receive either 1 g of methylprednisolone intravenously or placebo on the day before PTCA. However, no statistical difference was noted between groups, with angiographic restenosis occurring in 40% (117 of 291 lesions) after steroid treatment and 39% (120 of 307 lesions) after placebo. The results of this large, well-designed clinical trial indicate that there is no likely role for short term steroids in restenosis prevention, although the use of more prolonged, orally administered corticosteroids has not been evaluated. Nonsteroidal antiinflammatory drugs (NSAIDs) which, unlike aspirin, competitively inhibit platelet cyclooxygenase, have also been evaluated to prevent restenosis. Ebselen, a selenium-containing heterocyclic NSAID, with an additional antioxidant capacity and ability to reduce activation of leukocytes and peroxidation of lipids, has been tested in a small clinical trial of 80 patients undergoing PTCA,

with positive results.36 Angiographic restenosis at 3 months’ follow-up was found to occur in 18.6% of actively treated patients and in 38.2% of placebo treated patients (p ⬍ 0.05). However, trials with more patients and longer follow-up are needed to verify the efficacy of NSAIDs in preventing restenosis. Tranilast is an antiallergic drug that suppresses the release of cytokines such as PDGF, transforming growth factor-beta 1, and interleukin-1 beta and prevents keloid formation after skin injury. In a multicenter, randomized, double-blind, placebo-controlled trial, the Tranilast Restenosis Following Angioplasty Trial (TREAT), a total of 255 patients with 289 lesions were randomly assigned to treatment with the oral administration of 600 mg/day tranilast, 300 mg/day tranilast, or a placebo for 3 months after successful angioplasty.37 Angiographic follow-up was done at 3 months and a clinical follow-up examination was performed at 12 months. The restenosis rates defined as ⱖ 50% loss of the initial gain were 14.7% in the 600 mg/day group, 35.2% in the 300 mg/day group and 46.5% in the placebo group (p ⬍ 0.0001 for 600 mg/day tranilast vs placebo). The restenosis rates defined as percent diameter stenosis of ⱖ 50% at follow-up were 17.6% in the 600 mg/day tranilast group, 38.6% in the 300 mg/day tranilast group and 39.4% in the placebo group (p ⫽ 0.005 for 600 mg/day tranilast vs placebo). The Prevention of Restenosis by Tranilast and its Outcomes (PRESTO) trial, a double-blind, randomized, placebo-controlled, 9-month trial involving 11 500 patients who have undergone a successful PCI has been recently completed. The primary efficacy parameter was the composite clinical endpoint of death, MI or ischemia-driven target vessel revascularization. Out of a subset of 1960 patients who underwent angiographic followup at 9 months, approximately 1000 patients

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have undergone IVUS. The results of the trial are awaited and will be able to conclusively determine if tranilast has a beneficial role in reducing restenosis.

Specific growth factor antagonists (Table 7.3) Smooth muscle migration and proliferation from the media into the intima is a key event in restenosis. PDGF, secreted by platelets, endothelium, smooth muscle, and monocyte/macrophages, is a strong chemoattractant and mitogen for vascular smooth muscle and is currently thought to play the most important role in restenosis. Trapidil, a PDGF antagonist, was evaluated by the Italian Studio Trapidil vs Aspirin nella Restenosis Coronarica (STARC) trial.38 Of the 254 patients who completed this study, angiographic restenosis at 6 months occurred in 24.2% of those actively treated and in 39.7% of the placebo group. Similar results were

Platelet-derived growth factor (PDGF) antagonists Trapidil PDGF antibodies Pituitary growth hormone antagonists Angiopeptin Octreotide Serotonin receptor antagonist Ketanserine Angiotensin converting enzyme inhibitors Cilazapril Fosinopril Enalapril Nitric oxide donors Linsidomine Molsidomine

Table 7.3 Growth factor antagonists.

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obtained by a study of 160 patients randomized to receive trapidil or dipyridamole, both in combination with aspirin for 6 months, with restenosis rates of 20% and 38%, respectively.39 These results are exciting and need confirmation by a large multicenter trial. An immunologic approach to PDGF antagonism, using polyclonal PDGF antibodies has been shown to dramatically reduce neointimal formation after vascular injury in an animal model. Further animal and early clinical testing are needed to determine the potential usefulness of this line of therapy. Pituitary hormones such as growth hormone and somatomedin intermediaries have been found to exert an influence on smooth muscle cell proliferation in restenosis. Synthetic analogues of somatostatin, including angiopeptin and octreotide, act on the pituitary to reduce growth hormone secretion and can prevent an increase in insulin-like growth factor (IGF-I), which is responsible for cell proliferation in various tissues, including the vascular wall. In a pilot study by Eriksen et al, 112 patients were randomized to subcutaneous angiopeptin or placebo, to determine the effect of angiopeptin on clinical events and restenosis in patients undergoing successful PTCA.40 Eighty patients had a successful PTCA and 75 of these patients with 94 lesions underwent angiography 4–8 months after PTCA. Restenosis was significantly reduced with angiopeptin vs placebo (12% vs 40%; p ⫽ 0.003), with significant reduction in late lumen loss after angiopeptin treatment (0.12 ⫾ 0.46 mm vs 0.52 ⫾ 0.64 mm; p ⫽ 0.003). However, in a larger trial by Emanuelsson et al, that randomized 553 patients to angiopeptin vs placebo, angiopeptin decreased the clinical events during 12 months of follow-up from 36.4% in the placebo-treated group to 28.4% in the angiopeptin-treated patients (p ⫽ 0.046),

SPECIFIC GROWTH FACTOR ANTAGONISTS

while the minimal lumen diameter, late losses and restenosis rates at follow-up were not statistically significant between the two groups.41 In the largest angiopeptin trial to date, 1246 patients were randomized to receive twice daily subcutaneous injections of placebo or one of three varying doses of angiopeptin for 10 days after PTCA.42 Angiographic restenosis rates were not statistically significant in all groups, making it unlikely that angiopeptin reduces restenosis. Serotonin, a vasoregulatory substance, released from platelet granules after vascular injury, is thought to contribute to the process of restenosis both by direct mitogenic effects on smooth muscle cells and by stimulating platelet activation and vasoconstriction. Ketanserin, a serotonin receptor antagonist was evaluated in the Dutch, multicenter, PostAngioplasty Restenosis Ketanserin (PARK) trial for prevention of restenosis.43 However, oral ketanserine at a dose of 80 mg/day failed to reduce restenosis rate and did not lower the incidence of adverse clinical events at 6 months. Angiotensin converting enzyme (ACE) inhibitors have been considered for restenosis prevention, since angiotensin II produced at the site of balloon injury has been shown to induce expression of several growth factor genes, such as genes encoding PDGF, transforming growth factor-beta, and thrombosondin. This stimulates DNA synthesis and promotes migration and proliferation of arterial smooth muscle. This concept led to the Multicenter European Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) trial.44 This was a large, prospective, multicenter, randomized, doubleblind, placebo controlled trial that tested cilazapril, an ACE inhibitor, 5 mg given twice daily for 6 months to prevent restenosis. Clini-

cal evaluation, exercise testing and repeat angiographic follow-up at 6 months failed to show any statistically significant reduction in angiographic restenosis or improvement in clinical outcome. Similarly, negative results were obtained in a Belgian study of 509 patients using fosinopril and in an Indian study of 95 patients using enalapril.45,46 To assess the effect of high and low dose ACE inhibition on restenosis after coronary angioplasty, the Multicenter American Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) group tested doses of 1, 5, and 10 mg twice daily of cilazapril for a 6-month course against placebo (in addition to aspirin) after successful PTCA.47 Among the 1436 patients enrolled in the study, no benefit in reducing restenosis was observed with active therapy at any of the doses. Thus, systemically administered ACE inhibitors have not been shown to reduce restenosis after angioplasty. Recently, attention has been directed towards accentuating certain naturally occurring inhibitors to smooth muscle cell proliferation. Nitric oxide, secreted by intact endothelial cells, in addition to locally regulating vasomotor tone, probably exerts a natural defense to intimal overgrowth by direct smooth muscle cell cytostasis and by reducing platelet and inflammatory cell adhesion. A French trial, The Angioplastie Coronaire Corvasal Diltiazem (ACCORD) trial, randomized 700 patients undergoing lower-risk PTCA to nitric oxide donor therapy (consisting of periprocedural intravenous linsidomine followed by molsidomine therapy for 6 months) or diltiazem treatment, both in combination with aspirin.48 Nitric oxide donor-treated patients were found to have larger minimal luminal diameters at 6 month follow-up (1.54 vs 1.38 mm, p ⫽ 0.009) and lower restenosis

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rates by 50% stenosis criterion (38% vs 36.5%, p ⫽ 0.052) than diltiazem-treated patients. However, the late luminal loss did not differ between the groups and there was no difference in the occurrence of major clinical events. These results need to be confirmed by larger studies, since this trial showed nitric oxide donors to have a potentially promising role in restenosis prevention.

Antiproliferatives and antineoplastics (Table 7.4) Since smooth muscle proliferation is the final common pathway in restenosis, researchers have attempted to block cell division in smooth muscle cells using nonspecific antiproliferative and antineoplastic agents. Colchicine has been considered as a potential inhibitor of leukocyte and smooth muscle cell migration and proliferation. When clinically tested, 1.2 mg of colchicine daily for 6 months yielded no benefit over placebo in an angiographically determined restenosis trial of 197 patients.49 Another study which randomized 253 patients for 1 month to colchicine 1 mg daily and used clinical variables and exercise thallium tests as restenosis endpoints, failed to

Colchicine Other antineoplastic agents Cyclosporin Azathioprine Methotrexate Microtubule stabilizing agent Paclitaxel (Taxol™) Immunosuppressive agent Rapamycin

Table 7.4 Antiproliferatives and antineoplastics.

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show any benefit of colchicines in reducing restenosis.50 Potent anticancer therapy agents such as cyclosporine, azathioprine and methotrexate have shown promising results in animal models of restenosis. Paclitaxel (Taxol™), a microtubule stabilizing agent with potent antiproliferative activity, has been shown to inhibit smooth muscle cell migration and proliferation in vitro and in vivo in animal models. In a rabbit carotid model, local delivery of paclitaxel (Taxol™) has shown reduction of neointimal proliferation and enlargement in vessel size.51 Based on promising results from animal studies, future clinical trials with paclitaxel-coated stents are underway. Rapamycin, an immunosuppressive agent with potent antiproliferative action has been shown to inhibit vascular smooth muscle cell proliferation and migration and significantly reduce arterial proliferative response after PTCA in vivo in a porcine animal model. Further clinical trials are needed to confirm the beneficial effect of rapamycin.52

Vasodilators Calcium channel antagonists have been considered for restenosis prevention owing to their ability to reduce elastic recoil and vasoconstriction, which are thought to be contributing factors in restenosis. In addition, there is some evidence to suggest that they reduce growth factor-dependent proliferation and migration of smooth muscle cells. A metaanalysis performed by Hillegass et al of several trials suggested a 30% reduction in the odds of angiographic restenosis by calcium antagonism (p ⫽ 0.003).53 Nifedipine did not reduce restenosis rates, but verapamil showed reduction in restenosis rate in some studies. Studies using diltiazem have had mixed results, with one study showing benefit and two studies showing no benefit. The results with diltiazem

LIPID-LOWERING AGENTS AND ANTIOXIDANTS

and verapamil indicate the need for a large multicenter trial with more conclusive results.

Lipid-lowering agents and antioxidants Since lipid lowering agents have shown dramatic effects in reducing clinically relevant ischemic events in patients with coronary artery disease, it is important to consider whether modification of lipid profile, including reduction of LDL cholesterol and raising of HDL cholesterol would help reduce restenosis. A study by Shah and Amin on the relationship of restenosis to serum lipid fractions, found that a low HDL fraction is independently and strongly related to the risk of restenosis and the brevity of the time interval to restenosis.54 Restenosis occurred in 64% of patients with HDL ⱕ 40 mg/dL as opposed to 17% of patients with HDL ⬎ 40 mg/dL (p ⬍ 0.002). A number of trials have been performed that attempted to reduce the incidence of restenosis with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors, which not only modify lipid levels, but also have some antiproliferative effect. However, in the Lovastatin Restenosis Trial Study, a prospective, randomized, double-blind study of 404 patients, treatment with lovastatin (40 mg orally twice daily) starting 7–10 days before PTCA and extending for 6 months, there was no reduction in 6-month angiographic restenosis in the lovastatin-treated patients over the placebo-treated patients.55 Restenosis rates were identical, despite a 42% reduction in serum LDL-C in the actively-treated group. The Fluvastatin Angioplasty Restenosis (FLARE) study trial randomized 1054 patients to fluvastatin 40 mg twice a day, starting 2 weeks before coronary angioplasty and continuing for 26 weeks or placebo (all patients

received aspirin).56 Angiographic follow-up done at 26 ⫾ 2 weeks did not show a reduction in the rate of restenosis. The results described above not only show HMG CoA reductase inhibitors to be generally ineffective in preventing restenosis, but also suggest that LDL-C and total cholesterol do not contribute much to the process of restenosis, despite their known importance in primary and secondary prophylaxis. Vascular injury induced by percutaneous coronary intervention is known to cause the release of oxygen free radicals, which stimulate growth factors causing smooth muscle proliferation. Although probucol is a lipidlowering agent, which reduces total and LDLC and increases HDL cholesterol, its antioxidant action has been considered to be more important in reducing restenosis. The multivitamins and probucol (MVP) study, a double-blind, placebo controlled trial, randomized 317 patients to placebo, probucol (500 mg), and probucol with multivitamins starting 4 weeks prior to and continuing 6 months after angioplasty.57 Restenosis rates were 20.7, 28.9, 40.3 and 38.9 in the probucol, probucol with multivitamins, and placebo groups, respectively (p ⫽ 0.003 for probucol vs no probucol). Mean reduction in luminal diameter at 6 months was significant in probucol-treated patients vs placebo (p ⫽ 0.006). Probucol also reduced restenosis in small coronary arteries and showed a reduction in absolute lumen loss. The MVP substudy, in which 94 patients underwent intravascular ultrasound, showed that the benefit was vascular remodeling following angioplasty.58 Similarly, other small trials have shown a reduction in restenosis by 30–60% with probucol therapy. Larger trials to confirm the safety and efficacy of probucol therapy need to be done in the future to confirm this dramatic effect of probucol.

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Another antioxidant, vitamin E or alphatocopherol, has been studied in a small clinical trial and failed to show a statistically significant difference in angiographic or clinical restenosis.59 More extensive clinical trials are needed to evaluate the role of vitamin E in reducing the restenosis rates after angioplasty.

Local drug delivery and molecular strategies With the development of number of local delivery devices such as infusion balloon catheters, coated stents and techniques for facilitated diffusion, and coated microspheres, as well as the development of newer agents such as antisense oligonucleotides, promising new studies are underway to assess the efficacy and safety of drugs like heparin, low-molecular-weight heparin, angiotensin II antagonists, antisense oligonucleotides, alcohol, steroids and radiation.60 The theory of local delivery is very promising, however, more research is clearly needed before wide-scale clinical applications can be considered. Perhaps the secret of restenosis prophylaxis lies in molecular biology. Use of chimeric toxins using recombinant DNA, antisense approaches, and gene therapy to suppress smooth muscle cell proliferation are some of the exciting approaches under investigation. However, most of this work is still at the

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animal testing stage. This is a very extensive field and is outside the scope of this chapter.

Conclusion Coronary restenosis is the ‘Achilles heel’ of percutaneous coronary intervention. Despite advances in the understanding of the pathophysiology of coronary restenosis, the extensive search for an effective agent to prevent restenosis has not yet been fruitful. No systemic pharmacologic agent has been unambiguously shown to reduce restenosis after coronary angioplasty (Fig. 7.2). Agents such as cilazapril, ketanserine and glucocorticoids have been proven to show no benefit and probably do not warrant further studies. Other agents such as tranilast, trapidil, ebselen, ciprostene, probucol, some calcium channel antagonist, paclitaxel and rapamycin have shown some promise in reducing restenosis and warrant further well-designed trials. One exciting possibility for preventing restenosis is the area of local drug delivery using percutaneous devices and this merits further animal and human clinical trials. Another area of interest is gene therapy to control smooth muscle proliferation, the key process in the development of restenosis. Hope definitely exists that we will eventually be able to end the struggle with restenosis.

CONCLUSION

Agent

Relative risk ratio

Aspirin Aspirin (various doses) Ticlopidine Tx A2 inhibitors Prostacyclin analogs Anticoagulants Calcium antagonists Steroids ACE inhibitors Trapidil Fish oils Lipid lowering agents Antioxidants Antiproliferative agents Seratonin antagonists Angiopeptin 0

0.5

1

1.5

2

Figure 7.2 The relative risks of various drug classes investigated in the prevention of restenosis in humans with 95% confidence intervals (CI). A risk ratio (RR) ⬍ 1 indicates lower restenosis rate with the drug compared to placebo. When the 95% CI does not cross the RR of 1, the difference is statistically significant (p ⬍ 0.05). Adapted from Miller JM, Ohman EM, Moliterno DJ, Califf RM. Restenosis: the clinical issues. In: Textbook of Interventional Cardiology (Topol E, ed.) 1999; 379–415, Saunders, Philadelphia, PA.

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Pathophysiology and pharmacological approaches for prevention of coronary artery restenosis following coronary artery balloon angioplasty and related procedures. Landsberg BR, Frishman WH, Lerrick K. Progress in Cardiovascular diseases, Vol XXXIX, No 4, 1997: pp 361–398. Dangas G, Fuster V. Management of restenosis after coronary intervention. Am Heart J 1996; 132:428–436. Oates JA, Fitzgerald GA, Branch RA et al. Clinical implications of prostaglandins and thromboxane A2 formation. N Engl J Med 1988; 319:689–698. Herrman JPR, Hermans WRM, Vos J et al. Pharmacologic approaches to prevention of restenosis following angioplasty (Part 1). Drugs 1993; 46:18–52. Antiplatelet Trialists Collaboration: Collaborative overview of randomized trials of antiplatelet therapy. II. Maintenance of vascular grafts or arterial patency by antiplatelet therapy. Br Med J 1994; 308:159–168. Serruys PW, Rutsch W, Heyndrickx OR et al. Prevention of restenosis after percutaneous transluminal coronary angioplasty with thromboxane A2 receptor blockade. A randomized, double-blind, placebo-controlled trial. Coronary Artery Restenosis Prevention on Repeated Thromboxane Antagonism Study (CARPORT). Circulation 1991; 84: 1568–1580. Feldman RL, Bengtson JR, Pryor DP et al. The GRASP study: use of a thromboxane A2 receptor blocker to reduce adverse clinical events after coronary angioplasty. J Am Coll Cardiol 1992; 19:259A (abst). Savage MP, Goldberg S, Bove A et al. Effect of thromboxane A2 blockade on clinical outcome and restenosis after successful coronary angioplasty: Multi-Hospital Eastern Atlantic Restenosis Trial (M-HEART II). Circulation 1995; 92:3194–3200. Knudtson ML, Flintoft VF, Roth DL et al.

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Effect of short-term prostacyclin administration on restenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1990; 15:691–697. Gershlick AH, Spriggins D, Davies SW et al. Failure of epoprostenol (prostacyclin P012) to inhibit platelet aggregation and to prevent restenosis after coronary angioplasty: results of a randomised placebo controlled trial. Br Heart J 1994; 71:7–15. Raizner AE, Hollman J, Abukhalil I et al. Ciprostene for restenosis revisited: quantitative analysis of angiograms. J Am Coll Cardiol 1993; 21:321A (abst). O’Connor GT, Malenka DJ, Olamstead EM et al. A meta-analysis of randomized trials of fish oil in prevention of restenosis following coronary angioplasty. Am J Prev Med 1992; 8:186–192. Leaf A, Jorgensen MB, Jacobs AK et al. Do fish oils prevent restenosis after coronary angioplasty? Circulation 1994; 90:2248–2257. Cairns JA, Gill J, Morton B et al. Enoxaparine and maxepa for the prevention of angioplasty restenosis (EMPAR). Circulation 1996; 94:1553–1560. White CW, Knudson M, Schmidt D et al. Neither ticlopidine nor aspirin-dipyridamole prevents restenosis post PTCA: results from a randomized, placebo-controlled. multicenter trial. Circulation 1987; 76:2–13 (abst). Bertrand ME, Allain H, Lablanche IM et al. Results of a randomized trial of ticlopidine vs placebo for prevention of acute closure and restenosis after coronary angioplasty. Circulation 1990; 82:190 (abst). Swanson KT, Vlietstra RE, Holmes DR et al. Efficacy of adjunctive dextran during percutaneous transluminal coronary angioplasty. Am J Cardiol 1984; 54:447–448. Ellis SO, Roubin OS, Wilentz I et al. Effect of 18–24 hour heparin administration for prevention of restenosis after uncomplicated coronary angioplasty. Am Heart J 1989; 117:777–782.

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19. Brach MI, Ray S, Chauhan A et al. The Subcutaneous Heparin and Angioplasty Restenosis Prevention (SHARP) Trials: results of a multicenter randomized trial investigating the effects of high dose unfractionated heparin on angiographic restenosis and clinical outcome. J Am Coll Cardiol 1995; 26:947–954. 20. Vrolix MC, Legrand VM, Reiber JH et al. Heparin-coated Wiktor stents in human coronary arteries (MENTOR trial). Am J Cardiol 2000; 86:385–389. 21. Bartorelli AL, De Cesare NB, Kaplan AV et al. Local heparin delivery prior to coronary stent implantation: acute and six-month clinical and angiographic results. Cathet Cardiovasc Diagn 1997; 42:313–320. 22. Faxon DP, Spiro TE, Minor S et al. Low molecular weight heparin in prevention of restenosis after angioplasty. Results of enoxaparin restenosis (ERA) trial. 1994; Circulation 90:908–914. 23. Karsch KR, Preisack MB, Bonan R et al. Low molecular weight heparin, reviparin, in prevention of restenosis after PTCA. J Am Coll Cardiol 1996; 27:113A (abst). 24. Lablanch JM, McFadden EP, Meneveau N et al. Effect of nadroparin (Fraxiparin), a low molecular weight heparin, on clinical and angiographic restenosis after coronary balloon angioplasty. The FACT study. Circulation 1997; 96:3396–3402. 25. Serruys PW, Herrmann J-PR, Simon R et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. N Engl J Med 1995; 333:757–763. 26. Burchenal JEB, Marks DS, Schweiger MI. Hirulog does not prevent restenosis after coronary angioplasty. Circulation 1995; 92:1–608 (abst). 27. Thomton MA, Oruentzig AR, Hollman I et al. Coumadin and aspirin in the prevention of restenosis after transluminal coronary angioplasty: a randomized study. Circulation 1984; 69:721–727. 28. Topol EJ, Califf RM, Weisman HF et al. Randomised trial of coronary intervention with antibody directed against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. Lancet 1994; 343:881–886. 29. Topol E et al. Evaluation of IIb/IIIa Platelet Inhibitor for Stenting. EPISTENT, 6 month

follow-up. Circulation 1999; 99:1127–1131. 30. Ellis SG, Effron MB, Gold HK et al. (ERASER study investigators). Acute platelet inhibition with abciximab does not reduce in-stent restenosis. Circulation 1999; 100:799–806. 31. Lincoff AM, Tcheng JE, Ellis SO et al. Randomized trial of platelet glycoprotein IIb/IIIa inhibition with integrelin for prevention of restenosis following coronary intervention. The IMPACT-Angiographic Substudy. Circulation 1997; 96:1–607 (abst). 32. Gibson CM, Goel M, Cohen DJ et al. Sixmonth angiographic and clinical follow-up of patients prospectively randomized to receive either tirofiban or placebo during angioplasty in the RESTORE Trial. J Am Coll Cardiol 1998; 32:28–34. 33. Stone OW, Rutherford BD, McConahay DR et al. A randomized trial of corticosteroids for the prevention of restenosis in 102 patients undergoing repeat coronary angioplasty. Cath Cardiovasc Diagn 1989; 18:227–231. 34. Rose TE, Beauchamp BO. Short term high dose steroid treatment to prevent restenosis in PTCA. Circulation 1987; 76:371. 35. Pepine CI, Hirshfeld JW, MacDonald RG et al. A controlled trial of corticosteroids to prevent restenosis after coronary angioplasty. Circulation 1990; 81:1753–1761. 36. Hirayama A, Nanto S, Ohara T et al. Preventive effect on restenosis after PTCA by ebselen: a newly synthesized antiinflammatory agent. J Am Coll Cardiol 1992; 19:259A (abst). 37. The TREAT Study Investigators. The impact of tranilast on restenosis following coronary angioplasty: the Tranilast Restenosis Following Angioplasty Trial (TREAT). Circulation 1994; 90:65–2 (abst). 38. Maresta A, Balducelli M, Cantini L et al. Trapidil (triazolopyrimidine), a platelet-derived growth factor antagonist, reduces restenosis after percutaneous transluminal coronary angioplasty: results of the randomized, doubleblind STARC study. Circulation 1994; 90:2710–2715. 39. Nishikawa H, Ono N, Motoyasu M et al. Preventive effects of trapidil on restenosis after PTCA. Circulation 1992; 86:53 (abst). 40. Eriksen UH, Amtorp O, Bagger JP et al. Randomized double-blind Scandinavian trial of

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angiopeptin vs placebo for the prevention of clinical events and restenosis after coronary balloon angioplasty. Am Heart J 1995; 130:1–8. Emanuelsson H, Bagger IP, Balcon R et al. Long-term effects of angiopeptin treatment in coronary angioplasty: reduction of clinical events but not of angiographic restenosis. Circulation 1995; 91:1689–1696. Kent KM, Williams DO, Cassagneau B et al. Double-blind, controlled trial of the effect of angiopeptin on coronary restenosis following balloon angioplasty. Circulation 1993; 88:506 (abst). Serruys PW, Klein W, Tijssen IP et al. Evaluation of ketanserin in the prevention of restenosis after percutaneous transluminal coronary angioplasty. A multicenter randomized doubleblind placebo-controlled trial. Circulation 1993; 88:1588–1601. Multicenter European Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) Study Group. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind, placebo-controlled trial. Circulation 1992; 86:100–110. Desmet W, Vrolix M, DeScheerder I et al. Angiotensin converting enzyme inhibition with fosinopril sodium in the prevention of restenosis after coronary angioplasty. Circulation 1994; 89:385–92. Kaul U, Chandra S, Bahl VK et al. Enalapril for prevention of restenosis after coronary angioplasty. Indian Heart 1993; 145:469–473. Faxon DP, on behalf of the Multicenter American Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) Study Group. Effect of high dose angiotensinconverting enzyme inhibition on restenosis: final results of the MARCATOR study, a multicenter, double-blind, placebo-controlled trial of cilazapril. J Am Coll Cardiol 1995; 25:362–369. Lablanche JM, Grollier G, Lusson JR et al. Effect of the direct nitric oxide donors linsidomine and molsidomine on angiographic restenosis after coronary balloon angioplasty.

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The ACCORD study. Circulation 1997; 95:83–89. O’Keefe JH, McCallister BD, Bateman TM et al. Ineffectiveness of colchicine for the prevention of restenosis after coronary angioplasty. J Am Coll Cardiol 1992; 19:1597–1600. Grines CL, Rizik D, Levine A et al. Colchicine angioplasty restenosis trial (CART). Circulation 1991; 84:365 (abst). Herdeg C, Oberhoff M, Baumbach A et al. Local paclitaxel delivery for the prevention of restenosis: biological effects and efficacy in vivo. J Am Coll Cardiol 2000; 35:1969–1976. Gallo R, Padurean A, Jayaraman T et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 1999; 99:2164–2170. Hillegass WB, Ohman EM, Leimberger ID et al. A meta-analysis of randomized trials of calcium antagonists to reduce restenosis after coronary angioplasty. Am J Cardiol 1994; 73:835–839. Shah PK, Amin I. Low high-density lipoprotein level is associated with increased restenosis rate after coronary angioplasty. Circulation 1992; 85:1279–1285. Weintraub WS, Boccuzzi SI, Klein IL et al. Lack of effect of lovastatin on restenosis after coronary angioplasty. N Engl J Med 1994; 331:1331–1337. Serruys PW, Foley DP, Jackson G et al. Fluvastatin for prevention of restenosis after coronary balloon angioplasty: final results of the Fluvastatin Angioplasty Restenosis (FLARE) trial. Eur Heart J 1999; 20:58–69. Tardif JC, Cote G, Lesperance J et al. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. N Engl J Med 1997; 337:365–372. Cote G, Tardif J-C, Lesperance J et al. Effects of probucol on vascular remodeling after coronary angioplasty. Circulation 1999; 99:30–35. DeMaio SI, King III SB, Lembo NI et al. Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transluminal coronary angioplasty. J Am Coll Nutr 1992; 11:68–73. Lincoff AM, Topol EL, Ellis SG. Local drug delivery for the prevention of restenosis. Circulation 1994; 90:2070–2084.

8 Drug-coated stent for restenosis Marco A Costa

Despite major technological advances in the past few decades, the frequency of restenosis still represents a vexing problem for the percutaneous approach to treating coronary artery disease. Unfavorable or negative vascular remodeling and neointimal hyperplasia represent the ultimate consequence of a puzzling healing process involving thrombosis, inflammation, cellular (smooth muscle cell and fibroblast) migration/proliferation and extracellular matrix formation/degradation. The ability of a given therapy to prevent both remodeling and intimal hyperplasia determines its potential to eradicate restenosis. Stents, certainly a step forward since the invention of balloon angioplasty, effectively prevent the remodeling component of restenosis.1 The advent of neointimal proliferation, however, is still not counteracted and poses the last hurdle in the percutaneous treatment of coronary artery disease. Thus, the focus of the prevention of restenosis over the past two decades has been through the application of antiproliferative pharmacological agents. Recently, attention has turned towards the development of novel systems for local drug delivery, with drug-coated stents representing the foremost innovation.

Rationale for drug-coated stent Several systemic antiproliferative approaches have been tested, but promising results from experimental laboratories have not been translated into clinical effectiveness.2,3 Only a small number of studies on systemic pharmacological intervention to prevent restenosis have shown satisfactory results.4–8 The failure to achieve adequate drug concentrations where they are required, i.e. the coronary injured segment, is the major drawback of systemic drug therapy. Nevertheless, it is important to note that most of the clinical investigations assessed the efficacy of these agents in the setting of balloon angioplasty and that negative remodeling was not targeted in most of the cases. Consequently, one cannot completely rule out the possibility that vessel ‘shrinkage’ may have jeopardized the potential clinical benefit of these antiproliferative therapies. Driven by the need for high drug concentrations at the site of vascular injury, local drug delivery systems have been developed. Clinical experience with microporous, hydrogel balloons, iontophoretic catheters, dispatch catheters and infusion sleeves have been The recently published reported.9–13 POLONIA trial is the only randomized investigation that demonstrates a significant reduction in in-stent restenosis by local drug administration.14 In this study, 100 patients

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DRUG-COATED STENT FOR RESTENOSIS

were randomly assigned to either local administration of enoxaparin during predilation with reduced systemic heparinization or stenting with standard, systemic heparinization. Late luminal loss was 0.76 ± 0.42 mm in the local enoxaparin delivery group vs 1. 07 ± 0.49 mm in the systemic heparinization group. Binary restenosis occurred in 10% (8% target lesion revascularization [TLR]) of patients in the enoxaparin group and in 24% (22% TLR) of those receiving systemic heparinization. Unfortunately these results have not been corroborated by others. The HIPS study showed no favorable effect of locally delivered heparin on angiographic restenosis or intravascular ultrasound (IVUS) measured intimal hyperplasia.15 The IMPRESS trial also investigated the application of low molecular weight (MW) heparin to decrease restenosis.16 In 250 patients treated with stent implantation, intramural delivery of nadroparin (2 ml of 2500 anti-Xa-units per ml) via microporous catheter had no effect in restenosis rate. The rapid washout of the drug downstream into the coronary circulation, decreasing the amount of agent actually deposited within the arterial wall to < 5%, may explain these negative results.9,17 Furthermore, drug penetrance into the lesion depends on a head of driven pressure which may induce flow or pressure-mediated vessel wall injury.18 As a result of their permanent scaffolding action, stents have become an attractive reservoir for delivering medications locally. Prolonged and sufficient intramural drugconcentration may be achieved via drug-eluting stents. However, a number of factors should be addressed when considering stent-based local drug delivery: • The cardiovascular system demands both blood and tissue compatibility;19

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• only a limited amount of drug can be loaded onto the stent – stents usually cover < 10% of the target coronary segment; • the type of drug binding must be such that it does not decrease the biological activities of the compound or the mechanical properties of the stent; • local tissue properties and drug solubility may interfere with pharmacokinetics;20 • stent expansion and sterilization should not affect polymer or drug properties (Fig. 8.1); • polymer coatings and the antiproliferative agents may themselves induce inflammation and other detrimental vascular responses.21

Stent coating – a crucial step Coating materials may be categorized as organic, inorganic, bioerodable, nonbioerodable, synthetic or naturally occurring substances. Polymers are long-chain molecules consisting of small repeating units. Their ability to adhere medications to metallic surfaces and facilitate prolonged drug delivery makes polymers a very attractive material to serve as coating matrices. The list of candidate substances for stent coatings is long and everexpanding (Table 8.1). Most polymers have been tested as a biologically inert barrier to improve the quality of stent surface. Only a few, however, have attained this goal.21–23 Indeed, the selection of an inert coating matrix is the first challenge one may face when developing a drug-eluting stent. Van der Giessen et al21 tested eight different polymers, five biodegradable and three nonbiodegradable, attached longitudinally across 90° of the circumferential surface of coil wire stents (Meditronic Inc. Minneapolis, MN, USA). These coated stents were implanted in porcine coronary arteries and none of them proved to be inert.

STENT COATING – A CRUCIAL STEP

Figure 8.1 Potential alterations in stent surface after expansion (left panel) and sterilization (right panel) of polymer-coated stent.

Synthetic polymers While problems have been observed with the use of synthetic polymers in the vascular bed, their ability to adhere, incorporate, degrade and release pharmacological agents still places these substances among the leading candidates for coating metallic stents (Table 8.1). As mentioned previously, having the ability to expand uniformly with the stent and keeping its smoothness and chemical characteristics after sterilization are prerequisites for all coating substances (Fig. 8.1). Furthermore, the degree of degradation as well as its product, the MW, and the thickness of the coating layer are some of the key factors that directly interfere with polymer toxicity. It is speculated that slow degrading coatings elicit less inflamma-

tory reaction, whereas thick (> 10 µm) layers may stimulate vessel wall reaction.24 Poly-L-lactic acid (PLLA) is a synthetic polymer completely degraded in vivo by enzymatic or nonenzymatic hydrolysis.25 Entirely biodegradable stents have been constructed with this polymer, while others have tested PLLA as a coating matrix for metallic prostheses. Interestingly, different inflammatory reactions have been observed with PLLA, which illustrates the complexity of manufacturing inert polymer-coated stents. Lincoff et al proved that low molecular mass PLLA (80 kD) elicited marked inflammatory response in a coronary pig model.26 Conversely, the same polymer but with a high MW (321 kD) appears to be well-tolerated.26 In another investigation using both sheep and pig models,

115

116 Stainless steel

Yes No

No No

Poly(organo)phosphazene43 Polyurethane21,33,43–45

Poly(lactide-co-Σ-Caprolactone)48 Methylmethacrylate/ 2-hydroxyethyl methacrylate49

Pig coronary

Pig coronary Pig coronary Pig coronary Pig coronary23 Pig coronary26 Human coronary27 Pig coronary Pig coronary21,33 Rabbit carotid44 Pig ex vivo fistula45 Pig coronary23 Pig coronary

Pig coronary Pig coronary Pig coronary21 Pig iliac41 Pig coronary22

Pig coronary Rabbit iliac and pig coronary30 Human coronary32 Pig coronary29 Pig carotid Baboon AV shunt

Rabbit iliac

Experimental model/ humans

28 d

28 d 28 d 28 d 21 d 28 d 180 d 42 d 28 d 28 d 2h 42 d 7, 28, 56 d

28 d 28 d 28 d 42 d 28-42 d

30, 180 d 5, 28, 90 d 2h 2h

28, 90, 180, 360 d 28 d

28 d

Follow-up

↓ ↑↓ ↑↓

↑↓

0% SA thrombosis

↑↓ ↑↓ ↑↓ ↑↓

↑↓ ↑↓ ↑↓ ↑ ↑

↓ ↓

↓ (plus GPIIb/IIIa antibody) ↑↓ ↑↓ 0.4% SA thrombosis ↑↓

Thrombosis

↓

↑↓ ↑↓

↑ ↑ ↑ ↑↓ ↑ (80kD) 10.5% restenosis ↑ ↑

↑ ↑ ↑ ↑ ↑

↑↓

↑↓ ↑↓ ↑↓

Neointimal hyperplasia

Table 8.1 Candidate substances for stent coatings.

degrad. = degradation, h = hours, d = days, w = weeks, m = months, y = years, GP = glycoprotein, SA = subacute, ↑ = increase, ↓ = decrease, ↑↓ = no influence.

Tantalum Tantalum Tantalum PLLA Tantalum PLLA Stainless steel Tantalum Nitinol Tantalum Stainless steel Stainless steel

Tantalum Tantalum Tantalum PET PET

Stainless steel Stainless steel

Yes, 50% in 52 w Yes, 60-90 d Yes, 20% in 26 w Yes, > 3 m

No Yes, 50% in 4 y No

Yes

Tantalum Stainless steel

Stainless steel

Stent

Polyethyleneoxide/polybutylene terephthalate21 Polyglycolic acid/polylactic acid21 Polyhydroxy-butyrate/valerate21 Poly-l-lactic acid (PLLA)26,27,42

Synthetic substances Poly(dimethyl)-siloxane21 Polycaprolactone21 Polyethene Terephthalate (PET)21,22,41

Polynitrosated albumin Hyaluronic acid40

Yes, 1–3 months No

Fibrin33,34 Phosphorylcholine29,30,32

36

Yes

Biodegradable, degrad. time

Naturally occurring substances Cellulose35

Coating material


DRUG LOADING AND RELEASE KINETICS

PLLA (MW 30 kD) has been applied as a coating matrix to release hirudin and iloprost with satisfactory results (reduction in mean restenosis area by 22% compared with noncoated Palmaz–Schatz stents).43 Lately, the Igaki–Tamai stent (Igaki Medical Planning, Kyoto, Japan), a biodegradable prosthesis completely produced from PLLA (MW 185 kD), has been implanted in human coronary arteries with satisfactory 6-month angiographic outcomes (Table 8.1).27

Biomimicry The importance of bio- and hemocompatible passive surface in vascular prosthesis is crucial.19 Thus, coating metallic surfaces with substances that mimic a biological vascular structure is highly appealing. Phosphorylcoline (PC) is a neutral, zwitterionic naturally occurring substance that has been mimicked in the laboratory and used as coating to improve the biocompatibility of surfaces. In vitro studies have shown reduced fibrinogen adsorption and platelet activation on the surface of stainless steel coated with PC.45 In vivo experiments have shown that PC does not interfere with stent reendothelialization and elicits a similar amount of neointimal hyperplasia compared to uncoated stents 28 days after implantation.29,30,36 The commercially available PC-coated stent is the BiodivYsio (Biocompatibles plc, Farnham, UK). Out of 224 patients, there was one (0.4%) subacute stent thrombosis and 5.4% target vessel revascularization 6 months after the implantation of BioResults from large divYsio stents.32 randomized studies are still pending, but PC coating remains high on the list of candidates to be used as matrices for drug elution. Fibrin, cellulose and albumin, all naturally occurring substances, have been used to improve the quality of stent surfaces with

promising reports from the animal laboratories.33–36 The group from Mayo Clinic has tested the biocompatibility of fibrin-film covered stents in porcine coronary arteries. Only three of 34 stents implanted had thrombosis, while endothelialization was observed at 4 weeks in all patent vessels. At 28 days the mean neointimal thickness in the fibrin-stented and bare-stented groups were 0.57 ± 0.31 mm and 0.57 ± 0.27 mm, respectively.33,34 Comparable intimal proliferation was also observed at 90 days and at 6-month follow-up. The other substances were tested in combination with antiproliferative or antithrombotic agents and will be discussed further in this chapter.

Inorganic coating Inorganic substances have also been loaded onto stent surfaces to improve their electromechanical properties. Commercially available are the gold-coated InFlow (Inflow Dynamics AG, Munich, Germany) and NIR (Boston Scientific Corporation, Maple Grove, MN) stents and silicon carbide-coated Tensun and Tenax stents (Biotronik GmbH, Berlin, Germany).47,48 Recent reports have shown that both Inflow and NIR gold-coated stents are associated with increased neointimal proliferation,47,49 while the clinical benefit of siliconcarbide stents has yet to be demonstrated.

Drug loading and release kinetics There are several approaches to loading medications onto stents. Some drugs can be loaded directly onto metallic surfaces (e.g. prostacyclin).50 However, in most cases, a polymeric matrix is required for controlled release of the medication. Drugs can be held by covalent (C-C bonds, sulphur bridges, etc.) or non-covalent

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(ionic, hydrogen) bonds.51 The blended matrix can then be attached to the stent surface by dipping or spray coating. Basically, drugs can be released by particle dissolution or diffusion when non-bioerodable matrices are used, or during polymer breakdown when incorporated (absorbed) into a biodegradable substance. Drug elution kinetics from blended coating matrices are influenced by a number of factors, including: • the thickness of the coating; • physicochemical properties of the drug and polymer (soluble components diffuse faster than hydrophobic materials); • degree of cross-linking; • porosity of the polymer; • and ultimately, the amount of drug incorporated.20,52 Fortunately most of these factors can be modulated at a reasonable level during their manufacture, resulting in formulations with durations of release that may vary from hours to months.26,53 An entirely biodegradable stent is an alternative way to increase the amount of drug incorporated.27 Adding another layer of polymer on the top of the blended coating also lengthens the release time.37 Finally, by modeling the release kinetics of different drugs in the same coating matrix one can target distinct phases of the restenotic process. Alt et al tested a homogeneous thin layer coating of PLLA polymer releasing 2 antithrombotic and potentially antiproliferative agents, hirudin and iloprost.43 While iloprost was slowly released by the breakdown of the polymer, about 59% of the hirudin was eluted in the first 24 h as a result of the incorporation of crystals into the carrier. In this manner, a fast antithrombotic action and sustained antiproliferative effect for > 3 months was produced, which may have contributed to a decreased neointimal formation observed in

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both sheep and pig models treated with this drug-coated stent.43

Antithrombotic stent coating Because of the catastrophic consequences of stent thrombosis, development of an antithrombotic stent coating was the initial goal of stent-based drug therapies. In 1992, after 6 years of clinical implementation, stents were still facing skepticism owing to a high (20–25%) incidence of thrombotic complications.54,55 Systemic anticoagulation was the first attempt to reduce stent thrombosis, but the results were disappointing.54 Antithrombotic stent coatings were then proposed as a solution to decrease the inherent thrombogenicity of coronary metallic stents and potentially reduce neointimal proliferation, since thrombus formation is believed to be the leading cause of restenosis.56 Bonan et al were the first group to report the implantation of a zigzag heparin-coated stent in canine coronary arteries.57 So far, this is the only report showing no antithrombotic benefit of heparin coating. Thereafter, by improving the base polymer coating and increasing the biological activity of the drug, other groups have been able to demonstrate a marked reduction in thrombus formation in different animal models.42,58,59 Three heparin-coated stents are currently available for clinical use: Palmaz–Schatz/BXVelocity Carmeda-coated stent (Johnson & Johnson, Warren, NJ, USA), Wiktor Hepamed-coated stent (Medtronic, Inc., Minneapolis, MN, USA) and the JOSTENT Corline-coated stent (Jomed International AB, Helsingborg, Sweden).60–62 In the BENESTENT-II pilot study, heparin-coated Palmaz–Schatz stents were implanted in 202 human coronary arteries.63 For the first time, stent thrombosis did not occur in a large series


of patients. The BENESTENT-II, as well as other clinical studies testing different heparincoating matrices, further confirmed the near absence of stent thrombosis, but showed no influence on neointimal proliferation.61,62,64 Hirudin/iloprost (discussed previously), forskolin, nitric oxide (NO) and glycoprotein IIb/IIIa (GP IIb/IIIa ) inhibitors are other antithrombotic compounds tested as stent coatings.35,43,65 Forskolin, a nonpolar adenylate cyclase activator with antiplatelet and vasodilator properties, has been tested in a rabbit carotid model of temporary stenting. This study proved the concept of the drugeluting stent and demonstrated that high drug concentrations are dependent on both maintaining high stent-to-tissue gradients and chemical characteristics of the compounds.65 Both albumin and NO have been shown to exert antithrombotic function.66,67 Polynitrosated albumin has been tested as a coating matrix to decrease the platelet adhesion stimulus of Palmaz–Schatz stents.36 These Palmaz–Schatz stents were implanted in pig carotid arteries and showed a significant decrease in average gamma ray count from 111 In-labeled platelets attached to the stent surface 2 h after implantation. The authors speculate that these findings are attributable to the direct antiplatelet actions of NO combined with the antiadhesive properties of albumin.36 Additional in vivo experiments are required. A cellulose polymer-coated stent adsorbed with AZ1 antibody was implanted in rabbit balloon-damaged iliac arteries and significantly reduced platelet deposition and improved patency rates compared to control.35 This platelet GP IIb/IIIa antibody eluting stent had no effect on neointimal proliferation.35 As a result of the inefficiency of antithrombotic stent-coating in reducing neointimal hyperplasia and the extremely low incidence of stent thrombosis in contemporary practice,

efforts have been focused on developing stentcoating matrices loaded with antiproliferative agents to reduce restenosis.

Antiproliferative stent coatings Neointimal hyperplasia with its clinical consequence, in-stent restenosis, represents the ultimate obstacle that must be mastered for the percutaneous approach to become the definitive therapy of choice in coronary revascularization. After years of continuous research, antiproliferative drug-eluting stents have appeared to be a potential solution for restenosis. Most of these devices are still subject of animal studies and only a few have already been implanted in humans. Preliminary results are encouraging. The inflammatory character of the pathophysiology of restenosis has led some researchers to test the hypothesis that antiinflammatory agents inhibit intimal proliferation. Indeed, corticosteroids have long been shown to reduce the influx of mononuclear cells, to inhibit monocyte and macrophage function and to influence smooth muscle cell proliferation.68,69 Nonetheless, clinical trials have failed to demonstrate the benefit of systemic steroid therapy given for 1 or 7 days.70–72 Sustained local delivery of methylprednisolone (300 mg) by eluting tantalum stents coated with poly(organo)phosphazene was tested in porcine coronary arteries.53 About 96% of the drug was released within 24 h, which resulted in a reduction in neointimal proliferation compared to a severe foreign-body reaction promoted by the polymer-coated stent.53 On the other hand, Lincoff et al did not show the benefit of the dexamethasone (0.8 mg) coated stent in reducing restenosis in a pig model.26 The drug was suspended in a matrix of either low or high MW PLLA, as discussed previously. Tissue concentration was 3000-fold higher than those

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in the serum 28 days after stenting, which proved the theory of prolonged drug residence time within the injured tissue.26 Another agent subject to investigation is the somatostatin analogue angiopeptin. This substance has been shown to reduce tissue response to growth hormone.73 De Scheerder et al demonstrated that stents loaded with angiopeptin produced high local tissue concentrations that gradually declined over > 8 days after implantation in porcine coronary arteries.74 These high local and prolonged drug concentrations resulted in decreased neointimal proliferation compared to poly(organo)phosphazene-coated stents.74 In humans, systemic administration of angiopeptin has improved the clinical outcome after angioplasty but showed no effect in restenosis.3,75 The clinical effectiveness of angiopeptin-coated stents remains to be investigated. It has also been demonstrated that tyrosine kinase inhibitors suppress neointimal formation induced by a variety of stimuli including balloon injury.76 Tyrosine kinases are fundamental transducers of a number of extracellular signals that regulate proliferation, differentiation and specific functions of differentiated cells.23,77 Yamawaki et al coated PLLA (185 kD) biodegradable stents with ST638 (0.8 mg), a specific tyrosine kinase inhibitor, and implanted these devices in pig coronary arteries.23 After 3 weeks, the amount of neointimal proliferation was significantly less in the ST638 stents compared to its inactive metabolite (ST494).23 In vitro study showed a linear release of ST638 from the biodegradable stent for the initial 2 weeks followed by a gradual release for 21 days.23 Results are promising but long-term biocompatibility of PLLA biodegradable stents remains to be demonstrated. Of all the recently developed intracoronary local drug delivery devices, stents loaded

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with the aniproliferative agents sirolimus (rapamycin) and placlitaxel (Taxol®) deserve special attention, since these are the only drugcoated stents that effectively reduced restenosis in humans.

Rapamycin-eluting stents Sirolimus (rapamycin, Rapamune®), a natural macrocyclic lactone unearthed in Easter Island, is a potent immunosuppressive agent approved in 1999 by the Food and Drug Administration (FDA) for the prophylaxis of renal transplant rejection.78 Sirolimus binds to an intracellular receptor protein, elevates p27 levels, which leads to inhibition of cyclin/CDK complexes and ultimately induces cell-cycle arrest in the late G1 phase. Its cytostatic effects have been shown to inhibit proliferation of both rat and human smooth muscle cells in vitro,79,80 and to reduce intimal thickening in models of vascular injury.81–83 Sirolimus was blended in a mixture of nonerodable polymers that have been used clinically in bone cements, ocular devices, and in a drug-releasing intrauterine device.84,85 The BXVelocity™ stent (Cordis, Warren, NJ, USA), a laser-cut 316L stainless steel stent, was loaded with a fixed amount of sirolimus per unit of metal surface area (140 µg sirolimus/cm2). The release kinetics were modulated in such a way that both fast release (< 15-day drug release) and slow release formulations (> 28-day drug release) were obtained. Carter et al tested these drug-coated stents in porcine 30-day restenosis models.31 While a similar degree of reendothelialization was observed in both drug-eluting and bare stents, neointimal proliferation was markedly reduced by rapamycin-coated stents. Klugherz et al tested the effectiveness of sirolimuseluting stents in rabbit iliac arteries.86 Again, drug-coated stents showed a 23–45% reduc-


tion in neointimal proliferation compared to both bare and polymer coated stents.86 Sirolimus levels in whole blood peaked at 1 hour (0.9 ± 0.2 ng/ml) after implantation and fell below the lower limit of quantification by 72 hr (0.4 ng/ml).87 Sousa et al in Brazil performed the implantation of a sirolimus-coated stent in human coronary arteries for the first time.37 Thirty patients with angina pectoris were electively treated with two different formulations of sirolimuscoated stents (slow release [SR], n = 15 and fast release [FR], n = 15). There was minimal neointimal hyperplasia in both groups by IVUS (Fig. 8.2) or quantitative coronary angiography (instent late loss = 0.09 ± 0.3 mm [SR] and –0.02 ± 0.3 mm [FR]; in-lesion late loss = 0.16

± 0.3mm [SR] and –0.1mm ± 0.3 mm [FR]). No in-stent or edge restenosis (diameter stenosis ≥ 50%) was observed at 4-month follow-up. No major clinical event (thrombosis, repeat revascularization, myocardial infarction or death) occurred up to 11 months. Serruys et al have also implanted 15 slow release rapamycin-coated BX-velocity stents in human coronary arteries. Thirteen patients returned for 6-month follow-up and none had restenosis (Serruys PW, personal communication). Twelve- (Brazilian study) and eighteen- (Dutch Study) month angiographic and IVUS followup are planned and will determine whether these results are sustained. Two multicenter randomized trials are already underway. The enrollment phase of the RAVEL trial, which

Figure 8.2 Intravascular ultrasound (IVUS) planar (left panel) and ‘endoscopic’ (reconstructed from 3D-IVUS, right panel) visualization of rapamycin-coated stent 1 year after implantation in human coronary artery. Almost complete absence of neointimal hyperplasia is noted in both views. Black arrow indicates stent struts in black (negative image), and white arrow indicates the shadow of the metallic wire. (Courtesy of Nico Bruining, Thoraxcenter, Erasmus University Rotterdam, The Netherlands.)

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includes Latin American and European centers, has been completed and results will be available by the end of 2001. The US randomized study has already commenced the enrollment phase, with results expected in 2002. Delayed restenosis and late side effects were not yet observed in the pilot study but represent a matter of concern, since long-term animal (> 30 days) and clinical results (> 1 year) are still pending.

Paclitaxel-eluting stents Paclitaxel (Taxol), originally isolated from the bark of the Pacific yew Taxus brevifolia, is a microtubule-stabilizing agent with potent antitumor activity. Unlike other antimitotic agents, it shifts the cytoskeleton equilibrium towards assembly, leading to reduced vascular cell proliferation, migration and signal transduction.88,89 Activation of some protein kinases associated with microtubule depolymerization are consequently inhibited by paclitaxel. It is highly lipophilic, which promotes a rapid cellular uptake, and has a long-lasting effect in the cell.90 Stainless steel NIR stents (Medinol Inc, Maple Grove, MN, USA) were coated with poly(lactideco-∑-caprolactone) copolymer with paclitaxel (200µg/stent) and implanted in porcine coronary arteries. Tissue analyses were performed 7, 28, 56 and 180 days after implantation. Paclitaxelcoated stents showed a marked reduction in intimal and medial cell proliferation at all time points. Tissue responses in paclitaxel-treated arteries included: • incomplete healing, • few smooth muscle cells, • late persistence of a large number of macrophages • dense fibrin with little collagen.

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These tissue alterations were not observed in the control bare stents.38 Paclitaxel release from pLA/pCL-coated stents followed first order kinetics with 36% ± 10% released after day 1 and 91% of the drug released at 56 days.38 The Quanam metal stent, a specially designed slotted tube stent made of 316L steel, was covered with a nonbiodegradable polymer loaded in its matrix with a slow release microtubular inhibitor. These stents were first implanted in human coronary arteries by Grube et al in Germany.91 Twenty-six patients were randomly assigned to receive drugloaded stents (n =13, 14 stents) or bare stents (n = 13, 18 stents). At 18-month follow-up, there was no restenosis (DS ≥ 50%) in the drug-eluting group. A five-fold decrease in neointimal proliferation was detected by IVUS. None of the patients treated with Quanam drug eluting stents had any cardiac events.91 After these promising results, a 60patient randomized study was started at two sites in Germany. This trial is designed to demonstrate the safety of implanting paclitaxel-coated NIR stents (Boston Scientific Corporation, Maple Grove, MN, USA) prior to commencing a dose-ranging study. Again, long-term safety and effectiveness of these new stent technologies are required.

Future Directions Percutaneous coronary intervention is now safer than ever and, as a result, the percentage of patients treated with this less invasive revascularization approach is constantly expanding. Nevertheless, at the dawn of the new Millennium, the problem of restenosis remains unresolved. There is little doubt that drug-coated stents have the potential to eradicate restenosis, yet technological refinements are still needed. As novel inert coating matrices are developed, pharmacological compounds that

FUTURE DIRECTIONS

showed promise in reducing restenosis when given systemically, and even those that failed clinically, will now be reexamined. Genetically modified cell seeding of coronary stents and coating matrices incorporating antisense

oligonucleotides and DNA will further enhance the antirestenosis armamentarium.92–94 We may have not yet found the panacea but, certainly, we have never been so close.

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9 Gene transfer for coronary restenosis Ripudamanjit Singh and Robert D Simari

Introduction Percutaneous transluminal coronary angioplasty (PTCA) was introduced 22 years ago as a nonsurgical catheter-based treatment for obstructive coronary artery disease. Since its introduction, major advances in equipment and techniques have led to a tremendous growth in the use of PTCA and other percutaneous coronary interventions (PCI) to treat coronary artery disease and angina. All forms of PCI, whether balloon angioplasty, atherectomy, laser ablation or stenting, are direct forms of vascular injury. Restenosis or arterial renarrowing following PCI persists as a limiting factor in the maintenance of vessel patency after PCI, occurring in up to 30% of patients, and accounts for significant morbidity and health care expenditures. Plaque persistence and vessel recoil, thrombus formation, constrictive remodeling, neointimal proliferation and matrix production are the primary contributors to the development of restenosis. Early clinical trials in restenosis prevention using coronary atherectomy,1,2 other revascularization devices, antiplatelet drugs, angiotensin converting enzyme (ACE) inhibitors,3,4 antithrombotic drugs, and antiinflammatory drugs have been uniformly negative. After years of unsuccessful clinical trials, a few interventions have been shown recently to decrease rates of restenosis. In both the STRESS (Stent Restenosis Study) and BENE-

STENT (Belgian Netherlands Stent Study) trials, intracoronary stent placement reduced angiographic restenosis rates to as low as 13%.5,6 Infusion of a humanized antibody to the platelet fibrinogen receptor (glycoprotein IIb/IIIa, also known as the integrin alpha IIb/beta III) also decreased clinical restenosis rates to 16%.7 Oral administration of either trapidil (a platelet-derived growth factor antagonist) or probucol (an antioxidant) has also shown efficacy in reducing restenosis rates.8,9 Although these reports are encouraging, they were performed in optimized lesions in specific patient populations and therefore may not be applicable to all lesions in all patients. Gene transfer is the introduction of foreign or native genetic material aimed at modulating native gene expression. Owing to the lack of universally effective therapies, gene transfer strategies aimed at limiting restenosis are currently being developed. Early studies of gene transfer aimed at modulating native gene expression demonstrated that each cell type present within the normal and atherosclerotic vessel wall is capable of expressing transgenes using several vectors. The transfer of genes encoding biologically active proteins has resulted in altered vascular phenotypes expanding our knowledge of vascular pathophysiology. Therapeutic strategies to approach each of the components of restenosis has been developed and tested in preclinical studies.

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GENE TRANSFER FOR CORONARY RESTENOSIS

Although thrombosis and vascular remodeling are potential targets for gene transfer, the primary target for restenosis has been the regulation of cell proliferation. These preclinical studies have proven the principle that gene transfer can inhibit neointimal formation. Translations of these studies to humans has begun, but have been limited by concerns regarding the toxicity of vectors and the safety and feasibility of clinical delivery systems.

Therapeutic strategies Antiproliferative Most studies targeting restenosis have been based on the paradigm that cellular proliferation plays a major role in its development and thus have focused on strategies to reduce vascular smooth muscle cellular proliferation. These studies have attempted to either inhibit cell cycle entry (‘cytostatic’ strategy) or cause the death of cells (‘cytotoxic’ strategy). The cytostatic approach is exemplified by the induction of growth arrest in vascular endothelial and smooth muscle cells by the direct transfer of p21 into injured porcine arteries.10 The protein p21 is a cyclin-dependent kinase inhibitor and blocks the progression through the cell cycle. In this study it was shown that following injury to porcine arteries, p21 expression was detected in the neointima and correlated inversely with the location and kinetics of intimal cell proliferation. Direct gene transfer of p21 using an adenoviral vector into balloon-injured porcine arteries inhibited the development of intimal hyperplasia. These findings and related studies by Chang et al in rats11 have suggested that strategies to increase the expression of p21 and possibly other related cyclin-dependent kinase inhibitors might prove therapeutically beneficial in vascular diseases. Other genes that have

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been found to be cytostatic in vivo have included the homeodomain gene gax,12 a constitutively active form of the retinoblastoma protein, Rb, and a dominant-negative mutant of ras.13,14 In contrast to cytostatic strategies, cytotoxic strategies induce cell death. One prominent example involves the heterologous expression of enzymes capable of converting nucleoside analogues into toxic metabolites killing cells entering the S phase in the presence of the nucleoside herpes virus analogue. The best known of these gene/drug combinations is the herpes virus thymidine kinase, which can phosphorylate the inactive drug ganciclovir to an active form, which, in turn, is capable of interrupting DNA synthesis (Fig. 9.1). The expression of this enzyme and drug activation have been tested using adenoviral delivery, resulting in a 35–87% reduction of the neointima formation following actual injury, depending on the specific model and degree of injury.15–17 An analogous approach has used the expression of cytosine deaminase and coadministration of 5-fluorocytosine,18 with a 45% reduction of neointimal proliferation.19

GC-P GC

tk

Figure 9.1 Cytotoxic prodrug gene therapy strategy. The vector encoding for herpes virus thymidine kinase (tk) generates tk within a transduced cell. Tk activates the prodrug ganciclovir (GC) leading to the death of the transduced cell (†). Neighboring cells may be killed by the ‘bystander effect’ whereby active GC diffuses through gap junctions with toxic effects.

THERAPEUTIC STRATEGIES

In addition, the recent recognition of substantial frequencies of apoptosis or programmed cell death in native atherosclerotic plaques and in vascular tissues after balloon injury20,21 suggests that the induction of apoptosis may represent a cytotoxic approach of potential interest. Whether the expression of genes enhancing the incidence of apoptosis within the vessel wall would be specifically desirable remains to be tested.

Antimigratory The extent to which neointimal expansion is dependent on the migration of preexisting smooth muscle cells or myofibroblasts has only recently been investigated.22–24 Key elements of the migratory process include activation of signaling pathways involving tyrosine kinases, such as the receptors for platelet-derived growth factor,25–27 cytoskeletal reorganization, and the expression and activation of a variety of proteases directed to facilitating migration through the extracellular matrix. These proteases include plasminogen activators28,29 as well as the family of matrix Such observations metalloproteases.30,31 suggest several potential approaches to the modulation of cell migration, including the local overexpression of protease inhibitors such as the tissue inhibitor of metalloprotease (TIMP) family.32,33 Indeed, overexpression of TIMP has reduced intimal formation in injured rat carotid artery.34 However, such approaches are presumably in opposition to the processes involving the migration of endothelial cells required for reendothelialization as well as angiogenesis.35,36 Therefore, genetic (as well as nongenetic) manipulations designed to reduce or enhance migration will require careful studies to ensure that they do not inadvertently promote adverse outcomes.

Antithrombotic strategies Vascular thrombosis, in addition to its role as a proximate cause of myocardial infarction and stroke, has been recognized as a complication of PCI and a risk factor for restenosis. Gene-based therapies to prevent thrombosis have proven effective in animal models.37–39 Since tissue factor, factor Xa, and thrombin are known mitogens for vascular smooth muscle cells (VSMCs), antithrombotic strategies might successfully inhibit two key factors in restenosis: thrombosis and cellular proliferation. In fact, inhibition of tissue factor-mediated coagulation by intravenous infusion of recombinant tissue factor pathway inhibitor (rTFPI) after deep arterial injury was shown to be particularly effective in attenuating subsequent neointimal formation and stenosis in minipigs and rabbits.40,41 Rade et al delivered an adenovirus expressing hirudin, a leech protein following arterial injury in the rat.42 This expression decreased neointimal formation in this model. These results were somewhat surprising given that the rat model is not very thrombogenic and the gene transfer was performed concurrently with arterial injury. However, these results highlight the potential of antithrombotic gene transfer strategies in restenosis. A number of studies have examined the possibility of seeding stents or grafts with genetically modified prothrombolytic or anticoagulant endothelial cells either before43–45 or after placement. These cells have overexpressed tissue plasminogen activator as well as urokinase plasminogen activator and have been shown to possess enhanced local antithrombotic activity in vivo.44 Recent experiments have revealed an unexpected adverse effect of the endothelial overexpression of tissue plasminogen activator, in that the transduced cells were demonstrated to

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show a significantly increased rate of detachment from seeded stent surfaces after their in vivo placement.45 This observation highlights the potential for unexpected and potentially pathological results occurring when the ‘genetic balance’ of the vascular wall is disturbed by the overexpression of specific genes in the absence of appropriate physiological regulation and feedback controls.46

Pleotropic strategies Another group of genes directed at inhibiting restenosis as well as associated vasospasm and platelet deposition act through multiple pathways. These include two enzyme families: the NO synthases (inducible, constitutive, or neuronal isoforms) and the cyclooxygenases (prostaglandin H synthases I and II); and a member of the natriuretic peptide family, c-type natriuretic peptide (CNP). The local expression of these enzymes increases the synthesis of small molecules, which are, in turn, the true vasoactive agents, NO and prostacyclin, respectively. The hemagglutinating virus of Japan (HVJ)/liposome-based overexpression of constitutive (endothelial) NO synthase in the setting of balloon injury has reduced neointimal formation after balloon injury.47 The introduction of adenoviral vectors encoding endothelial NO synthase using a catheter capable of direct intramural injection (described below) has been demonstrated to inhibit neointimal accumulation in the porcine coronary balloon overstretch model by up to 50% at 4 weeks after injury.48 Local transduction of prostaglandin H by adenoviral vectors has resulted in substantial reductions in cyclic flow variations occurring as a consequence of platelet thrombi dynamically forming after arterial injury.49 Overexpression of CNP, likely through cyclic GMP-dependent pathways has limited neointimal formation in a rat model.14

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Therapeutic reendothelialization The expression of factors promoting endothelial growth may accelerate the recovery of vascular physiology after mechanical injury by the facilitated restitution of endothelial surface coverage. This, in turn, is potentially associated with reduction in the thrombotic and proliferative environment of the vascular wall. Evidence supporting the utility of this approach has recently been generated by preclinical studies in carotid50,51 as well as iliofemoral arteries,52 in which the local intravascular44,46 or extravascular51 expression of vascular endothelial cell growth factor (VEGF) was associated with accelerated endothelial coverage and also with significantly diminished medial proliferation. Furthermore, the gene transfer of VEGF has been demonstrated to accelerate stent endothelialization and diminish intimal thickening by 56% in stented rabbit iliac arteries.53

Vector systems Vectors for vascular gene transfer include nonviral and viral systems. The choice of a vector depends on the requirements of the particular therapeutic strategy. In addition, the arterial wall presents inherent barriers to gene transfer. These barriers are structural and functional. The trilaminar vascular structure provides several layers of cellular and extracellular components that might limit gene delivery. The elastic laminae within the media are important barriers to delivery. The frequent branching of the coronary arteries and myocardial ischemia associated with prolonged flow interruption are practical barriers to catheter-based gene delivery. Therefore, gene transfer into vascular smooth muscle cells to achieve widespread intercellular effects requires potent vectors and efficient delivery

VECTOR SYSTEMS

systems. Transfer into endothelial cells or adventitial fibroblasts to achieve paracrine or endocrine effects may be achieved with lower efficiency vectors.54 An ideal vector for gene transfer to inhibit restenosis would be safe, capable of efficient gene delivery, simple to construct and provide for cell-specific and perhaps regulatable gene expression. Each of the current vectors will require further modifications to achieve this ultimate goal.

Nonviral vectors ‘Naked DNA’ Expression plasmids are double-stranded circular DNA that contain regulatory sequences designed to enable and enhance the expression of foreign genes in target cells. Plasmid DNA alone or ‘naked DNA’ is relatively inefficient in its ability to transfect vascular cells and consequently has been delivered to the vascular wall with the use of polymeric gels and coatings. A balloon catheter coated with a hydrophilic polymer coating (Hydroplus, Boston Scientific, Watertown, MA, USA) has been used to deliver DNA to vascular cells.55 The DNA is applied to the balloon and delivered to the wall when the balloon is inflated. Although the majority of material to be delivered may be washed off the balloon prior to delivery, gene transfer to endothelial cells can be achieved using this system. Delivery of plasmid DNA encoding for vascular endothelial growth factor (VEGF) has been demonstrated to result in accelerated reendothelialization limiting restenosis.52,56 Two human gene therapy trials to induce angiogenesis and to reduce restenosis in peripheral arteries use this system for intraarterial gene delivery.54 In animal models, polymeric gels have been used to enhance adventitial delivery of plasmid DNA.13 The use of polymers allows for application of DNA to the vessel wall,

either intraluminally or adventitially. Taken together, the level of expression resulting from the delivery of ‘naked DNA’ is relatively low, requiring potent and secretable gene products to result in important biologic effects.

DNA liposomes DNA has an inherent negative charge that limits interactions with cellular membranes and thus may be delivered to vascular cells with adjuvants to enhance cell entry. Cationic liposomes, consisting of cationic and neutral lipids, have been used to condense plasmid DNA into neutral particles.57,58 DNA liposomes are able to bind to the cell surface and be internalized. Like plasmid DNA, endosomal degradation limits the amount of DNA delivered by this method.58 Lipofectin(DOTMA/DOPE, Gibco/BRL, Gaithersburg, MD, USA) mediated intravascular gene transfer resulted in ⬍ 1% to 1% transfection of vascular cells.59 Cationic liposomes have been shown to have little toxicity in animal studies and in nonvascular human gene therapy trials.60,61 New lipids are being developed to enhance vascular gene transfer while maintaining their excellent safety profile. One of these new compounds, GAP DLRIE/DOPE, has been shown to increase the vascular delivery of plasmid DNA 15-fold compared to DMRIE/DOPE, a cationic liposome previously used for intravascular delivery.62 However, this lipid-mediated gene transfer resulted in a much lower degree of expression compared to adenoviral-mediated transfer. More potent lipids will need to be developed for clinical use of these compounds for efficient gene delivery.

DNA/viral conjugates Viral proteins have been added to DNA liposomes to enhance cellular uptake and

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expression. The protein coat of the HVJ has been used to increase transfection of VSMCs without associated toxicity.63 Ultraviolet inactivated HVJ forms a complex with DNA liposomes that binds to the cell surface and is internalized. This strategy avoids the potential toxicity of complete viral particles while increasing the transfection efficiency of DNA liposomes. Gene transfer of the nitric oxide synthetase gene into injured rat carotid arteries using the HVJ DNA/liposome vector restored nitric oxide production to near normal levels.47 Taken together, nonviral vectors may play a limited role in vascular gene transfer in clinical situations whereby low efficiency delivery of potent transgenes is needed. The clinical applicability of this approach remains to be defined.

Viral vectors Retroviruses Retroviruses were among the first vectors tested in the field of vascular gene transfer. Recombinant retroviruses are RNA viruses that are capable of gene transfer resulting in stable integration of foreign DNA sequences into the host genome. This leads to long-term gene expression.59,64 However, this integration increases the theoretic potential for insertional mutagenesis. Other disadvantages of retroviruses include their inability to infect nonreplicating cells,65 limiting their vascular transfer efficiencies to less than 1% of vascular cells. Also, retroviral vector production results in lower viral titers as compared to adenoviral vectors. Retroviral vectors have been used to establish stable gene expression in vascular cells in culture for reimplantation into the vessel wall.64 However, this strategy involves harvesting donor tissue, ex vivo transfection followed by reimplantation and may have

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limited use in the vascular system. Overall, the direct use of retroviral vectors in clinical vascular gene therapy is unlikely.

Adenoviruses Unlike retroviruses, adenoviruses are DNA viruses which are capable of infecting replicating and nonreplicating cells. Viral genes essential to adenoviral replication (E1, E3 and E4) may be deleted and replaced with a foreign gene creating a replication deficient adenoviral vector.66–68 Adenoviral vectors escape the degree of endosomal degradation seen with other vectors69 and are expressed transiently (weeks) outside of chromosomal DNA rather than integrated into the host genome. Adenoviral vectors can be produced in high titers (⬎ 1012 viral particles/ml) and can infect most mammalian cells. The efficiency of adenoviral gene transfer is higher compared to retroviral or nonviral methods and has been demonstrated in normal, injured and atherosclerotic arteries.62,70–74 (Figs 9.2, 9.3) Adenoviral vectors provide an excellent opportunity for vascular gene transfer if concerns regarding safety are addressed. Direct vascular toxicity of adenoviral vectors has been demonstrated in normal rabbit arteries leading to neointimal formation.75 However, other studies suggest that the inflammation and intimal expansion seen in normal arteries may not be as important following gene transfer in the rabbit atherosclerotic model.17,76 This discrepancy may be due to the fact that any potential toxicity of these vectors is not measurable owing to the background inflammation seen in these hyperlipidemic rabbits. Further modifications of recombinant adenoviruses are being tested to increase the duration of transgene expression while decreasing their potential toxicity.77 However, for gene therapy of restenosis, longterm expression may not be necessary.

SHORTCOMINGS OF AVAILABLE VECTORS FOR RESTENOSIS

(a)

(b)

opments have allowed for high titer viral stock preparation and exclusion of helper virus. The viruses are limited to cDNA inserts of less than 5 kb. There have been two reports on the use of AAV in vascular gene transfer.78,79 These reports verify the potential for AAV delivery but further studies will be required to determine the ultimate role of AAV in vascular gene transfer, in particular for restenosis.

Shortcomings of available vectors for restenosis Inflammatory response

Figure 9.2 Transgene expression in atherosclerotic arteries 2 days after balloon injury and adenoviral infection. A. Transgene expression (dark staining) was observed in the intima and media of ballooninjured atherosclerotic arteries. B. Transgene expression in the media was prominent along a dissection plane where the internal elastic lamina was fractured.

Gene transfer vectors, particularly viral vectors, have the potential for inducing an inflammatory response.75 This in turn can cause tissue damage as well as shorten the duration of transgene expression. The longterm safety of adenoviral vectors for human use is being investigated. Potential toxicity of intraarterial delivery of adenoviral vectors has been recently described.80 One approach to overcoming this problem has been to delete the adenoviral vectors of all transcriptional coding regions, i.e. ‘Gutless’ vectors. These ‘gutless’ vectors may elicit minimal inflammatory or immune response. Other potential solutions include administration of immunosuppressant drugs or cotransfection of vectors expressing immunomodulatory genes.

Adeno-associated viruses

Lack of cell or tissue specificity

Adeno-associated viruses (AAV) are singlestranded DNA viruses having several unique features that might have specific benefits as vascular gene transfer vectors. First, they are capable of long-term expression owing to their stable integration into the host genome. Second, vectors lack viral sequences resulting in less immunogenic potential. Recent devel-

Currently available vectors lack cell or tissue specificity and require targeted delivery. The two main methods of obtaining targeted gene expression include the use of cell/tissue-specific promoters or constructing vectors with defined cell tropism. Tissue-specific expression can be achieved by using a tissue- or cell-specific promoter to drive the transgene. Examples of

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(a)

(b) 8 7 6

6 5 4 3

**

2 1 0

⫺GC

⫹GC

Medial BrdC Labelling Index (%)

Intimal BrdC Labelling Index (%)

7

5 4 3 *

2 1 0

⫺GC

⫹GC

Figure 9.3 Inhibition of intimal cell proliferation after arterial injury. Arterial segments transduced with HSV-tk and exposed to ganciclovir (⫹GC) attenuated cellular proliferation compared to segments exposed to saline (⫺GC). A. Intimal B. Medial.

endothelium-specific promoters include thrombomodulin, von Willebrand factor, and tie-2. An arterial smooth muscle cell (SMC) specific promoter, SM22 alpha, that activates transcription exclusively in arterial SMCs has been used to restrict expression of a recombinant adenoviral vector to SMCs.81 No similar system exists for plaque-derived cells. Several different strategies have been used to construct vectors with defined cell tropism. For viral vectors, one approach for altering tropism is to modify surface proteins that interact with cell surface receptors. This has been demonstrated for retroviral vectors.82 In the case of adenoviral vectors, tissue specificity may be altered by modifying either the fiber or penton capsid proteins that mediate interaction with cell surface receptors. Plasmid DNA can be tissue-targeted using receptormediated gene delivery. After a unique protein

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in the tissue of interest has been identified, a natural ligand or an antibody to the receptor can be conjugated to polylysine or some other coupling agent to deliver DNA.83

Delivery techniques Preclinical animal studies have often used nonclinical approaches to deliver vectors. Clinical devices have been developed for local delivery but have not been rigorously tested in patients. Similar to the choice of vectors, the selection of delivery devices must be based upon the specific requirements of the gene transfer strategy. For instance, delivery to deeper medial portions of the vessel may require different features than delivery to more lumenal regions. Two catheters have been used for local gene delivery in human arteries. Gene transfer to

SHORTCOMINGS OF AVAILABLE VECTORS FOR RESTENOSIS

the vessel wall has been performed with standard balloon angioplasty catheters coated with a hydrophilic polymer containing plasmid DNA. This hydrophilic coating (Hydroplus, Boston Scientific, Watertown, MA, USA) is able to absorb plasmid DNA prior to use. Vascular gene transfer using this system has been demonstrated in rabbit arteries using a brief inflation of 30 seconds55 and was used in a human gene therapy protocol for angiogenesis and restenosis in peripheral arteries.54 Data demonstrating the efficiency of this delivery system in humans are currently not available. The advantages of this delivery strategy are that it may be used in coronary and peripheral arteries and may not require autoperfusion capabilities owing to the brief inflation times required for delivery. This device may be appropriate with the use of secreted potent transgenes in therapeutic strategies that do not require large numbers of transfected cells. The other delivery catheter used in a human gene transfer trial is a helical infusion/perfusion delivery balloon (Dispatch, Boston Scientific, Watertown, MA, USA).84 The Dispatch catheter combines autoperfusion capabilities with the capacity for local drug delivery and is approved for clinical infusion of drugs. In a study of 10 patients, catheter-mediated adenoviral delivery of Lac Z was performed in peripheral arteries in patients with chronic critical leg ischemia. One to 2 days following delivery, the patients underwent clinically indicated amputations and an assessment of gene transfer was made. Adenoviral delivery was performed in a dose escalation manner from 1 ⫻ 108 to 4 ⫻ 1010 pfu (1.2 ⫻ 1010 to 4.2 ⫻ 1012 viral particles). The study was well tolerated by all patients. No adverse effects were observed. Quantitative assessment of gene transfer revealed a dose response with increasing titer ranging from 0.04% to 5.0%

of the vascular cells transfected. Histologically, transgene expression was found primarily in SMCs or reactions were seen in this brief period of follow up. Although small in number, this study was the first to clearly document the possibility of catheter-mediated adenoviral delivery to atherosclerotic human arteries. Other catheters have been tested in animal models. These include microporous catheters85 and channeled balloon catheters which combine an inner dilating balloon with peripheral channels for drug delivery. Using adenoviral vectors in normal and atherosclerotic rabbit arteries, gene expression was seen in medial cells 3 days following balloon injury using the channeled balloon.74 However, this catheter has no autoperfusion capabilities and may require prolonged inflation times.

Clinical applications Human gene transfer trials for cardiovascular disease are underway. Vector and delivery issues have limited the clinical translation of gene transfer for coronary restenosis. In fact, many agree that given the concerns regarding safety and delivery, initial studies with vascular gene transfer will initially be performed in the peripheral circulation. Following their initial study in peripheral arteries prior to amputation, a human study of VEGF gene transfer using DNA liposomes and adenoviral vectors in Finland has been started using catheter delivery in the setting of peripheral angioplasty (Yla-Herttuala, personal communication). In addition, other clinical gene transfer studies for angiogenesis will help define the safety of adenoviral vascular delivery. For instance, a clinical study by Giordano et al using first generation adenoviruses infused into coronary arteries to induce angiogenesis will help in this regard.86

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Remaining challenges Translation of the preclinical studies to humans must utilize vectors shown to have preclinical efficacy, effective delivery catheters and be tested in an appropriate patient population. The most important remaining challenge for this field is that with few exceptions, effective gene transfer strategies to prevent restenosis have required adenoviral vectors. As discussed, first generation adenoviral vectors have attendant concerns regarding their potential toxicity. Studies to define the safety and function of vascular delivery are currently needed. These studies will define the delivery and safety characteristics of peripheral arterial delivery before therapeutic trials can be undertaken in peripheral and coronary arteries. Taken together, these studies will result in thoughtful adaptations required to bring gene therapy to the catheterization lab to treat restenosis (Fig. 9.4).

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‘Unbridled enthusiasm’

‘Harsh realities’

‘Ultimate applicability’

‘Innovation’

‘Thoughtful adaptations’

Time

Figure 9.4 Schematic representation of the time course of the adaptations of new technologies as they may apply to gene therapy for restenosis.

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50. Asahara J, Bauters C, Pastore C et al. Local delivery of vascular endothelial growth factor accelerates reendothelialization and attenuates intimal hyperplasia in balloon-injured rat carotid artery. Circulation 1995; 91:2793–2801. 51. Laitinen M, Zachary I, Breier G et al. VEGF gene transfer reduces intimal thickening via increased production of nitric oxide in carotid arteries. Hum Gene Ther 1997; 8:1737–1744. 52. Asahara T, Chen D, Tsurumi Y et al. Accelerated restitution of endothelial integrity and endothelium-dependent function after phVEGF165 gene transfer. Circulation 1996; 94:3291–3302. 53. Van Belle E, Tio F, Chen D et al. Passivation of metallic stents after arterial gene transfer of phVEGF165 inhibits thrombus formation and intimal thickening. J Am Coll Cardiol 1997; 29:1371–1379. 54. Isner J, Walsh K, Symes J et al. Arterial gene therapy for therapeutic angiogenesis in patients with peripheral artery disease. Circulation 1995; 91:2687–2692. 55. Riessen R, Rahimizadeh H, Blessing E et al. Arterial gene transfer using pure DNA applied directly to a hydrogel-coated angioplasty balloon. Hum Gene Ther 1993; 4:749–758. 56. Takeshita S, Weir L, Chen D et al. Therapeutic angiogenesis following arterial gene transfer of vascular endothelial growth factor in a rabbit model of hindlimb ischemia. Biochem Biophys Res Comm 1996; 227:628–635. 57. Felgner PL, Gadek TR, Holm M et al. Lipofection: a highly efficient, lipid-mediated DNAtransfection procedure. Proc Natl Acad Sci USA 1987; 84:7413–7417. 58. Felgner P. Particulate systems and polymers for in vitro and in vivo delivery of polynucleotides. Adv Drug Deliv Rev 1990; 5:163–187. 59. Nabel E, Plautz G, Nabel G. Site-specific gene expression in vivo by direct gene transfer into the arterial wall. Science 1990; 249:1285–1288. 60. San H, Yang Z, Pompili V et al. Safety and short-term toxicity of a novel cationic lipid formulation of human gene therapy. Hum Gene Ther 1993; 4:781–788. 61. Stewart M, Plautz G, Buono L et al. Gene transfer in vivo with DNA-liposome

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complexes: safety and acute toxicity in mice. Hum Gene Ther 1992; 3:267–275. Stephan DS, Yang ZY, San H et al. A new cationic liposome DNA complex enhances the efficiency of arterial gene transfer in vivo. Hum Gene Ther 1996; 7:1803–1812. Morishita R, Gibbons G, Kaneda Y. Novel in vitro gene transfer method for study of local modulators in vascular smooth muscle cells. Hypertension 1993; 21:894–899. Wilson J, Birinyi L, Salomon R et al. Implantation of vascular grafts lined with genetically modified endothelial cells. Science 1989; 244:1344–1346. Miller D, Adam M, Miller A. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol Cell Biol 1990; 10:4239–4242. Davidson B, Allen E, Kozarsky K et al. A model system for in vivo gene transfer into the central nervous system using an adenovirus vector. Nat Genet 1993; 3:219–223. Graham F, Prevec L. Manipulation of adenovirus vectors. In: Murray E, ed. Methods in Molecular Biology, Vol 7: Gene Transfer and Expression Protocols. Clifton: The Humana Press, Inc., 1991, 109–128. Berkner K. Expression of heterologous sequences in adenoviral vectors. Curr Top Microbiol 1992; 158:39–66. Horwitz M. Adenoviridae and their replication. In: Fields BN, Knipe DM et al, eds. Fundamental Virology, 2nd edition, New York: Raven Press Ltd., 1991; 772–804. Lemarchand P, Jones M, Yamada I, Crystal R. In vivo gene transfer and expression in normal uninjured blood vessels using replication-deficient recombinant adenovirus vectors. Circ Res 1993; 72:1132–1138. Guzman R, Lemarchand P, Crystal R. Efficient and selective adenovirus-mediated gene transfer into vascular neointima. Circulation 1993; 88:2838–2848. Barr E, Carroll J, Kalynych A et al. Efficient catheter-mediated gene transfer into the heart using replication-defective adenovirus. Gene Ther 1994; 1:51–58. Steg P, Feldman L, Scoazec J et al. Arterial gene transfer to rabbit endothelial and smooth muscle cells using percutaneous delivery of an

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REFERENCES

balloon catheter to deliver concentrated heparin into the wall of the normal canine artery. J Am Coll Cardiol 1991; 15:475–481. 86. Giordano F, Ping P, McKirnan M et al. Intra-

coronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nat Med 1996; 2:534–539.

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10 Stenting to prevent restenosis J Aaron Grantham and David R Holmes, Jr

Introduction No single technical advance in interventional cardiology has had a greater impact on procedural success than the development and clinical application of intracoronary stents. While initial enthusiasm for coronary stenting was tempered by high rates of acute thrombosis, the feasibility of stenting was improved by oral anticoagulation.1–3 Once the importance of the platelet in stent thrombosis was appreciated, replacement of warfarin with antiplatelet agents4,5 and the associated reductions in vascular complications and hospital stay has led to the current era in which coronary stenting is performed in 80–90% of patients undergoing percutaneous coronary intervention (PCI). This chapter will review the data on primary stenting and focus upon patient and lesion characteristics that warrant consideration of primary stenting over percutaneous transluminal coronary angioplasty (PTCA) alone for the prevention of restenosis. Restenosis will refer to binary angiographic restenosis (⬎ 50% renarrowing) unless otherwise stated. Where available, target vessel and target lesion revascularization (TVR, TLR), the ultimate clinical markers of restenosis will also be reported.

Provisional stenting Recent trials comparing primary stenting with stent-like PTCA results suggest that stenting is

not always indicated in all PCIs.6–8 The concept of provisional stenting evolved as efforts to optimize outcomes and control the costs of PCIs have intensified. A recently published survey of European interventional cardiologists reported that 2% unconditionally stent focal de novo lesions in native coronary arteries and 44% refrain from stenting after optimal ‘stent-like’ results (⬍ 30% residual stenosis).9 The ability to identify patients at risk for restenosis, thus warranting stent placement, remains suboptimal. Several strategies were developed to identify lesion characteristics predictive of restenosis after PTCA. Rodriguez et al identified early lumen loss after PTCA as an important predictor of angiographic restenosis at 6 months.10 As a result, the Optimal Coronary Balloon Angioplasty (OCBAS) investigators randomized 116 patients who underwent PTCA and had optimal angiographic results (⬍ 30% diameter stenosis and no indication for bailout stenting) to primary stenting (57 patients) or no further therapy.11 Eight patients (14%) in the PTCA alone group crossed over to the stent group owing to early lumen loss (⬎ 0.3 mm or ⬎ 10% increase in diameter stenosis) at angiography 30 minutes after the initial PTCA. Using this strategy, angiographic restenosis occurred in 19.2% of the stent group and 16.1% (p ⫽ ns) of the PTCA group when analysed as intention to treat. TVR was 17.5% and 13.5%, respectively (p ⫽ ns). Cost

145

STENTING TO PREVENT RESTENOSIS

analysis revealed added expense to the stent strategy owing primarily to the cost of stents (estimated at $3000/stent at that time) in accordance with the cost analysis results of BENESTENT which were done in the setting of full anticoagulation. Of note, 206 patients were screened for the study, and 86 (42%) were not randomized owing to suboptimal results or complications of PTCA. Other investigators have utilized physiologic assessment of the coronary flow either with coronary flow reserve (CFR)12 or fractional flow reserve (FFR)13 after PTCA to predict restenosis. The utility of this approach in various subgroups guiding the utilization of stents remains untested. More recently, the EPISTENT trial has demonstrated superior results in terms of TVR after stenting compared to PTCA when abciximab is used during the intervention (8.7% vs 15.4%, stent vs PTCA, p ⬍ 0.05).14 These far superior results were obtained despite much less stringent inclusion criteria compared to the OCBAS study, and did not include an assessment of PTCA results before proceeding to stenting. The preliminary results reported

by the Optimal Angioplasty vs Primary Stenting (OPUS) investigators also appear to favor the strategy of primary stenting over provisional stenting.15 In the OPUS trial TVR was 4.0% in the primary stenting group compared with 10.7% in the primary PTCA groups (p ⫽ 0.003). Furthermore, stenting saved $200 per patient on average at 6 months. Based upon OPUS and EPISTENT, a strategy of primary stenting to prevent restenosis can now be considered appropriate in many patients based upon lesion characteristics. In addition, as the cost of stents declines, this strategy would become more cost effective than PTCA alone. Certain patient characteristics outlined below warrant unconditional stenting for improved immediate outcomes and lower restenosis rates (Table 10.1).

Acute myocardial infarction Primary PTCA as reperfusion therapy in acute myocardial infarction (AMI) results in improved short-term survival, and lower rates of reinfarction and stroke than thrombolytic therapy.16 These benefits are, however, lost at

Restenosis

STRESS1,3 BENESTENT2 OCBAS11 EPISTENT14 OPUS15

TVR

PTCA

Stent

p value

PTCA

Stent

p value

42.1% 32% 16.4%

31.6% 22% 19.2%

0.046 0.02 ns

15.4% 23.3%* 13.5% 15.4% 10.7%

10.2% 13.5%* 17.5% 8.7% 4.0%

0.16 ⬍ 0.05 ns ⬍ 0.05 Not given

*Any repeat PTCA at seven months.

Table 10.1 Summary of the angiographic restenosis and TVR rates in the major clinical trials of angioplasty vs stenting in native coronary vessels.

146

ACUTE MYOCARDIAL INFARCTION

6 months owing to high rates of restenosis (40–50%) and reocclusion of the infarctrelated artery (IRA). Several observational studies have confirmed the safety and suggested improved outcomes of either bailout or primary stenting in AMI.17–20 These findings have now been confirmed in randomized trials, several of which have demonstrated lower rates of TLR and restenosis (Table 10.2). The GRAMI trial investigators21 randomized 104 patients with AMI to PTCA alone vs PTCA with subsequent stenting using second generation Gianturco–Rubin stents. They demonstrated a reduction of in-hospital complications in the stented patients compared to the PTCA alone group (3.8% vs 19.2%, p ⬍ 0.05). Angiographic restenosis was not reported, however, TLR at 1 year did not achieve statistical significance (14% vs 21%, p ⫽ ns), and perhaps relates to the 25% crossover to bailout stenting in the PTCA arm. The Florence Randomized Elective Stenting in acute Coronary Occlusions (FRESCO) trial22 and the Zwolle trial23 were the first trials to directly compare optimal primary PTCA with optimal PTCA followed by stenting in AMI. In FRESCO, 150 patients were

randomized to stenting vs usual care after predefined PTCA results were obtained and judged to be ‘optimal’. Randomization occurred irrespective of the angiographic appearance of the culprit lesion. Ninety-five percent of patients who were randomized underwent angiographic and clinical follow-up at 6 months. The angiographic restenosis or reocclusion rate was 15% in the stent group and 30% in the PTCA group (p ⬍ 0.05). The cumulative incidence of early and late restenosis or reocclusion was 17% vs 43% (stent vs PTCA group, p ⫽ 0.01). These findings were corroborated by a reduction in cumulative early and late ischemic events in the stent group compared with the PTCA group (9% vs 28%, p ⬍ 0.01) and a reduction in the rate of TVR at 6 months (7% vs 25%, p ⫽ 0.01). Stenting was the only independent predictor of freedom from recurrent ischemia (odds ratio (OR) 0.30, 95% CI 0.11–0.84, p ⬍ 0.03). These authors now employ a strategy of unconditional IRA stenting in vessels greater than 2.5 mm in diameter and have demonstrated in a registry study restenosis rates of 24% in patients treated with one stent, and 42% in patients treated with multiple stents.24 The cost-effectiveness of such an approach has not

Restenosis PTCA GRAMI21 Zwolle23 FRESCO22 PAMI-Stent65 PASTA66

43% 33.5% 37.5%

Stent

17% 20.3% 17%

TVR p value

0.001 ⬍ 0.001 0.02

PTCA

Stent

p value

21% 17% 25% 17%

14% 4% 7% 7.7%

ns 0.002 0.002 ⬍ 0.001

Table 10.2 Summary of the angiographic restenosis and TVR rates in the major clinical trials of angioplasty vs stenting in AMI.

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yet been analysed. The Zwolle trial investigators23 also demonstrated a significant reduction in TVR at 6 months in the stent compared to the PTCA alone groups (4% vs 17%, p ⫽ 0.01). The lower rates of TVR compared to FRESCO are likely due to the more stringent inclusion and exclusion criterion of the Zwolle trial. The Primary Angioplasty in Myocardial Infarction (PAMI) stent pilot study investigators enrolled 312 patients to receive stents after PTCA for AMI. The selection process was less inclusive than FRESCO and similar to the Zwolle study. Two hundred and forty patients (77% of those screened) were deemed feasible for stenting. Seventy-two lesions were not stented because of small vessel size (⬍ 3.0 mm), excessive lesion length (requiring ⱖ 3 stents), proximal tortuosity, ostial left anterior descending (LAD) or circumflex lesions, large thrombus burden (5 patients) and major side-branch involvement.25 Stents were successfully placed in 236 patients (98%). Long term angiographic follow-up demonstrated angiographic restenosis in 27.5% of patients treated with stents after PTCA for AMI. Cumulative TLR was similar to Zwolle (13.9%). Interestingly, the PAMI stent pilot study investigators identified the number of stents used and the absence of thrombus as independent determinants of binary restenosis. In the PAMI-STENT randomized trial of angioplasty vs stenting in AMI, angiographic restenosis rates and TVR rates were lower in the stenting group compared to PTCA alone, consistent with other trials listed in Table 10.2. Taken together, the data currently available supports the use of primary stenting in the setting of AMI for the prevention of restenosis, particularly when the IRA can be treated with a single stent. The association of thrombus and restenosis is intriguing and warrants

148

further investigation, as does the observation that a nonsignificant trend for increased mortality in the stent group compared to PTCA alone exists. Final results of the CADILLAC trial are forthcoming and should resolve the controversy surrounding the role of adjunctive glycoprotein (GP) IIb/IIIa inhibitor use in combination with stents or PTCA alone for optimal treatment of AMI and prevention of restenosis. These agents have the potential to prevent reductions in TIMI flow seen more often after stenting than PTCA alone. However, it is unclear whether they agents will improve restenosis rates.

Saphenous vein graft interventions Over 600 000 coronary artery bypass graft (CABG) operations are performed annually in the United States; the majority of these operations involve at least one saphenous vein graft (SVG) implantation. Within 10 years, half of all SVGs will fail because of complete occlusion or atherosclerotic disease.26 Owing to the considerable increase in risk of reoperation in these patients,27 percutaneous vein graft intervention for the relief of angina in this population is increasing in frequency. Controversy persists over the optimal percutaneous approach to these patients, since the results of PTCA and atherectomy have been disappointing.28–31 Over half of the European interventional cardiologists surveyed considered stenting the treatment of choice in SVG disease.9 Early observational studies of stenting in vein grafts suggested high rates of procedural success (⬎ 98%), and significantly lower rates of angiographic and clinical restenosis than previously reported with PTCA alone.32–34 The Saphenous Vein De Novo Trial Investigators

SAPHENOUS VEIN GRAFT INTERVENTIONS

(SAVED) performed the only randomized trial published to date, comparing elective stenting to conventional PTCA in saphenous vein graft lesions (Table 10.3).35 Interestingly, the primary endpoint of the trial, the rate of angiographic restenosis at 6 months, was not statistically significant when analysed by intention to treat principles, despite increased minimal lumen diameter (MLD) (2.81 vs 2.16 mm) and fewer dissections (7% vs 29%, p ⬍ 0.001) in the stent group. When the analysis was performed on only those patients who actually received the assigned therapy, the result achieved statistical significance with angiographic restenosis in 34% of the stent group and 48% in the PTCA group (p ⬍ 0.05). The rate of angiographic restenosis in the randomized patients was much higher than in the registry patients (17%). This difference could not be accounted for by differences in inclusion criteria, and the authors state that ‘bias toward favorable outcomes in registries of interventional devices may have played a role’. While the occurrence of angiographic restenosis was not different, the rate of major cardiac events was less (24.1% vs 36.4%, p ⫽ 0.04) primarily because of a reduction in TLR. Similar results were achieved in the recently reported VENE-

STENT study36 in which 23.6% of patients randomized to angioplasty crossed-over to stenting. When analysed by intention to treat, binary restenosis was 36% vs 22% in the PTCA vs stent groups (p ⫽ 0.09). Taken together, the results of these trials suggest that stenting of older saphenous vein grafts may not prevent angiographic restenosis, but does reduce the risk of major cardiac events, and in particular TLR. The answer to the question of why stents failed to reduce the incidence of restenosis despite increased MLD in these patients may relate to unidentified pathological mechanisms of in-stent restenosis unique to old vein grafts. Notably, despite increased MLD with atherectomy compared to PTCA in the CAVEAT-II trial,31 there was no difference in angiographic restenosis, but a reduction in TLR similar to that in the SAVED trial. Because of the diffuse nature of vein graft disease, major portions of abnormal vessels may be uncovered and could develop more severe narrowing. If this occurred at the stent margins, it might be counted as stent restenosis. This theory was addressed in a nonrandomized fashion using the less-shortening WALLSTENT for endoluminal reconstruction of old SVGs.37 The investigators reported very high rates of major

Restenosis

SAVED35* VENESTENT36

TLR

PTCA

Stent

p value

PTCA

Stent

p value

48% 35.6%

34% 21.9%

⬍ 0.05 0.09

26% 25%

17% 11.5%

0.09 0.03

*Results of only the patients who received the therapy to which they were randomized. When analysed by intention-to-treat the difference did not achieve statistical significance (46% vs 37%, PTCA vs stent).

Table 10.3 Summary of the angiographic restenosis and TVR rates in the major clinical trials of angioplasty vs stenting for vein graft lesions.

149


adverse cardiac events (MACE) (10.3% in hospital) and repeat PTCA in 31.6%, however, randomized trials are needed to definitively test the hypothesis. Alternatively, Painter et al38 found that despite excellent angiographic results, intravascular ultrasound (IVUS) identified inadequate stent apposition in 47%, incomplete stent expansion in 91%, and symmetry index below the threshold of 0.70 in 15% of stents deployed in vein grafts. These factors may be important in SVG instent restenosis, and the utility of IVUS in optimizing stent deployment and predicting restenosis in vein graft stents remains unknown.

Chronic total occlusions Successful recanalization of chronic total occlusions (CTO) in patients with documented ischemia results in symptom relief, improvement in left ventricular function, and lower rates of CABG surgery.39,40 PTCA alone is associated with increased risk of reocclusion and restenosis (44–65%) compared to PTCA of nonocclusive stenoses, thus raising concerns about the longer-term outcomes after such an

approach. Based upon previous trials documenting reductions in restenosis rates in de novo coronary lesions with intracoronary stents, five randomized trials have been designed to test the hypothesis that stenting after recanalization with PTCA results in better clinical outcomes and lower restenosis/reocclusion rates than PTCA alone in CTOs. All of these trials demonstrated superior angiographic and clinical outcomes in patients randomized to stenting after successful recanalization of CTO (Table 10.4). The SICCO41 and GISSOC42 investigators adhered to stringent inclusion and exclusion criteria and utilized Palmaz–Schatz stents, while the TOSCA43 trialists utilized more liberal criteria and Palmaz–Schatz stents. SPACTO44 was a trial of the Wiktor stent with liberal inclusion criterion. The SPACTO investigators also performed a pooled analysis on the available data from their trial and three others.41,42,45 The pooled analysis included 374 patients and was performed by intention to treat principles. They demonstrate pooled reocclusion rates of 24% vs 8% (PTCA vs stent, p ⬍ 0.001) and restenosis rates of 66% vs 31% (PTCA vs stent, p ⬍ 0.001). The results of all of these

Restenosis

SICCO41 GISSOC42 SPACTO44 SARECCO46 TOSCA43

TLR

PTCA

Stent

p value

PTCA

Stent

p value

74% 68% 64% 62% 70%

32% 32% 32% 26% 55%

⬍ 0.001 ⬍ 0.001 0.010 ⬍ 0.05 ⬍ 0.01

39% 22% 40% 52% 15%

21% 5.3% 25% 26% 8.4%

⬍ 0.05 0.038 0.024** ⬍ 0.05* 0.003

*24 month follow-up. **Repeat PCI.

Table 10.4 Summary of the angiographic restenosis and TVR rates in major clinical trials of angioplasty vs stenting in chronic total occlusions of native coronary arteries.

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DIABETES MELLITUS

trials and the more recent SARECCO trial,46 were highly concordant and support the use of stents in the treatment of CTO. An exception might be made when the reference vessel is small (⬍ 3.0 mm). If the CTO supplies a very diminutive or infarcted bed, stent implantation may be neither feasible nor optimal.

Diabetes mellitus Several studies have demonstrated increased rates of angiographic and clinical restenosis after PTCA in diabetics compared to nondiabetics.47–49 Kornowski et al50 utilized IVUS to investigate the relative importance of vascular remodeling and intimal hyperplasia in late lumen loss after PTCA in diabetics. They concluded that late lumen loss in diabetics was predominantly a result of intimal hyperplasia. No randomized study to date has prospectively evaluated the efficacy of stenting in the prevention of restenosis in diabetics. Observational data does suggest that stenting is associated with lower restenosis rates in diabetics. Specifically, Van Belle et al51 analysed their experience with PTCA and stenting in diabetic patients comparing these results to a cohort of nondiabetic patients. They found that after PTCA, angiographic restenosis occurred in

63% of diabetics and 36% of nondiabetics (p ⬍ 0.001). Stenting was associated with improved angiographic restenosis rates in diabetics (25%) and nondiabetics (27%). These authors concluded that diabetic patients have the same improved outcomes as nondiabetics after native coronary stenting. While this study supports a role for stenting to prevent restenosis in diabetics, it is not clear that these patients are not at increased risk of in-stent restenosis, a problem with limited treatment options. Elezi et al,52 analysed their experience with stenting in 715 diabetics and 2839 nondiabetic patients demonstrating angiographic restenosis rates of 37.5% and 28.3% (p ⬍ 0.001) in diabetics compared to nondiabetics at 6 months. Finally, Kastrati et al53 identified diabetes as a significant risk factor associated with in-stent restenosis (OR 1.86, 95% CI 1.56–2.16). An analysis of the diabetic subgroup in the EPISTENT trial has shown that diabetics treated with stenting plus abciximab had a repeat TVR rate of 8.1% compared to 16.6% in the stent without abciximab and 18.4% in the PTCA plus abciximab groups.54 This provocative finding warrants direct investigation and is one subject of the proposed BARI-II trial. In summary, consideration of elective or

Restenosis

Van Belle51 Marso54

TVR

PTCA

Stent

p value

63%

25%

⬍ 0.05

PTCA

Stent

p value

18.4%

8.1%

⬍ 0.05*

*Both groups received Abciximab.

Table 10.5 Summary of the angiographic restenosis and TVR rates in studies of angioplasty vs stenting in diabetic patients.

151


direct stenting in diabetics should be made only after other risk factors for in-stent restenosis have been thoroughly evaluated. Further trials are needed to determine the optimal therapy in this large subset of patients with cardiovascular disease, including the potential benefits of adjuncts to PCI such as the platelet GP IIb/IIIa inhibitors.

Complex angioplasty Several other angiographic factors have been associated with increased risk of restenosis and warrant consideration of direct stenting to prevent restenosis. Randomized trials are lacking in many of these subsets and the decision to stent must be based on data from nonrandomized trials or inferred from subset analysis of randomized trials which can be misleading. Under special circumstances, left main coronary artery disease, either protected or unprotected, requires PCI. Angioplasty of the left main coronary artery has been performed with a high degree of initial success and rates of restenosis similar to other native coronary arteries.55 Since the consequences of restenosis in this location are grave, some authors recommend that every effort to prevent restenosis be employed empirically. This should include stenting if the risk of proximal LAD and circumflex coronary artery entrapment is sufficiently low. It is unlikely that randomized trials will be undertaken to address this issue definitively. Ostial coronary artery lesions are at increased risk of restenosis after PTCA (38–58%).56,57 Elastic recoil and suboptimal lumen enlargement contribute to this increased risk. While technically challenging, stenting improves procedural success by preventing recoil. Whether the initial improvement in luminal gain over PTCA, achieved by direc-

152

tional coronary atherectomy or rotational atherectomy translates into improved restenosis rates has not yet been proven in randomized trials. Observational data supports the use of stents in aorto-ostial and LAD ostial stenoses, to prevent restenosis. Randomized trials are needed before unconditional stenting of such lesions can be recommended. Small coronary arteries defined as vessel diameter ⬍ 3.0 mm account for 30–40% of all PCIs and are at increased risk of restenosis after PTCA compared to larger vessels.58,59 Controversy was raised regarding the role of stenting to prevent restenosis in small vessels when conflicting results were obtained between the STRESS and BENESTENT trials. In STRESS I and II, stenting of small vessels resulted in reduced rates of binary restenosis compared to PTCA alone (34% vs 54%),60 while in BENESTENT, stenting was associated with increased rates of angiographic restenosis.61 These data were derived form subgroup analysis of large randomized trials. Additionally, both trials intended to enroll patients with reference vessel size ⬎ 3.0 mm. The small vessel patients were only identified after quantitative coronary angiographic analysis. Finally, the stents utilized in STRESS and BENESTENT were not specifically designed for small vessels. To date, no prospective trial has been specifically designed to compare PTCA with stenting in small coronary vessels. In summary, observational and prospective studies confirm the increased rate of restenosis in small vessels compared to larger vessels, however, the role of stenting to prevent restenosis in this setting remains undefined.

Restenotic lesions after PTCA Even though plain old balloon angioplasty appears to be a fading practice, the treatment of restenosis after PTCA warrants a brief

FUTURE OF STENTING TO PREVENT RESTENOSIS

discussion. The Restenosis Stent Trial (REST)62 was the first prospective randomized trial of PTCA vs stenting for the treatment of restenosis following PTCA. Clinical and angiographic follow-up at 6 months was available in 93% of the 383 patients randomized. The binary second restenosis rate was 32% vs 18% (p ⫽ 0.03) in the PTCA vs stent groups. TVR was required in 27% vs 10% (p ⬍ 0.001), and event-free survival at 250 days of follow-up was 72% vs 84% (p ⫽ 0.04), despite increased subacute thrombosis (0.6% vs 3.9%) in the stent group. Stenting is now the recommended percutaneous treatment for restenosis after PTCA in appropriately sized vessels.

A

B

Future of stenting to prevent restenosis The single greatest challenge in the treatment of lesions at increased risk of restenosis is the problem of in-stent restenosis. The pathophysiology of in-stent restenosis differs considerably from that of restenosis after PTCA. Whereas the latter represents the combined effects of elastic recoil, arterial constriction, and neointimal hyperplasia, in-stent restenosis is due predominantly to neointimal hyperplasia, which may be made worse by suboptimal deployment. Figure 10.1 is an angiographic image of a restenotic lesion of the proximal LAD occurring three months after direct stenting in a 48 year old man. Figure 10.2A is an IVUS image of the stent from that same patient and illustrates the characteristics of an undersized stent. Figure 10.2B is the IVUS image of the minimal stent diameter after redilatation of the stent with a larger balloon. Studies utilizing IVUS have identified inadequate stent deployment, despite angiographically acceptable results, as a potential

Figure 10.1 Angiographic image of a restenotic lesion that developed three months after stent deployment in the proximal LAD of a 48 year old man before (A) and after (B) redilation with a larger balloon.

contributor to the development of stent thrombosis and in-stent restenosis. This observation has resulted in improved deployment success using high-pressure inflation techniques, and supports the ‘bigger is better’ hypothesis of stenting to reduce restenosis. Despite this major advance in stent-deployment technique, there are patient and lesion characteristics that predict increased risk of instent restenosis. Kastrati et al have utilized

153


A

B

Figure 10.2 Intravascular ultrasound image of the previously deployed stent from the patient in Figure 1 demonstrating undersizing of the stent (A). The minimal luminal diameter and cross sectional area of the vessel are 5.5 mm and 21.4 mm2, respectively. The minimal luminal diameter and cross sectional area of the stent are 3.0 mm and 7.2 mm2, respectively. After redilation with a 4.0 mm balloon the minimal diameter and crosssectional area of the stent are 4.2 mm and 14.1 mm2, respectively (B).

154

multivariate modelling to identify clinical, lesional, and technical predictors of in-stent restenosis.53 Diabetes mellitus, multiple stents, and final angiographic MLD ⬍ 3 mm were independently predictive of in-stent restenosis. Regression analysis indicated that restenosis rates as high as 59% are predicted by the combination of these three factors. Kobayashi et al have demonstrated that stent length is another powerful and independent predictor of restenosis, such that the risk of in-stent restenosis is approximately 1% per mm stent placed.63 Finally, Serruys et al have performed a meta-analysis of the BENESTENT trials and the MUSIC trial to develop a model for predicting restenosis rates based on QCA after stenting with the Palmaz–Shatz stent. Percent diameter stenosis after the procedure and vessel size best fit the data, highlighting the importance of early results.64 Thus, the decision to stent or not, must be made in the context of these multiple clinical, angiographic and prognostic factors and with the knowledge that in-stent restenosis remains a considerable challenge. Therefore optimal stent utilization involves minimizing stent number and length and maximizing MLD. The strategies of provisional stenting in small vessels, and ‘spot stenting’ in diffusely diseased vessels are currently the topics of intense debate. The development of technology to prevent in-stent restenosis has centered on stent coating (heparin, endothelial cells, or saphenous vein tissue), growth regulating factors, and radiation. These adjuncts will be addressed elsewhere in this book. As long as in-stent restenosis remains a problem, clinical trials designed to delineate the risk benefit relationship of stenting vs PTCA alone are still needed.

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11 Debulk/stenting Antonio Colombo and Evangelia Karvouni

Rationale for plaque removal prior to stenting Coronary stents, achieving greater acute gain and providing effective lumen scaffolding, are associated with better short term and long outcome compared to standard balloon angioplasty. These results were achieved in lesions located on relative large coronary arteries and in discrete saphenous vein graft (SVG) stenosis.1–3 However, these favorable results do not apply for all coronary lesions treated with catheter-based interventions in daily practice. For complex lesions such as long lesions,4 lesions located in small vessels,5,6 chronic total ostial9,10 and bifurcation occlusions,7,8 11 lesions restenosis after stenting remains a vexing problem. Both intravascular ultrasound (IVUS) and pathology studies12,13 have shown that in-stent restenosis is mainly due to neointima formation, since the mechanical scaffolding provided by metallic stents is preventing late vessel wall constriction (negative remodeling). In addition, pathologic specimens of stented arterial segments have shown that the amount of formed neointima is greater when the media layer of vessel wall is damaged, a finding which supports the use of stent deployment techniques that reduce arterial injury or vessel wall stretching.13 The stretching force needed to expand the vessel is proportional to the vessel wall resistance, which

depends on the amount and consistency of the plaque. The presence of a large plaque burden may prevent optimal stent expansion even with high inflation pressure or large balloons. IVUS studies have shown that both preinterventional and post interventional plaque burden are predictors of restenosis.14,15 Observational angiographic data confirm IVUS studies, showing that after stent implantation, restenosis tends to occur at the original lesion site.16 One of the major frustrations of IVUSguided stenting is the need to accept that optimal and symmetrical stent expansion cannot be achieved in a very large number of occasions. For example, in the MUSIC study, criteria for optimal stent deployment were achieved in only 80% of the lesions;17 the amount of plaque behind the stent appears to be the logical limitation. These data were adequate to advocate plaque removal with debulking techniques prior to stenting, in an attempt to optimize acute and long term outcome. Although it is not clear whether the favorable results of debulking prior to stenting are because of facilitated stent expansion or plaque removal itself, recent data suggest that plaque removal with directional coronary atherectomy (DCA) prior to stenting reduces restenosis independently of the post procedure lumen diameter achieved.18 This means that residual plaque after stenting may act as a source of proliferating smooth

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muscle cells involved in stent restenosis process.

Directional coronary atherectomy prior to stenting From the early days of DCA, this debulking technique has been shown to be an efficient method of removing noncalcified atherosclerotic plaque, using a rotating cutter blade which shaves off the atherosclerotic material. Its efficacy has been confirmed in many randomized trials comparing DCA with balloon angioplasty.19–23 Removing coronary plaque by DCA led to a larger acute gain in lumen diameter and a small but no significant reduction in angiographic restenosis at 6-month follow-up in an early randomized trial comparing coronary angioplasty with DCA (CAVEAT I).19 However, this did not translate into an advantage in clinical outcomes. DCA was associated with a higher rate of in-hospital myocardial infarction, increased hospitalization costs and an excess in mortality at 1-year follow-up.24 The increase in acute complications with DCA was not confirmed in another early randomized trial (CCAT) that compared coronary angioplasty with DCA in lesions located at the left anterior descending coronary artery.20 One major limitation of these studies was the use of a limited debulking approach. In the CAVEAT study a 7F atherectomy device was used in only 47% of the lesions. The ‘Optimal’ Atherectomy Restenosis Study (OARS) showed that use of an ‘optimal’ atherectomy technique to produce larger early lumen diameters translated to a lower restenosis rate (28.9%) at 6 months without an increase in early or late major adverse events.21 In a randomized trial evaluating the short

160

and long term outcome of optimal DCA compared with balloon angioplasty (Balloon vs Optimal Atherectomy Trial, BOAT), the encouraging results of the OARS study were confirmed for angiographic restenosis rates and early adverse events (death, Q-wave myocardial infarction (MI) or emergency coronary artery bypass graft surgery) but not for late clinical events (death, Q-wave MI or target vessel revascularization).22 Finally, in the ABACAS Trial (Adjunctive Balloon Angioplasty after Coronary Atherectomy Study), IVUS-guided aggressive DCA with or without adjunctive percutaneous transluminal coronary angioplasty (PTCA) showed impressive restenosis rates of 23% and 19%, respectively, at 6 months (Fig. 11.1),23 although the most promising results ever shown with DCA were with the combined strategy of DCA and stenting.25–29

Our experience In the SOLD Registry (Stenting after Optimal Lesion Debulking) we examined the feasibility, safety and efficacy of DCA before stent implantation. Between February 1996 and January 1998 a total of 128 patients with 168 lesions were enrolled. Inclusion criteria were: (a) (b) (c) (d) (e)

clinical or functional evidence of ischemia, no MI within 48 hours, reference vessel diameter ⱖ 2.75, diameter stenosis ⬎ 70%, lesion length ⬎ 15 mm by visual estimate.

Complex lesions such as ostial and bifurcation lesions were included regardless of vessel size and lesion length. Chronic total occlusions and restenotic lesions were also included. DCA was performed using methods previously described.20 The end point of the atherectomy procedure was the achievement of a ⬍ 20% residual diameter stenosis by visual estimate.

DIRECTIONAL CORONARY ATHERECTOMY PRIOR TO STENTING

CAVEAT 50% BOAT 31.4%

OARS 28.9%

ABACAS 19.6%

Figure 11.1 Different angiographic restenosis rates in the major atherectomy studies. More intense debulking is associated with a lower restenosis rate.

A 7 Fr GTO cutter was used in 96% of lesions with an average of 14 ⫾ 7 cuts per lesion. Following DCA, stents were implanted in all lesions with the goal of achieving a near-zero angiographic residual stenosis. No limitations were set about the use of an aggressive post stenting dilatation with large balloons and high pressure. The stents used were: (a) the Multilink stent (15 mm and 25 mm long) (Guidant, Inc, Temecula, CA, USA) was used in 51 lesions (30%), (b) the Palmaz–Schatz stent (Johnson and Johnson Interventional Systems, Warren, NJ, USA) was used in 45 lesions (27%), (c) the NIR stent (16 mm, 19 mm, 25 mm and 32 mm long) (Boston Scientific, SciMed, Inc, Minneapolis, MN, USA; Medinol Jerusalem, Israel) in 26 lesions (15%) and, (d) other slotted tube stents in 46 lesions (28%). IVUS guidance was used in a subset of patients before intervention, after DCA and after stenting. Patients were discharged on routine

antiplatelet therapy (oral aspirin 325 mg qid and oral ticlopidine 250 mg bd for 2 weeks). Clinical follow-up was obtained in all patients at 1 month and 1 year after the procedure. Typical lesions where debulking appears to be an appropriate strategy prior to stenting are bifurcations, where both branches are large enough to be treated by atherectomy with subsequent implantation of two stents (Fig. 11.2), or ostial lesions close to another branch, where atherectomy will limit plaque shift (Fig. 11.3). Results Patient and lesion characteristics are shown in Table 11.1. IVUS-guided stent implantation was used in 95% of lesions. The final balloonto-artery ratio for stent expansion was 1.19 ⫾ 0.16 and the final inflation pressure was 16 ⫾ 4 atm. Quantitative angiographic and IVUS measurements are presented in Table 11.2. Mean residual percentage plaque area after DCA was 54 ⫾ 14%, although residual plaque area ⬎ 60% was left behind in about 30% of lesions. Clinical success was achieved in 96% of patients. Procedural and

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DEBULK/STENTING

Baseline

DCA

Final Result

162

Figure 11.2 A typical bifurcational lesion involving left anterior descending artery and diagonal branch, which is treated with atherectomy followed by stenting on both branches.


Final Result Baseline

Follow-up

Figure 11.3 A lesion involving the ostium of the left anterior descending artery where the removal of the plaque with atherectomy may limit the compromise of the other branch during stent placement. Sometimes a final kissing inflation in both branches may become necessary anyway to maintain a reasonable lumen at the ostium of the vessel not stented. Note the minimal late loss at 8-month follow-up angiogram.

in-hospital major adverse cardiac events (MACE) defined as death, Q-wave myocardial infarction or emergency repeat revascularization occurred in four patients (3.2%): emergency bypass surgery was required in two patients (1.6%), both of whom died during hospitalization; two other patients suffered from non-fatal Q-wave MI. Non-Q-wave MI occurred in 17 patients (13.3%). No other events occurred during 1-month follow-up. Angiographic follow-up was performed in

132 of 168 lesions (80%) at 5.3 ⫾ 1.4 months. Angiographic restenosis (defined as diameter stenosis ⬎ 50%) occurred in 18 lesions (13.6%): intra-stent in 11 lesions (8.3%) and at stent edges in 7 lesions (5.3%). The majority of these restenotic lesions were focal and only 14 lesions (8%) needed repeat intervention (PTCA in 13 patients and coronary artery bypass grafts in one patient) at long term follow-up (12 ⫾ 5 months). The cumulative composite endpoint of MACE

163

DEBULK/STENTING

Patient characteristics

n ⫽ 128

Age Male Smoking (past or current) Hypertension Diabetes mellitus Hyperlipedemia Prior MI Unstable angina LVEF Number of diseased vessels 1 vessel 2 vessel 3 vessel

58 ⫾ 10 118 (92%) 77 (60%) 53 (41%) 10 (8%) 74 (58%) 54 (42%) 23 (18%) 61 ⫾ 11%

Lesions Vessel treated LAD LCX RCA LM Lesion location Ostial Proximal Mid Distal Lesion type A B1 B2 C Chronic total occlusion Major bifurcations Restenotic lesions

n ⫽ 168

60 (47%) 31 (24%) 37 (29%)

102 (61%) 27 (16%) 32 (19%) 7 (4%) 26 (15%) 72 (43%) 55 (33%) 15 (9%) 1 (0.6%) 34 (20%) 97 (58%) 36 (21.4%) 13 (8%) 40 (23%) 18 (11%)

MI, myocardial infarction; LVEF, left ventricular ejection fraction; LAD, left anterior descending; LCX, left circumflex; RCA, right coronary artery; LM, left main.

Table 11.1 Patients and lesions characteristics in the Stent after Optimal Lesion Debulking (SOLD) Registry.

164

(death, non-fatal Q-wave MI, and repeat revascularization) occurred in 18 patients (14%). In the absence of a control group of patients who had stent implantation without prior atherectomy, a matching study utilizing patients with similar clinical, lesion and angiographic characteristics may compensate for some of the limitations of a nonrandomized study. Matching was performed in terms of the presence of diabetes mellitus, previous PTCA, reference vessel diameter, lesion length, lesion severity, type of stent, and total stent length. All 132 lesions from the study group with angiographic follow-up were matched with 132 lesions in patients who underwent stenting alone (Table 11.3). Loss index in the DCA and stenting group was significantly lower compared with the loss index measured in the stent alone group (0.39 ⫾ 0.35 vs 0.48 ⫾ 0.35, p ⫽ 0.04). This fact translates into a 13.6% restenosis rate in the DCA and stenting group compared with 23.5% in the stent alone group (p ⫽ 0.04). Target lesion revascularization (TLR) during the first year after the index procedure was needed in only 8% of lesions. Predictors of restenosis by multivariate logistic regression analysis are shown in Table 11.4. In the combined population of 264 lesions, the only independent predictors of restenosis were stent length and the use of DCA. The performance of DCA predicted a lower probability of restenosis, and stent length predicted a higher probability of restenosis. Other common variables such as reference diameter, final minimum lumen diameter (MLD) or lesion length were not independent predictors of restenosis. For the DCA and the stenting group, residual plaque burden post DCA was the only independent predictor of restenosis. A larger residual plaque burden predicted a higher probability of restenosis.


Pre-intervention

Post-DCA

Post-stenting

n ⫽ 168 3.37 ⫾ 0.50

n ⫽ 168 3.50 ⫾ 0.57

2.42 ⫾ 0.64 28 ⫾ 16 –

3.51 ⫾ 0.53 0.04 ⫾ 9 –

Stent length (mm)

n ⫽ 168 3.25 ⫾ 0.54 (*3.18 ⫾ 0.50) 0.84 ⫾ 0.48 74 ⫾ 14 12.80 ⫾ 7.66 (*13.8 ⫾ 7.6) –

–

22 ⫾ 13

IVUS Minimum lumen CSA (mm2) Vessel CSA (mm2) Percent plaque area

n ⫽ 100 2.57 ⫾ 1.07 13.23 ⫾ 4.12 80 ⫾ 7

n ⫽ 116 6.59 ⫾ 2.08 14.88 ⫾ 4.24 54 ⫾ 14

Angiographic Reference diameter (mm) Minimum lumen diameter (mm) Diameter stenosis (%) Lesion length (mm)

n ⫽ 142 8.85 ⫾ 2.15 – –

*Ostial lesions excluded. DCA, directional coronary atherectomy; CSA, cross-sectional area.

Table 11.2 Quantitative angiographic and intravascular ultrasound (IVUS) measurements.

Baseline RD (mm) MLD (mm) DS (%) LL (mm) Post-intervention RD (mm) MLD (mm) DS (%) Stent length (mm) Follow-up RD (mm) MLD (mm) DS (%) Loss index Restenosis (%) Focal in-stent Focal edge Diffuse Reocclusion

DCA ⫹ stent n ⫽ 132

Stent n ⫽ 132

p Value

3.22 ⫾ 0.53 0.83 ⫾ 0.47 74 ⫾ 13 12.34 ⫾ 7.35

3.21 ⫾ 0.35 0.76 ⫾ 0.34 76 ⫾ 11 12.28 ⫾ 5.93

NS NS NS NS

3.48 ⫾ 0.52 3.47 ⫾ 0.57 ⫺0.1 ⫾ 10 21 ⫾ 10

3.27 ⫾ 0.38 3.28 ⫾ 0.48 ⫺0.6 ⫾ 12 22 ⫾ 11

0.001 0.003 NS NS

3.21 ⫾ 0.48 2.43 ⫾ 0.92 25 ⫾ 25 0.39 ⫾ 0.35 18 (13.6%) 5 (3.8%) 7 (5.3%) 3 (2.3%) 3 (2.3%)

3.07 ⫾ 0.50 2.09 ⫾ 0.86 32 ⫾ 25 0.48 ⫾ 0.35 31 (23.5%) 11 (11.4%) 2 (1.5%) 10 (7.6%) 4 (3%)

0.02 0.002 0.02 0.04 0.04

RD, reference diameter; MLD, minimum lumen diameter; DS, diameter stenosis; LL, lesion length.

Table 11.3 A matched group comparison of stenting after DCA (SOLD) versus stenting alone (Columbus database).

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B coefficient ⫾ SE

Study population

Variable

*DCA ⫹ stent group (n ⫽ 64)

Residual % plaque area Post-DCA Intrastent MLCSA

8.52 ⫾ 3.88

0.03

⫺0.50 ⫾ 0.29

0.08

Stent length DCA performed

0.05 ⫾ 0.02 ⫺0.35 ⫾ 0.17

0.0003 0.047

**DCA ⫹ stent group and Stent alone group (n ⫽ 264)

p

*Only lesions that had post-DCA and post-stent IVUS and returned for angiographic follow-up are included. **All lesions in the study group and the control group are included. DCA, directional coronary atherectomy; IVUS, intravascular ultrasound; MLCSA, minimum lumen cross-sectional area.

Table 11.4 Predictors of restenosis by multivariate logistic regression analysis.

Conservation of lumen gain achieved by stenting after DCA 100

100 pStent

% Lesions

80 FU 60

Baseline pDCA

80 60

FU pDCA

40

40

20

20

0

0

⫺40 ⫺20

0

20

40

60

80

100

120

⫺1

Baseline pStent

0

1

2

3

4

Percent diameter stenosis (%)

Minimum lumen diameter (mm)

A

B

5

6

Figure 11.4 (A) Frequency distribution curves for angiographic percentage diameter stenosis preintervention, after directional coronary atherectomy DCA (pDCA), after stenting (pStent), and at follow-up. (B) Frequency distribution curves for angiographic minimal lumen diameter MLD preintervention, after DCA (pDCA), after stenting (pStent), and at follow-up. Note that the curves for MLD and percentage diameter stenosis at follow-up overlap those after atherectomy for the majority of lesions.

The lower late lumen loss in the DCA plus stent group is illustrated in Fig. 11.4. In this figure, the frequency distribution curves after DCA and at follow-up almost overlap both for

166

MLD and percentage diameter stenosis. This means that stent implantation after plaque removal may ‘preserve’ the lumen gain achieved with debulking.


These findings strongly suggest that plaque removal before stenting attenuates the intensity of neointimal hyperplasia, mainly responsible for restenosis after stent implantation. This is illustrated in Fig. 11.5, where it appears that for any given amount of acute gain there is less late lumen loss when atherectomy is performed before stenting (note the downward shift in the regression line). However, the regression lines converge and intersect when large acute lumen gain is achieved. This may suggest that in vessels where a large acute lumen gain can be achieved with stenting alone, such as large vessels, the addition of DCA might be of little or no benefit. In conclusion, DCA before stent implantation reduces late lumen loss, with subsequent reduction in restenosis and the need for repeat interventions. This raises an important question. Is the lower restenosis rate in the atherectomy plus 3

Late loss (LL) mm

2.5 2 1.5 1 0.5 0

⫺0.5 ⫺1 1

1.5

2 2.5 3 Acute gain (AG) mm

Stent: LL ⫽ 0.25* AG ⫹0.55 Alone: r⫽0.17, p⫽0.05

3.5

4

DCA⫹ Stent: LL ⫽0.41* AG ⫺0.05 r⫽0.28, p⫽ 0.002

Figure 11.5 Simple linear regression lines of late loss (LL) plotted against acute gain (AG) for the atherectomy stent group (solid line) and the stent alone group (dotted line). Note the downward shift in the regression line.

stent group entirely due to the acute lumen gain achieved or is it also due to the attenuation of late lumen loss arising from plaque removal? To answer this question we performed multivariate logistic regression analysis in the group of patients that had IVUS interrogation post DCA and post stenting and who returned for angiographic follow-up (Table 11.4). In this model, only a lower residual plaque burden after DCA and a larger lumen area after stenting predicted a lower probability of restenosis. A larger lumen area after stenting had a tendency (p ⫽ 0.08) towards predicting a lower probability of restenosis. Interestingly, the influence of residual plaque burden after DCA (before stent implantation) on the probability of restenosis was more prominent than that of the post procedure lumen cross-sectional area. The positive linear relationship between residual plaque burden after DCA and late lumen loss following atherectomy plus stenting is illustrated in Fig. 11.6. Plaque removal before stent implantation reduces restenosis in proportion to the amount of plaque removed. We conclude that DCA before stent implantation reduces restenosis by two mechanisms: first, by facilitating stent expansion, thus leading to a large post-procedure lumen and, more importantly by reducing the propensity for late neointimal hyperplasia; this effect is proportional to the magnitude of plaque removal.

Comparison with other studies Early outcome We report an incidence of early MACE of 3.2% at 1-month follow-up. This is in agreement with the incidence of early MACE in large randomized trials of either stenting or DCA alone in a more selected patient’s

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DEBULK/STENTING

Relationship between residual plaque area after DCA and late lumen loss after stenting Late loss⫽0.19⫹1.42* residual % PA (r ⫽ 0.25, p ⫽ 0.02) 4 Late lumen loss (LL) mm

3.5 3 2.5 2 1.5 1 0.5 0

⫺0.5 ⫺1 10

20 30 40 50 60 70 80 Residual percent plaque area after DCA

90

Figure 11.6 Simple linear regression of late lumen loss after stent placement vs residual percentage plaque area after atherectomy. Note that the larger the residual plaque burden is before stent implantation, the larger the late lumen loss is at follow-up.

population.1,2,20,21 In the BENESTENT1 and STRESS2 trials, early MACE occurred in 5.4% and 5.9% of patients, respectively. Similarly in the OARS20 and BOAT21 trials the incidence of early MACE was 2.5% and 2.8%, respectively. If we consider the high risk lesions (ostial, bifurcations, chronic total occlusions, restenotic) included in SOLD Registry, it seems that DCA prior to stenting is a safe strategy in terms of early MACE. An objection to this view may arise, however, based on the high incidence of nonQ-wave MI in patients treated with DCA and stenting. In our study, non-Q-wave MI occurred in 13.3% of patients, similar to what has been reported in both the OARS20 (14%) and the BOAT21 (16%) trials. It has been shown that CK–MB elevation

168

after coronary percutaneous intervention is device-specific, enzyme release is higher for non-balloon devices,30,31 and particularly after DCA, is platelet-dependent.32 These findings are supported by the observation of more extended platelet activation in patients treated with DCA compared with balloon angioplasty.33 In addition, recent studies have stressed the prognostic significance of even mild CK–MB elevation for short and long term outcome,34–36 although the cut-off point for this elevation is still controversial.35,36 Finally, it seems that diffuse disease is an independent predictor of CK–MB elevation. In a recent IVUS study, the authors correlated different levels of CK–MB elevation with plaque burden at both the lesion and reference segment, and other plaque characteristics. In this study, independent predictors of CK–MB elevation were plaque burden at both the lesion and reference segments, the use of atheroablative technique, the presence of de novo lesion(s) and the final MLD achieved after the procedure.37 This means that one can expect more frequent non-Q-wave MI in complex lesions (diffuse disease), while strategies that maximize lumen dimensions (to reduce restenosis) may result in the tradeoff of greater CK–MB release. In our study, the inclusion of complex lesions and the achievement of greater acute gain with DCA and stenting may account for the high incidence of non-Q-wave MI. In the EPIC trial,38 the use of a platelet glycoprotein IIb/IIIa inhibitor reduced the ischemic complications by 35% in high risk patients undergoing coronary angioplasty and atherectomy, although at the cost of increased bleeding. Adjustment of heparin dose in combination with abciximab reduced the incidence of acute ischemic complications, without increased bleeding risk in the EPILOG39 and EPISTENT40 trials.

ROTATIONAL ATHERECTOMY PRIOR TO STENTING

Since our study was conducted in the era before routine use of platelet glycoprotein IIb/IIIa inhibitors, one can be more optimistic with the encouraging results of trials using these new antiplatelet agents.

Late outcome In our study, we report a restenosis rate after DCA and stenting of 13.6%, which compares favorably with a restenosis rate of 23.5% with stent alone. Other studies addressing the issue of plaque removal with directional atherectomy before stenting have shown similar results.26,28,29 Bramucci et al26 showed that DCA before stenting was associated with greater acute gain, lower loss index and lower restenosis rate (6.8%) in a matched comparison study with stent alone. Similar findings were also reported in the ADAPTS (Acute Directional Atherectomy Prior To Stenting in complex coronary lesions) Study,28 in which the combined approach of DCA and stenting yielded a restenosis rate of 13.3% in high risk lesions. Finally, data from the German Atherolink Registry29 show a restenosis rate of 10.5% after DCA and stenting. Ongoing randomized trials (DESIRE, ESPRIT, AMIGO) are assessing these observational findings. We are currently running the AMIGO (Atherectomy before MULTI-LINK Improves Lumen Gain and Clinical Outcomes) trial at our center. The primary goal of this study is to demonstrate that treatment with combined therapy of stenting with the ACS MULTILINK™ – Duet Stent following DCA will have a lower restenosis rate at 8-month follow-up when compared to stent alone. The enrollment phase has been completed and follow-up results are being analysed. Preliminary results from the 93 patients enrolled in our center show a significantly lower angiographic

restenosis rate for the patients randomized in the debulking plus stenting group. Preliminary results from two other randomized trials (DESIRE, ESPRIT) confirm the greater acute gain with DCA and stenting compared with stent alone,41,42 while the longterm results are still pending.

Rotational atherectomy prior to stenting Rotational atherectomy increases luminal dimensions by ablating atherosclerotic plaque in a selective manner, using an elliptical diamond-coated burr spinning at high speeds.43 The rotating burr selectively removes hard tissue, whereas the elastic recoil of normal segments of the vessel deflects soft tissue. The plaque is pulverized and removed downstream in the coronary microcirculation as microparticles. Early IVUS studies have demonstrated the efficacy of rotational atherectomy in ablating calcified atherosclerotic plaque in humans.44,45 In addition, IVUS volumetric studies have shown that even in noncalcified lesions, rotational atherectomy ablates noncalcified plaque and contributes to lumen enlargement.46 Coronary stents applied to calcified vessels are incompletely and asymmetrically expanded in up to 50% of patients.47 Even high inflation pressures (up to 20 atm) may be insufficient to overcome the vessel wall resistance imposed by a severely calcified plaque. In addition, attempts to obtain full expansion of a stent may cause vessel rupture instead of further enlargement of the stent.48 Based on these findings, two approaches for the use of rotational atherectomy have arisen: ‘facilitated expansion’ which uses a single burr with a small burr-to-artery ratio in an attempt to modify plaque structure and allow better

169

DEBULK/STENTING

balloon expansion, and ‘debulking’ which uses progressively larger burrs to decrease plaque mass.

Our experience To evaluate the safety and efficacy of rotational atherectomy before stenting in the treatment of calcified and complex lesions, we studied 75 consecutive patients with 106 lesions who underwent this combined approach between March 1993 and June 1995.49 Indications for rotablation were calcified, undilatable and uncrossable lesions (90%) and long lesions (10%). IVUS-guided stenting was performed in the majority of patients. Procedural success was achieved in 93% of lesions. Acute stent thrombosis occurred in two lesions (1.9%) and subacute thrombosis occurred in one lesion (0.9%). Angiographic follow-up was performed

Lesions

Angiographic measurements Proximal reference diameter (mm) Post-procedure MLD (mm) Post-procedure percent diameter stenosis IVUS measurements* Stent minimum LCSA (mm2) Symmetry index Average reference vessel CSA (mm2) Stent minimum LCSA/vessel CSA** Procedural data Stents per lesion Balloon to vessel ratio Balloon inflation pressure (atm)

in 83% of lesions at 4.6 ⫾ 1.9 months and the restenosis rate was 22.5%. Clinical follow-up was performed in all patients at 6.4 ⫾ 3 months. Late events occurred in 18 patients (24%). The majority of these events were due to repeat angioplasty for restenosis, which was performed in 13 patients (17%) on 19 lesions (18%). In this study, we performed a comparative analysis between calcified lesions treated with elective Palmaz–Schatz stenting with and without rotablation over the same time period. The stent alone approach without rotational atherectomy was used for shorter lesions in larger vessels (Table 11.5). After adjusting for vessel size, the rotational atherectomy plus stenting group had a lower residual angiographic percentage diameter stenosis, a higher ratio of minimal stent-to-vessel cross-sectional area and higher symmetry index.

Rota-stent n ⫽ 71

Stent alone n ⫽ 46

3.24 ⫾ 0.51 3.25 ⫾ 0.55 ⫺3 ⫾ 13

3.50 ⫾ 0.61 3.29 ⫾ 0.58 2 ⫾ 10

7.60 ⫾ 1.94 0.87 ⫾ 0.11 11.18 ⫾ 3.96 0.71 ⫾ 0.32

8.25 ⫾ 2.07 0.83 ⫾ 0.09 15.14 ⫾ 4.78 0.57 ⫾ 0.32

1.9 ⫾ 1.1 1.15 ⫾ 0.18 16 ⫾ 3

1.3 ⫾ 0.9 1.11 ⫾ 0.17 15 ⫾ 3

p value

0.01 NS 0.03 NS 0.05 ⬍ 0.0001 0.03 0.003 NS NS

MLD, minimum lumen diameter; IVUS, intravascular ultrasound; LCSA, lumen cross-sectional area; *IVUS performed in 65 lesions in the rotastent group and 43 lesions in the stent alone group; values are presented as mean ⫾ SD.

Table 11.5 A comparison between elective Palmaz–Schatz stenting alone vs Palmaz–Schatz stenting after rotablation for calcified lesions (Columbus database).

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COMPARISON WITH OTHER STUDIES

In an attempt to address the issue of aggressive debulking on long term outcome, we evaluated the acute and long term outcome after stenting following rotational atherectomy aimed at debulking the lesion as much as possible. We compared this aggressive debulking technique with a less aggressive rotational atherectomy strategy aimed at modifying the lesion compliance to allow better stent expansion.50 Between May 1995 and February 1997, 126 consecutive patients underwent stenting following rotational atherectomy. Indications for rotational atherectomy were lesion calcification (95%) and long lesions without calcification (2%). All lesions were type B2 or C, and 39% were longer than 15 mm, necessitating a long stent or multiple stents. Lesions were divided into two groups: (a) Group 1 (56 lesions), in which aggressive rotational atherectomy was performed (defined as the use of a final burr size ⱖ 2.25 mm and/or a final burr-to-vessel ratio ⱖ 0.8). (b) Group 2 (106 lesions), in which less aggressive rotational atherectomy was performed; the target was to alter vessel wall compliance and facilitate optimal stent expansion. Most of the patients underwent optimization of stent deployment with high-pressure final balloon dilatation and received routine antiplatelet therapy with aspirin and ticlopidine. In cases of persistent no-reflow phenomenon, intraaortic balloon pumping was inserted and abciximab was infused. In the aggressive rotational atherectomy group, the incidence of procedural Q-wave and non-Q-wave MI was higher (8.9% vs 1.9%, p ⬍ 0.05 and 11% vs 1.9%, p ⬍ 0.05, respectively), compared with the less aggressive rotational atherectomy group. Although

there was no significant difference in MLD after the procedure between the aggressive and less aggressive groups (3.11 ⫾ 0.68 mm vs 2.99 ⫾ 0.48 mm), a greater MLD was observed at follow-up in the lesions treated with aggressive rotational atherectomy (2.12 ⫾ 1.31 mm vs 1.56 ⫾ 0.89 mm, p ⬍ 0.01). Restenosis rates were 30.9% in the lesions treated with aggressive rotational atherectomy and 50% in those treated without aggressive rotational atherectomy (p ⬍ 0.05). In addition, lesions treated with aggressive rotational atherectomy had a lower incidence of diffuse restenosis than lesions treated with less aggressive rotational atherectomy (9.5% vs 25%, p ⬍ 0.05), despite similar lesion and stent lengths. Based on these findings we conclude that aggressive rotational atherectomy followed by stenting is a promising strategy for reducing restenosis in calcified lesions, however, this strategy is associated with an increased risk of procedural myocardial infarction.

Comparison with other studies Procedural complications In our studies, procedural complications occurred in 6.6% of patients (mainly MI). Use of more aggressive rotational atherectomy increased the incidence of periprocedural MI (8.9% Q-wave and 11% non-Q-wave). From the early days of rotational atherectomy there has been concern about the incidence of slow flow/no reflow phenomena in association with this procedure. Slow flow is defined as absent or decreased distal runoff without obvious proximal obstruction or distal filling defects in the epicardial arteries.51,52 The mechanism of slow flow/no reflow occurrence after rotational atherectomy is multifactorial, and atheromatous debris,

171

DEBULK/STENTING

platelet aggregation, heat generation, cavitation, microcirculatory spasm or neurohumoral reflex have been implicated.53,54 The slow flow/ no reflow phenomenon may lead to transient myocardial hypoperfusion with subsequent myocardial injury. Recent in vitro experiments have shown that rotational atherectomy induces platelet activation, whereas blockade of IIb/IIIa platelet receptor reduces platelet aggregation.55,56 The clinical importance of these findings is obvious, since routine use of IIb/IIIa inhibitors during rotational atherectomy seems to reduce the incidence, extent and severity of transient hypoperfusion. Our findings are similar to those in previous studies of rotational atherectomy applied in complex and calcified lesions.57–60 In a comparative study of rotational atherectomy plus adjunct balloon angioplasty with stent alone and rotational atherectomy plus stenting in treatment of calcified lesions, the incidence of non-Q-wave MI was higher in patients treated with the combined strategy of rotational atherectomy and stenting (25.4% vs 15.4% after stent alone and 14.7% after rotational atherectomy plus adjunct balloon angioplasty).61 No difference in major complications was observed in another study, which compared the two strategies of rotational atherectomy plus stenting and stenting alone (1.3% vs 2.5%, p ⫽ ns).62 The aggressiveness of the combined strategy may account for the controversial findings of these two studies.

Late outcome According to our findings the restenosis rate after treatment of high-risk (calcified and complex) lesions with rotational atherectomy and stenting was 22.5%. Employment of a more aggressive rotational atherectomy strategy did not reduce the restenosis rates any further; it was also associated with an

172

increased risk of procedural myocardial infarction and thus, could not be recommended routinely. Hoffman et al.61 report favorable late clinical event rates in patients treated with rotational atherectomy and stenting (15% event rate at 9-month follow-up). At present there are few published data to compare restenosis rates after the combined strategy of rotational atherectomy prior to stenting. A recently completed randomized trial (SPORT: Stenting POst Rotational atherectomy Trial) evaluating the role of rotational atherectomy prior to stenting vs angioplasty prior to stenting did not show any lower restenosis rate with stenting preceeded by rotablation or by angioplasty (29.9% vs 25.8% respectively, p = ns). The lack of difference in post procedural minimal lumen diameter between the two strategies may explain the lack of difference at follow-up.

Other mechanical debulking devices One of the first debulking devices was the transluminal extraction catheter (TEC) (IVT Inc, San Diego, CA, USA). This device was introduced mainly to remove thrombus or other friable material and has been used extensively in the treatment of lesions located in SVG.63 A randomized trial, Transluminal Extraction Atherectomy Or PTCA In Thrombus-containing lesions (TOPIT), comparing TEC vs PTCA in thrombus-containing lesions in native vessels has just been completed.64 This 2.5 mm device has important limitations. It needs a 10F guiding catheter, has a relatively complex set up and limited applicability in native coronary arteries. The Pullback Atherectomy Catheter (PAC) (Arrow International, Inc. Reading, PA, USA) has been used for treatment of bifurcation

FUTURE DIRECTIONS

lesions,65 whereas a randomized trial (PAIR trial) is currently randomizing patients with in-stent restenosis to PAC or PTCA.66

Cutting balloon: ‘the poor man debulking device’ Cutting balloon angioplasty with subsequent stent implantation has been reported occasionally.67–69 Kurbaan et al67 report their experience with a small series of patients in which residual stenosis was 44% after cutting balloon angioplasty, and further reduced to 10% after high-pressure stent deployment. In two more recent studies, the restenosis rate after treatment with the combined approach of cutting balloon angioplasty and stenting was ⬍ 10%.68,69 In general, it is logical to assume that treatment with the cutting balloon prior to stenting may allow for a more complete stent expansion and the achievement of a larger final lumen cross-sectional area. The value of IVUS evaluation in order to properly size the cutting balloon is open to question. The use of an undersized cutting balloon will defeat the purpose of this device. It is for this reason that an appropriate estimation of the plaque thickness may be important; this information is obtained only with IVUS. A randomized study, REDUCE III, has been launched in Japan to evaluate the role of the cutting balloon prior to stenting vs traditional stenting.

Excimer laser angioplasty Excimer laser coronary angioplasty (ELCA), utilizing the photoablative properties of excimer lasers, results in atheroablation, with minimal thermal injury and shock wave effect provided careful saline flush is adopted.70 An IVUS study showed that ELCA increased

lumen area by both atheroablation and vessel expansion without calcium ablation.71 A registry of the first 3000 patients treated with laser in ELCA trial showed the safety and efficacy of ELCA in complex coronary lesions,72 but restenosis was still high (44% for de novo and 49% for restenotic lesions).73 In addition, randomized trials (ERBAC, LAVA, AMRO) comparing ELCA with balloon angioplasty and other atherectomy techniques suggested that ELCA had no additional beneficial effects.74–76 ELCA has also been tried for treatment of in-stent restenosis.77,78 An ongoing randomized trial (LARS trial)78 showed the safety and efficacy of this ablative technique for treatment of in-stent restenosis, while long term data are pending. These results are not very different from the results obtained with the other atheroablative techniques. A few differences compared to the other techniques need to be pointed out. Laser angioplasty seems to cause less distal embolization and usually can be performed with an 8F guiding catheter without the need for dedicated guide wires. The amount of plaque debulking is clearly inferior compared to directional atherectomy, and excimer laser is very much limited in its ablative power by calcium. It may be possible that the recent introduction of the eccentric laser catheter may improve debulking effectiveness. At present no information is available about the role of laser debulking prior to stent implantation.

Future directions The future of debulking technologies depends on the availability of new devices more efficient in plaque removal and more userfriendly.

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DEBULK/STENTING

A new thrombectomy/atherectomy catheter (X-SIZER, EndiCOR, Carlsbad, CA, USA) is currently being tested in thrombi containing native coronary lesions and SVGs. The X-SIZER catheter is a novel single-use device designed to remove thrombi from coronary arteries and SVGs, using standard catheter techniques compatible with 8 Fr guiding catheters and 0.014 inch wires. It consists of a unibody 6F dual lumen catheter with a battery driven hollow torque cable attached to a distal helical cutter. Catheter rotations over any 0.014-inch guide wire under saline flush results in extraction atherectomy into a proximal vacuum chamber. Preliminary data suggest that the use of this new atherectomy device is feasible and safe and efficient in removing thrombi from native coronary arteries and SVGs.79,80 In-stent restenosis is an area where atherectomy devices may have a role. A new atherectomy device (Helixcision Atherectomy) has been tested in a porcine in vivo model of instent restenosis.81 Helixcision utilizes a 4.0F Helixcisor Catheter (Prolifix Medical Inc, CA, USA) placed over a 0.014-inch lumenconforming helical guidewire. The Helixcisor catheter is rotated at 17 500 rpm with internal aspiration of tissue contents. Lumen size is increased by passive mechanical expansion of the guidewire coil diameter. Device sizing is accomplished by varying the guidewire coil diameter, pitch and length. In this initial experience with Helixcision Atherectomy, successful and efficient debulking of the neointima was accomplished with preservation of stent integrity. Additional acute and chronic in vivo studies are in progress. In peripheral interventions a new debulking device (Redha-Cut, Sherine Med, AG, Utzenstorf, Switzerland), which exerts a mechanical atherectomy, is being used to treat in-stent restenosis82 and it could become a new tool to prepare the lumen of the vessel for brachyther-

174

apy or local drug delivery. We do not know about its use in the removal of plaque prior to stenting.

Conclusions The most important condition for survival of the field of debulking lies in the demonstration of a benefit in terms of restenosis and long term outcome when this technique is combined with stenting. The Interventional Community has the responsibility to provide data to support this hypothesis. The Industry, which is the ultimate developer of new debulking devices, needs to know that the efforts and money invested in new technologies will have a clinical application rewarded with benefits for our patients. The next step will be the development of new debulking devices which should be efficient, capable of removing different types of plaque including calcium, easy to use and compatible with 8F guiding catheters, if not with 6F. When a panel of expert interventionists was asked to name the most important features of a debulking device they suggested that lesion access, ability to cut calcium, safety in terms of no distal embolization and 8F guiding catheter compatibility were the most important attributes. Secondary features, but still important, were IVUS guidance incorporated in the device and 6F compatibility. The strategy of debulking prior to stenting must take into account the developments in competing fields such as brachytherapy and local drug delivery. It is reasonable to imagine that restenosis prevention could be conquered by different approaches at the same time. The ultimate winner will not necessarily be the first who arrives at the objectives, but the one who provides the technology, which is most cost effective, easily implemented and with the best guarantee for a long term outcome.

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20. Adelman AG, Cohen EA, Kimball BP et al. A comparison of directional atherectomy with balloon angioplasty for lesions of the left anterior descending artery. N Engl J Med 1993; 329:228–233. 21. Simonton C, Leon MB, Baim DS et al. ‘Optimal’ Directional Coronary Atherectomy: Final results of the Optimal Atherectomy Restenosis Study (OARS). Circulation 1998; 97:332–339. 22. Baim DS, Cutlip CE, Sharma SK et al. Final results of the Balloon vs Optimal Atherectomy Trial (BOAT). Circulation 1998; 97:322–1. 23. Suzuki T, Hosokawa H, Katoh O et al. Effects of adjunctive balloon angioplasty after intravascular ultrasound-guided optimal directional coronary atherectomy. J Am Coll Cardiol 1999; 34:1028–1035. 24. Elliott JM, Berdan LG, Holmes DR et al. Oneyear follow up in the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT I). Circulation 1995; 91:2158–2166. 25. Moussa I, Moses J, Di Mario C et al. Stenting after Optimal Lesion Debulking (SOLD) Registry: angiographic and clinical outcome. Circulation 1998; 98:1604–1609. 26. Bramucci E, Angoli L, Merlini PA et al. Adjunctive stent implantation following directional coronary atherectomy in patients with coronary artery disease. J Am Coll Cardiol 1998; 32:1855–1860. 27. Kobayashi Y, Moussa I, Akiyama T et al. Low restenosis rate in lesions of the left anterior descending coronary artery with stenting following directional coronary atherectomy. Cathet Cardiovasc Diagn 1998; 45:131–138. 28. Stefan Kiesz R, Marius Rozek M, Mego DM et al. Acute directional coronary atherectomy prior to stenting in complex coronary lesions: ADAPTS Study. Cathet Cardiovasc Diagn 1998; 45:105–112. 29. Höpp HW, Baer FM, Özbek C et al. Directional atherectomy prior to stent implantation – the Atherolink registry J Am Coll Cardiol 2000; 36:1853–1859. 30. Kugelmass A, Cohen C, Moscucci M et al. Elevation of creatine kinase myocardial isoform following otherwise successful directional coronary atherectomy and stenting. Am J Cardiol 1994; 74:748–754.

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31. Harrington R, Lincoff A, Califf R et al. Characteristics and consequences of myocardial infarction after percutaneous coronary interventions: insights from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). J Am Coll Cardiol 1995; 25:1693–1699. 32. Lefkovits J, Blankenship JC, Anderson KM et al. Increased risk of non-Q wave myocardial infarction after directional atherectomy is platelet dependent: evidence from the EPIC (Evaluation of the c7E3 for the Prevention of Ischemic Complications) trial. J Am Coll Cardiol 1996; 28:849–855. 33. Dehmer GJ, Nichols TC, Bode AP et al. Assessment of platelet activation by coronary sinus blood sampling during balloon angioplasty and directional coronary atherectomy. Am J Cardiol 1997; 80:871–877. 34. Kong TQ, Davidson CJ, Meyers SN et al. Prognostic implication of creatine kinase elevation following elective coronary artery interventions. JAMA 1997; 277:461–466. 35. Tardiff BE, Califf RM, Tcheng JE et al, for the IMPACT-II Investigators. Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention. J Am Coll Cardiol 1999; 33:88–96. 36. Kini A, Marmur JD, Kini S et al. Creatine kinase-MB elevation after coronary intervention correlates with diffuse atherosclerosis, and low-to-medium level elevation has a benign clinical course. J Am Coll Cardiol 1999; 34:663–671. 37. Mehran R, Dangas G, Mintz GS et al. Atherosclerotic plaque burden and CK-MB enzyme elevation after coronary interventions: intravascular ultrasound study of 2256 patients. Circulation 2000; 101:604–610. 38. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high risk coronary angioplasty. N Engl J Med 1994; 330:956–961. 39. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336:1689–1696. 40. The EPISTENT Investigators. Randomized

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51. Safian RD, Niazi KA, Strzelecki M et al. Detailed angiographic analysis of high speed mechanical rotational atherectomy in human coronary arteries. Circulation 1993; 88:961–968. 52. Warth DC, Leon MB, O’Neil W et al. Rotational atherectomy multicenter registry: acute results, complications and 6-month angiographic follow-up in 709 patients. J Am Coll Cardiol 1994; 24:641–648. 53. George B. Theoretical and clinical aspects of slow-flow and no-reflow phenomenon. J Invasive Cardiol 1996; 8:10C–15C. 54. Sharma S, Dangas G, Mehran R et al. Risk factors for the development of slow flow during rotational coronary atherectomy. Am J Cardiol 1997; 80:219–222. 55. Williams MS, Coler BS, Vàànànen HJ et al. Activation of platelets in platelet-rich plasma by rotablation is speed-dependent and can be inhibited by abciximab (c7E3 Fab; Reopro). Circulation 1998; 98:742–748. 56. Koch KC, Vom Dahl J, Kleinhans E et al. Influence of a platelet GPIIb/IIIa receptor antagonist on myocardial hypoperfusion during rotational atherectomy as assessed by myocardial TC-99m sestamibi scintigraphy. J Am Coll Cardiol 1999; 33:998–1004. 57. Reisman M, Harms V, Whitlow P et al. Comparison of early and recent results with rotational atherectomy. J Am Coll Cardiol 1997; 29:353–357. 58. Levin TN, Holloway S, Feldman T. Acute and late clinical outcome after rotational atherectomy for complex coronary disease. Catheter Cardiovasc Diagn 1998; 45:122–130. 59. Kini A, Marmur JD, Duvvuri S et al. Rotational atherectomy: improved procedural outcome with evolution of technique and equipment. Single-center results of first 1000 patients. Catheter Cardiovasc Intervent 1999; 46:305–311. 60. Bersin RM, Cedarholm JC, Kowalchuk GJ, Fitzgerald PJ. Long-term clinical follow-up of patients treated with the coronary rotablator: a single-center experience. Catheter Cardiovasc Intervent 1999; 46:399–405. 61. Hoffman R, Mintz GS, Kent KM et al. Comparative early and nine-month results of rotational atherectomy, stents, and the

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73. Reeder GS, Bresnahan JF, Holmes DR et al, for the ELCA Investigators. Excimer Laser Coronary Angioplasty: results in restenosis vs de novo coronary lesions. Cathet Cardiovasc Diagn 1992; 25:195–199. 74. Reifart N, Vandormael M, Krajcar M et al. Randomized comparison of angioplasty of complex coronary lesions at a single center. Excimer Laser, Rotational Atherectomy, and Balloon Angioplasty Comparison (ERBAC) study. Circulation 1997; 96:91–98. 75. Appelman YEA, Piek JJ, Strikwerda S et al. Randomized trial of excimer laser vs balloon angioplasty for treatment of obstructive coronary artery disease. Lancet 1996; 347:79–84. 76. Stone GW, De Marchena E, Dageforde D et al, for the Laser Angioplasty Versus Angioplasty (LAVA) Trial Investigators. J Am Coll Cardiol 1997; 30:1714–1721. 77. Mehran R, Mintz GS, Satler LF et al. Treatment of in-stent restenosis with Excimer Laser Coronary Angioplasty: mechanisms and results compared with PTCA alone. Circulation 1997; 96:2183–2189. 78. Kòster R, Hamm CW, Seabra-Gomes R et al, for the Laser Angioplasty of Restenosed Stents (LARS) Investigators. Laser Angioplasty of restenosed coronary stents: results of a multicenter surveillance trial. J Am Coll Cardiol 1999; 34:25–32. 79. Stone GW, Cox D, Low RI et al. First United States experience with a novel atherectomy and thrombectomy device in thrombotic lesions in native coronary arteries and saphenous vein grafts. J Am Coll Cardiol 2000; 35(Suppl A):40 (abst). 80. Ischinger TA. A novel device for removal of thrombus from coronary arteries: the X-SIZER Multicenter Trial. J Am Coll Cardiol 2000; 35(Suppl A):41 (abst). 81. Davidson CJ, Gershony G, Lo S et al. Helixcision atherectomy for in-stent restenosis: initial in vivo experience. J Am Coll Cardiol 2000; 35(Suppl A):41(abst). 82. Link J, Voshage G, Brossmann J et al. Initial experience with the REDHA-CUT atherectomy device in high grade restenoses after previous PTA. Cardiovasc Intervent Radiol 1998; 21(Suppl I):S83.

12 Management of in-stent restenosis Richard A Howard and Alice K Jacobs

The use of coronary stents has increased exponentially since their introduction into clinical practice in the early 1990s. It is currently estimated that stents are used in 60–70% of all percutaneous coronary revascularization procedures. Enthusiasm for the widespread use of stents is based not only on the ability to achieve a large, smooth lumen and effectively treat acute or threatened vessel closure but also upon their ability to reduce restenosis.1–4 However, with the increased use of coronary stents, in-stent restenosis has developed as an important clinical problem. The reaction to the placement of a coronary stent has been shown to involve both the stented and adjacent vessel and consists of a combination of intimal hyperplasia and tissue remodeling, which tapers off as the distance from the stented segment increases.5 In-stent restenosis is generally defined as a 50% or greater narrowing within, or at the proximal or distal sites of (or ⬍ 5 mm from) a previously placed stent.6 Recurrent in-stent restenosis is defined as a 50% or greater stenosis, which occurs more than 1 month after treatment of in-stent restenosis. Rates of primary and recurrent in-stent restenosis vary considerably depending on many factors including whether the initial lesion was ‘focal’ (⬍ 10 mm in length) or diffuse (ⱖ 10 mm in length). In-stent restenosis is mainly the result of

neointimal hyperplasia which grows into the lumen of the stent and creates a stenosis. This chapter will focus on the management of in-stent restenosis and will provide the interventional cardiologist with an evidencebased approach for dealing with this vexing clinical problem.

Pathophysiology and incidence In comparison to balloon angioplasty, coronary stents have the potential to prevent negative remodeling and recoil and several studies have shown that stent recoil and stent compression does not occur.4,7 The need for repeat intervention, instead, is mainly due to tissue ingrowth, or neointimal hyperplasia.5 While angioplasty has also been shown to stimulate neointimal hyperplasia, recent studies using intravascular ultrasound have shown that stenting evokes this response to a greater degree.8 The placement of the stent results in disruption of the endothelial barrier and the medial smooth muscle layer. The physical presence of the stent also induces a giant cell-based inflammatory reaction centered on the stent strut.9 These stimuli, in turn, induce smooth muscle cell migration through the internal elastic lamina and proliferation in the newly formed intima.10 Exposure of the disrupted intima to

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MANAGEMENT OF IN-STENT RESTENOSIS

circulating blood factors and mitogens, such as thrombin, platelet derived growth factor, interleukin-1, insulin growth factor, and basic fibroblast growth factor also contributes to the hyperplastic response seen in the neointima.11 The end result is tissue ingrowth, which narrows the lumen of the stented coronary artery resulting in in-stent restenosis. The actual rates of in-stent restenosis vary according to many factors, such as the size of the vessel, the location of the lesion in a native vessel or in a vein graft, the length of the stented segment, the number of stents deployed, and the presence of comorbid conditions such as diabetes mellitus.12 Indeed, the rates of in-stent restenosis have ranged from 14% to 80%.13–15 The factors influencing whether in-stent restenosis occurs and whether neointimal hyperplasia is focal or diffuse are not completely understood.

Therapeutic options Current approaches in the management of instent restenosis have focused on neointimal compression or ablation within the stent and most recently, intracoronary radiation has been shown to be effective in the treatment of this problem (see Chapter 14).

Coronary balloon angioplasty Balloon angioplasty has been a mainstay in the percutaneous management of coronary artery disease since its introduction into clinical practice in 1977. It is not surprising, then, that it was one of the first and most widely studied techniques utilized in the management of in-stent restenosis. The majority of the studies are small, usually reporting the outcomes in 100 patients or less, and retrospective or prospective in nature. The Palmaz–Schatz coronary stent has been the

180

most widely studied stent design, which may make it difficult to apply the results of these trials to other stent designs. Nonetheless, important information and conclusions may be obtained by reviewing the results of the major studies (Table 12.1). Most trials investigating the utility of coronary angioplasty in the management of in-stent restenosis utilized ‘high’ inflation pressures of approximately 13–15 atm16–19 and balloon-to-artery ratios ⬎ 1. Other standard therapies, such as heparin and aspirin, were employed. Adenosine diphosphate inhibitors of platelet aggregation, such as ticlopidine, were generally not administered following repeat intervention, with one exception.16 Glycoprotein IIb/IIIa platelet inhibitors were generally not given in these studies.

Procedural success and complications The initial angiographic and procedural success rates for coronary angioplasty in treating in-stent restenosis have been excellent. Success rates ranging from 95% to 100% have been reported.16,18,20 While the definition of success varies somewhat among studies, it generally refers to a final residual stenosis ⱕ 30%, although some trials use 50%. Coronary angioplasty for in-stent restenosis has been shown to be safe, without instances of abrupt closure, acute myocardial infarction, urgent coronary bypass surgery, dissection or thrombus formation reported in over 200 patients treated.6,20 Many studies did not mention complication rates, however,16–19 and routine measurement of cardiac enzymes was usually not performed. Coronary angioplasty was successful in increasing luminal diameter. The percentage

56 consecutive prospective




52 64 lesions

105

Alfonso19

Eltchaninoff20

Reimers18

Bauters16

Mehran17

Baim6

QCA

QCA

QCA

QCA

QCA or IVUS

Balloon angioplasty

Caliper

Balloon IVUS angioplasty 14.3 atm 53% ⬎ 16 atm. B/A 1.39 ⫾ 2.6

Balloon angioplasty 87% 12.8 atm Stent 13%

Balloon angioplasty Mean 15.5 atm 59% ⬎ 14 atm B/A 1.16

Balloon angioplasty 10 atm B/A 1

Balloon angioplasty 9.9 atm B/A 1

Method

PS

PS

PS 55% Witkor 36% Other 9%

Other 7%

PS 83% Wall 6% G-R 4%

PS 63% AVE 13%

Stent type

Focal 71% Diffuse 29%



Lesion length

Angio 48% 6 ⫾ 2 months

Angio 85% 6.3 ⫾ 2.1 months

Clinical 100%, ETT 71%,

Angio 100% 5.73 months, Clinical 92% 5.3 ⫾ 4 months

Clinical 58% 14 ⫾ 20 months

Follow-up

54%

Overall 22% Focal 14% Diffuse 42% (p ⬍ 0.06) PTCA 22% Stent 15%

Other 7%

Overall 54% Focal 31% Diffuse 63% (p ⫽ 0.046)

45%

Recurrent restenosis

56%

17%

11%

Overall 35% Focal 8% Diffuse 49% (p ⫽ 0.009)

18%

TVR

Diffuse lesions, severe in-stent Restenosis (⬎70%)

Saphenous vein graft, LVEF ⬍ 30%, multi-vessel disease, short time to restenosis (⬍ 3 months)

Diffuse pattern

Diabetes mellitus, short time to restenosis (⬍ 3 months)

Predictors

Established mechanisms by which balloon angioplasty increases lumen size: Stent expansion 56% ⫾ 28%, tissue extrusion/ compression 44 ⫾ 28%

No routine angiographic follow-up

High angio follow-up, low inflation pressures

Comment

Table 12.1 Coronary balloon angioplasty in the management of in-stent restenosis.

ACC/AHA ⫽ American College of Cardiology/American Heart Association; Angio ⫽ angiography; Atm ⫽ atmospheres; AVE ⫽ Applied Vascular Engineering stent; B/A ⫽ balloon to artery ratio; Burr/A ⫽ burr to artery ratio; DCA ⫽ directional coronary atherectomy; Diffuse ⫽ ⬎ / ⫽ 10 mm in length; ELCA ⫽ excimer laser coronary angioplasty; ETT ⫽ exercise treadmill test; Focal ⫽ lesion ⬍ 10 mm in length; G-R ⫽ Gianturco–Roubin stent; IVUS ⫽ intravascular ultrasound; LVEF ⫽ left ventricular ejection fraction; MLD ⫽ minimal luminal diameter; mm ⫽ millimeter; NS ⫽ non significant; PS ⫽ Palmaz–Schatz stent; QCA ⫽ quantitative coronary angiography; RA ⫽ rotational atherectomy; TVR ⫽ target vessel revascularization; Wall ⫽ wallstent

Number of patients

Author

PROCEDURAL SUCCESS AND COMPLICATIONS

181


luminal stenosis decreased from 70% to 80% to approximately 20%, as measured by quantitative coronary angiography16,19 with one study reporting a final luminal stenosis of 6%.18 The acute lumen gain was 2.0–2.2 mm18,19 with an increase in minimal lumen diameter from 0.85 mm at baseline to 2.3 mm after intervention reported in one trial with over 100 patients.16 Although coronary angioplasty has proven successful in increasing luminal diameter in the treatment of in-stent stenosis, it has also become apparent that the final angiographic result is not as good as that obtained following the initial stent placement. The minimal lumen diameter obtained is consistently and significantly less than that of the original stent placement (2.3 vs 2.91 mm).16 The acute luminal gain (2.01 vs 2.36 mm) and the final cross-sectional area (6.12 vs 7.2 mm2) are less, while the final residual percent stenosis is greater (21% vs 12%) following the original stent deployment in comparison to subsequent balloon dilation of the in-stent stenosis.19 Serial intravascular ultrasound studies have shown that stent dimensions do not change over time,7,14 thus eliminating stent recoil as an explanation. The presence of residual neointimal hyperplasia, which was not extruded through the stent, limiting the struts in addition to the residual plaque, media and adventitia, may contribute to the comparatively smaller luminal expansion. These findings led to the enthusiasm for tissue debulking procedures in the treatment of in-stent restenosis. Mechanisms of luminal gain following coronary angioplasty Neo-intimal compression and extrusion through the stent struts and further stent expansion seem to contribute to the luminal gain following angioplasty. In an important

182

trial that utilized intravascular ultrasound, Mehran et al,17 systematically studied vessel characteristics before and after coronary angioplasty for in-stent restenosis. Balloon angioplasty was performed with an average inflation pressure of 14.3 atm. In the majority of cases (53%), inflation pressures greater than 16 atm were used. The cross-sectional area increased from 2.3 to 6.1 mm2 following angioplasty, and the increase was significantly less than that following the initial stenting procedure. In addition, it was determined that 56% ⫾ 28% of the luminal gain was due to expansion of the stent, while 44% ⫾ 28% was due to tissue extrusion from, or redistribution within, the stent. Complication rates and follow-up were not provided. Similar observations were noted in a trial comparing rotational atherectomy and balloon angioplasty in the treatment of diffuse in-stent restenosis.21 In this trial, 44% of the luminal gain obtained was owing to further expansion of the stent. Recurrent in-stent restenosis and target vessel revascularization The rates of recurrent in-stent restenosis following coronary angioplasty vary. Rates as low as 10%18 and as high as 80%15 have been reported. At least part of this variability relates to a lack of consistent methods of follow-up. In a minority of studies, angiography was performed in all patients. In some trials, angiography was performed only in symptomatic patients, while in other trials, stress testing was performed in all patients and angiography performed only for symptoms or exercise tests revealing an ischemic response. ‘Clinical’ restenosis, with angiography dictated by symptoms or abnormal stress test, may be a more relevant marker in clinical practice. With these considerations in mind, trials with systematic angiographic


follow-up in all patients reported recurrent in-stent restenosis rates ranging from 22%16 to 54%.20 Those trials in which patients underwent clinical follow up with angiography dictated by symptoms or positive exercise tests reported recurrent in-stent restenosis rates ranging from 45%19 to 54%.6 While differences in trial design and follow-up may partly explain discrepancies in reported rates of recurrent in-stent restenosis, other factors have also been identified. The length of the lesion treated also plays a role. Diffuse (ⱖ 10 mm) lesions tended to have higher rates of recurrent in-stent restenosis than focal (⬍ 10 mm) lesions. In one study,20 the overall rate of recurrent in-stent restenosis was 54%. However, the rate was 63% in the 71% of lesions that were diffuse in length compared to 31% in the lesions that were focal in length. In a similar study,16 the overall rate of recurrent in-stent restenosis was 22% with a rate of 14% in focal lesions and 42% in diffuse lesions. In addition, it has been shown that rates of recurrent in-stent restenosis increase as the segment length stented increases without an increase in the incidence of subacute stent thrombosis.12 Clearly, it is important to examine these variables when comparing studies dealing with the management of in-stent restenosis. Target vessel revascularization is often used as a surrogate for in-stent restenosis in trials lacking routine angiographic follow-up and may be the more important clinical outcome. Similar to the rates of recurrent instent restenosis, there is variability in rates of target vessel revascularization among the various trials. Rates ranging from 11%18 to 56%6 have been reported. The reported rates are influenced by the method of follow-up, and are higher in trials employing routine angiography.22 Lesion length also influences target vessel revascularization. A rate of 49%

was reported in one study in which 71% of the initial lesions were diffuse.20 In this same trial, the rate of target vessel revascularization was 8% in focal lesions. Using multivariate analysis, several variables have been identified which predict recurrent in-stent restenosis and target vessel revascularization (Table 12.1) and include lesion length,16,20 diabetes mellitus,19,23 and brief interval between initial stent deployment and in-stent restenosis.18,19 In one study,19 patients with diabetes mellitus and a short time to the occurrence of in-stent restenosis (⬍ 3 months), were found to have more clinical events (myocardial infarction, death, and target vessel revascularization). The Evaluation of Platelet IIb/IIIa Inhibitor for Stenting Trial (EPISTENT) diabetic substudy23 demonstrated higher rates of death, myocardial infarction and target vessel revascularization in diabetic patients receiving stents in comparison to non-diabetic patients. Furthermore, when diabetic patients were stratified according to the presence of the clinical syndrome of insulin resistance (obesity, diabetes, hypertension), the rate of target vessel revascularization was more than twice that of diabetics without the insulin resistance syndrome. In other trials, interventions in saphenous vein grafts18 were predictive of recurrent in-stent restenosis. These findings are consistent with the known high restenosis rates observed in saphenous vein grafts in other trials24,25 with restenosis rates as high as 70% reported. Finally, tobacco use also was identified as a risk factor for restenosis.26 Of note, these trials contain relatively small numbers of patients and many trials lack the power to determine significant differences in the variables studied. Although the type of stent used in the initial procedure does not appear to affect recurrent in-stent restenosis and target

183


vessel revascularization rates, the Palmaz–Schatz stent design has been used in most of the studies reported and therefore precludes this type of assessment. Several conclusions may be drawn from these studies 1. Coronary balloon angioplasty is safe and effective for the management of in-stent restenosis with a low reported incidence of dissection, myocardial infarction, and urgent coronary bypass surgery despite relatively high inflation pressures. 2. The rate of recurrent in-stent restenosis and target vessel revascularization are lowest for focal lesions in native coronary arteries. Coronary angioplasty appears to be the procedure of choice for these lesions. 3. Coronary angioplasty increases the lumen diameter and cross-sectional area through a combination of tissue extrusion and compression within the stent, coupled with significant further stent expansion as demonstrated by intravascular ultrasound. 4. Despite a high success rate and significant decreases in luminal stenosis, the angiographic and ultrasound-measured results following coronary angioplasty for in-stent restenosis are inferior to those obtained after the initial placement of the stent. This is likely because of residual neointimal hyperplasia that was not extruded though the stent struts despite high inflation pressures. 5. The rates of recurrent in-stent restenosis and target vessel revascularization are unacceptably high for diffuse lesions, and for lesions located in saphenous vein grafts. Other predictors of recurrent instent restenosis are the presence of diabetes mellitus and short interval (⬍ 3 months) to in-stent restenosis.

184

Tissue ablation Since in-stent restenosis is predominantly due to neointimal hyperplasia, techniques aimed at removing the neointimal tissue have been investigated. This section will focus on directional coronary atherectomy, rotational atherectomy, and excimer laser coronary angioplasty (Tables 12.2, 12.3, 12.4).

Directional coronary atherectomy In one of the largest studies of directional coronary atherectomy for treating in-stent restenosis, Mahdi et al27 studied 45 patients with mostly diffuse (76%) in-stent restenosis in Palmaz–Schatz stents (Table 12.2). The average lesion length was not provided. Intravascular ultrasound was utilized in 40% of patients. The technique proved effective, with a 100% procedural success rate, and safe, with no reports of abrupt closure, noreflow, stent dislodgment or disruption. NonQ-wave myocardial infarction occurred in four patients (9%). Two patients required additional stent placement for edge dissections. Importantly, directional coronary atherectomy decreased diameter stenosis from 75 ⫾ 12 to 17 ⫾ 10% (p ⫽ 0.001), and increased the minimal lumen diameter from 0.8 ⫾ 0.5 to 2.7 ⫾ 0.7 mm (p ⫽ 0.0001). The mean luminal cross-sectional area increased from 3.34 ⫾ 1.17 to 7.20 ⫾ 1.74 mm2 (p ⫽ 0.0001), and the cross-sectional area of neointimal hyperplasia decreased from 5.05 ⫾ 1.96 to 2.0 ⫾ 0.70 mm2 (p ⫽ 0.0001). Initial minimal lumen diameter and crosssectional area following stent placement were not provided for comparison. However, the reference vessel diameter (2.9 ⫾ 0.6 mm) compared favorably to the vessel diameter following directional coronary atherectomy (2.7 mm). There was a nonsignificant trend



45 49 lesions prospective


153 lesions Registry

Mahdi27

vom Dahl33

Radke21

Sharma35

Goldberg34 RA 28% Burr/A 0.7 RA/balloon angioplasty 72%

RA/balloon angioplasty 4.2 ⫾ 2.1 atm B/A 1.1 Burr/A 0.7

RA/balloon angioplasty 8 atm B/A 1.3 Burr/A 0.8

RA/balloon angioplasty 8 atm Burr/A⬎ / ⫽ 0.7

DCA/Balloon angioplasty 11 atm B/A 1.1 85% used 7 French device

Method

QCA 100% IVUS 37%

QCA 100% IVUS 100%

QCA 100% IVUS 88%

QCA 100% IVUS 8/45

QCA or IVUS

Palmaz– Schatz 90%

Various

Various (excluded coil)

Palmaz– Schatz

Stent type

Focal 15% Diffuse 85% Mean 21 ⫾ 12 mm

Focal 19% Diffuse 81% Mean 17 ⫾ 11 mm

Mean 22.4 ⫾ 20 mm 94% ⬎ 10 mm

Mean 21.8 mm


Lesion length

Clinical 100% 6 ⫾ 3 months

Clinical 100%, angio 44% 13 ⫾ 5 months

Angio 89% 6.6 ⫾ 2.5 months

Clinical 100%, angio 72% 5 ⫾ 4 months

Clinical 100% 10 ⫾ 4.6 months

Follow-up

50% RA alone 67% RA/balloon Angioplasty 42% (p ⫽ 0.01)

28%

Overall 49% ⬍ 10 mm–9% 11–20 mm–42% 21–40 mm–69% ⬎ 40 mm–78% 45%


40%

26%

38%

35%

29%

TVR

Early restenosis (⬍ 3 months), Burr/A ⬍ 0.6 Ostial lesions ACC/AHA, TYPE C lesions None

Neo-intimal recoil

Saphenous vein grafts, Smaller MLD (post-procedure), lesion length, early restenosis (⬍ 3 months) Lesion length, early restenosis (⬍ 3 months)

Predictors

2 under-deployed stents found by IVUS, no stent destruction, NQWMI 2% MLD underestimated by QCA, no stent destruction/ NQMI, demonstrated acute recoil 22% stents underdeployed by IVUS, demonstrated acute recoil, no stent destruction Established importance of adjunctive balloon angioplasty with RA, safe; no burr entrapment

Safe/feasible, no systematic angio, TVR used as surrogate for recurrent restenosis

Comments

Table 12.2 Directional and rotational atherectomy in the management of in-stent restenosis.


Number of patients

Author


185

186

52 randomized



160 202 lesions retrospective cohort

Roster38

Lee39

Dauerman31

Jolly26

RA/balloon angioplasty 13 atm, Burr/A ⬍ 0.7 vs balloon angioplasty 12 atm RA/balloon angioplasty 13, 3 atm, burr/A 0.6–0.8 versus balloon angioplasty 11.9 atm RA/balloon angioplasty 9.8 atm, burr/A 0.75 B/A 1.17 balloon angioplasty 12.3 atm B/A 1.11

RA/balloon angioplasty 4.4 atm, Burr/A 0.7 vs balloon angioplasty 12 atm

Method

QCA

QCA

QCA

IVUS

QCA or IVUS

Focal 32% Diffuse 68% RA/balloon angioplasty mean 18.4 mm balloon angioplasty mean 13.5 mm Focal 56% Diffuse 44% RA/balloon angioplasty mean 13.4 mm balloon angioplasty mean 10.51 mm

Diffuse

Mean 13.9 ⫾ 4.0 mm

Lesion length

Clinical 8 months

Clinical 1, 3, 12 months

Clinical 1, 3, 6 months

Clinical 5 ⫾ 3 months

Follow-up

RA/balloon angioplasty 25%, balloon angioplasty 47% (p ⬍ 0.05)

RA/balloon angioplasty 4% (1 patient) vs balloon angioplasty 27% (7 patients) p ⫽ 0.03


RA/balloon angioplasty 16% balloon angioplasty 21% (p ⫽ 0.9)

RA 28% balloon angioplasty 46% (p ⫽ 0.18)

RA/balloon angioplasty 0% balloon angioplasty 45% (p ⫽ NS)

TVR

Smoking, saphenous vein graft location

Diabetes mellitus lesion length MLD (post-procedure) Final % stenosis

Predictors

Underpowered to detect difference in TVR

Underpowered to detect difference in TVR

No complications RA/balloon angioplasty: 74% luminal gain due to debulking 26% due to tissue compression/extrusion balloon angioplasty: 62% luminal gain due to compression 38% due to further stent expansion Angina-free survival 72% RA versus 49% balloon angioplasty (p ⫽ 0.02)

Comments

Table 12.3 Coronary balloon angioplasty compared with rotational atherectomy in the management of in-stent restenosis.


Number of patients

Author


70 107 lesions

440 527 lesions prospective

98 107 lesions retrospective

Koster44

Koster45

Mehran47 ELCA/ balloon angioplasty 16.5 atm B/A 1.42 vs balloon angioplasty 15 atm B/A 1.33

ELCA/ balloon angioplasty 13 atm

ELCA/ balloon angioplasty

Method

QCA 100% IVUS 100%

QCA (no core lab)

QcA 100% IVUS (20%)

QCA or IVUS

AVE 26% Palmaz– Schatz 19% G-R 9% Witkor 8% Multilink 6% Palmaz– Schatz

Palmaz– Schatz 30% AVE 61% Other 3%

Stent type

Focal 48% Diffuse 52% mean 13 mm

Focal 29% Diffuse 71% mean 19 mm 82% ⬎ 10 mm

Focal 13% Diffuse 87% mean 14 mm

Lesion length

1, 3, 6 months phone/office visit

In-hospital

In-hospital

Follow-up

ELCA 21% PTCA 38% (p ⫽ 0.08)

TVR

Ostial lesions Initial decrease MLD

Predictors

ELCA more effective in diabetics, longer lesions Large volume neointima remained (? due to single pass with catheter)

No follow-up Safe – 10% dissections 2 minor perforations 1 stent disruption Laser related 1.4% Established eccentric catheter ⬎ 2 mm as optimal

Comments

Table 12.4 Excimer laser coronary angioplasty in the management of in-stent restenosis.


Number of patients

Author


187


(p ⫽ 0.07) toward an increase in stent crosssectional area. That further stent expansion did not occur may be explained by lower balloon pressures used during adjunctive angioplasty in comparison with the coronary angioplasty trials. Rates of recurrent in-stent restenosis were not provided in this trial. Instead, all patients underwent angiography for recurrent symptoms or an abnormal exercise test. Target vessel revascularization was used as a surrogate for in-stent restenosis, and a rate of 29% (13/46 patients) was observed. After excluding interventions performed in saphenous vein graft locations, multiple stepwise regression analysis identified minimal lumen diameter following directional coronary atherectomy as the only predictor of target vessel revascularization. Directional coronary atherectomy proved safe and effective in this trial, with a favorable rate of target vessel revascularization in these diffuse restenotic lesions. However, target vessel revascularization was not separated according to lesion length. The authors recommended the use of intravascular ultrasound prior to directional coronary atherectomy to exclude underdeployed or mal-deployed stents. Although results from this study seem favorable, directional coronary atherectomy in the treatment of in-stent restenosis has received relatively little attention likely owing to safety concerns as well as the decreased use of this technique overall. There have been several reports of stent disruption during directional coronary atherectomy28–30 and the recovery of small segments of stent struts has been noted.31 Despite these findings, there have been no adverse outcomes including subacute stent thrombosis. In fact, the presence of a stent may theoretically help protect against vessel disruption. Intravascular ultrasound may help to minimize risk by exclud-

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ing underdeployed stents prior to atherectomy, guiding tissue removal, and providing maximal gain.

Rotational atherectomy Although rotational atherectomy has been designed for the treatment of heavily calcified lesions in native vessels, intravascular ultrasound has demonstrated that rotational atherectomy effectively ablates non-calcified plaque,32 implicating a potential role for this technique in the treatment of in-stent restenosis (Fig. 12.1). To date, rotational atherectomy has been studied in several trials in over 500 patients (Table 12.2). Various stent designs have been studied, although the Palmaz–Schatz stent was used most frequently.33 A stepped burr approach with typical burr-to-artery ratios of 0.7–0.8 and saline flushes were utilized in most trials. Findings from the Rotational Atherectomy or Balloon Angioplasty in the Treatment of Intra-stent Restenosis (BARASTER) registry emphasized the importance of adjunctive coronary angioplasty.34 In this registry, a larger minimal lumen diameter (1.9 vs 2.2 mm) and lower rates of recurrent in-stent restenosis (67% vs 42%) were observed when coronary angioplasty was performed in addition to rotational atherectomy. Since this important study was published, the use of adjunctive coronary angioplasty following rotational atherectomy has become standard. In the rotational atherectomy trials that followed, coronary angioplasty was performed with non-compliant or minimally compliant balloons and inflation pressures ranging from 4 to 11 atm. Lesions were generally diffuse in nature, with average lesions measuring 17–22 mm in length. Measurements were made using quantitative coronary angiography; intravas-

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(a)

(c)

(b)

Figure 12.1 Single frame cineangiogram of the right coronary artery in the left anterior oblique position in a 65-year-old patient with recurrent angina in an unstable pattern two months following percutaneous intervention with a 3.5 ⫻ 15 mm stent (a) revealing diffuse in-stent restenosis; (b) after rotational atherectomy using a 1.5 and 2.0 mm burr; and (c) after dilation with a 3.75 mm balloon at 12 atm.

cular ultrasound was used in the majority of lesions, especially in the more recent trials. Procedural success and complications In general, rotational atherectomy was safe and effective. Procedural success ranged from 97% to 100%. There were no cases of stent disruption or dislodgment reported. In fact, in one study intravascular ultrasound

revealed that 22% of stents were underdeployed.35 There was a 1% incidence of dissection in one trial33 and a 7% incidence of minor dissections in another trial.35 Both trials managed these dissections with stents and there were no major sequelae reported. In one trial35 three patients (3%) developed a rise in creatine kinase isoenzymes to greater than three times normal without significant

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clinical sequelae. In another trial,33 only a rise in troponin I was noted. Otherwise, there were no reported cases of Q-wave or non-Qwave myocardial infarction, death, urgent coronary bypass surgery, or abrupt vessel closure. Slow-flow occurred in only 3% of patients in the two trials33,35 and in none of the patients in the other trials, including the BARASTER registry.34 Indeed, the rates of complications reported in these trials seem lower than those reported in trials studying rotational atherectomy in native coronary arteries.36 The comparatively lower complication rate observed using rotational atherectomy in the treatment of in-stent restenosis was attributed to the absence of calcification, which could, in turn, decrease the incidence of distal embolization. In addition, stent struts may offer protection against damage to the vessel. The combination of rotational atherectomy with adjunctive coronary angioplasty was effective in improving luminal dimensions. In one study33 the percentage diameter stenosis decreased significantly, from an average of 76 ⫾ 19 to 32 ⫾ 10% following rotational atherectomy. With adjunctive coronary angioplasty using an average inflation pressure of 8 atm, the final residual stenosis was 21 ⫾ 10%, which was still significantly greater than the 12% stenosis observed after placement of the original stent. The minimal lumen diameter increased from 0.56 ⫾ 0.24 to 1.77 ⫾ 0.19 mm following rotational atherectomy, to 2.02 ⫾ 0.23 mm following adjunctive coronary angioplasty. This, again, was less than the minimal lumen diameter of 2.29 ⫾ 0.33 mm observed after placement of the original stent. The luminal cross-sectional area increased significantly, from 2.4 ⫾ 0.5 to 4.4 ⫾ 0.9 mm2 following rotational atherectomy to 5 ⫾ 1.1 mm2 following coro-

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nary angioplasty. The stent cross-sectional area did not change. Two other studies21,35 also revealed a decrease in percent diameter stenosis, an increase in minimal lumen diameter and an increase in cross-sectional area. Neither of these trials provided measurements after the initial stent placement for comparison. However, in both trials the minimal lumen diameter obtained after rotational atherectomy and adjunctive coronary angioplasty was less than that of the reference minimal lumen diameter (1.89 vs 2.22 mm21 and 2.56 vs 3.13 mm35). The stent cross-sectional area did not change in one study35 perhaps because of low inflation pressures (4.2 ⫾ 2.1 atm), and increased significantly in another study21 from 7.59 to 8.49 mm2. Mechanisms of luminal gain following rotational atherectomy and adjunctive coronary angioplasty Intravascular ultrasound was used to study the relative contributions of each technique to the gain in lumen dimensions. In the study by Sharma,35 it was calculated that 77% of the luminal gain was owing to removal of neointimal hyperplasia via rotational atherectomy, and 23% was secondary to compression or extrusion of neointimal hyperplasia via coronary angioplasty. In the study by Radke,21 it was calculated that 37 ⫾ 11% of the luminal gain was due to rotational atherectomy, and 14 ⫾ 10% was due to compression or extrusion of the neointima. In addition, 46 ⫾ 15% of the luminal gain was due to stent expansion. It is interesting that in two of the above trials,33,35 the stent cross-sectional area did not change. Therefore, further stent expansion, as was seen with previous studies of coronary angioplasty17 and with rotational atherectomy,21 did not occur. One explanation is

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that comparatively lower inflation pressures were used. There may be other explanations for the failure to obtain optimal lumen dimensions in these trials. It was observed that the minimal lumen diameter was less than the final burr size used by roughly 10–15%.21,35 This was explained by the presence of plaque recoil, or in this case, neointimal recoil. The most recoil seemed to occur in the arteries with the largest plaque burden. Such recoil has been demonstrated in non-stented and non-calcified lesions32 but not in fibrotic and calcified lesions.36,37 Another explanation may be focal plaque ablation. Neointimal tissue is usually not evenly distributed along the length of the lesion. As a result, the Rotablator may only remove tissue accessible to the device. Ineffective cutting may also be due to ‘skipping’ of the burr into distal segments of the vessel. Recurrent in-stent restenosis and target vessel revascularization The rate of recurrent in-stent restenosis ranged from 28–49%.21,33–35 In the studies by vom Dahl,33 Radke21 and the BARASTER registry34 (the latter with the use of adjunctive coronary angioplasty), the recurrent instent restenosis rates were nearly identical, and ranged from 42% to 49%. These were higher than the 28% observed in the trial by Sharma.35 In two of the studies,21,33 angiography was performed in 72% and 89% of patients, whereas in the study by Sharma,35 angiography was performed in only 44% of patients. In addition, the trials with higher recurrent in-stent restenosis rates contained longer lesions (21 and 22 mm),21,33,34 compared to the study by Sharma,35 which may have further influenced recurrent restenosis. In fact, as was appreciated with the studies of coronary angioplasty for in-stent restenosis,

longer lesions had higher restenosis rates. In lesions 11–20 mm in length, the recurrent instent restenosis rate was 42%; in lesions 21–40 mm, the rate was 69%, and in lesions greater than 40 mm, the rate was 78%.33 Conversely, there may have been other factors causing the recurrent in-stent restenosis rates to be lower in the study by Sharma.35 Intravascular ultrasound revealed that 22% of the stents were underdeployed, and these were not treated with high-pressure inflation. Rates of target vessel revascularization ranged from 28–40% and were generally higher than those observed in the coronary angioplasty trials. However, the original lesions in these rotational atherectomy trials were longer in length than those treated with balloon angioplasty. Certain variables were found to predict recurrent in-stent restenosis (Table 12.2). Multivariate analysis revealed that longer lesions, shorter time to restenosis and the degree of acute plaque recoil were independent predictors of recurrent in-stent restenosis in two trials.21,33 Univariate analysis35 revealed that short time to in-stent restenosis, lesion length, ostial lesion location and burrartery ratio less than 0.6 were associated with in-stent restenosis. Several conclusions may be drawn from trials studying directional coronary atherectomy and rotational atherectomy in the management of in-stent restenosis 1. Directional coronary atherectomy has received relatively little attention in the literature, mainly owing to safety concerns. In slotted tube stents, however, complications have been minimal. Improvements in luminal dimensions and rates of target vessel revascularization have been favorable in the mostly diffuse lesions studied.

191


2. Rotational atherectomy is safe and effective, with low complication rates. In fact, the complication rate seems lower than that observed when rotational atherectomy is used in native vessels. This may be because of the absence of calcification in neointimal tissue and to a protective effect of the stent. 3. Adjunctive coronary angioplasty following rotational atherectomy has been shown to improve luminal dimensions and decrease the rates of recurrent in-stent restenosis compared to rotational atherectomy alone. 4. Gains in luminal dimensions following rotational atherectomy with adjunctive coronary angioplasty are still less than those obtained after initial placement of the stent, or compared to reference vessel dimensions. This may be because relatively low inflation pressures used during adjunctive coronary angioplasty in some of these trials, to acute plaque (or neointimal) recoil, or to ‘skipping’ of the burr with ineffective cutting and hence removal of the neointima. 5. The rate of recurrent restenosis is high, especially for diffuse lesions, and seems to relate to lesion length, short time to instent restenosis, ostial location and possibly to a burr–artery ratio less than 0.6.

Rotational atherectomy compared to percutaneous transluminal coronary angioplasty Four studies have compared rotational atherectomy to coronary angioplasty (Table 12.3).26,31,38,39 The Rotational Atherectomy for In-Stent Restenosis (ROSTER) trial38 randomized 52 patients to rotational atherectomy/adjunctive coronary angioplasty or coronary angioplasty alone. The average lesion length was 13.9 ⫾ 4.7 mm. Measure-

192

ments were made with intravascular ultrasound. The minimal lumen diameter was significantly larger (2.8 ⫾ 0.4 vs 2.5 ⫾ 0.4 mm, p ⫽ 0.04), dissection and stent use were lower (8 vs 50%, p ⬍ 0.01), and there was significantly less clinical restenosis in the rotational atherectomy compared to the coronary angioplasty group (4 vs 27%, p ⫽ 0.03). The rates of target vessel revascularization were not provided. Moreover, 74% of luminal gain was attributed to plaque debulking and 26% was owing to tissue compression in the rotational atherectomy group. Further stent expansion was not appreciated. In contrast, 62% of luminal gain was due to plaque compression and 38% was due to further stent expansion in the coronary angioplasty group. There were no procedural complications and creatine kinase isoenzyme release was similar in the two groups (16 vs 12%, p ⫽ NS). While the number of patients and outcomes were small (there was only one patient with clinical restenosis in the rotational atherectomy group and seven in the coronary angioplasty group), these preliminary results are encouraging. The study by Lee39 was a nonrandomized comparison between rotational atherectomy with adjunctive coronary angioplasty and coronary angioplasty alone in 81 patients. All lesions were diffuse, although the average lesion length was not provided. Quantitative coronary angiography revealed the acute lumen gain was significantly lower than that achieved after the original stenting procedure in the coronary angioplasty group (1.94 vs 2.37 mm, p ⬍ 0.05), but similar in the rotational atherectomy/coronary angioplasty group (2.16 vs 2.26 mm, p ⫽ NS). There was a trend toward an increase in acute luminal gain in the rotational atherectomy/coronary angioplasty group, which did not reach

TISSUE ABLATION

statistical significance. Other angiographic parameters were similar. All patients underwent functional testing at follow up, and ‘clinical restenosis’ was determined based on these results. Details on follow-up angiography were not provided. Clinical restenosis was significantly less in the rotational atherectomy/coronary angioplasty group than in the coronary angioplasty alone group (25 vs 47%, p ⬍ 0.05) as was long term angina-free survival (72 vs 49%, p ⫽ 0.02) respectively. The rates of target vessel revascularization were low in both groups. In a nonrandomized, prospective study of 60 consecutive patients presenting with symptomatic in-stent restenosis in native coronary arteries, Dauerman et al31 reported the results of rotational atherectomy or directional coronary atherectomy, with adjunctive coronary angioplasty compared to coronary angioplasty alone. The mean lesion length tended to be longer in the coronary angioplasty group then in the debulking group (18.4 ⫾ 13.2 mm vs 13.5 ⫾ 8.3 mm, p ⫽ 0.09). Overall, 68% of lesions were diffuse in length. Twenty-six patients underwent rotational atherectomy and four patients underwent directional coronary atherectomy. The procedural success was 100% in both treatment groups. The placement of two additional stents was required in the rotational atherectomy group, one for edge dissection and one for inadequate lumen expansion. Two additional stents were required in the directional coronary atherectomy group as well, both for inadequate lumen expansion. There were no deaths or myocardial infarction observed and repeat revascularization was not required during hospitalization. Two patients in the directional coronary atherectomy group developed minor elevations of creatine kinase isoenzymes to less than two times the upper

limit of normal. In two of four patients treated with directional coronary atherectomy, small, ⬍ 1 mm stent fragments were recovered from the device. The final residual stenosis was lower in the debulking group than in the coronary angioplasty group (18 ⫾ 10 vs 26 ⫾ 13%, p ⫽ 0.01). The final flow velocities were higher in the debulking vs coronary angioplasty group respectively (8.8 ⫾ 2.1 vs 11.4 ⫾ 2.8 frames, p ⬍ 0.001), as measured by Thrombolysis in Myocardial Infarction (TIMI) frame counts. All patients underwent clinical follow up. Routine angiography was not performed, and information regarding stress testing and other noninvasive assessment of restenosis was not provided. There was a nonsignificant trend toward reduced target vessel revascularization in the debulking group at one year 27% (8 patients) in comparison to 43% (13 patients) in the coronary angioplasty group (p ⫽ 0.18). As noted by the authors, this study had insufficient power to detect a statistically significant difference in target vessel revascularization, and calculated that a study with over 200 patients would be required to do so. Using multivariate analysis, they determined that the presence of diabetes mellitus, greater lesion length, and smaller post procedure minimal lumen diameter predicted target vessel revascularization. After controlling for post procedure minimal lumen diameter, the debulking strategy did not have an impact on subsequent target vessel revascularization. They recommended that the largest post procedure minimal lumen diameter be obtained, and suggested that tissue debulking with adjunctive coronary angioplasty be used to achieve this goal. Rotational atherectomy was recommended for lesions in vessels ⱕ 3.0 mm diameter and directional coronary atherectomy for lesions ⱖ 4.0 mm in diameter. They reasoned that

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rotational atherectomy with a 2.0–2.25 mm burr could effectively remove 50–60% of plaque volume in 3.0 mm or smaller vessels, but could remove, at most, 40% of plaque volume in a 4.0 mm or larger vessels. The effects acute plaque recoil might have on these results were not discussed. In a non-randomized, prospective trial, Jolly et al26 compared 33 lesions treated with rotational atherectomy and adjunctive coronary angioplasty to 155 lesions treated with coronary angioplasty. Measurements were taken with electronic calipers. Fifty of the lesions were located in saphenous vein grafts. Fifty-six percent of lesions were focal and 44% were diffuse. The average lesion length was 13.41 mm in the rotational atherectomy group and 10.51 mm in the coronary angioplasty group. After therapy, final residual diameter stenosis was similar in each group (14 ⫾ 13% for rotational atherectomy vs 18 ⫾ 17% for coronary angioplasty), as was the rate of target vessel revascularization (16 vs 21%, p ⫽ 0.87) respectively. Target vessel revascularization was performed in 41% of lesions located in saphenous vein grafts. This study also had insufficient power to detect significant differences between the two techniques. The majority of the lesions were focal in nature, which explains the relatively low rate of target vessel revascularization. Moreover, focal lesions have been shown to respond favorably to coronary angioplasty. Using multivariate analysis, current smoking and saphenous vein graft location were the only predictors of target vessel revascularization. Together, these studies suggest that rotational atherectomy with adjunctive coronary angioplasty achieves greater gain in luminal dimensions, as evidenced by lower final residual stenosis. While these trials were underpowered to detect differences in target vessel

194

revascularization, clinical restenosis was less and angina-free survival was higher when lesions were treated with rotational atherectomy and adjunctive coronary angioplasty. Although by no means definitive, these studies provide evidence that rotational atherectomy with adjunctive coronary angioplasty is safe and effective and provides additional benefit over coronary angioplasty alone, especially in diffuse lesions. Given the high rates of recurrent in-stent restenosis when coronary angioplasty is used to treat diffuse in-stent restenosis, rotational atherectomy with adjunctive coronary angioplasty seems to provide some advantages.

Excimer laser coronary angioplasty Excimer laser coronary angioplasty (Table 12.4) has also been studied in the treatment of in-stent restenosis. While previous studies comparing laser angioplasty to coronary angioplasty suggested no benefit with the routine use of laser in non-stented vessels,40,41 it is thought that neointimal hyperplasia is softer and may be more amenable to ablation via laser angioplasty. This technique provides ablation of tissue via delivery of laser energy through either concentric or eccentric multifiber catheters, which vary in diameter. Pulses of energy density (usually equal to 30–60 mJ/mm2) are delivered at frequencies of 25–40 Hz. Saline flush is used during laser angioplasty therapy, as studies have shown that it decreases the intravascular peak pressure by 50%,42 the extent of bubble formation, and the number of severe dissections by 71%.43 Laser therapy is usually followed by adjunctive coronary angioplasty. A study by Koster et al,45 reported on the safety and efficacy of laser angioplasty in the treatment of in-stent restenosis in 70 patients

TISSUE ABLATION

with 107 lesions. Adjunctive coronary angioplasty was used, although the inflation pressures were not provided. The mean lesion length was 14.6 mm and 87% of lesions were diffuse in nature. The catheters were maneuverable and easily advanced into vessels with multiple stents. Procedural success (residual diameter ⬍ 30%) was obtained in 90% of patients. The minimal lumen diameter increased from 0.58 ⫾ 0.34 mm to 2.48 ⫾ 0.41 mm after laser angioplasty with coronary angioplasty (p ⬍ 0.001). This compared favorably to the reference diameter of 2.85 ⫾ 0.32 mm. The final diameter stenosis decreased from 80% to 45% following laser angioplasty (p ⬍ 0.001) and to 13% following adjunctive coronary angioplasty (p ⬍ 0.001). Intravascular ultrasound was utilized in a minority (20%) of cases, revealing that laser angioplasty reduced plaque area by 34 ⫾ 22% while coronary angioplasty further reduced plaque area by 65 ⫾ 16% (p ⬍ 0.01). Stent diameter increased 21 ⫾ 14% (p ⬍ 0.01) following adjunctive angioplasty, thus contributing moderately to the final lumen gain. Perforations in stented vessels were not observed, while there were two perforations in vessel segments distal to stents, one of which was attributed to adjunctive coronary angioplasty. There were no cases of pericardial tamponade. Eight major dissections (10%) were observed; one was owing to laser therapy while the others occurred with adjunctive coronary angioplasty. There were two cases of abrupt vessel closure and resultant increase in creatine kinase isoenzymes owing to flow limiting dissections. Intravascular ultrasound detected small intimal fissures in 6 of 21 lesions analysed that were not detected using angiography. One additional case of abrupt closure with no re-flow was attributed to the laser treatment and one

case of subacute thrombosis was observed. A large, multicenter registry, the Laser Angioplasty of Restenosed coronary Stents (LARS) study group,45 reported on the outcomes in 440 patients and 527 lesions treated with laser angioplasty and adjunctive coronary angioplasty for in-stent restenosis within a variety of stent designs. The majority (71%) of lesions were diffuse in length and the mean lesion length was 19 mm. Procedural success (defined as residual stenosis ⱕ 30% following laser angioplasty and coronary angioplasty) occurred in 91% of patients. There was no difference in success in native vessels compared to saphenous vein grafts or in focal vs diffuse lesions. The residual stenosis was lowest when larger diameter (catheter/vessel ratio ⬎ 0.8 compared to ⬍ 0.8, p ⫽ 0.04) and eccentric catheters were used. The best technical results were obtained when the 2.0 mm eccentric catheter was employed in which case the final residual stenosis after laser angioplasty was 33%. Following adjunctive coronary angioplasty, the final diameter stenosis was reduced to 7 ⫾ 13% (p ⬍ 0.0001). Clinical success, defined as procedural success without any major complications, was achieved in 84% of patients in the LARS trial. Dissections were noted in 14% of patients, but only 5% were visible following laser angioplasty. Most dissections occurred after adjunctive coronary angioplasty and were noted outside of the stented vessel. Noreflow occurred in 2% of patients, perforation in 1.1% (0.9% following laser angioplasty and 0.2% following coronary angioplasty), abrupt closure in 0.4% (0.2% following laser angioplasty, 0.4% following coronary angioplasty). Additional stents were required in 17% (75 patients) to treat these complications. Cardiac enzymes were not recorded routinely in this trial. The rate of Q-wave myocardial infarction was 0.5%.

195


As both authors note, the complication rates in these trials were lower than those reported in previous trials studying laser angioplasty in non-stented vessels.40,41,43,46 They attribute this to the use of saline flushes and perhaps to the protective role of the stent. The rate of complications is higher, though, than that reported in patients with in-stent restenosis treated with coronary angioplasty and rotational atherectomy. The rate of dissection was also higher following adjunctive coronary angioplasty for reasons which are unclear. Rates of recurrent in-stent restenosis and target vessel revascularization were not provided. A retrospective and non-randomized study comparing laser angioplasty to coronary angioplasty47 in the treatment of in-stent restenosis in Palmaz–Schatz stents matched 45 cases of coronary angioplasty to 47 cases of laser angioplasty. The mean lesion length was 12.7 mm and only 52% of lesions were diffuse in nature, although the laser angioplasty group contained an average lesion length of 19.6 mm. Procedural success was obtained in 98% of patients. There were two minor dissections following laser angioplasty, which were treated with adjunctive coronary angioplasty, and one dissection requiring coronary bypass surgery. No cases of perforation were noted. Four patients had a post-procedure non-Q-wave myocardial infarction. As measured by intravascular ultrasound, the increase in lumen volume was due to tissue ablation after laser angioplasty in 29 ⫾ 15%; tissue extrusion following coronary angioplasty in 31 ⫾ 14%; and further stent expansion following coronary angioplasty in 40 ⫾ 16% of patients. Compared to coronary angioplasty, lesions treated with laser angioplasty had greater acute gain (change in luminal cross-sectional area of 6.42 ⫾ 1.77

196

vs 5.35 ⫾ 1.49 mm2, p ⫽ 0.002), more intimal hyperplasia ablation/extrusion as measured by the change in intimal hyperplasia cross-sectional area, and larger final lumens. The minimal lumen diameter, final diameter stenosis, procedural success and complication rates were similar. There was a trend toward lower target vessel revascularization at 6 months in the laser angioplasty group which did not reach statistical significance (21 vs 38%, p ⫽ 0.08). As the authors noted, the lesions treated with laser angioplasty were longer, more complex lesions, which were found more often in diabetic patients. Additionally, only 85% of the initial luminal cross-sectional area was recovered following laser angioplasty. Only one pass was made with the laser angioplasty catheter in the majority of patients. Additional passes may have ablated more neointimal hyperplasia and recovered more of the luminal cross-sectional area. In addition, concentric rather than eccentric catheters were used in most patients. As discussed above,45 eccentric catheters seem to provide the most efficient tissue ablation. The rates of recurrent in-stent restenosis were not provided. The target vessel revascularization seems high for the coronary angioplasty group, considering most of the lesions were focal in length, compared to other trials of coronary angioplasty for in-stent restenosis. Despite these shortcomings, laser angioplasty proved safe and superior to coronary angioplasty with respect to angiographic and ultrasound outcomes and displayed a trend toward lower target vessel revascularization. Conclusions regarding laser angioplasty and adjunctive coronary angioplasty 1. Laser angioplasty with adjunctive coronary angioplasty effectively increases lumen dimensions, and ablates approxi-

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mately 30–35% of neointimal hyperplasia. Multiple passes with the largest diameter (preferably 2.0 mm) eccentric catheter should be used. Adjunctive coronary angioplasty contributes roughly 70% of the luminal gain. This is owing, in part, to further stent expansion. 2. The complication rate seems high, despite improvements in techniques in recent years. Complications in the form of dissections, abrupt closure, perforations, and non-Q wave myocardial infarction seem to occur with greater frequency compared to other techniques studied in the treatment of in-stent restenosis. 3. A trend toward a reduction in target vessel revascularization was observed with laser angioplasty and adjunctive coronary angioplasty compared to coronary angioplasty alone.

Repeat stenting The use of coronary stents in the management of in-stent restenosis has not been systematically studied. While repeat stenting has been proposed to help prevent protrusion of restenotic plaque within the stent after revascularization,48 it is not known to what extent new intimal hyperplasia contributes to recurrent in-stent restenosis. In a study by Bauters,16 repeat stenting was used in 14 patients (13% of the total number of patients requiring revascularization in that trial). The rate of recurrent in-stent restenosis was 15%, which was not significantly different from the rate of 23% seen with coronary angioplasty. Reimers18 employed stenting in 13 patients undergoing revascularization for in-stent restenosis. Stents were mainly used in this group to cover lesions adjacent to the stented segment, for adjacent dissections, or for recoil after coronary angioplasty. The imme-

diate success rate (100%) and long-term clinical outcome did not differ from that in patients treated with coronary angioplasty. However, in both of these trials the number of patients receiving stents was too small to allow for definitive conclusions. A trial by Teirstein49 evaluated catheter-based radiotherapy to inhibit restenosis after coronary stenting. In this trial, both groups of patients were treated with stents for in-stent restenosis; the placebo group received no further intervention after stent placement. There were no complications reported. Follow-up angiography revealed a late luminal loss of 1.03 ⫾ 0.97 mm in the placebo group and the angiographically determined recurrent instent restenosis rate was 54%. The mean lesion length was 11.86 ⫾ 6.77 mm and 45% of lesions were ⱖ 10 mm in length. While there was no direct comparison with other treatment modalities, this recurrent instent restenosis seems higher than that discussed previously for other treatment modalities, albeit in shorter lesions. A high percentage of these patients were diabetic (41%), which may also confound the results. Currently, use of stents in the treatment of in-stent restenosis is limited to treating edge stenoses or stenoses between the original stents.

Vascular radiation therapy Finally, the application of vascular radiation therapy, also known as brachytherapy, to prevent restenosis and recurrent restenosis is currently under active investigation. This topic will be covered in more detail in Chapter 14. Since restenosis results mainly from proliferation of the neointima, and given relatively high rates of recurrent instent restenosis using coronary angioplasty and ablative techniques, new methods aimed

197


at preventing formation of the neo-intima have been investigated. Results of the Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting (SCRIPPS)49,50 trial using 192 Iridium demonstrated a 69% reduction in angiographic restenosis at 6 months (54% in placebo vs 17% 192Iridium groups, p ⫽ 0.01) and a 48% reduction at three years (64% in placebo vs 33% 192Iridium groups, p ⬍ 0.05) in 55 patients with restenosis randomized to either radiation treatment or placebo. Rates of target lesion revascularization were 74% lower at 3 months (44.8% placebo vs 11.5% 192 Iridium groups, p ⫽ 0.01) and 68% lower at 3 years (48.3% vs 15.4%, p ⬍ 0.01). At the 3-year follow up, there were no reports of aneurysm or pseudoaneurysm formation, and progression of native coronary artery disease was similar in both treatment and control groups. While this trial represents a mixed group of patients treated for both in-stent and post-angioplasty restenosis, the results are nonetheless encouraging and demonstrate a dramatic and durable decrease in the rates of restenosis and target lesion revascularization without an increase in adverse effects. Similar results have been obtained using beta radiation.51 While prevention of neointimal formation may prove more successful than removal of neointimal hyperplasia, we await further the results of ongoing clinical trials using both beta and gamma radiation in this promising field of research.

Adjunctive therapies While the use of Glycoprotein IIb/IIIa platelet receptor antagonists has been reported to decrease target vessel revascularization following percutaneous coronary intervention using intracoronary stents in a variety of clinical syndromes,52–54 their use in the treatment of in-stent restenosis has not

198

been systematically studied. Aspirin should be continued in all patients in whom it is not contraindicated given its important role in secondary prevention of cardiovascular events. The routine use of other antiplatelet agents, such as ticlopidine and clopidogrel, in the management of recurrent in-stent restenosis is less clear. Given the exposure of stent struts during ablative procedures such as directional coronary atherectomy, rotational atherectomy, and even laser angioplasty, it seems reasonable to institute one of these agents for 2–4 weeks even in the absence of repeat stenting.

Management algorithm Using information presented in this chapter, it is possible to construct an algorithm for use in the management of in-stent restenosis (Fig. 12.1). In treating in-stent restenosis, the decision tree first branches at lesion length. In focal lesions, coronary angioplasty with high-pressure inflation (⬎ 12–14 atm) should be performed, as rates of recurrent in-stent restenosis are acceptable. In diffuse lesions, the use of an ablative procedure followed by high-pressure balloon angioplasty should be considered. Given the potential for stent damage, intravascular ultrasound prior to ablative procedures is potentially helpful to exclude the presence of underdeployed stents which could become ensnared in the device. However, this complication has only been demonstrated with directional coronary atherectomy in non-slotted-tube design stents. The various ablative procedures have not been compared to one another. As discussed, it is reasonable to choose rotational atherectomy for diffuse lesions in vessels ⱕ 3.0 mm, and directional coronary atherectomy for lesions in vessels ⱖ 4.0 mm in order to maximize luminal gain. At the present

MANAGEMENT ALGORITHM

In-stent restenosis

? Intravascular radiation therapy

FOCAL (⬍10 mm)

DIFFUSE (ⱖ 10 mm)

Coronary angioplasty (high pressure inflation)

Consider IVUS to exclude underdeployed stent

VESSEL DIAMETER

ⱕ 3 mm

RA/PTCA B/Aⱖ0.7

⬎ 3 mm

Also consider DCA or ELCA with PTCA (eccentric catheter⬎2 mm)

DCA/PTCA

Also consider RA or ELCA with PTCA (eccentric catheter⬎2 mm)

Consider GP IIb/IIIa inhibitors (especially in patients with diabetes mellitus) Use ticlopidine or clopidogrel for 2–4 weeks

Figure 12.2 Proposed algorithm for the management of in-stent restenosis. B/A ⫽ balloon to artery ratio; DCA ⫽ directional coronary angioplasty; ELCA ⫽ excimer laser coronary angioplasty; GP ⫽ glycoprotein; mm ⫽ millimeter; IVUS ⫽ intravascular ultrasound; PTCA ⫽ coronary balloon angioplasty; RA ⫽ rotational atherectomy.

199


time, however, the hypothetical benefit of directional coronary atherectomy over rotational atherectomy in larger diameter vessels has not been reported. The use of laser angioplasty with saline flush and multiple passes using eccentric catheters should also

be considered, although this technique needs further study and refinement. The application of vascular radiation therapy to prevent the formation of neointimal hyperplasia or its recurrence holds promise as a future treatment modality.

References 1.

2.

3.

4.

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6.

7.

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Fischman DL, Leon MB, Baim DS et al. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994; 331:496–501. Serruys PW, de Jaegere P, Kiemeneij F et al, for the BENESTENT study group. A comparison of balloon expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331:489–495. George BS, Voorhoees WD III, Roubin GS et al. Multicenter investigation of coronary stenting to treat acute or threatened closure after PTCA: clinical and angiographic outcomes. J Am Coll Cardiol 1993; 22:135–143. Schomig A, Kastrati A, Mudratt et al. Fouryear experience with Palmaz–Schatz stenting in coronary angioplasty complicated by dissection with threatened or present vessel closure. Circulation 1994; 90:2716–2724. Hoffman R, Mintz GS, Dussaillant GR et al. Patterns and mechanisms of in-stent restenosis: a serial intravascular ultrasound study. Circulation 1996; 94:1247–1254. Baim DS, Levine MJ, Leon MB, Levine S, Ellis SG, Schatz RA, for the US Palmaz–Schatz Stent Investigators. Management of restenosis within the Palmaz–Schatz coronary stent. Am J Cardiol 1993; 71:564–566. Painter JA, Mintz GS, Wong SC et al. Serial intravascular ultrasound studies fail to show evidence of chronic Palmaz–Schatz stent

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recoil. Am J Cardiol 1995; 75:398–400. Dussaillant GR, Mintz GS, Prichard AD et al. Small stent size and intimal hyperplasia contribute to restenosis; a volumetric intravascular ultrasound analysis. J Am Coll Cardiol 1995; 26:720–724. Van Beusekom HM, van der Giessen, van Suylen R et al. Histology after stenting of human saphenous vein bypass grafts; observations from surgically excised grafts 3–20 days after stent implantation. J Am Coll Cardiol 1993; 21:45–54. Carter AJ, Laird JR, Farb A et al. Morphological characteristics of lesion formation and time course of smooth cell proliferation in a porcine proliferative restenosis model. J Am Coll Cardiol 1994; 24:1398–1405. Topol EJ, Serruys PW. Frontiers in interventional cardiology. Circulation 1998; 98:1802–1820. Kobayashi Y, DeGregorio JD, Kobayashi N et al. Stented segment length as an independent predictor of restenosis. J Am Coll Cardiol 1999; 34:651–659. Ikari Y, Hara K, Tamura T, Saeki F, Yamaguchi K. Luminal loss and site of restenosis after Palmaz–Schatz coronary stent implantation. Am J Cardiol 1995; 76:117–120. Savage MP, Fischman DL, Schatz RA et al. Long term angiographic and clinical outcome after implantation of balloon expandable stents in the native coronary circulation. Palmaz–Schatz Stent Study Group. J Am Coll Cardiol 1994; 24:1207–1212.

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in calcified and non-calcified coronary artery lesions. J Am Coll Cardiol 1995; 26:731–736. Mintz G, Potkin BN, Keren G et al. Intravascular evaluation of the effect of rotational atherectomy in obstructive atherosclerotic coronary artery disease. Circulation 1992; 86:1383–1393. Sharma AK, Duvvuri S, D-Sterling F et al. Rotational atherectomy for in-stent restenosis: acute and long-term results of the first 100 cases. J Am Coll Cardiol 1998; 32:1358–1365. Lee SG, Lee CW, Cheong SS et al. Immediate and long-term outcomes of rotational atherectomy vs balloon angioplasty alone for treatment of in-stent restenosis. Am J Cardiol 1998; 82:140–143. Appelman YE, Piek JJ, Strikwerda S et al. Randomised trial of excimer laser coronary angioplasty vs balloon angioplasty for treatment of obstructive coronary artery disease. Lancet 1996; 347:79–84. Litvack F, Eigler N, Margolis J et al. Percutaneous excimer laser coronary angioplasty: results in the first 3000 patients. J Am Coll Cardiol 1994; 23:323–329. Baumbach A, Haase KK, Rose C, Oberhoff M, Hanke H, Karsch K. Formation of pressure waves during in vitro excimer laser irradiation in whole blood and the effect of dilution with contrast media and saline. Laser Surg Med 1994; 14:3–6. Deckelbaum LI, Natarajan MK, Bittl JA et al. Effect of intracoronary saline infusion on dissection during excimer laser angioplasty: a randomized trial. J Am Coll Cardiol 1995; 26:1264–1269. Koster R, Hamm CW, Terres W et al. Treatment of in-stent coronary restenosis by excimer laser angioplasty. Am J Cardiol 1997; 80:1424–1428. Koster R, Hamm CW, Seabra-Gomes R et al. Laser angioplasty of restenosed coronary

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13 Management of restenosis through radiation therapy Ron Waksman

Post angioplasty restenosis continues to be a major obstacle in catheter-based cardiovascular interventions. While cellular proliferation after balloon injury is most likely the mechanism for the development of clinical restenosis, the degree of the proliferative response remains unknown.1–4 Early and late remodeling of the vessel lumen following angioplasty have been identified as contributors to restenosis.5–8 Stents have been used to eliminate vessel remodeling, and maintain a higher patency rate compared to angioplasty alone.9,10 Often, however, a higher degree of proliferative response and an increase in late lumen loss occurs with stent placement.11 Used in other clinical situations to stunt excess growth, vascular brachytherapy, the intraluminal delivery of radiation following angioplasty, was viewed as a viable solution to inhibit restenosis.12,13 Introduced in 1992, several investigators performed preclinical studies using both beta and gamma emitters to effectively demonstrate consistently profound reductions in neointimal formation following balloon injury, compared to control (Fig. 13.1).14–37 In these experiments, radiation was delivered into the vessel wall either through high dose rate catheter-based systems or through low dose rate radioactive implants, such as radioactive stents. The results of these preclinical trials were so encouraging that they facilitated the initiation of feasibility clinical trials in peripheral arteries first, and later in

Intra-Arterial Radiation Following Balloon and Stent Angioplasty

90 Sr/Y

Control Ir-192

Figure 13.1 Intraarterial radiation vs control. Histology example of intraarterial radiation following balloon and stent angioplasty, comparing the effectiveness of both ␤ (90Sr/Y) and ␥ (192Ir) vs control.

coronary arteries through pivotal trials. Beginning in 1999, the success from these studies led to the technology’s commercialization in Europe for clinical use.

Radiation biology and mechanism The principal of radiation biology for prevention of restenosis is to induce apoptosis (programmed cell death) to radiosensitive cells, especially those that are undergoing mitosis

203

MANAGEMENT OF RESTENOSIS THROUGH RADIATION THERAPY

following vascular injury. The administration of subtherapeutic doses of irradiation will only delay the eventual process of restenosis, as an inadequate dose will not eliminate enough cells to prevent cell division. This will also occur if the vessel is not exposed to radiation for a long enough period of time. Therefore, the overall effect of radiation therapy is strongly dependent on the cumulative dose, dose rate, and cell cycle.38 Through a series of studies on the coronary arteries of pigs by Waksman et al the potential mechanisms associated with using radiation therapy to reduce restenosis were attributable to the fact that radiation inhibits the first wave of cell proliferation in the adventitia and the media, thereby inducing favorable remodeling (Fig. 13.2).39

Radiation physics and radiation systems Different isotopes on various platforms and systems have been developed for the use of endovascular brachytherapy. There are multiple platforms for radiation delivery, however, the main platforms are catheter-

Thrombosis platelet deposition fibrin formation

Inflammation leukocyte chemotaxis cytokine induction

Radiation SMC proliferation Intimal hyperplasia

Remodeling SMC migration

Matrix secretion

Figure 13.2 The biology of ionizing radiation depicting the mechanisms of action of ionizing radiation (SMC, smooth muscle cells).

204

based systems varying from line source wires embedded with radioactive seeds, to radioactive gas and liquid filled balloons or stents utilizing beta or gamma emitters. The decision making process in determining which isotope to use for vascular brachytherapy is complicated by a number of factors. Before this decision can be reached, the anatomy of the vessel, properties of the treated lesion, and identification of the target tissue need to be examined. Other important parameters are the diameter and the curvature of the vessel, the eccentricity of the plaque, the lesion length, the composition of the plaque, the amount of calcium, and the presence or absence of a stent in the treated segment. The ideal radioisotope would have a minimal dose gradient which could deliver a therapeutic effect within a treatment time of 10 minutes. Dose distribution within a few millimetres from the source resulting in low dose exposure to surrounding tissues with a sufficient halflife is particularly favorable for use with catheter-based systems. Other aspects that need consideration include taking into account the potential radiation exposure to the patient and operator, necessary shielding equipment, and associated costs.

Understanding gamma radiation Gamma rays are photons originating from the center of the nucleus and differ from x-rays, which originate from the orbital outside of the nucleus. Gamma rays have deep penetrating energies, between 20 keV and 20 MeV, which require an excess of shielding, compared to beta and x-ray emitters. The only gamma ray isotope currently in use is Iridium-192 (192Ir). There are isotopes that emit both gamma and x-rays, such as Iodine-125 (125I) and Palladium-103 (103Pd). These isotopes have lower energies, however, and require higher activity

THE CLINICAL TRIALS

levels in order to deliver a prescribed dose in the acceptable dwell time (< 20 minutes). Using these isotopes for vascular brachytherapy is difficult, as they are either not available in high activity levels or too expensive for this application. The dosimetry of Ir-192 is well understood and is associated with an acceptable dose gradient, as 192Ir has a lesser fall-off in dose than beta emitters. 192Ir is available in activities of up to 10 Ci, but owing to high penetration, additional shielding will be needed, as the average shielding of a catheterization lab will not be enough to handle more than 500 mCi source in activity. This limitation is associated with dwell times of more than 12 minutes for doses above 15 Gy when prescribed at 2 mm radial distance from the source.

Understanding beta radiation Beta rays are high-energy electrons emitted by nuclei and contain too many or too few neutrons. These negatively charged particles have a wide variety of energies, including transition energies, particularly between parent–daughter cells and a diverse range of half-lives from several minutes (62Cu) up to 30 years (90Sr/Y). Beta emitters are associated with a high gradient to the near wall, as they lose their energy rapidly to surrounding tissue and their range is within 1 cm of tissue. Vascular brachytherapy using beta emitters appears promising, as safety levels are higher because of the limited range of these emitters. Several dosimetry issues remain controversial, namely the choice of isotope, beta vs gamma emitting radioisotopes, centering vs non-centering devices, and the administration of high vs low dose rates of radiation. In order to determine an accurate dosimetry, it is essential to identify the treatment dose and the exact tissue needing treatment. Despite the

notion that the adventitia is the target, it is difficult to ignore that the wall and the residual plaque receive much higher doses which may be essential in obtaining efficacy. The doses prescribed today in clinical studies are empirical; they are based on doses used in animal studies and the limited experience gained from treating other benign diseases. Since a wide range of doses demonstrated effectiveness in preclinical studies, a therapeutic window must exist that allows some flexibility in selecting the isotope for this application.

Dosimetric calculations Isotope selection should take into account the influence that variables such as effective energy, penetration properties, and different dose gradients have on potential target areas and different half-lives of beta and gamma isotopes. Ignoring these dosimetric considerations may result in treatment failure. The dosimetry of radioactive stents is even more complicated and depends on the geometry of the stent which varies across stent designs. Current tested radioactive stents lack dose homogeneity across the entire length of the stent. This could affect the biological response to radiation, especially at the stent edges. Also, low activity radioactive stents may be associated with an ineffective low dose rate. While radioactive stents with high activities may deliver toxic doses to the stented area that delay reendothelialization, too much radiation might promote stent thrombosis and tissue necrosis to the area surrounding the stent.

The clinical trials An analysis and update of the current status of clinical trials in vascular brachytherapy for the

205


last quarter of 2000 have been extremely positive in identifying other patient subsets that would benefit from the technology. Long term follow-up (1–3 years) of clinical and angiographic data from several early US studies indicates that the safety and effectiveness of radiation therapy for the prevention of restenosis is maintained beyond 6–8 months, demonstrating late-term benefits. Clinical and angiographic follow-up of these studies continues, evaluating over 4000 patients. All points of follow-up from these initial trials, along with new data from larger trials demonstrate different levels of efficacy and raise questions regarding dosimetry perfection and its impact on related complications, such as edge effect, late thrombosis, and late restenosis. Despite the differences in trial designs, more trials in the last year have focused on examining the use of vascular brachytherapy for preventing the recurrence of in-stent restenosis. New data related to the use of radioactive stents, liquid filled balloons and the use of intravascular radiation for the peripheral system are now being collected. Questions still remain, however, as to whether beta emitters will be as effective as gamma and whether centering delivery systems perform better than non-centering systems. Various pilot studies with intracoronary brachytherapy have examined the feasibility and safety of this technology with new systems utilizing different emitters. The following is a summary of some clinical trials conducted with gamma and beta emitters. A listing of all clinical trials using gamma emitters is displayed in Table 13.1; beta trials are featured in Table 13.2.

Gamma trials The first clinical trial using intracoronary radiation in human coronary arteries was con-

206

ducted five years ago by Condado et al.40 In this study, 21 patients (22 arteries) with unstable angina underwent percutaneous transluminal coronary angioplasty PTCA followed by intracoronary radiation using a 192Ir source wire hand-delivered to the angioplasty site (19–55 Gy). All patients were followed clinically and quantitative coronary analysis (QCA) was performed at 6, 24, 36 and 60 months. Repeat angiography at 30–60 days demonstrated total occlusions in two arteries and a new psuedoaneurysm in one artery. Target lesion revascularization occurred in six lesions, three of which were total occlusions (two, early within 30 days, and one occurred at 2 years), and one patient had a myocardial infarction to a non-target vessel. Serial QCA detected a binary restenosis rate of 28.6% (n ⫽ 6) at 6 months which remained the same at 5 years. The late loss (0.29 mm) and loss index (0.25) did not change and remained low at 2, 3 and 5 years. Angiographic complications included four aneurysms (two procedurerelated and two occurring within 3 months). At 2 years, only one aneurysm increased in size (46 vs 27 mm2); and at 3 and 5 years, all aneurysms remained unchanged. No other angiographic complications were observed.41 SCRIPPS (Scripps Coronary Radiation to Inhibit Proliferation Post Stenting) is the first randomized trial on the safety and efficacy of intracoronary gamma radiation given as adjunct therapy to stents to reduce in-stent restenosis. In this study, 26 of 54 patients were randomized to receive 192Ir (8–30 Gy, dosimetry guided by intravascular ultrasound (IVUS) utilizing a ribbon (19–35 mm) delivered in a noncentered, closed-end lumen catheter at the treatment site (dwell time: 20–45 minutes). Only 35 patients in this cohort were patients with in-stent restenosis. This study demonstrated a 6-month angiographic restenosis rate of 17% vs 54% in the

THE CLINICAL TRIALS

Study name

Design

Radiation system

Dose (Gy)

Results and status

SCRIPPS

Single center, doubleblind, randomized in 55 patients with restenosis.

Hand delivered 0.030⬙ nylon ribbon with seeds (Best Medical) into a noncentered closed end lumen 4.5F catheter (Navius)

ⱖ 8–< 30 to media by IVUS

Completed. Showed reduction of restenosis in the irradiated group maintained at 3 years.

WRIST

Single center, doubleblind, randomized in 130 patients with instent restenosis (100 natives, 30 vein grafts).

Hand delivered 0.030⬙ nylon ribbon with 192Ir seeds (Best Medical) into a non-centered closed end lumen 5.0F catheter (Medtronic)

15 at 2.0 mm for vessels 3–4 mm. 18 for vessels > 4 mm

Completed. Showed reduction in restenosis (67%) and revascularization (63%). At 2 years reduction in TLR and TVR < 40%.

SVG WRIST

Multicenter, doubleblind, randomized in 120 patients with instent restenosis.

Hand delivered 0.030⬙ nylon ribbon with seeds (Best Medical) into a noncentered closed end lumen 5.0F catheter (Medtronic)

15 at 2.4 mm for vessels > 4 mm

Enrollment completed. Initial results in 30 patients showed reduction in restenosis in the irradiated vein grafts.

LONG WRIST

Two-center, doubleblind, randomized in 120 patients with instent restenosis. Lesions (36–80 mm)


15 at 2.0 mm for vessels 3–4 mm

Completed. At 6 months data restenosis rates lower in irradiated group 32% vs control 71%.

LONG WRIST HD

Single center, registry in 120 patients with in-stent restenosis. Lesions (36–80 mm)


18 at 20 mm for vessels 3–4 mm

Enrollment completed. Initial results in 60 patients demonstrated further reduction of the restenosis rate compared to 15 Gy.

GAMMA 1

Multicenter, randomized doubleblind study in 252 patients with in-stent restenosis.

Hand delivered 0.030⬙ nylon ribbon with seeds (Best Medical) into a noncentered closed end lumen 4.0F catheter (Cordis)


Completed. Patients with radiation therapy has significant reduction of the restenosis 21.6 vs 50.5% and the clinical TLR at 9 months.

GAMMA 2

Multicenter, registry in 125 patients with in-stent restenosis.


14 at 2 mm from the source

Completed. Similar to GAMMA 1. MACE was reduced by 36% and TLR was reduced by 48% as compared to placebo.

Table 13.1 Clinical trials for in-stent restenosis using catheter-based systems with gamma radiation.

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Study name

Design

Radiation system

Dose (Gy)

Results and status

ARTISTIC

Multicenter, doubleblind, randomized in 110 patients with instent restenosis.

Mechanical delivery of 0.014⬙ fixed wire 30 mm (Angiorad) into a monorail closed end lumen with small balloon 3.2F catheter

12–15–18 at 2.0 mm from the source

Feasibility phase completed, with low restenosis rate. Pivotal study will be started in 2001.

PLAVIX WRIST

A registry of 120 patients with in-stent restenosis with 6 months of PLAVIX 75 mg qd.

Hand delivered 0.030⬙ nylon ribbon with 192Ir seeds into a non-centered closed end lumen 4.0F catheter (Cordis)

14 at 2 mm distance from the source

Enrollment completed. 6 months’ angiogram showed significant reduction of late total occlusion with PLAVIX.

SCRIPPS 2

Single center randomized study for patients with diffuse in-stent restenosis.



Enrollment completed follow-up will be available in the fall of 2000.

SCRIPPS 3

A registry of 320 patients with in-stent restenosis with 6 months of PLAVIX.



Enrollment completed Clinical follow-up only will be available in the summer of 2001.

WRIST 12

A registry of 120 patients with in-stent restenosis with 12 months of PLAVIX and 15 months angiographic study.



Enrollment completed 15 months’ angiographic followup will be available in the December of 2001.

EDGE WRIST

A registry of 120 patients with in-stent restenosis with longer margin treatment.

Hand delivered 0.030⬙ nylon ribbon with 192Ir seeds into closed end lumen 4.0F catheter (Cordis)


Study initiated in the fall of 2000.

CURE

A registry of 120 patients with in-stent restenosis not considered good candidates for CABG or medical therapy.

Hand delivered 0.030⬙ nylon ribbon with 192Ir seeds into closed end lumen 4.0F catheter (Cordis)


Enrollment extended. Clinical follow-up available for initial 120 patients. 31% TVR and 33% MACE at 6 months.

GAMMA 5

Multicenter, registry in 600 patients. With 12 months PLAVIX for new stent and 6 months for non-stent.



Study initiated in the summer of 2000.

WRIST, Washington Radiation for In-Stent Restenosis Trial; SCRIPPS, Scripps Coronary Radiation to Inhibit Proliferation Post Stenting; IVUS, intravascular ultrasound; TLR, target lesion revascularization; TVR, target vessel revascularization; MACE, major adverse cardiac events; CABG, coronary artery bypass graft; ARTISTIC, Angiorad Radiation Technology for In-Stent Restenosis Trials in Native Coronaries; CURE, Columbia University Radiation Energy.

Table 13.1 Continued

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THE CLINICAL TRIALS

Study name

Design

Radiation system

Isotope and dose (Gy)

Results and status

BETA WRIST

Registry for 50 patients with in-stent restenosis.

Schneider System 90Y source centering balloon and an afterloader

Dose 20.6 at 1 mm from the balloon surface

Completed. Restenosis rate of 22% at 6 M. MACE 46% at 2 years. Similar results to the gamma WRIST group.

INHIBIT

Multicenter, double blind randomized for patients with in-stent restenosis for 332 patients.

Automatic afterloader (Nucletron) 0.018⬙ 27 mm fixed wire via a helical centering balloon

32

P, dose 20 Gy at 1 mm into vessel wall

Completed. Demonstrated reduction of 50% in restenosis (analysis segment) and 55% in MACE.

START

Multicenter randomized double blind design for 476 in-stent restenosis. Lesions (20 mm)

Beta CATH system 30 mm source train

90

Sr/Y, 18–20 Gy at 2 mm

Completed. Showed reduction in TLR, TVR and MACE (35%) in the irradiated group. No late thrombosis.

START 40/20

A registry of 250 patients with in-stent restenosis.

Beta CATH system 40 mm source train

90

Sr/Y, 18–20 Gy at 2 mm

Completed. Results will be available in Dec 2000

BRITE

Feasibility study in patients with in-stent restenosis. Lesions < 25 mm.

The radiance system with a deployable 32P balloon

32

P, 20 Gy at 1.0 mm from the balloon

Enrollment completed demonstrated safety at 30 days. And lower restenosis rates at 6 months.

R4

Registry in 50 patients with in-stent restenosis in South Korea.

Liquid filled balloon 36 mm in length

188 Re 15 Gy at 1 mm into the vessel wall

Showed that 6-month angiographic restenosis rate was 10.4%.

GALILEO INHIBIT

International multicenter registry in 120 patients with in-stent restenosis.

Automatic afterloader (Guidant GALILEO system) via a helical centering balloon

32

Enrollment will be completed in December 2000.

P, 20 Gy at 1 mm into vessel wall

MACE, major adverse cardiac events; TLR, target lesion revascularization; TVR, target vessel revascularization; START, STents And Radiation Therapy; BRITE, Beta Radiation to prevent In-sTent REstenosis.

Table 13.2 Clinical trials for in-stent restenosis using catheter-based systems with beta radiation.

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placebo group. At 3 years, these results remained consistent (15.4% vs 48.3%, respectively). Subanalysis of the lumen diameter for patients who did not have intervention demonstrated minimal reduction of the minimal lumen diameter (MLD) of the irradiated segments vs control at 3 years. There were no evident clinical complications resulting from the radiation treatment, and clinical benefits were maintained at 3 years with a significant reduction in the need for target lesion revascularization at 3 years, p ⫽ 0.004. A subgroup analysis for the 35 patients with in-stent restenosis has shown a 70% reduction in the recurrence rate of the irradiated group vs the placebo group.42,43 WRIST (Washington Radiation for In-Stent Restenosis Trial) is a series of studies that are designed to evaluate the effectiveness of radiation therapy for in-stent restenosis.41 The gamma radiation in these studies is composed of ribbon with different trains of radioactive (192Ir) seeds, which is inserted manually into a closed-end lumen catheter. In the first study, 130 patients (100 patients with native coronaries and 30 patients with vein grafts) with in-stent restenotic lesions (up to 47 mm in length) were blindly randomized to treatment with either placebo or 15 Gy of 192Ir at 2 mm from the source of the vessel wall. At 6 months, clinical and angiographic follow-up showed a dramatic reduction of the restenosis rate between the irradiated group and the control group, 19% vs 58%, respectively. There was a 79% reduction in the need for revascularization and a 63% reduction in major adverse cardiac events (death and Qwave myocardial infarction) in the irradiated group compared to control. Intravascular ultrasound subanalysis demonstrated 53% of lesions from the irradiated group had increased luminal dimensions and regression of neointimal tissue at 6 months. At 1 year,

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the irradiated group had a 48% reduction in major adverse clinical events (MACE) compared to placebo.44 The WRIST study is considered to be a landmark in establishing gamma radiation for the treatment of in-stent restenosis. A brief overview of the other studies in this series can be found in Table 13.1. GAMMA 1 is a multicenter, randomized, double-blind trial studying the effects of handdelivered 192Ir ribbon using intravascular ultrasound to guide dosimetry (dose range between 8 and 30 Gy) in 252 patients with in-stent restenosis. Six-month angiographic results revealed significant reductions in the in-stent angiographic restenosis rate of the radiation group vs control (21.6% vs 52%). Subanalysis for lesion length demonstrated a 70% reduction in the angiographic restenosis rate for lesions < 30 mm in length vs 48% for 30–45 mm lesions.45 Fig. 13.3 capture the 6month angiographic and IVUS results of a patient from GAMMA 1, emphasizing the fact that acute gain resulting from angioplasty and radiation therapy is maintained at 6 months. In addition, edge effect was noted in patients who did not have enough coverage of the lesion by the radioactive seeds. Clinical events demonstrated a reduction of target lesion revascularization (TLR) from 42.1% to 24.4%. However, the rate of death (3.12% vs 0.8%) and the rate of acute myocardial infarction MI (12.2% vs 6.2%) were higher in the irradiated group vs control. These complications were related in part to the late thrombosis phenomenon. GAMMA 2 is a registry of 125 patients who were treated for the same inclusion/exclusion criteria as GAMMA 1 but with a fixed dosimetry of 14 Gy at 2 mm from the center of the source. The treated lesions in Gamma 2 were more heavily calcified, whereby 45% of patients required rotoblation in contrast to

THE CLINICAL TRIALS

(a)

(b)

(c)

Figure 13.3 Angiograms (top) and intravascular ultrasound (IVUS) (bottom) images following a GAMMA 1 patient (a) to 6-month follow-up indicating the fact that the immediate benefits of radiation therapy (post procedure) (b) are maintained at 6 months (c).

26% of patients in GAMMA 1. Despite the differences in lesions, the results between GAMMA 1 and 2 were remarkably similar. Both studies had similar and infrequent inhospital adverse events (1.6%). GAMMA 2 patients had a lower post procedural MLD. This is perhaps owing to increased lesion complexity and the fact that fewer stents were placed in GAMMA 2 patients,

compared to GAMMA 1 patients. Similar to GAMMA 1, there was a 52% in-stent and a 40% in-lesion reduction in restenosis frequency. MACE was reduced by 36% and TLR was reduced by 48%. The late thrombosis rate was 4.0% at 270 days with only 8 weeks of antiplatelet therapy. It is believed that prolonged antiplatelet therapy will remedy the incidence of late thrombosis.

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ARTISTIC (Angiorad Radiation Technology for In-Stent Restenosis Trial in Native Coronaries) is a blinded, randomized trial examining the benefits of using a flexible 30 mm 192Ir wire in 300 patients with in-stent restenosis in native coronary arteries. The pilot phase of the study was recently completed and involved 26 patients at two centers, all of whom received radiation treatment. Inclusion criteria consisted of lesions < 25 mm in length with a reference vessel diameter between 2.5 and 5.0 mm, and a degree of stenosis between 50% and 99%. Radiation was successfully delivered to 25 of 26 patients. At 6-month angiographic follow-up, low binary restenosis rates of 14% were reported with a late loss index of 0.12, and a 15% rate of major adverse cardiac events.46 A randomized study using the same system was halted after enrolling 110 patients. Preliminary result of this study demonstrated significant reduction in the angiographic restenosis rate in the irradiated arm. A pivotal trial with the Angiorad system will be launched in the last quarter of 2000. New gamma studies for in-stent restenosis that have been initiated but are not yet completed are SCRIPPS III, WRIST 12, and GAMMA-5. These studies are designed to address the issue of prolonged antiplatelet therapy and prevention of late thrombosis. Preliminary analysis of SCRIPPS III suggest no late thrombosis in 500 patients with 6 months of Plavix therapy after radiation.

Beta trials Initial clinical trials using beta emitters used designs to examine the effectiveness of beta radiation therapy for the prevention of restenosis in de novo lesions found in native coronaries. New studies have been initiated to test the effectiveness of beta radiation for postintervention restenosis.

212

THE GENEVA EXPERIENCE examined an Yttrium-90 (90Y) source, and a centering balloon catheter following PTCA in a small cohort of 15 patients. Although the investigators were able to demonstrate feasibility of the radiation system, the outcome of this study was disappointing, since five of the 15 patients experienced angiographic and clinical restenosis.47 The investigators related their results to insufficient doses to the adventitia (less than 5 Gy). THE DOSE FINDING study evaluated 160 patients throughout five centers in Europe using the same 90Y radiation system. Doses of 9, 12, 15, and 18 Gy at 1 mm from the surface of the balloon were examined. Patients and investigators were blinded to dose administration. Angiographic follow-up was conducted at 6 months. A dose response was demonstrated and an 8% angiographic restenosis rate was reported in patients who had received the highest dose of 18 Gy and a 28% restenosis rate was reported in patients receiving the lowest rate of 9 Gy. The intermediate doses of 12 and 15 Gy were associated with similar restenosis rate of 15% and 16%, respectively. An analysis for patients who were treated without stents demonstrated restenosis rates of 4.2% when receiving the highest dose. The late thrombosis rate was about 10%. Edge effect was not evaluated in this study. The results from this study indicate that restenosis rates can be dramatically changed with the correct dose. BERT (Beta Energy Restenosis Trial) is a feasibility study approved by the FDA and limited to 23 patients in two centers (Emory and Brown Universities). The study is designed to test the 90Sr/Y source delivered by a hydraulic system. The prescribed doses in this study were 12, 14, 16 Gy and the treatment time did not exceed 3.5 minutes. The radiation was successfully delivered to 21 of 23 patients

THE CLINICAL TRIALS

following conventional PTCA without any complications or adverse events at 30 days. At follow-up, two patients at 6 months, and one patient at 9 months underwent repeat revascularization to the target lesion.48 At the 6month follow-up, the angiographic restenosis rate for the entire cohort of 83 patients was 17% with a low late loss of 9%. However, six additional patients required revascularization owing to edge effect near the treated lesion. BRIE (Beta Radiation in Europe) is a registry in 180 patients who were enrolled in nine sites in Europe. In this trial, treatment of up to two vessels were allowed with the BetaCath system using the 90Sr/Y source doses 14 and 16 Gy. The primary angiographic endpoints of the BRIE registry were target lesion revascularization, and late loss index measured at 6 months. The first 90 patients with 98 lesions at angiographic follow-up evaluation had a target vessel revascularization rate of 30% with 19% in the PTCA subgroup and 35% in the stent group. The late loss index for the total population was 12% with 3% in the PTCA subgroup and 17% in the stent group. The main problem in this study was an incomplete coverage of the treated area resulting in ‘geographical miss’; this was found in 30% of the treated lesions. The study supports the notion that radiation and stenting resulted in more events than radiation and balloon angioplasty. PREVENT (Proliferation Reduction with Vascular Energy Trial) is a prospective, randomized, blinded, multinational, and multicenter study. The objective of this study is to demonstrate the safety of the beta radiation system in human coronaries immediately following PTCA or stent placement. The system consists of a 27 mm, 32P isotope delivered into a centering helical balloon delivery catheter via an automatic afterloader apparatus. The doses utilized in this open-label

phase are 16, 20, and 24 Gy prescribed to 1 mm from the source. Preliminary results suggested low rates of late loss in the irradiated group compared to control, 4.8% vs 51.3%, respectively. There was a significant reduction in the need for target lesion revascularization, 4% vs 18%. However, owing to an increase of edge effect, the target lesion revascularization rates were similar in the treated vessels compared to the control vessels, 24% vs 29%, respectively. Subanalysis of patients with instent restenosis treated with 32P demonstrated lower rates of recurrences compared to a matched control group from the WRIST study. CURE (Columbia University Radiation Energy) is the first liquid-filled balloon system used in a feasibility clinical trial for either post-intracoronary stenting or post-balloon angioplasty patients (25 patients).49,50 The liquid form of the 188Re isotope is retrieved from a Tungsten-188 generator and injected via a syringe into a perfusion balloon and allowed to dwell for up to 10 minutes. The prescribed dose was 13 Gy to the adventitia and the clinical restenosis rate with the need for target vessel revascularization was nearly 17%. MARS (Mallinckrodt Angioplasty Radiation Study) is a multicenter, feasibility study utilizing a liquid 186Re beta emitter source for the prevention of restenosis in de novo and restenotic lesions. Preliminary results demonstrated angiographic restenosis > 30% with evidence of high rates of edge effect.

Beta radiation for in-stent restenosis BETA WRIST was the first study to examine the efficacy of beta radiation for prevention of in-stent restenosis. This registry included 50 patients who underwent treatment for in-stent

213


restenosis in native coronaries and were treated with beta radiation using the 90Y source, centering catheter and an afterloader system. The clinical outcomes of these patients were compared to the control group of the original cohort of WRIST (randomized to either placebo or 192Ir). The reported angiographic restenosis rate at 6 months in BETA WRIST was 22% with late total occlusion in 12% of the patients. The use of beta radiation for the treatment of in-stent restenosis demonstrated 58% reduction in the need for target lesion revascularization and a 53% reduction in the need for target vessel revascularization at 6 months compared to the historical control group of WRIST. No major differences were detected when comparing the outcome of the irradiated beta group with the gamma group of WRIST.17 This benefit has been maintained at 2-year follow-up with beta radiation reducing target lesion revascularization (42% vs 66%, p ⫽ 0.016), target-vessel revascularization (46% vs 72%, p ⫽ 0.009) and the composite clinical end point of death, Q-wave myocardial infarction or target vessel revascularization (46% vs 72%, p ⫽ 0.008) compared to placebo.52 The efficacy of beta and gamma emitters for the treatment of in-stent restenosis appears similar at longer term follow-up. START (STents And Radiation Therapy) is pivotal multicenter randomized trial involving 485 patients in over 55 centers in the US and Europe, designed to determine the efficacy and safety of the BetaCath™ system for the treatment of in-stent restenosis. Patients eligible for the START Trial included those with native artery lesions < 20 mm in length. On average, patients enrolled in the study had 16 mm long lesions in arteries 2.8 mm in diameter. Following angioplasty, these patients were treated with the BetaCath system containing 90Sr/Y seeds that deliver beta radiation through a

214

closed-end lumen catheter following angioplasty. Patients were randomized to either placebo or an active radiation train 30 mm in length. Depending on the diameter of the target vessel, a dose of either 16 or 20 Gy was administered at 2 mm from the center of the source. The antiplatelet therapy in this study consisted of at least 3 months of clopidogrel 75 mg qd. At 8 months, angiographic restenosis rates in the irradiated segments were 29% vs 45% in the placebo group (p ⫽ 0.001). TLR was 16% in the irradiated group, compared to 22% in control (p ⫽ 0.008). Rates for TVR were also similar (16% and 24%, respectively). Additionally, patients treated with radiation had a considerably lower rate of major adverse cardiac events than those in the placebo group (18% vs 26%). Importantly there were no events of late thrombosis and none of the patients developed acute MI. Similar to the findings of BETA WRIST, results from the START trial indicate the safety and effectiveness of using beta emitters for vascular brachytherapy. INHIBIT, a multicenter randomized study involving 332 patients in 29 US and international sites, examined the efficacy of the GALILEO system for the treatment of in-stent restenosis. The GALILEO system uses a 32P source with a dose of 20 Gy at a depth of 1 mm into the vessel wall. The study mandated at least 3 months of antiplatelet therapy and 307 patients completed 9 months clinical follow-up. The radiation was delivered successfully in 315 of the patients and tolerated well in all but two patients. At 30 days, 11 patients had clinical events (two death, two Qwave MI, three non-Q-wave MI, three PTCA, and one misadministration of the radiation dose). There were not adverse effects related to the radiation procedure. At 9 months, treatment with 32P reduced the primary angiographic endpoint of binary restenosis by 66%

THE CLINICAL TRIALS

(p ⫽ 0.0001) in the stented segment and by 50% (p ⫽ 0.0003) in the analysis segment. There were no differences in the edge effect rates between the active and the control treated groups. The radiated patients had improved MLD (1.52 vs 1.38 mm, p ⫽ 0.01) and reduced late loss (0.4 vs 0.6 mm, p < 0.001). 32P significantly reduced rates of TLR (11% vs 29%, p < 0.001) and MACE (14% vs 31%, p < 0.001). Tandem positioning to cover diffuse lesions > 22 mm with 32P was feasible, safe and effective. The results from INHIBIT demonstrate that beta radiation can be delivered safely and effectively to reduce the recurrence of restenosis following treatment of in-stent restenosis. BRITE (Beta Radiation to Prevent In-sTent REstenosis) is a US feasibility study to test the Radiance Radiation System which uses a balloon catheter encapsulating a 32P radioactive sleeve for the treatment of in-stent restenosis. In the BRITE Trial, 30 patients gave consent, 27 of whom were treated with PTCA (26 balloon, one rotoblator) for lesions < 25 mm in length. Following intervention, the RDX catheter was successfully delivered in 26/27 attempts (one catheter did not reach the target location and was withdrawn after a 70second attempt, delivering less than 1 Gy to adjacent tissue). The prescribed mean dose was 19.8 ⫾ 0.4 Gy at 1 mm from the inflated source surface and delivered in an average dwell time of 482 ⫾39 seconds. Seventy per cent of the dose was administered when the balloon was inflated. The transit time was 8.5 seconds. None of the cases required interruption. The interventional procedure was predominantly PTCA (24/27). All patients were prescribed 250 mg qd ASA and 75 mg qd clopidogrel for 3 months following the procedure. There were no procedural complications or major adverse cardiac events at 30-day clinical follow-up. It is anticipated that

this pilot study will have low restenosis and revascularization rates. The randomized study with 500 patients is planned to be launched by the last quarter of 2000. Thus far, the lessons from the beta feasibility studies are that radiation effect is confined to the length of the source and longer beta sources are required to cover the entire segment undergoing intervention to eliminate the edge effect phenomenon. Additional studies examining beta emitters can be found in Table 13.2.

Radioactive beta emitting stents The clinical trials with the radioactive stent have demonstrated safety but were disappointing in efficacy. The isotope examined on this radioactive stent is 32P. IRIS (Isotent for Restenosis Intervention Study) was the first feasibility study using radioactive 32P Palmaz–Schatz stents. In this study, 30 patients with stenosis in de novo or restenotic lesions of native coronaries underwent radioactive stent implantation (activity between 0.5–1.0 µCi) with a mean stent activity of 0.69 µCi. There were no adverse effects at 30 days in any of the treated patients, however, at the 6-month angiographic followup there was a binary restenosis rate of 31% and clinically driven target lesion revascularization rate of 21%. Late loss data by segment was 0.94 mm for de novo and 0.70 mm for restenosis lesions. IVUS detected a significant amount of diffuse disease with a mean CSA stenosis of 41% in the reference vessel at the time of the stent implantation.52,53 The IRIS trial was expanded to include an additional 25 patients who underwent intracoronary stent implantation with a higher activity (0.75–1.5 µCi) stent. This cohort indicated that the radioactive stent was safe with no evidence of thrombus or subacute closure.

215


The overall restenosis rate, however, was higher than rates reported with non-radioactive stents.54 In a dose-finding study conducted in Milan, higher activities, about 6 µCi, detected nearly complete neointima formation in the body of the stent, but were associated with high degrees of restenosis at the edges of the stent range of 36–44% with a unique angiographic pattern of stenosis at the edges, known as the ‘candy wrapper’ effect.55 Studies with activities of up to 20 µCi are being conducted to evaluate whether higher activities will minimize the edge effect phenomenon. Other approaches to eliminate the edge effect are being investigated; for instance, cold end radioactive stents have failed and hot end radioactive stents with an activity of up to 50 µCi also did not eliminate the edge effect phenomenon. New isotopes and delivery system platforms such as nitinol stents are currently under investigation to overcome the limitations of radioactive stent.

Limitations to brachytherapy Although clinical trials using vascular brachytherapy for both coronary and peripheral applications have demonstrated positive results in reducing restenosis rates, these trials have also identified two major serious complications related to the technology; late thrombosis and edge stenosis effects seen at the edges of radiation treatment segments. Late thrombosis is probably due to the delay in healing associated with radiation. It has been estimated that late thrombosis can be remedied through the prolonged administration of antiplatelet therapy following intervention. Identified as a major limitation to radioactive stents and explained above, the edge effect phenomenon is not exclusive to stented lesions. The incidence of edge effect has also

216

been known to occur with catheter-based systems utilizing both beta and gamma emitters, especially when the treated area is not covered with wide enough margins. The main explanation for the incidence of edge effect is a combination of low dose at the edges of the radiation source and an injury created by the device for intervention which is not covered by the radiation source. It is hypothesized that wider radiation margins or radiation treatment to the intervening segment may eliminate or significantly reduce the edge effect seen so far in all radiation trials. Finally there is late restenosis reported in a small cohort of patients who were treated with radiation. In those patients radiation therapy only delays restenosis.

Conclusion Vascular branchytherapy has been proven to be a successful therapy to treat and prevent the incidence of restenosis. The technology is a moving target on its way of becoming a recognized standard of care for the treatment of restenosis. The revelation of the technology’s major complications has led to immediate solutions which we hope will be able to nearly eliminate late thrombosis and minimize the edge effect phenomenon. Currently, the studies both with beta and gamma radiation only serve as a proof of principle to the technology. It appears that if the right dose is used on the right target tissue, radiation will be an effective therapy for restenosis regardless of the type of isotope or delivery system used. Although caution must be applied to the interpretation of data from small cohorts of patients in non-randomized trials, it is hard to ignore the findings of minimal and occasionally negative late lumen loss after balloon angioplasty or extremely late low indices in patients with restenosis and

CONCLUSION

stenting. This phenomenon has not been demonstrated so far with any other alternative therapy, whether mechanical or pharmacological, proposed to combat restenosis. The positive results from the four major trials evaluating both gamma and beta (SCRIPPS, WRIST, GAMMA 1 and START) prompted the FDA to expeditiously review and approve delivery systems for both beta

and gamma. The FDA approved both systems only for the treatment of in-stent restenosis in native coronary arteries. It is expected that the continuation of positive results from the ongoing clinical trials and future randomized controlled studies will likely explore the expansion of vascular brachytherapy to treat high-risk patients with diabetes, small vessels, long lesions and vein grafts.

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20. Mazur W, Ali MN, Khan MM et al. High dose rate intracoronary radiation for inhibition of neointimal formation in the stented and balloon injured porcine models of restenosis: angiographic, morphometric and histopathological analyses. Int J Radiat Oncol Biol Phys 1996; 36:777–788. 21. Wiedermann JG, Leavy JA, Amols H et al. Effects of high-dose intracoronary irradiation on vasomotor function and smooth muscle histopathology. Am J Physiol 1994; 267:H125–H132. 22. Waksman R, Robinson KA, Crocker IR et al. Intracoronary radiation decreases new additional intimal hyperplasia in a repeat balloon angioplasty swine model of restenosis. Int J Radiat Oncol Biol Phys 1997; 376:767–777. 23. Verin V, Popowski Y, Urban P et al. Intra-arterial beta irradiation prevents neointimal hyperplasia in a hypercholesterolemic rabbit restenosis model. Circulation 1995; 92:2284–2290. 24. Waksman R, Robinson KA, Crocker IR et al. Intracoronary low-dose beta-irradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model. Circulation 1995; 92:3025–3031. 25. Weinberger J, Amols H, Ennis RD et al. Intracoronary irradiation: dose response for the prevention of restenosis in swine. Int J Radiat Oncol Biol Phys 1996; 36:767–775. 26. Raizner A. Endovascular radiation the Baylor experience. highlights in intracoronary radiation therapy, Thoraxcenter Rotterdam, 1996, December 10–11. 27. Fischell TA, Kharma BK, Fischell DR et al. Low dose beta particle emission from stent wire results in complete localized inhibition of smooth muscle cell proliferation. Circulation 1994; 90:2956–2963. 28. Hehrlein C, Kniser S, Kollum M et al. Effects of very low dose endovascular irradiation via an activated guidewire on neointima formation after stent implantation. Circulation 1995; I69. 29. Hehrlein C, Gollan C, Donges K et al. Lowdose radioactive endovascular stents prevent smooth muscle cell proliferation and neointimal hyperplasia in rabbits. Circulation 1995; 92:1570–1575.

30. Laird JR, Carter AJ, Kufs WM et al. Inhibition of neointimal proliferation with low-dose irradiation from a beta particle-emitting stent. Circulation 1996, 93:529–536. 31. Carter AJ, Laird JR, Bailey LR et al. Effects of endovascular radiation from a beta-particleemitting stent in a porcine coronary restenosis model. A dose-response study. Circulation 1996; 94:2364–2368. 32. Waksman R, Chan RC, Vodovotz Y et al. Radioactive 133-Xenon gas-filled angioplasty balloon: a novel intracoronary radiation system to prevent restenosis. J Am Coll Cardiol 1998; 31:356A. 33. Weinberger J. Solution-applied beta emitting radioisotope (SABER) system. In: Waksman R, Serruys P, eds. Handbook of Vascular Brachytherapy 1st edn. London: Martin Dunitz Ltd, 1998. 34. Robinson KA, Pipes DW, Bibber RV et al. Dose response evaluation in balloon injured pig coronary arteries of a beta emitting 186Re liquid balloon catheter system for endovascular brachytherapy. Advances in Cardiovascular Radiation Therapy II, Washington, DC, 1998, March 8–10 (abst). 35. Makkar R, Whiting J, Li A et al. A beta-emitting liquid isotope filled balloon markedly inhibits restenosis in stented porcine coronary arteries. J Am Coll Cardiol 1998; 31:351A (abst). 36. Kim HS, Cho YS, Kim JS et al. Effect of transcatheter endovascular holmium-166 irradiation on neointimal formation after balloon injury in porcine coronary artery. J Am Coll Cardiol 1998; 31:277A (abst). 37. Waksman R, Saucedo JF, Chan RC et al. Yttrium-90 delivered via a centering catheter and remote afterloader, uniformly inhibits neointima formation after balloon injury in swine coronary arteries. J Am Coll Cardiol 1998; 31:278A (abst). 38. Waksman R, Rodriquez JC, Robinson KA et al. Effect of intravascular irradiation on cell proliferation, apoptosis and vascular remodeling after balloon overstretch injury of porcine coronary arteries. Circulation 1996; 96:1944–1952. 39. Waksman R, Chan RC, Kim WH et al. Intracoronary delivery of rhenium-186 radioactive

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coil after balloon injury inhibits neointima formation in swine coronary arteries. Circulation 1998; 98,I-557:2933. Condado JA, Waksman R, Gurdiel O et al. Long-term angiographic and clinical outcomes after percutaneous transluminal coronary angioplasty and intracoronary radiation in humans. Circulation 1997; 96:727–32. Condado JA, Saucedo JF, Caldera C et al. Two-year angiographic evaluation after intracoronary radiation therapy in humans. Circulation 1997; 96:1–220. Teirstein PS, Massullo V, Jani S et al. Catheterbased radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997; 336:1697–1703. Teirstein PS, Massullo V, Jani S et al. Twoyear follow-up after catheter-based radiotherapy to inhibit coronary restenosis. Circulation 1999; 99:243–247. Waksman R, White RL, Chan RC et al. Intracoronary radiation therapy after angioplasty inhibits recurrence in patients with in-stent restenosis. Circulation 2000; 101:2165–2171. Leon MB, Teirstein PS, Lansky AJ et al. Intracoronary gamma radiation to reduce in-stent restenosis: the multicenter GAMMA 1 randomized clinical trial. J Am Coll Cardiol 1999; 33:56A (abst). Faxon DP, Buchbinder M, Cleman MW et al. Intracoronary radiation to prevent restenosis in native coronary lesions: the results of the pilot phase of the ARREST trial. J Am Coll Cardiol 1999; 33:19A (abst). Verin V, Urban P, Popowski Y et al. Feasibility of intracoronary beta-irradiation to reduce restenosis after balloon angioplasty. A clinical pilot study. Circulation 1997; 95:1138–1144.

48. King SB 3rd, Williams DO, Chougule P et al. Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty. Results of the beta energy restenosis trial (BERT). Circulation 1998; 97:2025–30. 49. Amols HI, Reinstein LE, Weinberger J. Dosimetry of a radioactive coronary balloon dilatation catheter for treatment of neointimal hyperplasia. Med Phys 1996; 23:1783–1788. 50. Weinberger J. Clinical experience with the liquid-filled balloon: the CURE study. Advances in Cardiovascular Radiation Therapy III, Washington, DC, 1999, Feb 17–19 (abst). 51. Waksman R, White RL, Chan RC et al. Intracoronary beta radiation therapy for in-stent restenosis: Preliminary report from a single center clinical study. J Am Coll Cardiol 1999; 3319A (abst). 52. Fishchell TA, Carter AJ, Laird JR. The betaparticle-emitting radioisotope stent (isotent): animal studies and planned clinical trials. Am J Cardiol 1996; 78(3A):45–50. 53. Baim DS, Fischell T, Weissman NJ et al. Short term (1 month) results of the IRIS feasibility study of a beta particle emitting radioisotope stent. Circulation 1997; 96:I-218. 54. Moses J. US IRIS Trials Low-Activity 32P Stent. Advances in Cardiovascular Radiation Therapy II, Washington, DC, 1999, Feb 17–19 (abst). 55. Colombo A. European High-Activity 32P Stent. Advances in Cardiovascular Radiation Therapy III, Washington, DC, 1999, Feb 17–19 (abst).

14 Radiation for restenosis Paul S Teirstein

Radiotherapy is one of the latest of a long line of potential antiproliferative agents to be enthusiastically tested as an adjunct to angioplasty. In over 100 years of clinical experience, radiotherapy has proven highly effective in inhibiting cellular proliferation, both in malignant and benign disease. Examples of benign hyperplastic entities effectively treated with radiotherapy include the exuberant fibroblastic activity of keloid scar formation, heterotopic ossification, desmoid/aggressive fibromatosis, Peyronie’s disease, and pterygium.1–5 In these benign proliferative disorders, doses of 700–1000 cGy in one treatment or fractionated treatments after the stimuli have proven effective in inhibiting fibroblastic activity without significantly interfering with the normal healing process.

Radiotherapy in animal models of restenosis Wiedermann and colleagues6,7 and Waksman and colleagues8–10 demonstrated significant reduction in intimal proliferation using radiotherapy in the swine model of restenosis. Wiedermann and colleagues used a swine balloon overstretch injury model of coronary injury to test iridium-192 (192Ir, a gamma emitter), delivering 2000 cGy over a 30–45 minute dwell time. Morphometric analysis at

30 days demonstrated a maximal neointimal area of 0.84 ⫾ 0.60 mm2 in control animals compared to only 0.24 ⫾ 0.13 mm2 in treated animals (p ⫽ 0.001). At 6-month follow-up these differences were vs 0.46 ⫾ 0.35 mm2 1.59 ⫾ 0.78 mm2 (p ⬍ 0.001).11 Waksman and colleagues used a similar model to deliver 192Ir at three doses (3500, 7000, or 14 000 cGy). An additional group received 7000 cGy delayed 48 hours after balloon injury. Measurement of the proliferative response to injury was normalized by the ratio of intimal area to medial fracture length (IA/FL), in addition to quantitation of the maximal intimal thickness (MIT). At 14day follow-up, all treated arteries demonstrated significantly decreased neointima formation compared to control arteries. In addition, a dose–response effect was found. Interestingly, delaying the treatment by 48 hours appeared to augment the responses. Inhibition of proliferation continued to be observed at 6-month follow-up. These investigators found similar results when a beta source (90Sr/Y) at 7000–56 000 cGy was used in the same animal model.12 In another trial, Waksman et al13 provided insight into the target of vascular radiotherapy and its mechanism of action. Balloon injury was performed on swine coronary arteries, followed immediately by either 90 Sr/Y or 192Ir sources designed to deliver

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RADIATION FOR RESTENOSIS

1400 or 2800 cGy at a depth of 2 mm from the source. Animals were sacrificed at 3, 7, or 14 days. Bromodeoxyuridine was administered 24 hours before euthanasia to label proliferating cells. On Day 3, cellular proliferation was significantly reduced in both the adventitia and the media of treated vessels compared to controls. At 2 weeks’ postinjury, there were fewer ␣-actin-positive myofibroblasts in the adventitia of treated compared to control animals and morphometric analysis indicated the vessel perimeter of treated vessels was significantly larger than controls. Apoptosis was estimated by terminal transferase dUTP-biotin nick-end labeling (TUNEL) at 3 and 7 days after injury. No differences in TUNEL-labeled cells were found between treated and control vessels. These studies suggested that intracoronary radiation primarily inhibits cellular proliferation in both the media and adventitia and suggests a mechanism other than apoptosis. It also demonstrates a favorable effect on late remodeling probably by preventing adventitial fibrosis at the injury site. Numerous other investigators have demonstrated the efficacy of both gamma and beta radiation in various animal models of restenosis.14,15–22 Others have successfully inhibited neointimal proliferation using betaemitting radioactive stents.23–29 Importantly, these animal models demonstrated efficacy without evidence of necrosis, significant fibrosis or aneurysm formation.

Clinical trials Clinical data derived from trials of intravascular gamma radiation therapy is rapidly accumulating. In one very early study, Bottcher, Liermann and colleagues30,31 used 192 Ir to treat 13 patients with angioplasty plus stent implantation for femoral artery

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restenosis. All 13 patients also received 12 Gy radiation immediately after the procedure. Clinical follow-up indicated no recurrent restenosis over 3–27 months. Steidle32 also used 192Ir to treat 24 patients following stent implantation for femoral artery stenosis. Percutaneous radiation therapy with 2.5 Gy per day for 5 days for a total of 12.5 Gy was administered to 11 of their 24 patients. Over a 7-month follow-up period, reocclusion occurred in 2/11 patients in the radiation group and 5/13 patients in the noradiation group. Condado et al33 treated 21 patients undergoing coronary angioplasty with 192Ir. While there was no control group, follow-up results were very encouraging with a reported late loss index of 0.19 and restenosis rate of 27.3%. In the Scripps Coronary Radiation to Inhibit Proliferation Post-Stenting (SCRIPPS) trial, patients with previous restenosis and stent implantation were randomized to receive a 0.03-inch ribbon containing either 192 Ir sealed sources at its tip or a ribbon containing placebo, inactive sources (Best Industries, Springfield, VA). 192Ir dosimetry was calculated using IVUS measurements. The radiation oncologist and physicist used information from the IVUS image to determine a dwell time that provided 800 cGy to the internal elastic membrane furthest from the radiation source, provided that no more than 3000 cGy was delivered to the internal elastic membrane closest to the radiation source. All angiographic and IVUS measurements were performed at an independent core ultrasound laboratory by investigators blinded to procedural information and patient assignment. Between 24 March and 22 December 1995, 55 patients were randomized; 26 were assigned to 192Ir and 29 to placebo. Angio-

CLINICAL TRIALS

graphic indices of restenosis at 6 months were markedly different in treated vs placebo patients (Fig. 14.1). Late luminal loss was significantly lower in the 192Ir group (0.38 ⫾ 1.06 mm vs 1.03 ⫾ 0.97 mm; p ⫽ 0.009). Notably, the late lumen loss index (a sensitive measure of a therapy’s ability to preserve the post-procedural luminal diameter) was significantly lower in the 192Ir group (0.12 ⫾ 0.63 vs 0.60 ⫾ 0.43; p ⫽ 0.002). Using a dichotomous definition, angiographic restenosis (ⱖ 50% diameter stenosis at follow-up) either within the stent or at the stent border (outside the stent but still covered by the study ribbon) was only 16.7% in the 192Ir group compared to 53.6% for placebo patients (p ⫽ 0.025). Restenosis

limited to the stented segment occurred in only 8.3% of the 192Ir group compared to 35.7% of placebo patients (p ⫽ 0.024). The difference in angiographic restenosis rates was supported by a reduction in target lesion revascularization in the 192Ir group (11.5% vs 44.8%; p ⫽ 0.008). Composite clinical events (death, myocardial infarction, stent thrombosis, or target lesion revascularization) were also significantly less frequent in 192 Ir patients (15.4% vs 48.3%; p ⫽ 0.011). The angiographic results were supported by the independent intravascular ultrasound analysis. By intravascular ultrasound analysis there was no significant change in stent area or stent volume between the immediate post procedure and follow-up period. The decrease

Restenosis of Stent ⫹ Border

3 Year Follow-up

6 Month Follow-up

63% 47%

54% 69%

33%

17% p ⫽ 0.01

Placebo n ⫽ 28

192 Ir n ⫽ 24

p ⬍ .05

Placebo n ⫽ 24

192 Ir n ⫽ 21

Figure 14.1 Comparison of a dichotomous definition of angiographic restenosis (⬎ 50% diameter stenosis) between placebo and 192Ir patients in the SCRIPPS trial. Restenosis, when both the stent and stent border are included in the analysis, was reduced by 69% at 6 months, and 47% at 3 years.

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in mean lumen area at follow-up was smaller in the 192Ir group (0.7 ⫾ 1.0 mm2 vs 2.2 ⫾ 1.8 mm2; p ⫽ 0.003), as was the increase in area of tissue growth within the stent struts (0.7 ⫾ 0.9 mm2 vs 2.2 ⫾ 1.8 mm2; p ⫽ 0.003). The decrease in lumen volume was 192 Ir group also smaller in the 3 vs 44.3 ⫾ 34.6 mm3; (16.4 ⫾ 24.0 mm p ⫽ 0.008), as was the increase in volume of tissue growth within stent struts vs 45.1 ⫾ 39.4 mm3; (15.5 ⫾ 22.7 mm3 p ⫽ 0.0091). Clinical and angiographic follow-up was obtained at the 3-year time point.34,35 At 3 years there was some late angiographic ‘catch up’ in the irradiated group. The reduction in

restenosis fell from 69% to 48%. However, at 3 years there was still a significant difference in restenosis rates (33% vs 64%). Importantly, at 3 years the clinical benefits were durable. Target lesion revascularization was 15.4% in treated compared to 4.3% in placebo patients (p ⬍ 0.01). The Washington Radiation for In-Stent Restenosis Trial (WRIST) randomized 130 patients with in-stent restenosis to 192Ir or placebo. At 6 months, the clinical and angiographic results were nearly identical to the SCRIPPS trial with a 67% reduction in angiographic restenosis (p ⬍ 0.001) and a 78% reduction in the need for target lesion revascularization. The GAMMA I trial

Figure 14.2 Hand-delivered distal radiation delivery system (Cordis, Miami, FL, USA).

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CLINICAL TRIALS

Guidant Intravascular Radiotherapy Source Delivery Unit

Caution-Investigational Device. Limited by U.S. Law to Investigational Use.

Figure 14.3 Remote afterloader (Guidant, Houston, TX, USA) is programmed to automatically deliver a radioactive line source for a specified dwell time.

randomized 252 patients with in-stent restenosis from 12 US centers to 192Ir or placebo.36 The results were also consistent with the previous single-center gamma radiation trials. Restenosis was reduced from 55.3% in placebo patients to 32.4% in treated patients (p ⫽ 0.01). Target lesion revascularization was reduced from 42.1% to 24.4% (p ⬍ 0.011). There was remarkable consistency between the results of the above three gamma vascular brachytherapy trials. Thus, gamma radiation using 192Ir is the very first therapeutic agent of more than 50 clinically tested37 to demonstrate an impact on neointima formation after angioplasty.

Beta emitters differ from the gamma energy used in the above trials in that they are less penetrating and easily shielded, making them somewhat easier to handle in the catheterization laboratory environment. However, questions have been raised concerning the ability of a beta emitter to provide therapeutic radiation doses to the required depth. Nonetheless, the results to date have been very encouraging.38 Verin et al39 initially treated 15 patients undergoing coronary angioplasty with 90Y, a beta emitter. The results were disappointing owing to a loss index of 50% and restenosis rate of 40% at 6 months. However, this led

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to the more encouraging European dosefinding study. This trial randomized 181 patients with de novo disease, 28 of whom received stents, to four doses of 90Y (9, 12, 15, and 18 Gy at 2 mm from the source). A pronounced dose–response effect was observed with 6-month restenosis rates falling from 27.5% in the lowest dose group to only 8.3% in the highest dose group.40 King et al41 used 90Sr/Y, also a beta emitter, to treat 21 patients undergoing coronary angioplasty in the BERT I trial. Although there was no control group, the reported 6month restenosis rate of 17% and loss index of 0.05% was very encouraging. In the expanded BERT II trial, 82 patients were treated with the same radiation delivery system. At 6-month follow-up, the restenosis rate was 17% and the late loss index was only 9%.42 The BERT trial similarly reported encouraging results and documented a pattern of favorable remodeling after beta radiation in non-stented patients.43 These favorable results inspired a 1400 patient multicenter randomized trial (the BetaCath™ trial) for de novo lesions and a 476 patient trial (the START trial) to test 90Sr/Y in patients with in-stent restenosis. The recently reported 6-month angiographic and clinical results of the START trial were strongly positive, providing significant confirmation of radiation’s efficacy in limiting restenosis. Compared to placebo, patients with in-stent restenosis who received radiation sustained a 36% reduction in subsequent restenosis; from 45% to 29% (p ⫽ 0.001). Clinical results were also impressive, with the need for target vessel revascularization falling from 24% in placebo to 16% in treated patients (p ⫽ 0.026) (NoVoste Announces Results of START TRIAL, NoVoste Press Release, March 12, 2000).

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The PREVENT trial used a balloon centered beta-emitting source to treat a similar patient group. Patients were randomized to either placebo or three different doses of 32P. At 6 months’ angiography, patients treated with 32P had a significant reduction in restenosis (44% vs 25%). However, these results were mitigated somewhat by the presence of new disease of the treatment margins (the ‘edge effect’). Thus, the need for target vessel revascularization was similar between the placebo (29%) and treated (24%) patients (p ⫽ ns). One potentially effective beta emitter is a radioactive, beta-emitting coronary stent. Beta-emitting radioactive stents hold the promise of a simple, easy to use, efficient radiotherapy delivery system. Metal stents have been made radioactive by ion implanting 31P beneath the metal surface and then exposing them to neutron irradiation to convert 31P into 32P,44 or by activating stainless steel stents in a cyclotron.25 The betaemitting radioactive stent is applied directly to the vessel wall, which may provide more favorable dosimetry. The IRIS feasibility trial (ISOSTENT, San Carlos, CA, USA) tested escalating doses of a 32 P radioactive stent for patients with de novo native coronary stenoses.45 While low doses ⬍ 6 ␮Ci were ineffective, at higher doses, the hyperplastic response was nearly abolished within the stent body. Unfortunately, at the stent margins this device elicited an intense hyperplastic response, resulting in clinically significant ‘edge restenosis’ in approximately 50% of patients. A variety of creative remedies for this ‘edge’ or ‘candy-wrapper’ effect have been tested including very high doses, low pressure delivery inflations, non-radioactive stent margins (‘cold ends’) and have, to date, been unsuccessful. Other approaches currently undergo-

GAMMA VERSUS BETA RADIATION

ing investigation include increased radioactivity at the stent margin (‘hot ends’) and implanting a more penetrating gamma isotope onto the stent struts.46,47

Gamma versus beta radiation A fundamental component of any radiation delivery system is the radioisotope itself. Each isotope has important physical characteristics such as energy and half-life. Perhaps the most important differentiating characteristics of a particular radiation source is its characterization as a gamma or beta energy source.48 The differences between gamma and beta sources underlie one of the current ‘hot debates’ in the vascular radiotherapy field. Radiation probably inhibits the cellular proliferative response to injury after angioplasty by creating a double-stranded break in the cell’s DNA, preventing cell division.49 It is important to understand that our current understanding of the mechanism of action of the radiotherapy on the cell cycle is that once radiation energy is delivered to a dividing cell, its effects are independent of the source used. That is, cell division will be equally inhibited by gamma and beta energy. As long as the required energy is brought to the intended target, either gamma or beta radiation will probably be equally effective.

Gamma radiation Gamma sources are photons and have several advantages when applied to vascular diseases. Early data from randomized trials indicate that gamma sources will be effective, particularly for the treatment of in-stent restenosis. Randomized data from the

SCRIPPS Trial, a randomized, double-blind, placebo-controlled study demonstrated a reduction in restenosis rates from 54% in the placebo group to 17% in patients treated with gamma radiation (192Ir).50,51 Gamma sources penetrate human tissues deeply. This makes gamma energy ideal for treating large vessels, especially if a line source is used, and especially if this source is not centered. Finally, gamma sources are not shielded by stents. This makes gamma sources ideal for the treatment of in-stent restenosis. There are, however, numerous disadvantages to using gamma sources. Photons are not blocked by the ‘usual’ lead shields.52 A heavy, 1-inch-thick lead shield is required. This is usually provided in the form of a very cumbersome lead device attached to rollers that allow it to be wheeled into the catheterization laboratory.53 Owing to the presence of deeply penetrating ionizing radiation, when high-energy gamma radiation is used in the catheterization laboratory, the procedure room must be cleared of all ‘nonessential’ personnel. The patient is observed from the control room which is protected by thick lead shielding. Also, the patient receives more radiation from a gamma radiation procedure than a beta procedure. The radiation oncologist, who delivers the actual radiation sources, also receives additional radiation exposure. This problem of radiation exposure in the catheterization laboratory environment limits the maximal specific activity of the radiation sources. If the sources are of very high activity, the exposure to health care personnel in the control room will be unacceptably high. To circumvent this problem, lower specific activity sources must be used. This requires a longer dwell time (8–20 minutes) to achieve therapeutic doses than that required for most beta sources (only 3–10 minutes).

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Beta radiation Beta sources are electrons that only penetrate several millimeters into the vessel wall.54,55 Beta energy is easily shielded, even by thick plastics. The fact that exposure from beta sources is limited allows the specific activity to be much higher than that of gamma sources. This translates into very short dwell times, adding only 3–10 minutes to the angioplasty procedure. Radiation safety concerns surrounding the use of beta sources are vastly reduced compared to that of gamma radiation. Heath care personnel can remain in the cardiac catheterization laboratory and additional exposure to the patient and radiation oncologist is negligible. The debate concerning gamma vs beta energy will continue until adequate clinical data is available. While beta energy is clearly easier to work with in the clinical environment, gamma radiation has now been routinely used in numerous catheterization laboratories for over 3 years without significant problems. Issues such as health care personnel leaving the catheterization room while the patient receives treatment have not been a practical problem. Patients have received excellent care and if a nurse or physician must enter the catheterization laboratory urgently, the gamma source can be withdrawn into a shielded container in under 20 seconds, allowing entry by all necessary personnel. Furthermore, the additional exposure to health care personnel by the use of gamma radiation has been quite minimal. Cardiologists receive little or no additional exposure during gamma radiation procedures because after delivering the afterloading catheter, they leave the room and receive no further radiation. Although the radiation oncologist receives extra radiation from gamma radiotherapy, this extra exposure is minimal and

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relatively small compared to the exposure received by radiation oncologists during the other kinds of brachytherapy treatment routinely performed, such as the treatment of prostate, pelvic, and head and neck malignancies. In the end, the debate between beta and gamma vascular radiotherapy will be won by the outcome of a relative efficacy analysis. Beta energy is unquestionably easier to use. However, gamma energy is not impractical and if beta sources prove to be less effective, the medical community will embrace gamma energy. Still, if beta energy is equally effective, beta radiation will prevail.

Long-term consequences of vascular radiotherapy While early safety and efficacy has been demonstrated in numerous animal studies and limited human trials, the long-term efficacy and, most importantly, safety of this technique has been questioned. The possibility of late untoward consequences such as aneurysm formation, perforation or accelerated vascular disease is a significant concern.9,11 In addition, it is not known if the beneficial effects of radiation therapy will be durable or if radiation will only delay and not permanently reduce restenosis. With the exposure of increasing numbers of patients to intravascular radiation, it is essential to obtain long-term clinical follow-up. Presently, long-term follow-up of patients enrolled in clinical trials using vascular radiotherapy is very limited. Two-year angiographic follow-up following intracoronary gamma radiation was reported by Condado et al.56 The restenosis rate was low at 28%, but this study lacked a control group for comparison. Several coronary aneurysms and

VASCULAR RADIOTHERAPY DELIVERY SYSTEMS CURRENTLY UNDER DEVELOPMENT

one definite pseudoaneurysm were reported in the Condado et al series, possibly because the vessels were potentially exposed to very high radiation doses (up to 9200 cGy) compared to the lower 800–5000 cGy used in most other series. In another report, longterm follow-up documented high patency rates after exposing femoropopliteal arteries undergoing angioplasty to intravascular gamma radiation.30–32 The SCRIPPS trial obtained angiographic follow-up in a modest number of patients at 3 years. So there were no perforations, aneurysms, pseudoaneurysms, or other special safety concerns.34 Long-term adverse events following radiation therapy for non-vascular indications are well documented. Potential complications include accelerated vascular disease, coronary perforation (including pseudoaneurysm) and late malignancy. Accelerated vascular disease has been reported in patients irradiated for treatment of Hodgkin’s disease followed beyond 9 years.57 The morphology of radiation-induced coronary artery disease appears to involve smaller diameter arteries (⬍ 0.5 mm) and is similar to spontaneous coronary artery disease.58 Larger arteries (⬎ 0.5 mm) appear more resistant to radiation.59–62 In intravascular brachytherapy, the volume of irradiation is small with significant radial dose fall-off from the lumen to the adventitia. Additionally, only a single vessel is radiated over a limited longitudinal segment with little exposure to the surrounding normal tissue. Therefore, the risk of radiation-induced fibrosis or atherosclerosis is believed to be much lower than that which occurs from the treatment of Hodgkin’s disease where a much larger volume of tissue is irradiated. High doses of radiation could also lead to arterial rupture.63,64 Perforation and/or pseudoaneurysm of coronary arteries would likely be detected in the first few

months after treatment. In some studies, such as the SCRIPPS trial, the careful avoidance of ⬎ 3000 cGy to any one part of the luminal surface, with much lower doses delivered to the adventitial layers, probably reduces the risk of vessel perforation. Secondary malignancies after radiation range from leukemia to solid tumors. Hematologic malignancies are usually seen within the first 3–7 years in cancer patients who receive combination chemotherapy and are often immunocompromised.65–68 Secondary solid tumors have a longer latent period of 7–10 years. These are occasionally soft tissue sarcomas, but are more often epithelial tumors of irradiated organs. Again, it is emphasized that the volume of radiation in intravascular brachytherapy is extremely small, making secondary malignancy unlikely. The application of radiation therapy in modest doses in other benign proliferative disorders (i.e. heterotopic ossification and keloid scars) appears to be safe, with no apparent long-term complications.

Vascular radiotherapy delivery systems currently under development Brachytherapy has been routinely used by radiation therapists for several decades. The concept of brachytherapy involves bringing the radioisotope in close proximity of the target, reducing the source to target distance (brachy: Greek from brackus, short). This minimizes undesired tissue exposure compared to treatment with external beam radiation. A tremendous amount of creativity and innovation has been brought to bear on the development of intravascular radiation delivery systems. While many traditional radiotherapy

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systems have been adapted for vascular use, a wide array of new concepts, specifically invented for coronary artery treatment are currently under development. This new technology encompasses line sources, liquid sources, gas and membrane sources, as well as stent-based delivery systems.

Catheter-based line sources Line sources are commonly employed to deliver radiation to a variety of benign and malignant disorders. These traditionally used devices can be easily adapted for the treatment of vascular disease. Radioactive sources such as 192Ir, 32P, 90Sr, and 90Sr/Y can be

encapsulated and manufactured in 0.014- to 0.040-inch diameters that can pass easily through intracoronary catheters. Typically, after dilatation and/or stenting of the target lesion, a 3–5 Fr catheter containing a blindend source delivery lumen is advanced over a guidewire and positioned across the target lesion. A ‘wire’ (typically composed of nylon or nitinol) containing radioactive sources at its distal tip is then loaded into the source lumen of the catheter and advanced distally until the radioactive sources span the target lesion (Fig. 14.2). This process, called ‘afterloading’ can either be accomplished manually, by the radiation oncologist advancing the source wire by hand,50,51 or automati-

Beta-Cath™ System

Flexible Handheld System Design

Physician Control

Safety Shields

Catheter Based System Potential Applications Coronary Peripheral Non-Vascular

Presently Under Product Development Not Commercially Available

Figure 14.4 The Beta-Cath™ (NoVoste, Atlanta, GA, USA) system delivers a ‘train’ of cylindrical sealed 90Sr sources via a hydraulic delivery system.

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cally, by a motor-driven unit.69–71 Remote automatic afterloaders can be programmed to advance and then withdraw the source wire at specific time intervals without the need for physician handling, thus reducing exposure to personnel (Fig. 14.3). One variation of the line source concept is a hydraulic delivery system (NoVoste, Atlanta, GA, USA), where encapsulated sources are injected into a blind-end catheter by a syringe or automated pumping system (Fig. 14.4).41 Radiation delivery via a line source with a simple catheter can result in a source placed eccentrically within the vessel lumen. Assuming the target for radiotherapy is the adventitial border, a non-centered source will deliver

a high radiation dose to the adventitia closest to the catheter, and a low radiation dose to the adventitia furthest from the catheter. This dose heterogeneity (maximum/minimum dose) is almost 3:1 for most non-centered gamma radiation systems.72 Alternatively, catheter centering systems, using either a segmented balloon (Fig. 14.5)39 (Schneider, Minneapolis, MN, USA) or a helical balloon (Fig. 14.6)15,19 that also allows perfusion while inflated (Guident, Santa Clara, CA, USA) can reduce dose heterogeneity by maintaining the source in the center of the lumen. While lumen centering does not center the source with respect to the adventitia, in non-eccentric lesions lumen centering can lower dose

Delivery catheter

• • • • • • •

Monorail™ Four centering segments Dia 2.5 - 4.0 mm Length 25 mm Closed-end design 6Fr compatible Single-use, disposable

Figure 14.5 Segmented balloon centering catheter (Schneider, Minneapolis, MN, USA). Distal tip ‘monorail’ design reduces profile.

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heterogeneity from about a 3:1 to about a 2.5:1 ratio.72

Radioactive filled balloons One method of centering a radioactive source is to use a radioactive liquid to inflate a balloon catheter.73,74 Isotopes such as rhenium-188 and rhenium-189 provide a homogeneous dose distribution surrounding an inflated balloon.52 The liquid filled balloon provides excellent lumen centering of the device. Also, by bringing the radioisotope to the outer edge of the balloon, penetration of a beta emitter deeper into the vessel wall may be achieved. Of course, a theoretical lia-

bility of a radioactive-filled balloon system is the very low but definite possibility of balloon or catheter leakage resulting in contamination of the catheterization laboratory, or, worse, exposure to a patient’s bloodstream. A spill of rhenium-188 (halflife ⫽ 20 hours) in the catheterization laboratory would require isolating the room for approximately 5 half-lives (i.e. about 3 days). Leakage of a radioactive liquid-filled balloon into a patient’s bloodstream can be managed by biochemically coupling the radioactive liquid to a substance that inhibits bone uptake and promotes renal excretion (i.e. mercaptoacetylglycylglycylglycine (MAB3)). While balloon breakage would still

Intravascular radiotherapy

Centered System

Caution-Investigational Device. Limited by U.S. Law to Investigational Use.

Figure 14.6 A spiral balloon catheter centering system (Guidant, Houston, TX, USA). The source lumen is centered within the vessel lumen while the helical balloon allows perfusion.

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be undesirable, its consequences could be minimized with intravenous hydration, diuretics, and placement of an in-dwelling urethral catheter with a collection bag. Another approach to a radioactive-filled balloon is to use a radioactive gas. Xenon133, routinely used for ventilation scans, is a combination beta and gamma emitter.75 Homogeneous dosimetry, similar to a liquidfilled balloon system can be achieved with a gas-filled balloon system. Leakage of xenon133 would likely be a less significant clinical and environmental problem because this radioactive gas would rapidly disperse into the atmosphere, resulting in very low local concentrations.

Beta emitting radioactive stents Permanent implantation of a beta emitting radioactive stent has significant practical advantages over other radiation delivery systems. Currently, the majority of patients undergoing percutaneous coronary interventions receive coronary stents. Coupling the radiation delivery to the stent itself makes radiation delivery more efficient, obviating the need for a separate radiation delivery step. Several radioactive stent systems have been developed including ion implantation of phosphorous-32 (32P)26,76,77 and activation of a stainless steel stent in a cyclotron producing a spectrum of radioisotopes.23–25,28,29,78 Most clinical investigation has been undertaken with the 32 P beta emitting stent (Fig. 14.7). Stents ion-

Figure 14.7 32 P radioactive stent mounted on a stent (Isostent, Menlo Park, CA, USA) mounted on a stent delivery system and covered with a protective lucite shield to prevent radiation exposure to the operator.

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implanted with 32P or containing a specific activity ranging from 0.5 to 20 ␮Ci have a 14.3-day half-life, thereby effectively exposing the vessel to beta radiation for about 45 days (approximately 3 half-lives). These stents are of extremely low activity and can be handled with the aid of a simple 1-cm thick acrylic shield.

Challenges to radiotherapy Despite the encouraging data emanating from the numerous clinical vascular radiation trials, challenges remain. The most significant remaining issues are late thrombosis and the so-called ‘edge effect’. Late vessel thrombosis was not appreciated until larger studies were undertaken. Most vascular radiation trials have documented a 5–10% rate of late vessel thrombosis occurring more than 30 days after the initial procedure. This is an important clinical problem because most patients with late thrombosis present with acute myocardial infarction. Late thrombosis has occurred almost exclusively in patients who receive new stents at the time of the index radiation procedure. Presumably, radiation is so effective in preventing smooth muscle proliferation that in some cases, these stent struts remain bare or poorly endothelized. Interestingly, nearly all patients who sustain late stent thrombosis have discontinued antiplatelet therapy. Continued antiplatelet therapy with aspirin and clopidogrel or aspirin and ticlopidine seems to be protective. There are several potential solutions to this problem. Clearly, in the setting of radiation therapy, placement of new stents should be avoided if possible. Furthermore, antiplatelet therapy with aspirin and clopidogrel (or ticlopidine) should be continued for 3–6 months in the absence of new stents and, when new stents are placed, an even longer

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treatment period may be necessary. Finally, newer treatment modalities such as heparincoated stents, or, antiplatelet stent coatings may be beneficial. The problem of ‘edge effect’ has been reported at varying rates dependent on the device used and procedural technique. On one end of the spectrum, the beta emitting 32 P stent has been particularly susceptible to this problem. Nearly 50% of patients treated with this stent sustained very significant restenosis at one or both of the stent edges. In contradistinction, clinical trials with gamma radiation have documented more minimal edge restenoses. In the GAMMA I trial, edge restenosis was responsible for onethird of the total restenosis rate. However, despite the presence of edge restenosis, this form of radiation therapy was still highly efficacious. One cause of ‘edge effect’ may be failure to cover the entire injured vessel segment with the radioactive device. This phenomena, termed ‘geographical miss’ by the radiation oncology community, is, undoubtedly responsible for some of the edge restenoses observed in clinical trials. However, in most trials, geographical miss does not explain all of the ‘edge effect’ observed. Other mechanisms, such as stimulation of neointimal proliferation by low doses of radiation at the source margins, may need to be invoked. Ultimately, edge effect will be limited in part by careful documentation of vessel injury during the preradiation angioplasty procedure and meticulous coverage of the entire injured segment plus an adequate margin by the radiation device. However, despite perfect procedural technique, ‘edge effect’ may still be a persistent limitation of vascular radiation therapy.

ACKNOWLEDGEMENTS

The future The work required to develop and refine clinically useful vascular radiotherapy systems is daunting. There are many unanswered questions. Will the problem of radiation associated late vessel thrombosis be resolved by placing fewer stents and prolonging antiplatelet therapy? What will be the most practical catheter-based radiation system? Will beta radiation penetrate deep enough into the diseased vessel wall to provide clinical efficacy? Will radioactive stents be effective or will they be limited by edge effect? If radiation is proven to have long lasting efficacy should it be used for all patients under-

going angioplasty or confined only to patients with restenosis and/or other subgroups? Will radiation therapy be so effective that it replaces coronary stents or will it be used as an adjunct to a stenting strategy? These questions lay the foundation for the next decade of investigation.

Acknowledgements The author is indebted to his colleagues in the Scripps Clinic Radiation Oncology Department, especially Vincent Massullo MD, Shirish Jani MD, and Prabhakar Tripuraneni MD, as well as to Krishnan Suthanthiran of Best Industries, Inc.

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30. Bottcher HD, Schopohl B, Liermann D et al. Endovascular irradiation – a new method to avoid recurrent stenosis after stent implantation in peripheral arteries: technique and preliminary results. Int J Radiat Oncol Biol Phys 1994; 29:183–186. 31. Liermann DD, Boottcher HD, Kollatch J et al. Prophylactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoro-popliteal arteries. Cardiovasc Intervent Radiol 1994; 17:12–16. 32. Steidle B. Preventive percutaneous radiotherapy for avoiding hyperplasia of the intima following angioplasty together with stent implantation [German]. Strahlenther Onkol 1994; 170:151–154. 33. Condado JA, Waksman R, Gurdiel O et al. Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation 1997; 96:727–732. 34. Teirstein PS, Massullo V, Jani S et al. Threeyear clinical and angiographic follow-up after intracoronary radiation. Results of a randomized clinical trial. Circulation 2000; 101:360–365. 35. Williams DO, Sharaf BL. Intracoronary radiation. It keeps on glowing. Circulation 2000; 101: 350–351. 36. Leon MB, Teirstein PS, Lansky AJ et al. Intracoronary gamma radiation to reduce in-stent restenosis: the Multicenter Gamma I Randomized Clinical Trial. J Am Coll Cardiol (Suppl A) 1999; 33:19A (abst). 37. Handley DA. Experimental therapeutics and clinical studies in (re)stenosis. Micron 1995; 26:51–68. 38. Teirstein P. ␤-radiation to reduce restenosis. Too little, too late. Circulation 1997; 95:1095–1097. 39. Verin V, Urban P, Popowski Y et al. Feasibility of intracoronary ␤-irradiation to reduce restenosis after balloon angioplasty. A clinical pilot study. Circulation 1997; 95:1138–1144. 40. Erbel R, Verin V, Popowski Y et al. Intracoronary beta-irradiation to reduce restenosis after balloon angioplasty: results of a multicenter European dose-finding study. Circulation (Suppl I) 1999; 100:I-154 (abst).

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41. King SB III, Williams DO, Chougule P et al. Endovascular ␤-radiation to reduce restenosis after coronary balloon angioplasty. Results of the Beta Energy Restenosis Trial (BERT). Circulation 1998; 97:2025–2030. 42. Joyal M, Meerkin D, Lespérance J et al. Two year follow-up after post-PTCA ␤-radiation: A QCA analysis. J Am Coll Cardiol (Suppl A) 2000; 35: 1A (abst). 43. Sabaté M, Serruys PW, van der Giessen WJ et al. Geometric vascular remodeling after balloon angioplasty and ␤-radiation therapy. A three-dimensional intravascular ultrasound study. Circulation 1999; 100:1182–1188. 44. Laird JR, Carter AJ, Kufs WM et al. Inhibition of neointimal proliferation with lowdose irradiation from a ␤-particle-emitting stent. Circulation 1996; 93:529–536. 45. Moses JW, Ellis SG, Bailey SR et al. Shortterm (1 month) results of the dose response IRIS feasibility study of a beta-particle emitting radioisotope stent. J Am Coll Cardiol (Suppl) 1998; 31:350A (abst). 46. Serruys PW, Kay IP. I like the candy, I hate the wrapper. The 32P radioactive stent. Circulation 2000; 101:3–7. 47. Albiero R, Adamian M, Kobayashi N et al. Short- and intermediate-term results of 32P radioactive ␤-emitting stent implantation in patients with coronary artery disease. The Milan Dose-Response Study. Circulation 2000; 101:18–26. 48. Jani SK. Handbook of Dosimetry for Radiotherapy. Boca Raton: CRC Press, 1993. 49. Hall EJ. DNA strand breaks and chromosomal aberrations. In: Hall EJ, ed. Radiobiology for the Radiologist 4th edn, Philadelphia: JB Lippincott Company, 1994, 15–73. 50. Teirstein PS, Massullo V, Jani S. Radiation therapy following coronary stenting – 6month follow-up of a randomized clinical trial. Circulation 1996; 94(Suppl 1):1–210. 51. Massullo VM, Teirstein PS, Jani SK et al. Endovascular brachytherapy to inhibit coronary artery restenosis: An introduction to the Scripps Coronary Radiation to inhibit proliferation post stenting trial. Int J Radiat Oncol Biol Phys 1996; 36:973–975. 52. Amols HI, Reinstein LE, Weinberger J. Dosimetry of a radioactive coronary balloon

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15 Radioisotope stents Tim A Fischell

Introduction Stents have revolutionized the catheter-based treatment of coronary artery disease. This device is now used in approximately 80–90% of coronary interventions. The stent’s great success has been driven by its ease of use, the predictability of the acute results, and the solution to the problem of stent thrombosis by high pressure deployment and potent antiplatelet therapy. Unfortunately, the widespread application of stenting has also created a new disease; ‘in-stent restenosis’. Although restenosis is very low for large diameter vessels with focal lesions, the overall restenosis rate after stenting of all lesions is close to 25%. The stent restenosis rate for high-risk lesions in small vessels and in diabetics remains in the range of 30–50%.1,2 Experimental and clinical data have demonstrated that in-stent restenosis is principally caused by neointimal formation.3–6 Endovascular radiation has been proposed as a method to reduce neointimal formation and prevent in-stent restenosis.7–14 Both gamma and beta irradiation delivered via a radioactive catheter-based line source has been shown to be efficacious in reducing restenosis.12,15,16 However, these catheterbased treatments have some limitations, including requirements for radiation oncology support, dwell times, and the safety of handling sources ranging from 30 mCi to

500 mCi. Alternatively, we have proposed the use of a stent as the platform for local radiation delivery as a means to prevent restenosis. Low dose, continuous, ␤-particle irradiation inhibits smooth muscle proliferation and migration in vitro.13 Experimental studies have demonstrated that stents ion-implanted with the ␤-particle emitter 32P can reduce neointimal formation in several animal models.7,8,10,14,17 Clinical evaluation of the radioisotope stent began in the fall of 1996. Worldwide dose escalation studies have now been completed in approximately 280 patients with 32P, betaparticle emitting stents ranging from 0.5 ␮Ci to 24 ␮Ci.18–21 The results of these studies will be discussed is some detail below. Overall, these feasibility trials have demonstrated a clear, dose-dependent reduction of neointimal hyperplasia within the stent structure, but with an unanticipated finding of an increased restenosis at the stent margins. The purpose of this paper is to review the current status of radioactive stents for the prevention of instent restenosis, and to specifically address the refined application of this concept, and the current approaches to reduce or eliminate the problem of edge restenosis.

Stent dosimetry The dosimetry of a 32P stent have previously been described in detail. Janicki et al charac241

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terized the near field dose of a 1.0 mCi 15 mm length Palmaz–Schatz (Cordis, a Johnson and Johnson Co., Warren, NJ, USA) using a modification of the dose-point-kernel method.22 Modification of the dose distribution around a uniform cylinder of 32P to account for the geometry of a tubular slotted Palmaz–Schatz stent with mathematical modeling allowed construction of three-dimensional dose maps. For a 1.0 mCi 15 mm length 32P stent, at a distance of 0.1 mm dose values of ⬇2500 cGy are delivered at the strut wires (peaks) and ⬇800 cGy between the wires (valleys) over 1 half-life (14.3 days). The non-uniformity of dosing reflective of the stent geometry decreases at distances of 1–2 mm from the surface. The dosimetry predicted by the dose calculations correlated well with measured dose using radiochromic film. While these data provide an in vitro analysis of dosing from a radioactive stent, the actual dose distribution will be affected by variations in atherosclerotic plaque morphology and the symmetry of stent expansion. A more detailed discussion of stent design and its impact on dosimetry will follow the overview of the clinical results.

Clinical studies Early clinical experience with radioisotope stents The initial clinical experience with ␤-particle emitting stents began in October 1996. The Phase 1 Isostent for Restenosis Intervention Study (IRIS) was a non-randomized trial designed to evaluate the safety of implanting very low activity (0.5–1.0 ␮Ci) 32P 15 mm length Palmaz–Schatz coronary stents in patients with symptomatic de novo or restenosis native coronary lesions. The enrollment for this trial was completed on January 14, 1997 with 32 patients receiving a ␤-particle emitting stent.18

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In this feasibility trial, stent placement was successful in all patients. The mean stent activity at the time of implant in the IRIS trial was 0.7 ␮Ci. There were no cases of subacute stent thrombosis, target lesion revascularization, death or other major cardiac events within the first 30 days (primary safety endpoint), thus, demonstrating acceptable early event free survival. At 6-month follow-up there was a binary restenosis rate of 31% (10/32) and a clinically driven target vessel revascularization (TVR) rate of 21%. Interestingly, there was only one restenosis (proximal to stent) of 10 patients treated for restenosis lesions (10%) and only 18% for patients receiving stents ⬎ 0.75 ␮Ci. There were no further TVR events between 6 and 24 months. Of note, in the de novo subgroup the mean reference vessel diameter was 2.85 mm, and 7/22 reference vessels in this subgroup were ⬍ 2.50 mm. Quantitative angiographic follow up at 6 months demonstrated a lesional late loss of 0.94 mm for the group as a whole and 0.70 mm for the restenosis subgroup. These data are similar to late loss data from contemporary stent trials with non-radioactive stents. The Phase 1 IRIS trial (1B) was a second low dose trial expanded to test the safety of higher activity (0.75–1.5 mCi) stents at five additional medical centers in the United States. Twenty-five patients were enrolled in this extension of the Phase 1 trial. The mean stent activity was 1.14 ␮Ci at the time of implantation. All 25 cases were performed successfully, without reported serious adverse events at 1 month safety follow-up. The restenosis rate (32%) and late loss data were similar to the 1A results. A small safety trial with 1.5–3.0 ␮Ci 15 mm length 32P stents was also performed in Heidelberg, Germany and Rotterdam in the Netherlands. Approximately 40 of these stents were implanted successfully. There were no adverse events noted in this

CLINICAL STUDIES

group at the 30-day safety endpoint. The Rotterdam experience with the low activity stents (1.0–1.5 ␮Ci, n ⫽ 23) was recently reported with a 13% target vessel revascularization rate.19 In the Rotterdam trial the late loss was 0.99 ⫾ 0.59 mm, which is similar to the IRIS 1A and 1B results. Overall, the restenosis data at these lower activities also did not suggest a significant beneficial effect compared to nonradioactive stents. In this cohort, as was seen in a number of the IRIS cases, restenosis was often caused by neointimal hyperplasia localized to the articulation site of the Palmaz–Schatz stent.20 Based upon human smooth muscle cell experiments looking at effects of continuous low-dose rate beta irradiation, it was determined that the likely effective stent activity for de novo coronary lesions should be in the 3.0–25.0 ␮Ci range (IRIS 1A mean activity was 0.7 ␮Ci). It should be noted that in some animal models the effective activity was as high as 26 ␮Ci for a 15 mm long 3.0 mm diameter 32P stent.10

Late follow-up data from these higher activity cohorts has recently been reported for the first 120 implants.20 In this cohort there was a clear dose-dependent reduction of neointimal hyperplasia within the stent (Fig. 15.1). If lesion restenosis rates were reported for within the stent only, as has been used in trials such as the Beta Energy Restenosis Trial (BERT) feasibility trial, the lesion restenosis rate in the patients with stent activities ⱖ 3.0 ␮Ci was 1.5% (vs 17% in BERT). However, in these higher activity stents there appears to be increased restenosis at or beyond the stent edges. This has been referred to as the ‘candy wrapper’, and is characterized by a widely patent middle zone within the stent itself but with narrowing at one or both edges (Fig. 15.2). The overall incidence of the edge effect restenosis varied in the Milan cohort from ⬃31% to as high as 39%.20 In this series, edge

0.75-3 µCi (n ⫽ 4) 3-6 µCi (n ⫽ 22) 5

Milan studies

4 ∆ CSA (mm2)

Approximately 220 32P stents with activities ranging between 1.5 and 24.0 ␮Ci have now been implanted in Milan by Dr. Antonio Colombo and his colleagues. There were no major adverse cardiac events reported at 30 days in this higher activity cohort. There have been two reported late stent thromboses (i.e. ⱕ 0.9% overall SAT rate). The first stent thrombosis occurred in a patient who had received three stents and was medically noncompliant with antiplatelet medications. Thus the safety of these implants appears quite good, particularly compared to recent reports of unacceptably high late thrombosis rates of 14.6% observed in catheter-based radiation treatment patients who received a nonradioactive stent.23

6-12 µCi (n ⫽ 11) 12-21 µCi (n ⫽ 23)

3 2 Distal edge

1 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Stent segment number

Figure 15.1 Graph depicting the quantitative in-stent intravascular ultrasound (IVUS) late follow-up results from the first sixty 0.75–21 ␮Ci radioisotope Palmaz–Schatz (0.75–3 ␮Ci) BX™ stents from Milan. Note marked inhibition of neointimal hyperplasia within the stent at stent activities ⬎ 1.5 ␮Ci. Data kindly provided by Drs Albiero and Colombo.

243

RADIOISOTOPE STENTS

(a)

(b)

barotrauma as predicted by a high balloon to artery (B/A) ratio at the time of implant appeared to be a significant predictor of this edge restenosis. The B/A ratio in the cohort without edge narrowing was 1.09, versus 1.22 in the group with edge restenosis (p ⬍ 0.05).

Stent design and future directions Stent design and stent delivery are likely to play a critical role in the future successful application of a radioisotope stent. There are stent structural features that are critical to the immediate and late success of both radioactive

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Figure 15.2 Example of edge restenosis in a 32P radioisotope stent. Panel A shows initial result after stenting. At angiographic follow-up (⬃5 months after implant) there is wide patency of the stent body (Panel B, black arrow), but with narrowing at stent edges (white arrows). Figures courtesy of Drs Albiero and Columbo.

and nonradioactive stents. Both types of stents are optimized with designs that allow for excellent plaque scaffolding and high radial hoop strength with minimal stent recoil. Stent delivery (e.g. direct stenting, self-expanding stent, etc.) and other factors may also play an important role in the late results with radioactive stents. Similar to nonradioactive stents,2,3 the radioisotope stent may fail at an articulation site. As suggested above, the early clinical data from the IRIS low activity stents in the United States, and the results from Rotterdam, Milan and Heidelberg using the original Palmaz–Schatz stent, demonstrated increased late loss at the stent articulation site (Fig. 15.1).

STENT DESIGN AND FUTURE DIRECTIONS

Figure 15.3 Long-axis intravascular ultrasound (IVUS) image of porcine iliac artery at 30 days following implantation of self-expanding (nitinol) radioactive (32P) SMART stent. This stent can be implanted in diseased vessels without any balloon trauma at stent edges, thereby having the potential to eliminate ‘edge restenosis’ with a radioisotope stent. Image shows the stent completely devoid of neointima (double white arrow). Minimal, focal neointimal hyperplasia (single white arrow) is seen at the site of end flaring (black arrow) of the stent. The 30-day angiogram of the iliac vessel is seen in the upper left corner of figure.

Following the initial experience with radioactive Palmaz–Schatz stents, and the dosing calculations with an articulated stent, it became clear that a gap in the middle of the stent was a poor stent design for a radioisotope stent. To eliminate problems of dose falloff in the central articulation zone of the Palmaz–Schatz stent, all recent and future radioisotope stent implants are now performed using the BX™ stent platform that has no central articulation. The first generation BX™ (Isostent Inc., San Carlos, CA, USA) is a novel stainless steel balloon expandable stent designed without a central articulation. The BX™ has honeycomb-shaped cells linked by alternating articulation geometries that provide longitudinal flexibility while maintaining the radial strength of the stent. The uniform geometry of the BX™ appears to

have a favorable effect on the dose distribution for a 32P stent. The difference between maximal and minimal near field tissue dose of irradiation is less for the BX™ than the Palmaz–Schatz design. It is anticipated that within the next 12 months, for radioisotope stent implants we will move towards to the more flexible, lower profile and more visible BX Velocity™ stent. This stent is well suited for direct stenting and is currently being introduced as a non-radioactive stent platform by Cordis Corporation (Miami, FLA, USA). Future clinical trials are now focusing upon the issue of edge restenosis. The cause of edge restenosis with both stent-based and catheterbased intravascular brachytherapy remains uncertain. There is, however, accumulating animal and clinical data to suggest that there is enhanced neointimal growth in zones of

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vessel barotrauma that are exposed to a lower than therapeutic dose of radiation.24 The experience to date suggests that when inhibitory levels of radiation are applied to the entire vessel segment that is injured (i.e., no ‘geographic miss’) that the edge effect is minimized or eliminated. With catheter-based treatments then, the goal is to provide a long enough source train to completely cover the injured zone with no dose falloff within the injured vessel segment. This goal of delivering therapeutic doses to and beyond the balloon-injured zone presents some challenges during the implantation of a radioisotope stent. It is important to recognize that all of the initial high activity implants have been performed using the original Palmaz–Schatz SDS delivery balloon with the first generation BX™ stent. The compliant balloon in this system extends for ⬃3 mm beyond the stent edge at the time of implantation, thus injuring a long segment well outside the dose-falloff zone for a 32P stent. The compliant nature of this balloon is also likely to cause ‘dog-boning’ of the balloon material and further aggravate barotrauma outside the stent margins. Further injury outside the stent is likely to occur during predilatation and post dilatation. With this system, the incidence of ‘geographic miss’ with all of these higher activity radioisotope stents was 100%. This should be compared to the catheter-based systems which have an estimated ‘geographic miss’ rate of 25–40%. In those cases of ‘geographic miss’ with a catheter-based system, it is estimated that the edge restenosis rate is approximately 40%. This could explain the edge restenosis rate of 10–20% observed with catheter-based treatments. Radioactive stents with a 100% ‘geographic miss’ rate would be expected to have a 40% edge restenosis rate, which is very close to the observed incidence. If ‘geographic miss’ with radioisotope stents is

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the cause of edge restenosis, changes in stent design, and/or stent delivery may solve this problem. There are a number of stent design features that may help to resolve the edge restenosis problem with radioisotope stents. Several of these approaches are designed to deliver the radioisotope stent with minimal barotrauma at or beyond the stent edge (e.g. direct stenting, self-expanding stent). Recent angiographic analysis of the BX Velocity™ stent implants have demonstrated that this stent is delivered with no measurable dog-bone effect and with a 1% residual stenosis. The transition to this platform, which is ideally suited for direct stenting, may move us a step closer to eliminating edge restenosis. Most recently, we have begun evaluation of a self-expanding (nitinol) 32P radioisotope stent. This may provide the most reliable means for eliminating balloon trauma at, or beyond, the stent margins. Using this device, the lesion can be predilated with a very short balloon. Then the self-expanding radioisotope stent will be advanced and deployed with 3–10 mm of stent beyond each margin of balloon trauma. In this manner, therapeutic dosing is delivered in the entire balloon trauma zone, with no trauma past the stent edge, thus eliminating ‘geographic miss’ with the radioactive stent. In the preliminary testing of this device in the iliac artery model, the results look encouraging (see Fig. 15.3). This device is scheduled for clinical feasibility testing by the end of 2000. Other approaches, such as gamma stents or ‘hot-ends’ are intended to enhance the dosing beyond the stent edge to help reduce ‘geographic miss’ at the proximal and distal stent margins. The dose-falloff is shown in Fig. 15.4 for beta (32P) and gamma (palladium 103, 103 Pd) emitting stents with varying lengths of barotrauma outside the stent edge. Preliminary

CONCLUSIONS

10

8

Dose Rate (cGy/hr)

7

Stent Edge

P32 Hot Ends Study Balloon Edge

9 All previous P32 Stents Balloon Edge

BX Velocity Balloon Edge

6 5 4 3 P32 4 Microcuries P32 24 Microcuries Pd103 0.7 mCi Pd103 3.5 mCi

2 1

Min. Dose Rate to Prevent Restenosis

0 ⫺2.8 ⫺2.6⫺2.4⫺2.2⫺2.0⫺1.8⫺1.6⫺1.4⫺1.2⫺1.0⫺0.8⫺0.6⫺0.4⫺0.2 0

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2

Distance from Stent End (mm)

Figure 15.4 Graph depicting the dose falloff from the edge of a beta particle emitting (32P) versus a gamma emitting (103Pd) radioactive stent. Note that the estimated therapeutic dose rate is ⬎ 3 cGy/hour at 4 weeks after stent implant. This dose rate can be achieved at a distance of 2.1 mm from stent edge with 103 Pd vs only 1.3 mm with a 24 ␮Ci 32P stent.

clinical results suggest that a dose rate of ⬎ 3 cGy/hour at the plane of the stent at 4 weeks after stent implantation correlates with inhibition of within stent restenosis. If this dose rate algorithm is applied to the vessel outside the stent margin, one can appreciate that one must move the barotrauma zone closer to the stent edge to stay at or above an inhibitory dose rate. Recent animal investigation using the relatively low energy gamma emitter 103Pd, has demonstrated significant inhibition of neointimal hyperplasia, without any sign of an ‘edge effect.’ An example from a 103Pd stent in a porcine model at 30-day follow up is shown in Fig. 15.5. One other novel approach would be to develop a stent with a very small cell size

which could allow therapeutic dosing at 4 weeks after stent implantation at the plane of the stent with a very low activity stent. In theory, this could eliminate the edge restenosis by having a very low and nonstimulating radiation dose outside the stent margins.

Conclusions In summary, the radioisotope stent remains an appealing and very safe means of delivering intravascular brachytherapy. Clinical studies using beta-particle emitting 32P stents have demonstrated a substantial dose-dependent inhibition of within stent neointimal hyperplasia. Edge restenosis may be increased with these stent activities, using current stent

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(a)

(b)

Figure 15.5 Histopathologic cross-sections of porcine coronary arteries comparing non-radioactive (control) stent to a 103Pd, gamma emitting stent (right) at 30 days following stent implantation. Note the reduction of neointimal hyperplasia in the radioactive, gamma stent.

designs and implantation techniques. There are a number of feasible stent design and delivery options that may reduce or eliminate edge restenosis and allow the radioisotope stent to emerge as a viable anti-restenosis therapy.

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Acknowledgments We would like to gratefully acknowledge the important contributions to this work made by Drs Albiero and Colombo in Milan, Italy, the IRIS investigators, and the engineers and staff at Isostent, Inc., Belmont, CA, USA.

REFERENCES

References

1.

Serruys PW, De Jaegere P, Kiemeneij F et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331:489–495. 2. Fischman DL, Leon MB, Baim DS et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994; 331:496–501. 3. Painter JA, Mintz GS, Wong SC et al. Serial intravascular ultrasound studies fail to show evidence of chronic Palmaz–Schatz stent recoil. Am J Cardiol 1995; 75:398–400. 4. Hoffmann R, Mintz G, Dussaillant G et al. Patterns and mechanisms of in-stent restenosis: a serial intravascular ultrasound study. Circulation 1996; 94:1247–1254. 5. Edelman ER, Rogers C. Hoop dreams: stents without restenosis. Circulation 1996; 94:1199–1202. 6. Serruys PW, Kutryk JB. The state of the stent: current practices, controversies, and future trends. Am J Cardiol 1996; 78(Suppl 3A):4–7. 7. Laird JR, Carter AJ, Kufs W et al. Inhibition of neointimal proliferation with a Beta particle emitting stent. Circulation 1996; 93:529–536. 8. Carter AJ, Laird JR, Bailey LR et al. The effects of endovascular radiation from a b-particle emitting stent in a porcine restenosis model: a dose response study. Circulation 1996; 94:2364–2368. 9. Hehrlein C, Gollan C, Dönges K et al. Lowdose radioactive endovascular stents prevent smooth muscle cell proliferation and neointimal hyperplasia in rabbits. Circulation 1995; 92:1570–1575. 10. Hehrlein C, Stintz M, Kinscherf R et al. Pure bparticle emitting stents inhibit neointima formation in rabbits. Circulation 1996; 93:641–645. 11. Waksman R, Robinson KA, Crocker IR et al. Intracoronary radiation before stent implantation inhibits neointima formation in stented

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canine coronary arteries. Circulation 1995; 92:1383–1386. Tierstein PS, Massullo V, Jani S et al. Radiotherapy reduces coronary restenosis; late follow-up. J Am Coll Cardiol 1997; 29:397A. Fischell TA, Kharma BK, Fischell DR et al. Low-dose, b-particle emission from stent wire results in complete, localized inhibition of smooth muscle cell proliferation. Circulation 1994; 90:2956–2963. Rivard A, Leclerc G, Bouchard M et al. Lowdose b-emitting radioactive stents inhibit neointimal hyperplasia in porcine coronary arteries; an histological assessment. J Am Coll Cardiol 1997; 29:238A. Verin V, Urban P, Popowski Y et al. Feasibility of intracoronary beta-irradiation to reduce restenosis after balloon angioplasty. A clinical pilot study. Circulation 1997; 95:1138–1144. King SB, William DO, Chougule P et al. Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty. Results of the beta energy restenosis trial (BERT). Circulation 1998; 97:2025–2030. Shroff SS, Farb A, Sweet WL, Virmani R. Sustained neointimal inhibition with delayed healing 6 months after placement of 32P ␤emitting stents. Circulation 1999; 803:I-154 (abst). Baim DS, Fischell T, Weissman NJ et al. Short term (1 month) results of the IRIS feasibility study of a beta particle emitting radioisotope stent. Circulation 1997; 91:I-218 (abst). Wardeh AJ, Kay IP, Sabate M et al. B-particleemitting radioactive stent implantation a safety and feasibility study. Circulation 1999; 100:1684–1689. Albiero R, Adamian M, Kobayashi N et al. Short and intermediate-term results of 32P radioactive B-emitting stent implantation in patients with coronary disease. Circulation 2000; 101:18–28. Fischell TA, Carter AJ, Laird JR. The betaparticle-emitting radioisotope stent (isostent):

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animal studies and planned clinical trials. Am J Cardiol 1996; 78:45–50. 22. Janicki C, Duggan DM, Coffey CW et al. Radiation dose from a phosphorous-32 impregnated wire mesh vascular stent. Med Phys 1997; 24:437–445. 23. Waksman R, Bhargava B, Chan RC et al. Late

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total occlusions following intracoronary radiation therapy for patients with in-stent restenosis. Circulation 1999; 1150:I-222 (abst). 24. Hausleiter J, Li AN, Honda H et al. Increased stenosis formation after low-dose radiation therapy in balloon-injured coronary arteries. Circulation 1999; 381:I-75 (abst).

16 Restenosis in the peripheral vasculature Manu Rajachandran and Robert Schainfeld

Restenosis remains the most frequent and recalcitrant problem encountered with percutaneous and surgical vascular intervention in the treatment of peripheral arterial disease (PAD). The cellular response to balloon injury of the vascular endothelium is characterized by a brisk proliferative response of smooth muscle cells (SMCs) and the deposition of extracellular matrix at the injury site, resulting in the formation of a neointima that eventually compromises luminal integrity. Although Glagovian remodeling1 allows for some compensatory enlargement at restenotic parameters of up to 40% diameter stenosis (first noted in human coronary arteries), this adaptive mechanism is lost at higher degrees of luminal narrowing. Abnormal endothelial function at the site of injury also contributes to the process by compromising the vessel’s ability to adaptively remodel. Endothelial damage and platelet activation cause the stimulation of the proliferative response by means of the mitogenic signal transducers plateletderived growth factor (PDGF), basic fibroblastic growth factor (bFGF), and angiotensin II. Fuster’s classification of the restenotic model has been extensively studied in both animals and humans. The immediate response to balloon injury occurs within the first 24 hours and is characterized by vessel recoil. Within 2 weeks of injury, there is the formation of mural thrombus at the injury site with connective tissue proliferation and organ-

ization. The activation of SMCs and the synthesis of extracellular matrix then ensue and may persist for up to 3 months post injury. In vessel segments covered early by regenerating endothelium, the proliferation of intimal SMCs is arrested prior to those in regions which remain denuded of endothelium.2,3 The clinical expression of this process is well documented in humans undergoing revascularization for PAD. Myointimal hyperplasia is a problem encountered in carotid endarterectomy (CEA) and infrainguinal surgical bypass grafting, leading to late operative failure with graft thrombosis, and in percutaneous transluminal angioplasty (PTA) with its attendant high restenosis rates. Post operative flow-limiting lesions tend to manifest within the first 6 months following surgery and are variably associated with symptoms, to the differing extents to which blood flow in the vessel becomes impeded. The incidence of restenosis is influenced by a multitude of technical and clinical factors including immediate angiographic/surgical result, lesion site (proximal or distal), sex, length of disease (short stenoses vs long occlusions), presence of diabetes, the grade of vascular ischemia and the quality of distal runoff. The contemporaneous evolution of reporting standards for trials in PAD, along with the growth of intervention in vascular disease, has generated a precise descriptive nomenclature to characterize the clinical sequelae of restenosis

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after both surgical and percutaneous intervention. Standardization in reporting of results is crucial and the recommendations of the committee on reporting standards of the Society for Vascular Surgery and the North American Chapter of the International Society for Cardiovascular Surgery are currently being widely adopted.4,5 Patency rates are specified to include or exclude technical failures. Primary patency is defined as uninterrupted patency following the procedure being evaluated. Assisted primary patency is the long term procedural success rate achieved with re-intervention on the target vessel or graft before occlusion. Secondary patency implies patency following the initial procedure or intervention to restore patency to an occluded graft or vessel. After either a surgical or endovascular procedure, secondary patency implies the need for re-opening of the treated segment by a second intervention.

Aortoiliac disease The results of PTA of the distal abdominal aorta are encouraging despite it being a relatively rare procedure in the invasive treatment of vascular disease. Three-year patency rates of up to 70% have been reported in small patient cohorts.6,7 Minimal restenosis has been observed following aortic PTA, probably owing to the large caliber of the vessel, which mitigates the clinical and angiographic severity of the restenotic process. Calcified lesions tend to respond less well to balloon dilatation with a higher risk of adverse acute procedural outcome, usually aortic dissection, and in rare cases, rupture (often due to overly aggressive dilatation). Audet et al,8 in a carefully selected population of 102 patients with distal aortic lesions < 4 cm length, demonstrated that the clinical patency rate of PTA was comparable to that of aortic surgery. In this relatively large

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study, the primary patency rate at 10 years of clinical and hemodynamic follow-up was 72% and the secondary patency rate, 76%. Twentyfour percent of patients were clinical failures, of which the majority suffered restenosis, at a mean follow-up of 51 months. Univariate predictors of clinical recurrence included the residual vessel diameter post dilatation, site of the stenosis (at or above the aortic bifurcation), type of PTA (single vs double ‘kissing’ balloon), and adjunctive stent deployment (which was performed for sub-optimal balloon PTA result in 12 patients). Patency results of aortic PTA tend to be poorer for patients with significant downstream disease of the iliofemoral and femoropopliteal segments. Interestingly, the preponderance of patients in these studies are female, smokers, with small ‘hypoplastic’ aortas and iliac vessels, and high aortic bifurcations. There are relatively few studies examining the outcome of stenting in isolated aortic segments, owing to the relatively uncommon occurrence of this entity. Most atherosclerotic aortic disease extends into the iliac arteries and requires dilation of both territories. In fact, revascularization at the aortic bifurcation commonly utilizes ‘kissing stents’.9 The long-term results of PTA have nowhere been more gratifying than in the treatment of iliac disease. With the technical and initial clinical success rates in the vicinity of 90–98% for PTA alone, the procedure is safe and effective in the management of most iliac stenoses. The technical success rate of recanalization of iliac artery occlusions is 80–85% with or without adjunctive thrombolysis. The mean immediate clinical patency rate in Becker et al’s retrospective review10 of 2697 iliac PTA procedures in the treatment of stenotic lesions was 90%, with a 5-year patency rate of 50–87%. The durability of the procedure was also demonstrated in Johnston

AORTOILIAC DISEASE

et al’s review11 of 667 procedures, with 1month patency rates of 97%, and patency at 1 and 5 years respectively, of 71% and 65%. These results rival the 5-year cumulative patency rates (75–90% in most series) of aortofemoral bypass surgery, which has long been the accepted modality of treatment for iliac disease. Lesion characteristics impact greatly on the initial and long term success of iliac PTA. Success rates vary directly with the severity of the lesion; the ideal lesion is an isolated stenosis, concentric, noncalcified and less than 3 cm in length, defined as Category 1 by the American Heart Association (AHA) guidelines12 for PTA of the lower extremity vessels. Category 2 disease includes concentric stenoses 3–5 cm in length or calcified eccentric lesions less than 3 cm in length, which have a less favorable long term patency rate and clinical outcome. Iliac stenoses between 5 and 10 cm in length or occlusions less than 5 cm in length accompanied by chronic symptoms (Category 3 disease) also suffer diminishing returns from PTA both in terms of initial technical success and long term patency. Category 4 disease or stenoses greater than 10 cm in length, occlusions greater than 5 cm in length, or lesions adjacent to aortic aneurysmal disease may have a more favorable long term patency rate with surgical revascularization, owing to the limited durability of PTA and its higher complication rates incurred with the endovascular treatment of this type of lesion. Other predictors of long term patency following iliac intervention include gender, clinical symptom status, lesion location (common iliac vs external iliac lesions) and status of the arterial runoff. PTA of the common iliac artery in Johnson et al’s retrospective analysis13 demonstrated a 5-year patency rate of 58% vs 46% for external iliac artery PTA. In Sullivan et al’s study14 of iliac PTA in 288 patients,

with criteria for restenosis established as luminal diameter narrowing ⱖ 50% on angiographic follow-up (or reintervention performed on the same vessel segment), factors associated with early and late failure included advanced age, baseline stenosis severity, status of the outflow vessels (notably, ipsilateral superficial femoral artery (SFA) occlusion), and severity of ischemia (claudication vs limb salvage). Unlike previous series, diabetes mellitus, female gender and presence of occlusive iliac artery disease were not predictive of restenosis. Hemodynamic parameters may also play an important role in the prediction of restenosis following PTA in iliac vessels. Kadir et al15 observed that a post angioplasty mean pressure gradient across the revascularized segment of ⱕ 10 mmHg was associated with symptom recurrence in 7% of 111 limbs undergoing iliac PTA, whereas a residual mean gradient > 10 mmHg was associated with symptom recurrence in 15% of limbs revascularized. This relationship has also been observed in claudicants undergoing surgical revascularization of inflow disease, with a close correlation being found between sustained clinical improvement post surgery and a reduction in the preoperative aortoiliac pressure gradient by more than 18% after pharmacologic vasodilation.16,17 Occlusions of the iliac artery are generally associated with a poorer immediate and late clinical outcome when treated with PTA alone. The one-year patency rate for iliac occlusions compared to stenoses drops off considerably, 77% to 48% respectively, in some series. Several studies of PTA for iliac occlusion have reported technical success rates in the 60–70% range, and 3–4-year cumulative patency rates of 60–78%.18 Technical success is strongly influenced by occlusion length, chronicity of the occlusion, and most

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importantly, successful intraluminal guidewire passage across the lesion. Inability to cross the occlusion, vessel rupture, distal embolization, and subintimal guidewire passage greatly impact negatively on immediate patency. Difficulty in passing a catheter through the obstruction is directly related to the length of the occlusion. In their study of 64 chronically occluded limbs, Colapinto et al,19 observed a 92% immediate patency rate in obstructions 5 cm or less in length, and a 70% patency rate in iliac obstructions longer than 5 cm; combined obstructions of both common and external iliac arteries were the most recalcitrant, with a technical success rate of only 37%. Cumulative long term patency at 4 years was 78% with balloon PTA alone in this study. The use of endovascular stents in the treatment of aortoiliac disease has considerably improved both immediate and late patency results, even in the case of iliac artery occlusion. Their ability to withstand the elastic recoil of the vessel wall following balloon PTA, exclude flow limiting dissections, and mitigate late lumen loss by achieving acute luminal gain, is increasingly making intravascular stents the adjunctive therapy of choice in the percutaneous treatment of vascular disease. Reyes et al20 reported a 92% immediate success rate with primary stent placement in the treatment of 61 chronic iliac artery occlusions after guidewire recanalization, and selective use of adjunctive thrombolytic therapy. The cumulative primary patency rate at 5 years was 66%, with a secondary patency rate of 87%. The length of the occlusion, diameter of the treated vessel, and clinical stage of the disease did not significantly affect the long term patency rate. Similar results were reported by Murphy et al21 in their study of PTA and Wallstent deployment in the treatment of 94 complex iliac stenoses and occlusions. Acute procedural

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success approached 91% with cumulative primary patency rates of 78% at 1 year and 53% at 2–3 years, and secondary patency rates of 86% at 1 year. Stenting of iliac stenoses generally predicts a more favorable long term outcome when compared to stenting of iliac occlusions. Subacute reocclusion of the stented iliac artery has been well described, albeit rarely. Vorwerk et al22 noted a reocclusion rate of less than 3% within 1 month of stent deployment in 118 (Categories 1–3) iliac lesions, and a late reocclusion rate that was higher than the late restenosis rate at 23–27 months. The reocclusion rate in Murphy et al’s study23 of Palmaz iliac stent placement in 108 limbs approached 13% at 10 months’ follow-up. Adverse prognosticators in this study included: multilevel disease, female gender, and clinical severity of ischemia in the index limb. Progressive disease in non-stented arterial segments has a profound effect on long term iliac stent patency; Palmaz et al attributed a 67% patency rate at 43 months post iliac stenting to a steady progression of atherosclerotic disease, in segments downstream from the stented segment, of approximately 5% per year. Few randomized trials comparing results of iliac angioplasty and stent deployment exist; Richter et al’s comparative study24 demonstrated the utility of stents in significantly reducing residual transstenotic pressure gradients post PTA. Early and long term angiographic patency was also superior with stents. The clinical cumulative patency rate at 5 years was 89% in the stent group vs 68% in the PTA group. A recent meta-analysis by Bosch and Hunink25 compared the results of aortoiliac PTA vs stenting. Technical success was higher for stenting, with comparable complication rates. The 4-year primary patency rates for PTA and stenting were 65% (PTA) vs 77%

FEMOROPOPLITEAL DISEASE

(stent) for stenoses and 54% (PTA) vs 61% (stent) for occlusions. The relative risk of long term failure was reduced by 39% after stent placement compared with PTA. In-stent restenosis remains a relatively rare late sequelae of iliac stent placement and appears to be difficult to treat effectively with compromised long-term durability. One of the few studies offering a window into this phenomenon26 noted in-stent restenosis or occlusion in 36 of 223 iliac lesions an average of 22 months following either Wallstent or Strecker stent placement. Most lesions occurred within the stent, with a minority occurring in the adjacent nonstented segment. All patients, the majority of whom were men, experienced clinical relapse of claudication, as the herald symptom of restenosis. Primary patency rates for stent reintervention in this study was only 51% at 2 years; there was no correlation between stent type and status (stenosed or occluded) and need for reintervention. Restenosis after the ‘salvage’ procedure was frequent, and there was an inverse relationship between the number of repeat interventions performed, and the long term stent patency rate. Stent occlusions, although exceedingly rare, fared worse in this respect than stenoses.

Femoropopliteal disease Revascularization of infrainguinal disease has not enjoyed the same measure of success that has been traditionally associated with treatment of aorto-iliac disease. It is useful to consider the femoral and popliteal arteries together since anatomically the one derives as the extension of the other, both are usually simultaneously diseased, and perhaps most important, the results and complications of PTA are very much the same. PTA has only been modestly successful in treating atherosclerotic disease of the femoropopliteal vessels,

with 1-year patency rates varying between 50% and 90% in some studies, depending on lesion length, severity and chronicity. In Johnston et al’s study11 of over 350 endovascular procedures, iliac results were significantly better overall than femoropopliteal results, in keeping with the dictum that success rates are highest when PTA is used to treat disease of large proximal, elastic arteries, in which flow rates are high. The evolution of interventional technology has improved the immediate technical success rates of femoropopliteal recanalization from 70% utilizing coaxial 8F/12F Dotter catheters, to over 90% with balloon PTA, over the past thirty years. However, long term outcome still lags far behind primary success rates. Becker et al’s retrospective review10 of patency data from over 4300 femoropopliteal PTA procedures recorded an initial patency rate of 81% in the treatment of both stenoses and occlusions, with identical 2and 4–5-year patency rates of 67%. Long occlusions and stenoses of the SFA seem especially prone to aggressive restenosis; although Murray et al’s27 long term follow-up of 193 femoropopliteal PTAs described immediate technical success rates of 93%, overall patency rates at 5 years were a lackluster 73% for SFA stenoses and 54% for occlusions. SFA stenoses greater than 7 cm in length in this study exhibited a dismal 6-month patency rate of only 23%. Capek et al28 in their detailed analysis of over 200 femoropopliteal procedures demonstrated similar acute success, with primary technical success rates of 93% for stenoses and 82% for occlusions. Long term follow-up utilizing noninvasive studies revealed satisfactory long term primary patency rates of 81% at 1 year, and as high as 58% at 5 years. Moreover, primary patency rates between 2 and 5 years remained relatively stable between 58% and 63% in this study, suggesting an indolent post PTA course

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in terms of restenosis, once initial 1-year patency is maintained. Secondary patency rates closely mirrored primary patency rates in this study. Restenosis after PTA was significantly higher for diabetic patients, and in patients with critical limb ischemia, in keeping with the anatomic severity of infrapopliteal runoff circulation usually present in these patient subgroups. Adverse prognostic variables included highly eccentric and occlusive lesions; however, once technical failures were excluded from the analysis, there was no significant outcome difference between stenoses and occlusions over the long term, lending credence to the argument that an aggressive PTA approach to occlusions of the femoropopliteal vessels can yield satisfactory long term patency results. Lesion length, as in other studies of femoropopliteal angioplasty, had a significant impact on long term patency, with short lesions faring better than long (> 2 cm length) lesions. Interestingly, the clinical factor most strongly correlating with long term patency was a palpable peripheral pulse after PTA, suggesting that both acute procedural success and the overall vascular status of the patient strongly influences patency. Although no significant prognostic differences were demonstrable between initial PTAs and subsequent redilatation of the same vessel segment, the presence of a significant residual stenosis post PTA was a strong adverse prognosticator of long term primary patency. Femoropopliteal occlusion, which anecdotally has remained a more commonly encountered angiographic phenomenon than stenosis in patients with infrainguinal vascular disease, is associated with a poorer long term outcome. Although published long term patency rates as high as 60–70% have been reported in selected patient and lesion subsets, the overall long term success of PTA remains adequate at best. Matsi et al’s prospective study29 of

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primary and long term results of PTA in occlusions of the SFA described modest primary and secondary patency rates of 41–43% and 55% respectively at 1–3 years’ post revascularization. Adverse prognosticators of vessel patency included the presence of thrombotic material within the primary occlusion at baseline and the presence of non-occlusive dissections post PTA. Longer occlusions fared worse than shorter lesions, as observed in prior studies; an acceptable 3-year secondary patency rate of 59% was observed in occlusions less than 10 cm in length. These results suggest that, at least in the treatment of chronic occlusions of the femoropopliteal vessels, the institution of thrombolytic therapy may improve both the immediate technical success rate by converting occlusions to underlying stenoses, and the long term clinical patency rate by perhaps reducing the chronic proliferative effects of platelet–fibrin thrombus at the lesion site and by reducing lesion length. The consistent correlation in this and other studies between lesion length and clinical patency suggests also that recanalization of femoropopliteal occlusions greater than 10 cm in length may be inferior to surgical bypass insofar as long term patency is concerned. The use of stents to optimize results after PTA of the femoropopliteal vessels has enjoyed mixed results. Henry et al,30 utilizing both duplex ultrasound and angiographic follow-up in over 1200 iliac and femoropopliteal procedures, noted relatively higher 6-month stent restenosis rates (10–20%) for lesions of the SFA and popliteal vessels, than for lesions of the iliac and proximal femoral arteries (0.5–4%). The 6-month restenosis rate for infrainguinal stenting in this study was in fact higher than the overall average restenosis rate for all lesions, which was an acceptable 4.8%. There was surprisingly no difference in short term restenosis

FEMOROPOPLITEAL DISEASE

rates between stenoses and occlusions or between long (> 3 cm) and short lesions. Predictors of poor 6-month outcome included the average number of stents placed per lesion, and the vessel reference diameter; smaller vessels tended to fare more poorly than larger (> 7 mm) arteries. Long term patency rates, both primary and secondary, were lowest for popliteal artery stents (50% and 70% at 4 years, respectively), and middling for femoral artery stents (65% 4-year primary patency rate). However, the marked difference in 4year primary patency between iliac and femoropopliteal stents in this study stood in contradistinction to 4-year secondary patency rates in these vessel segments, which were an identical 95% at 1-year of follow-up. Furthermore, the secondary patency rates achieved in the femoropopliteal segment were sustained (80–85%) over the entire 2–4-year period, suggesting that stent surveillance and patency maintenance (i.e. redilatation) strategies are more likely to yield durable long term clinical patency rates than primary stent placement alone. Lesion length, once again, was a prime determinant of overall clinical patency; longer lesions (requiring greater stent coverage) fared less well than shorter lesions (< 3 cm length). Other studies of femoropopliteal artery stent placement in smaller patient cohorts have also identified lesion length and lesion type as important prognosticators of patency; Strecker et al31 utilized tantalum stent implantation in the secondary treatment of femoropopliteal disease that failed conventional PTA in 80 of 970 patients and described 50% 2–3-year cumulative primary patency rates. Two-year primary patency was better for stenoses than for occlusions (73% vs 33%) and for shorter (< 4 cm) than for longer lesions (61% vs 39%). There was a nonsignificant trend towards greater 2-year primary patency with stents placed in the common femoral artery

(CFA) or proximal SFA than in the distal SFA/popliteal vessel, and in those patients with good infrageniculate runoff status. A stented segment length of > 4 cm was the most important prognosticator of in-stent restenosis at 12 months; lesion type, specifically vessel occlusions, was the most predictive factor for stent restenosis at 2 and 3 years of follow-up. No reported data from large randomized trials of PTA alone vs PTA and stent deployment in the treatment of infrainguinal disease currently exist. Results from small, randomized patient cohorts suggest a nonsignificant trend towards higher primary vessel patency with conventional PTA alone.32⫺35 Stent type does not appear to be a predictor of patency; non-randomized studies of Wallstent deployment in femoral arteries36 for bail out indications or 3month restenosis (following balloon PTA) have demonstrated primary patency rates rivaling those achieved with other stent types, at 2–3 years of follow-up, with a modestly higher secondary patency rate. The body of available evidence would indeed suggest that the femoropopliteal segment exhibits a different response to percutaneous revascularization than the iliac vessels. Factors such as vessel caliber, rigidity, and compressibility, especially at joint articulations, may conspire to compromise sustained long term patency. Balloon angioplasty of short lesions, with the aim of a ‘stent like’ result and minimal residual disease, stands as the initial therapy of choice in selected patients with adequate infrapopliteal runoff and moderate overall disease severity. Stent placement, when reserved for a bail out indication such as extensive vessel dissection or residual thrombus/plaque following aggressive PTA or for restenosis, may provide a better acute result that should then be closely monitored for patency, especially with data suggesting consistently high secondary patency rates over

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2–4 years following reintervention. In this regard, serial duplex ultrasonographic evaluation of the treated vessel may be superior to periodic screening with ABIs and segmental pressures, since the latter may be a less accurate method of identifying recurrent lesions in vessels that can traditionally mount a vigorous collateral resupply. Lesions longer than 10 cm may be better addressed with surgical bypass, although trials are now in progress to determine long term patency following percutaneous recanalization of such disease. In the absence of data to suggest significant differences in patency rates between balloon PTA alone and adjunctive debulking with second generation devices such as rotational, directional or extraction atherectomy, and between currently marketed stent types, no clear recommendations can be intelligently made. The long term impact of angiographic optimization of the acute result (whether this be achieved with or without stents), as opposed to specific stent type employed in the treatment of these lesions is one issue that merits further investigation. There is preliminary data to support the use of newer self-expanding nitinol stents in the femoropopliteal tree; small cohort studies37 indicate that the primary and secondary patency rates with these stents in carefully selected patients may approach 85–90% at 18 months of follow-up. These results await validation in larger, randomized, trials with uniform standards of noninvasive assessment.

Infrapopliteal disease The long term results of treatment of infrapopliteal disease have traditionally been confounded by a multitude of clinical and angiographic variables, not the least of which is the overall cardiovascular status of the patient in question. Five-year survival in patients with limb salvage indications for

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intervention is only 50%; most are high risk patients with hypertension, diabetes, renal insufficiency with excess mortality risk from concomitant coronary artery or cerebrovascular disease. Here again, large randomized trials of PTA vs surgery are nonexistent; direct comparisons of PTA and vascular reconstructive surgery are difficult because of intense selection bias. The poor long term results of femoral to below the knee bypass have been well documented,38 and may be part of the reason that the procedure is usually reserved for limb salvage situations in patients with significant cardiovascular comorbidity. Prosthetic bypass grafts below the knee have a poor outcome, with primary patency rates ranging between 12% and 33% in most series. Vein grafts have a more durable performance, with 4–5-year primary patency rates between 65% and 75%; however, some surgical reviews on the subject have revealed occlusion rates of up to 25% in the first year after vein bypass, with subsequent graft thrombosis rates of 6% thereafter.39 These results are not surprising in view of the fact that the anatomic status of the runoff vessels is probably the most significant predictor of clinical patency for both surgical and endovascular intervention at any vascular level. Comorbidities such as diabetes (60–90%) and end stage renal disease are usually associated with diffuse, calcific three-vessel occlusive disease of the calf, an entity that confers a high risk of procedural failure and poor long term patency. Endovascular therapy of infrapopliteal disease is often performed in conjunction with recanalization of tandem lesions at higher vascular levels, usually iliac or femoropopliteal. The advent of digital subtraction angiography, low profile balloon catheters and steerable guidewires has revolutionized the treatment of these lesions and has contributed to improving patency rates; Bull et al40 noted clinical success

INFRAPOPLITEAL DISEASE

rates approaching 80% with PTA in 168 patients with Rutherford Category 3–5 symptomatology and occlusive infrapopliteal disease. Patients with isolated single stenoses had the best clinical outcome with initial technical success rates of 89% and 2-year clinical patency of 83%. Multisegment disease was a strong prognosticator of both early vessel occlusion and late failure, with a 3-year primary patency rate of approximately 75%. The poorest outcomes were for those patients with femoropopliteal occlusions and distal disease who required thrombolytic therapy prior to PTA (55% patency at 2 years) and in those with failing distal bypass grafts who underwent dilatation of anastomotic lesions (14% patency at 3 years). Univariate predictors of poor long term patency included single vessel runoff, acute limb ischemia, occlusive disease of the runoff vessel, and anastomotic graft lesions. However, the overall amputation rate was an acceptable 7% in this cohort, suggesting a high rate of limb salvage in patients with critical limb ischemia, despite marginal long term patency rates post PTA in this patient subset. Similar success rates have been reported by other authors41,42 in smaller patient cohorts. The patency rate of below the knee angioplasty is also often dependent on, and confounded by, technical success achieved in lesions commonly present immediately upstream from the diseased infrapopliteal segment. Dorros et al43 reviewed the results of tibioperoneal angioplasty in 168 lesions in 111 patients, 47% of whom were claudicants. Acute technical success rates approached 90%, but were lower for occlusions than for stenoses. Over 60% of patients required either adjunctive distal SFA or popliteal angioplasty prior to below the knee PTA. Although angiographic restenosis rates were high at 9-month follow-up (44 of 111 patients), only 36% required reintervention. Clinical success,

defined as the abolition of symptoms and wound healing, was achieved in 96% of patients. Yet despite these constraints, careful attention to proper interventional technique combined with the judicious use of lytic therapy and vasodilators such as calcium channel blockers, nitroglycerine and papaverine, can result in acute and long term patency results comparable to bypass surgery. Schwarten and Cutcliff44 reported a primary patency rate of 97% in 114 endangered limbs undergoing PTA with adjunctive use of lytic and vasodilator therapy in selected cases. A total of 145 diseased vessels, the vast majority of these having multiple stenoses or occlusions, were treated for limb threatening ischemia in this study; the 1- and 2-year limb salvage rates in this cohort were an impressive 89% and 86%, respectively. These results were accompanied by significant, sustained increases in the mean ankle brachial index, from 0.27 preprocedure, to 0.61 immediately post angioplasty, and to 0.59 at 2-year followup, implying that wound healing mainly occurred in the context of a clinically patent vessel. Enthusiasm for percutaneous angioplasty of infrapopliteal disease has been tempered by the often gloomy clinical context in which this disease entity merits treatment. Since it is generally indicated in elderly, debilitated patients with severe multilevel vascular disease and varied comorbid conditions, all of which make some contribution or other to the overall vascular anatomical substrate, the long term patency is usually not as durable as in other vascular interventions. Neither, for that matter, is the eventual clinical outcome, given the coexistent morbidity and mortality of cardiac and cerebrovascular disease in these patients. Surprisingly, and perhaps to some extent counterintuitively, revascularization in the context of critical limb ischemia, although fraught with risks of acute vessel closure

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owing to dissection (especially in calcified vessels), distal embolization, acute thrombotic occlusion, can often result in adequate limb salvage. By providing a threshold level and duration of pulsatile flow to the affected limb, these salvage procedures facilitate the healing of lower extremity ulcers, and promote the healing of subsequent amputation sites. Once healed, these wounds rarely, if ever, recur, even in the face of a restenosed or reoccluded ‘target’ vessel. When utilized in selected patients, especially those subsets with isolated disease and focal stenoses with restorable runoff, PTA is generally an effective procedure to treat critical limb ischemia, with immediate technical success rates approaching 95% and 2-year limb salvage rates close to 80%. Although the paradigm in the past has focused on the limited applicability of PTA in the successful treatment of the 20–30% of patients with critical limb ischemia who also have anatomically ‘amenable’ runoff lesions, it is hoped that newer interventional techniques and stent technology will broaden the indications for infrapopliteal PTA in the future.

Renovascular disease It is clear from many longitudinal studies of untreated renovascular disease, that revascularization confers important clinical benefits that impact on preservation of renal function and parenchymal mass, control of renovascular hypertension and its systemic ill effects, and on the overall survival of patients with this disease entity. Many prospective studies of renovascular disease have confirmed the importance of an aggressive approach to the treatment of these patients. In patients randomized to medical vs surgical therapy for atherosclerotic renal artery stenosis (RAS), and followed over 14 years, the overall survival was significantly higher in those patients

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randomized to surgery (70% vs 38%).45 Dean et al’s46 longitudinal study of medical vs therapy of renovascular hypertension, demonstrated an unequivocal worsening of renal function and loss of parenchymal mass in the conservatively treated patients, even in those whose renovascular hypertension (RVH) was well controlled on antihypertensive medications. Early diagnosis and aggressive intervention is especially indicated in bilateral RAS, whose onset is often insidious and which is associated with high rates of morbidity and mortality.47 Although percutaneous transluminal renal angioplasty (PTRA), since its introduction in 1978 as an alternative to surgical bypass for the treatment of RVH, has enjoyed wide application over the past two decades, there remains a paucity of objective data on its long term results. However, some caveats bear mentioning: the etiology and anatomic location of the stenosis are important determinants of both acute technical success and long term patency. Overall procedural mortality is < 1%, an attractive statistic in comparison to renovascular bypass surgery, which carries a periprocedural mortality of 3–6% in most series.48 RAS owing to fibromuscular dysplasia (FMD) responds well to treatment with stand alone balloon dilatation, whereas atherosclerotic RAS is less amenable to this procedure. Close to 85% of atherosclerotic lesions are ostial in location, which represents an extension of aortic plaque into the origin of the renal artery. Balloon angioplasty of ostial lesions yields dismal results, with immediate success rates of only 20–30% in many series; this is presumed to be due to severe elastic recoil that occurs at the renal ostium, after balloon dilatation. Tullis et al,49 utilizing duplex ultrasound assessment, examined the outcome of 40 primary PTRA and 12 renal stent procedures up to 48 months following successful angio-

RENOVASCULAR DISEASE

plasty. Residual stenosis post PTRA correlated strongly with restenosis; the cumulative incidence of restenosis at 1 and 2 years was lower (13% and 19%, respectively) in the group with no residual stenosis than in the group judged to have a < 60% residual lesion post PTRA (44% and 55%, respectively). There was little correlation between clinical endpoints and restenosis; 83% of patients with ‘improved’ blood pressure control had a final duplex ultrasound-measured stenosis of > 60% at one year, suggesting that changes in this clinical parameter may not be a reliable marker of long term patency post PTRA and underscoring the contention of many that the routine diagnostic assessment of vessel patency (i.e. duplex ultrasonography) be performed at regular follow-up intervals to detect restenosis. Small retrospective studies comparing stand alone balloon PTRA with renal bypass have suggested that surgery is the more durable procedure. Erdoes et al50 demonstrated an actuarial 48-month patency rate of 81% for surgery and 17% for angioplasty in an unselected series of 63 patients undergoing 76 consecutive renal revascularization procedures for treatment of RVH. These results have been consistent with other published reports describing restenosis rates of 20–40% at 2–4years post procedure. The largest prospective randomized study of PTA vs surgery reported an initial success rate of 83% for angioplasty, with a 24-month primary patency rate of 75% and a secondary patency rate of 90% after repeat intervention. Patients randomized to surgery in this small study (58 patients), had the more durable result, with a primary patency rate of 96% and secondary patency rate of 97% at 24 months. The travails of balloon angioplasty were well documented by Sos et al51 in their review of PTRA for RVH in a mixed population of patients with both atherosclerotic and fibro-muscular disease

(FMD). In comparison to a technical success rate of over 86% for patients with fibromuscular disease, a dismal 57% of atherosclerotic lesions enjoyed initial success, defined as a residual stenosis < 50% on final angiography. The greater stenosis severity and complexity associated with atheromatous disease, and ostial stenosis location, were factors that lead to increased elastic recoil and dissection, ultimately compromising acute patency. Long term patency, assessed in only 16 vessels, was incomplete in this study, and probably significantly underestimated the true restenosis rate. In 469 patients with PTRA of atherosclerotic renal lesions with angiographic follow-up in 10 studies (reviewed in a recent multicenter study of renal stenting), the median restenosis rate over the 2 years reported was 31%, and ranged from 18% to 92%. The use of stents as adjunctive therapy in PTRA has revolutionized the treatment of atherosclerotic RAS. Henry et al,52 in their analysis of over 200 patients undergoing renal artery stent deployment for treatment of predominantly ostial lesions, described cumulative primary and secondary patency rates of 80% and 98%, respectively, at 5 years of follow-up. Arteriographic and duplex followup revealed no significant differences in patency rates between stent designs, or stent location (ostial vs nonostial). The overall restenosis rate was 11.4%, the majority occurring within the first year. In an elegant demonstration of the niche application of stents in the treatment of RAS, Tuttle et al53 reviewed patency results in 129 patients undergoing 148 renal artery stent procedures for suboptimal (residual stenosis > 30%, or dissection) balloon PTA results on predominantly ostial lesions. The initial technical success rate for stent placement was 98% in these vessels, compared to an initial PTRA success rate of only 11%. The restenosis rate for the stent

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group was an impressive 14% at a mean of 8 months of follow-up. White et al54 reported a 9-month angiographic restenosis rate of 19% in 100 consecutive patients receiving stents for ostial renal artery and restenotic lesions. The sole procedural variable that correlated with restenosis in this study was the post stent minimal luminal diameter, highlighting the importance of adequate stent expansion and achievement of the lowest residual narrowing possible post PTRA. These results have been corroborated by others; a multicenter study of Palmaz stent placement in the treatment of ostial lesions confirmed the importance of proper stent to vessel sizing, noting that a post procedure residual stenosis of > 15% was a significant predictor of restenosis. Similarly, Rocha-Singh et al55 demonstrated a 1-year restenosis rate of 12% in over 180 renal stent procedures assessed by duplex ultrasound or angiography. There were no significant differences in restenosis rates between ostial and nonostial deployed stents in their review. The dramatically lower restenosis rate observed in more recent studies of renal artery revascularization is reflective of several issues. Firstly, the routine application of angiographic follow-up in these studies has reduced the invariable selection bias favoring repeat angiography only in those patients with clinical evidence of restenosis. Also, the increasingly commonplace use of nonarticulated stents to treat ostial-proximal stenoses has resulted in better optimization of the acute result, leading to a better long term outcome. Reduction of the residual stenosis post PTRA, by either slight oversizing of the balloon, or by employing higher inflation pressures, has been demonstrated to be effective in reducing restenosis in atherosclerotic disease. The long term clinical benefit derived from the treatment of atherosclerotic RAS in terms of hypertension control and preservation of

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renal function remains mixed, despite the excellent angiographic results obtained with modern renal artery angioplasty and stenting. Ramsay and Waller56 in their meta-analysis of over 600 patients undergoing PTRA in the pre-stent era, observed a long term cure rate for RVH of only 19%. Lack of uniform reporting standards and incomplete clinical follow-up has clouded these early results. Dorros et al’s recent review57 of renal stenting in 92 atherosclerotic lesions demonstrated stabilization or improvement in renal function in 78%, and significant decreases in systolic and diastolic hypertension, with an angiographic restenosis rate of 25% at 6 months of nearly complete clinical (99%) and angiographic (73%) follow-up. Rocha-Singh et al55 however, reported a cure rate of only 6% for RVH and renal function improvement in only 28% in a cohort of 150 hypertensive patients with 180 renal artery lesions with 91% clinical follow-up. Isles et al58 in a recent systematic survey of renal stenting encompassing 10 studies involving 379 patients, reported similar results, with a blood pressure cure in only 9% and improvement in renal function in 26% of patients. In general, renal function does not appear to be significantly modified by the procedure, suggesting a multifactorial influence on preservation of renal mass outside the effects of arterial recanalization. The role of PTRA in the retardation and stabilization of renal insufficiency is increasingly recognized as a positive long term clinical effect, especially when viewed in the context of the relationship between renovascular disease and progressive deterioration of renal function. The clinical utility of renal PTA, independent of its effect on acute and long term patency, awaits further characterization in large randomized studies, before its universal acceptance as a substitute for surgery, and indeed, even medical therapy in the treatment

EXTRACRANIAL CAROTID DISEASE

of renovascular disease. For renal stent patients, obtaining the maximal acute luminal gain post PTRA, and close surveillance in follow-up is essential. Restenosis is usually silent, and may not be heralded by recurrent hypertension or deterioration in renal function. Periodic serial duplex ultrasound scanning and angiography remain the only reliable means of detecting restenosis.

Supraaortic disease Occlusive disease of the supraaortic vessels is a relatively infrequent reason for revascularization in the treatment of vascular disease. Whereas disease of the subclavian arteries is usually clinically silent, disease of the innominate and common/internal carotid vessels has great potential for irreversible cerebral and ophthalmologic injury. When symptomatic, subclavian artery stenosis is associated with subclavian steal syndrome, upper extremity claudication, vertebrobasilar insufficiency (VBI), atheroemboli to digits, and in patients with surgical left internal mammary artery conduits post coronary artery bypass surgery (CABG), coronarysubclavian steal with resulting exertional angina prectoris may ensue. Surgical revascularization for subclavian artery disease has proven durable long term patency but is fraught with immediate complications, including a 23% perioperative morbidity and mortality of up to 80% reported in some series. Since the first reported subclavian angioplasty was performed for subclavian steal syndrome in 198059 the procedure has gained wide acceptance as first line therapy for this disease entity, despite reported restenosis rates with balloon angioplasty alone of upwards of 40% in small patient cohorts. Stenting of these relatively large vessels has yielded promising acute and long term results,

akin to those reported in iliac stent deployment. Motarjeme60 noted an immediate patency rate of 91% in 67 subclavian stenoses undergoing angioplasty, and only three cases of reocclusion over a 5-year follow-up. The results for subclavian artery occlusions however, were less encouraging, with only a 46% technical success rate, and a restenosis rate of 25% at 6 months and 50% at 1 year, in this study. Kumar et al61 reported 100% immediate patency in 35 subclavian lesions treated with primary stenting, obtaining results comparable to those of Criado and Queral,62 who noted immediate success in 90% of 13 subclavian lesions treated with stents, and 2-year patency rates of nearly 80%. Direct comparison between surgery and PTA for subclavian disease is hampered by the absence of randomized controlled studies. Hadjipetrou et al,63 in their recent analysis, compared the results of primary subclavian stenting in 108 patients with those of 2496 surgical patients reported in 52 papers in the literature. The surgical series achieved a technical success in 96% of the patients with a 16% complication rate, 3% mortality, stroke in 2%, and recurrence in 16% at mean followup of 51 months. Of the 108 stented patients, technical success was 97%, complications developed in 6%, with no reported strokes or death, and with a 20-month patency rate of 97%.

Extracranial carotid disease A full comprehension of the incidence and implications of restenosis in the carotid artery following revascularization may be best facilitated by placing the stenotic process in its proper context. In most studies addressing the natural history of extracranial carotid disease, progression occurs in approximately 20–40% of cases.47 The risk of progression to severe

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disease (80–99% stenosis) is higher in patients with moderate disease (50–79% stenosis), as has been demonstrated in long term studies with annual serial duplex ultrasound followup. Since there still remains a paucity of data on the long term results of carotid PTA and stenting (CPTA), a relatively novel procedure in the treatment of carotid disease, results of long term follow-up after CEA remain the best available source of information on the outcome of revascularization. Pooled data from over 2300 CEA procedures indicates that hemodynamically significant carotid artery restenosis generally occurs in 10–12% of patients, the majority of lesions being identified by duplex scanning.64–68 Restenosis is usually clinically silent; however, in general, when symptomatic, it is usually expressed in the territory served by the ipsilateral restenotic lesion. Many surgical series have characterized the pathology of the restenotic process following endarterectomy and classified these lesions into two major types occurring within a broad spectrum of cellular changes.69 The first, occurring within 2 years of surgery, is attributed to intimal hyperplasia, and the second, occurring thereafter, is caused by recurrent or progressive atherosclerosis. Most restenotic lesions represent an amalgam of both processes, with evidence of both neointimal proliferation and atherosclerotic change with superimposed thrombi in up to 75% of lesions. Comparison of these human specimens with those from rat models after carotid balloon injury has indicated that the neointimal response following surgical endarterectomy is identical to that following balloon injury. However, the response rates differ markedly; whereas SMC proliferation commences with 24 hours of balloon injury, peaking at 4 weeks in the rat model, human endarterectomy samples exhibit low proliferation rates at time of removal, during reopera-

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tion. Angiographic expression of this process may include ring-like lesions, tubular stenoses, or as a markedly irregular lumen with focal areas of ulceration and stenosis, when atherosclerosis is the dominant process. In comparison to the time-tested procedure of surgical endarterectomy, the experience with angioplasty and stenting in the treatment of carotid artery occlusive disease is somewhat limited. There is a paucity of evidence from large, prospective randomized trials comparing carotid angioplasty with CEA to date. Results are pending from one such study, the Carotid and Vertebral Transluminal Angioplasty Study (CAVATAS), and recruitment is underway for a second, the Carotid Endarterectomy vs Stent Trial (CREST). However, the largest published single center experiences have enjoyed excellent success with the procedure. Deitrich et al70 reported immediate success rates of 99% with stentsupported carotid angioplasty in 110 patients with angiographic stenoses of 70% or greater. The cumulative primary patency rate by duplex ultrasound follow-up at 7 months was 89%; a total of three stents occluded, all without neurologic sequelae, and one stent restenosis, with ultrasound features suggestive of intimal hyperplasia, at 7 months. Technical factors such as incomplete stent apposition owing to heavy arterial calcification, hypertrophic tissue or the natural variations in diameters of the internal and common carotid arteries, were noted to play a role in long term patency. Stent deformation, a problem seen early in the learning curve with balloonexpandable rigid stents placed at the carotid bifurcation (in the mid-neck), was not observed in this study. Yadav et al71 reported a 6-month restenosis rate of 5% in 126 carotid lesions treated with stent-supported angioplasty in 107 high risk patients with previous ipsilateral endarterectomy and severe co-mor-

ENDOVASCULAR RADIATION BRACHYTHERAPY

bidity, traditional exclusion criteria in the large surgical endarterectomy trials (NASCET, ACAS). Stent deformation was noted in eight Palmaz stents, but only four patients (4.9%) underwent repeat PTA, two for in-stent restenosis and two for stent deformation. Large vessel caliber, and optimization of the angiographic result with high pressure stent deployment were felt to be mitigating factors in the low observed incidence of restenosis in this study. These results have been corroborated by others, notably Wholey et al,72 who demonstrated a 6-month angiographic restenosis rate of 1% in 108 patients with severe disease treated with stents. The single case of restenosis in this study was due to stent compression, effectively managed with repeat dilatation. A technical failure rate of 5.3% in this study was predominantly due to inability to track guiding catheters into tortuous carotid arteries. The Argentine Registry in Carotid Stent Assisted Angioplasty73 reported a 9-month angiographic restenosis rate of 6% and a stent deformation rate of 2.5% in over 100 procedures performed for severe disease. The longest follow-up to date of any study of carotid stenting was provided by Henry et al,74 in their longitudinal analysis of 174 treated lesions; in addition to a stunning technical success rate of 99%, the 12-month restenosis rate was a paltry 2.3%, with primary and secondary patency rates at 3 years of 96% and 99%, respectively. On the basis of these reports, it would appear that the restenosis rate associated with stent-supported carotid angioplasty is acceptably low and clinically asymptomatic if care is taken to ensure a good immediate angiographic result with maximization of acute stent luminal diameter. The ideal stent for treatment of these lesions remains to be determined, although nitinol self-expanding stents do not carry the liability of stent deformation

observed with rigid balloon-expandable stents. It would appear that the restenotic process, similar to that seen in iliac and other large caliber vessels, may be blunted by the large size of the vessel, making stent-supported angioplasty the procedure of choice in the percutaneous revascularization of carotid disease. Further conclusions as to the relative efficacy and safety of carotid artery stenting vs surgical CEA will have to await the results of planned ongoing randomized multicenter trials.

Endovascular radiation brachytherapy Endovascular radiation brachytherapy is a developing novel technology with a potential to reduce the rate of restenosis both in the coronary and peripheral vasculature. Observations from many animal studies using the porcine model have convincingly shown that when an appropriate dose of radiation was delivered intraluminally to the target area following balloon injury or stent, neointimal proliferation was inhibited and thus maintenance of luminal diameter was achieved by attenuation of the restenosis response after this therapy. The SFA represents one of the most common sites of peripheral vascular obstruction. Symptomatic femoropopliteal disease is generally twice as prevalent as iliac disease. Despite the fact that PTA has been widely used and successful in treating atherosclerotic obstructions in the peripheral and coronary circulations, restenosis continues to be a vexing sequelae of this otherwise efficacious intervention. An increased risk of compression of balloon-expandable stents in the femoropopliteal arteries has been observed, which may be caused by external trauma or muscle compression within the adductor

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canal.75 Therefore, the use of self-expandable stents in the SFA seems advisable. In view of the dismal long term patency results of SFA/popliteal revascularization compared to acceptable suprainguinal PTA results (e.g. aortoiliac, renal, subclavian, and carotid arteries) with adjunctive stenting, endovascular radiation may play a prominent role in this troublesome vascular bed. Liermann, Schopohl and colleagues76,77 in 1990 were the first to utilize brachytherapy to prevent restenosis in the peripheral vascular system. Employing a gamma source (192Ir), they locally irradiated femoropopliteal arteries with documented in-stent restenosis. This study consisted of 29 patients who had undergone prior SFA/popliteal artery stent implantation and developed restenosis, with the subsequent performance of directional atherectomy (DA) or PTA, followed by endovascular radiation. Utilizing as a source 192 Ir at the dose of 12 Gy delivered to the vessel wall with a 5-French (Fr) non-centering closed-end lumen, via a high-dose rate MicroSelectron afterloader (NucleotronOtelft; Veenendaal, The Netherlands). The procedure was well-tolerated with a 5-year patency rate of 75% at the site of the treated segment and no adverse events reported at 7 years following radiation treatment. Minar et al78 conducted a radiation trial using a similar system and protocol following SFA and popliteal PTA on 100 patients. At 6 months, this study demonstrated a reduction in clinical patency rates of 58% as assessed by color duplex ultrasonography and an approximately 30% reduction in angiographic restenosis in the radiation group compared to the placebo group. Currently, the Peripheral Arteries Radiation Investigational Study (PARIS), a national multicenter, randomized, double-blind control study, is analysing the utility of 192Ir gamma

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radiation at a dose of 14 Gy delivered to the adventitia using a centering catheter in 300 patients following PTA of stenotic SFAs (length ⫽ 5–15 mm). The objectives outlined are to determine: 1. angiographic evidence of patency and; 2. a > 30% reduction in restenosis rates of the treated lesion at 6 months. Secondary endpoints are to determine clinical patency at 6 and 12 months by both exercise treadmill and ankle:brachial indices (ABI). In the feasibility (Phase I Registry) portion of this study79,80 clinical success was achieved in 35 of the 40 patients (87%) who underwent radiation therapy without any reported adverse events and with angiographic restenosis rates of < 12% of the targeted artery at 6 months.81

Dialysis arteriovenous grafts More than 200 000 patients with end stage renal disease are maintained on long term hemodialysis. However, access to the circulation continues to remain the ‘achille’s heel’ of most patients continued on hemodialysis. Over the past 15 years, the percutaneous treatment of arteriovenous (AV) grafts has become commonplace, which has featured the use of PTA for maintaining and restoring patency of stenosed and occluded hemodialysis accesses. Despite its ability to markedly improve the care of the dialysis patient by promptly restoring patency and conserving venous conduit for future permanent access, poor long term patency results have necessitated the use of alternative treatment modalities, such as endovascular stents. Nevertheless, even with the advent of adjunctive stenting, maintaining long-term patency of AV grafts remains elusive, although somewhat improved with a vigilant noninvasive surveillance program. Nori et al82 were the first group to study

ARTERIAL GENE TRANSFER TO INHIBIT RESTENOSIS IN PATIENTS

patients treated with AV dialysis grafts stenoses utilizing external radiation therapy. In the phase I trial, 10 patients were successfully treated with total radiation doses of 8 or 12 Gy, without any reported complications. Despite a 6-month follow-up angiographic patency rate of 70%, all patients ultimately required reintervention owing to graft failure within 12 months of treatment. Waksman et al,83 have reported their preliminary experience with gamma irradiation for restenosis post PTA of AV graft stenoses. Eleven patients with 18 lesions were successfully treated with 14 Gy of 192Ir delivered to the arterial wall with a nucleotron afterloader. Once again, reported patency of only 40% of the treated grafts was achieved at 4 plus weeks. Owing to the emerging technology and lack of extensive clinical experience with vascular brachytherapy in the peripheral vasculature, its application should be confined only to randomized clinical trials, such as PARIS, to support its use in the future as a primary intervention. Not until all outstanding issues are addressed and the safety and efficacy of this modality are ultimately confirmed, can one implement this technology into routine clinical practice.

Arterial gene transfer to inhibit restenosis in patients with superficial femoral artery disease Previous strategies employed to limit the development of restenosis including nonmechanical means (antiproliferative, antiplatelet, antiinflamatory, spasmolytic and lipid-lowering agents) or mechanical devices (directional or rotational atherectomy and endovascular stents) have not proved to be

effective. Despite the fact that PTA routinely produces endothelial denudation and the roles of the endothelium in providing barrier function, reducing thrombogenicity, and inhibiting restenosis are well accepted, treatment strategies aimed at specifically restoring endothelial integrity have not been previously explored for restenosis prevention. Vale et al84 have attempted to improve upon the results of SFA/popliteal PTA, with the hypothesis that acceleration of re-endothelialization might be achieved following the administration of mitogens that promote endothelial cell migration and/or proliferation, including vascular endothelial growth factor (VEGF).84 Animal studies have demonstrated that VEGF accelerates re-endothelialization and thereby reduces intimal thickening. Accordingly, they initiated a phase I, single site, dose escalating, openlabel, unblinded clinical gene therapy protocol. The primary objective of the study was to document the safety of interventional reendothelialization, achieved in this case by percutaneous catheter-based delivery of naked plasmid DNA encoding for the 165-amino acid isoform of VEGF (phVEGF165) post PTA using a hydrogel-polymer-coated balloon angioplasty catheter in patients with claudication undergoing SFA revascularization. The secondary objective was to investigate the bioactivity of the strategy designed to facilitate endothelial cell regeneration and promote recovery of endothelial cell dysfunction following balloon injury, reduce neointimal thickening and accelerate reendothelialization of the denuded arterial segment, thereby inhibiting restenosis. Arterial VEGF gene transfer was successfully performed in 22 patients. Prior to gene transfer, all patients were classified as Rutherford Category 3. At 12 months following gene transfer, nine patients were asymptomatic and seven patients were Rutherford Category 1,

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with only mild claudication symptoms. After an initial improvement of two Rutherford categories following revascularization, five patients returned to Category 3. All five patients required repeat target vessel revascularization with restenosis as documented by ABI, duplex and angiographic criteria. One patient developed critical limb ischemia at 3 months following gene transfer with resultant rest pain (Category 4), an ABI of 0.41, an SFA occlusion by contrast angiography and anatomy not suitable for conventional revascularization, thus ultimately requiring treatment by intramuscular gene transfer of phVEGF165 as a limb-salvage procedure. Digital subtraction angiography was performed between 6 and 12 months post gene transfer and the degree of stenosis for all patients decreased from a mean of 86% at baseline to 45% at an average of 9 months following gene transfer. By angiographic criteria, five patients (23%) had evidence of restenosis and subsequently underwent repeat PTA with DA or deployment of an endovascular stent.

268

The nonrandomized feature of this investigation permitted the investigators to maximize information regarding the potential for adverse consequences. No serious complications attributable to phVEGF165 were observed up to 18-months’ follow-up, and no acute procedural complications were incurred, especially given the longer balloon inflations required during gene transfection. These and other preliminary results have established the feasibility of arterial gene transfer as a novel approach for preventing restenosis in patients undergoing lower extremity percutaneous revascularization of stenotic and/or occluded SFAs. In addition, they indicate that arterial gene transfer in this setting is safe and adds no increased morbidity to SFA percutaneous revascularization, although the routine use of this strategy need be reserved pending the results of future planned randomized, double-blind, placebocontrolled trials.

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Index Note: References to figures are indicated by ‘f’ and references to tables by ‘t’ when they fall on a page not covered by the text reference. abciximab, for restenosis prevention 98t, 102 amyloid A, as restenosis predictor 43 angiography angiographic definitions of restenosis 22 angiographic predictors for restenosis 43–45 comparison with intravascular ultrasound 77–79 angiopeptin, for restenosis prevention 104–105, 109f angioplasty see balloon angioplasty; percutaneous coronary intervention (PCI); percutaneous transluminal angioplasty (PTA); percutaneous transluminal coronary angioplasty (PTCA) angiotensin-converting enzyme (ACE), as restenosis predictor 43 angiotensin-converting enzyme (ACE) inhibitors, for restenosis prevention 104t, 105, 109f anti-inflammatory drugs, for restenosis prevention 102–104 antiallergic drugs, for restenosis prevention 103–104 anticoagulants, for restenosis prevention 109f antimigratory gene therapy 131 antineoplastic drugs, for restenosis prevention 106 antioxidants, for restenosis prevention 107–108, 109f antiplatelet agents and in-stent restenosis 198 for restenosis prevention 97–101 antiproliferative agents for restenosis prevention 106, 109f stent coating 119–120 antiproliferative gene therapy 130–131

antithrombotic agents for restenosis prevention 98t, 101–102 stent coating 118–119 antithrombotic gene therapy 131–132 aortoiliac disease 252–255 arterial gene transfer, for peripheral arterial disease 267–268 arteriovenous grafts percutaneous transluminal angioplasty (PTA) 266 vascular radiation therapy 266–267 ARTISTIC trial (Angiorad Radiation Technology for In-Stent Restenosis Trial in Native Coronaries) 207t, 212 aspirin, for restenosis prevention 98, 99f, 109f asymptomatic restenosis 26–27 atherectomy see directional coronary atherectomy (DCA); rotational atherectomy azathioprine, for restenosis prevention 106 balloon angioplasty history 1 for in-stent restenosis 180–184 comparison with rotational atherectomy 186t, 191–194 mechanism 1–3 BARASTER registry 190-191 BENESTENT trials 5–6, 80, 145–146 BERT trials (Beta Energy Restenosis Trial) 214–215, 228 beta emitting stents see radioisotope stents beta radiation, radiation physics 205, 228 beta radiation therapy see vascular radiation therapy BETA WRIST trial 209t, 213–214 Betacath trial 228

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INDEX

biochemical predictors for restenosis 41–43, 44t brachytherapy see vascular radiation therapy BRIE trial (Beta Radiation in Europe) 213 BRITE trial (Beta Radiation to Prevent In-sTent REstenosis) 209t, 215 C-reactive protein (CRP), as restenosis predictor 42 c-type natriuretic peptide (CNP), gene transfer strategies 132 calcium channel antagonists, for restenosis prevention 106–107, 109f cholesterol, as restenosis predictor 41–42 chronic total occlusions (CTO), primary stenting 150–151 cilazapril, for restenosis prevention 104t, 105 ciprostene, for restenosis prevention 98t, 100 clinical predictors for restenosis 4t, 5, 39–41 clinical presentation of restenosis asymptomatic restenosis 26–27 symptoms 23–26 time course 22–23, 24f clinical restenosis, definition 3, 21 CLOUT trial (Clinical Outcome with Ultrasound Trial) 80 colchicine, for restenosis prevention 106 coronary artery bypass grafting (CABG), primary stenting 148–150 coronary flow velocity reserve (CVR) measurement 57–59 and myocardial infarction 68–70 post-intervention assessment 64–67 pre-intervention assessment 62–64 coronary lesion assessment coronary flow velocity reserve (CVR) 57–59 and coronary physiology 56–57 direct and indirect methods 55–56 economic costs 70–71 fractional flow reserve (FFR) 60–62 and myocardial infarction 68–70 post-intervention assessment 64–68 pre-intervention assessment 62–64 relative coronary flow velocity reserve (rCVR) 59–60 corticosteroids, for restenosis prevention 102–103

274

CRUISE trial (Can Routine Intravascular Ultrasound Influence Stent Expansion) 86 CURE trial (Columbia University Radiation Energy) 213 cutting balloon angioplasty, for debulking 173 cyclooxygenases, gene transfer strategies 132 cyclosporin, for restenosis prevention 106 debulking cutting balloon angioplasty 173 directional coronary atherectomy (DCA) 160–169 excimer laser angioplasty 173 new devices 173–174 pullback atherectomy catheter 172 rationale for 159–160 rotational atherectomy 169–172 transluminal extraction catheter 172 DESIRE trial (DEbulking and Stenting in Restenosis Elimination) 83 dextran, for restenosis prevention 98t, 101 diabetes mellitus, primary stenting 151–152 dialysis arteriovenous grafts percutaneous transluminal angioplasty (PTA) 266 vascular radiation therapy 266–267 dipyridamole for restenosis prevention 98 directional coronary atherectomy (DCA) for debulking comparison with balloon angioplasty 160 early outcome studies 167–169 late outcome studies 169 SOLD (Stenting after Optimal Lesion Debulking) trial 160–167 for in-stent restenosis 184, 185t, 188 DOSE FINDING trial 212 drug-coated stents antiproliferative coating 119–120 antithrombotic coating 118–119 coating materials 114–117 drug loading and release kinetics 117–118 paclitaxel-eluting stents 122 rapamycin-eluting stents 120–122 rationale for 113–114

INDEX

drugs, for restenosis prevention anti-inflammatory drugs 102–104 antineoplastic drugs 106 antioxidants 107–108 antiplatelet agents 97–101 antiproliferative agents 106 antithrombotic agents 98t, 101–102 growth factor antagonists 104–106 lipid-lowering agents 107 local drug delivery 108 molecular biological approaches 108 relative risk ratios 108, 109f vasodilators 106–107 ebselen, for restenosis prevention 103 edge restenosis 234, 245–248 elastic recoil of arteries and mechanism of percutaneous coronary interventions 1–2 and pathophysiology of restenosis 9 enalapril, for restenosis prevention 104t, 105 endothelial cells, and pathophysiology of restenosis 11–12 EPISTENT trial 146, 183 epoprostanol, for restenosis prevention 98t, 100 eptifibatide, for restenosis prevention 98t, 102 excimer laser angioplasty (ELCA) for debulking 173 for in-stent restenosis 187t, 194–197 exercise electrocardiology 28–30 extracellular matrix (ECM), and restenosis pathophysiology 14–15 extracranial carotid disease 263–265 fatty acids, for restenosis prevention 98t, 100, 109f femoropopliteal disease 255–258 arterial gene transfer 267–268 vascular radiation therapy 265–266 fibrinogen, as restenosis predictor 42 fosinopril, for restenosis prevention 104t, 105 fractional flow reserve (FFR) measurement 60–62 post-intervention assessment 67 pre-intervention assessment 62–64 FRESCO trial (Florence Randomized Elective

Stenting in acute Coronary Occlusions) 147–148 GALILEO INHIBIT trial 209t, 214–215 gamma radiation, radiation physics 204–205, 224-30 gamma radiation therapy see vascular radiation therapy GAMMA trials 207t, 210–211, 226–227 gene transfer and cell/tissue specificity 135–136 clinical applications 137 delivery techniques 136–137 development of 129–130 future studies 138 and inflammatory response 135 for peripheral arterial disease 267–268 therapeutic strategies 130–132 vector systems 132–135, 136f genetic predictors for restenosis 43, 44t GENEVA EXPERIENCE trial 212 GISSOC trial 150–151 glycoprotein IIb/IIIa inhibitors, for restenosis prevention 98t, 102, 198 GRAMI trial 147 growth factor antagonists, for restenosis prevention 104–106 heparin, for restenosis prevention 98t, 101 hirulog, for restenosis prevention 98t, 101–102 hirundin, for restenosis prevention 98t, 101 immunosuppressive agents, for restenosis prevention 106 in-stent restenosis 153–154 antiplatelet agents 198 balloon angioplasty 180–184 beta radiation trials 213–215 definition 179 directional coronary atherectomy 184, 185t, 188 excimer laser angioplasty 187t, 194–197 incidence 180 management algorithm 198–200 pathophysiology 179–180 repeat stenting 197

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INDEX

in-stent restenosis continued rotational atherectomy 185t, 188–192 comparison with balloon angioplasty 186t, 191–194 vascular radiation therapy 197–198 infrapopliteal disease 258–260 INHIBIT trial 209t, 214–215 intravascular ultrasound (IVUS) plaque imaging 81–84 and restenosis prediction 45–48 stent optimization 84–86 therapeutic uses 88–89, 90f and vascular radiation therapy 86–88, 89f vessel length measurement 80–81 vessel size measurement 77–80 IRIS trial 228–229, 242–243 ketanserin, for restenosis prevention 104t, 105 late loss ratio, definition 3 Laser Angioplasty of Restenosed coronary Stents (LARS) 195 lesion length, and restenosis prediction 45 lesion location, and restenosis prediction 45 linsidomine, for restenosis prevention 104t, 105–106 lipid-lowering agents, for restenosis prevention 107, 109f lipoprotein (a), as restenosis predictor 42–43 MARS trial (Mallinckrodt Angioplasty Radiation Study) 213 methotrexate, for restenosis prevention 106 methylprednisolone, for restenosis prevention 102–103 microtubule stabilizing agents, for restenosis prevention 106 Milan trial, beta emitting stents 243–244 minimal lumen diameter (MLD) measurement, and restenosis prediction 44–45 molsidomine, for restenosis prevention 104t, 105–106 MUSIC trial (Multicenter Ultrasound Stent in Coronaries) 85–86 myocardial infarction coronary lesion assessment 68–70

276

primary stenting 146–148 neointima hyperplasia 12–14 pathophysiology of restenosis 10–11 nitric oxide donors, for restenosis prevention 104t, 105–106 nitric oxide synthase, gene transfer strategies 132 non-invasive testing effect of stenting 32 exercise electrocardiology 28–30 nuclear imaging 30–31 positron emission tomography (PET) 32 stress echocardiography 31–32 use of 27–28 nonsteroidal antiinflammatory drugs (NSAIDs), for restenosis prevention 103 nuclear imaging, non-invasive evaluation of restenosis 30–31 OCBAS trial (Optimal Coronary Balloon Angioplasty) 80, 145–146 octreotide, for restenosis prevention 104–105 omega-3 fatty acids, for restenosis prevention 98t, 100, 109f OPUS trial (Optimal Angioplasty vs Primary Stenting) 146 paclitaxel (Taxol) paclitaxel-eluting stents 122 for restenosis prevention 106 PAMI trial (Primary Angioplasty in Myocardial Infarction) 147t, 148 PASTA trial 147t pathophysiology of restenosis artery remodeling 15–17 elastic recoil 9 endothelial cell functions 11–12 extracellular matrix 14–15 neointimal formation 10–11 smooth muscle-like cells 12–14 thrombus formation 9–10 percutaneous coronary intervention (PCI) definition 1, 2t history 1 mechanism of action 1–3

INDEX

percutaneous transluminal angioplasty (PTA) aortoiliac disease 252–255 extracranial carotid disease 263–265 femoropopliteal disease 255–258 infrapopliteal disease 258–260 renovascular disease 260–263 supraaortic disease 263 percutaneous transluminal coronary angioplasty (PTCA) history 1 stenting after 152–153 peripheral arterial disease (PAD) 251–252 aortoiliac disease 252–255 arterial gene transfer 267–268 arteriovenous grafts 266–267 extracranial carotid disease 263–265 femoropopliteal disease 255–258 infrapopliteal disease 258–260 renovascular disease 260–263 supraaortic disease 263 vascular radiation therapy 265–266 pharmacological agents, for restenosis prevention see drugs, for restenosis prevention physiologic assessment, of coronary arteries see coronary lesion assessment pituitary growth hormone antagonists, for restenosis prevention 104–105 plaque intravascular ultrasound imaging 81–84 removal before stenting see debulking platelet-derived growth factor (PDGF) antagonists, for restenosis prevention 104 positron emission tomography (PET), noninvasive evaluation of restenosis 32 post-intervention physiologic assessment 64–68 pre-intervention physiologic assessment 62–64 prednisone, for restenosis prevention 102–103 PREVENT trial (Proliferation Reduction with Vascular Energy Trial) 213, 228 primary stenting for chronic total occlusions 150–151 and complex angioplasty 152 in diabetes mellitus 151–152 for myocardial infarction 146–148

provisional stenting 145–146 in saphenous vein graft interventions 148–150 prostacyclin analogues, for restenosis prevention 98t, 100, 109f provisional stenting 145–146 PTA (percutaneous transluminal angioplasty) see percutaneous transluminal angioplasty (PTA) PTCA (percutaneous transluminal coronary angioplasty) see percutaneous transluminal coronary angioplasty (PTCA) pullback atherectomy catheter, for debulking 172 radiation delivery systems catheter-based devices 226f, 227f, 232–234 radioactive filled balloons 232–233 stents see radioisotope stents radioisotope stents 233–234, 241 clinical trials 215–216, 242–244 edge effect 234, 245–248 radiation dosimetry 241–242 stent design 244–248 radioisotopes dosimetric calculations 205 radiation physics 204–205, 229–230 rapamycin rapamycin-eluting stents 120–122 for restenosis prevention 106 reference vessel diameter measurement, and restenosis prediction 45 relative coronary flow velocity (rCVR), measurement 59–60 remodeling of arteries, and restenosis 15–17 renovascular disease 260–263 RESIST trial (REStenosis after Ivus guide STenting) 86 REST trial (Restenosis Stent) 152–153 restenosis angiographic definitions 3, 22 clinical definition 21 clinical presentation asymptomatic restenosis 26–27 symptoms 23–26 timing of restenosis 22–23, 24f

277

INDEX

restenosis continued in-stent see in-stent restenosis management approach 32–33 risk factors for see risk factors for restenosis time course 3, 5 risk factors for restenosis angiographic measurements 43–45 biochemical markers 41–43, 44t clinical factors 39–41 genetic markers 43, 44t practical implications 48 ultrasound measurements 45–48 rotational atherectomy for debulking 169–172 for in-stent restenosis 185t, 188–192 comparison with balloon angioplasty 186t, 191–194 saphenous vein graft interventions, primary stenting 148–150 SARECCO trial 150–151 SAVED trial (Saphenous Vein De Novo Trial Investigators) 148–149 SCRIPPS trial (Scripps Coronary Radiation to Inhibit Proliferation Post Stenting) 206, 207t, 210, 224–226 serotonin receptor antagonists, for restenosis prevention 104t, 105, 109f serum markers, as restenosis predictors 41–43, 44t SICCO trial 150–151 silent restenosis 26–27 smooth muscle cells antimigratory gene transfer strategies 131 antiproliferative gene transfer strategies 130–131 smooth muscle-like cells, and restenosis pathophysiology 12–14 SOLD trial (Stenting after Optimal Lesion Debulking) 160–167 solutroban, for restenosis prevention 98–100 sonotherapy 88–89, 90f SPACTO trial 150–151 START trial (STents And Radiation Therapy) 87–88, 209t, 214, 228 stents after percutaneous transluminal coronary

278

angioplasty 152–153 for aortoiliac disease 254–255 for chronic total occlusions 150–151 and complex angioplasty 152 in diabetes mellitus 151–152 drug coated see drug-coated stents effect on non-invasive evaluation of restenosis 32 for femoropopliteal disease 256–258 history 5–6 in-stent restenosis see in-stent restenosis for myocardial infarction 146–148 optimization using intravascular ultrasound 84–86 provisional stenting 145–146 radioisotope see radioisotope stents in saphenous vein graft interventions 148–150 use of 5–6 steroids, for restenosis prevention 102–103, 109f stress echocardiography, non-invasive evaluation of restenosis 31–32 STRESS trial 5–6 supraaortic disease 263 target vessel revascularization (TVR), definition 3 Taxol (paclitaxel) for restenosis prevention 106 Taxol-eluting stents 122 thrombin inhibitors, for restenosis prevention 98t, 101–102 thromboxane receptor antagonists, for restenosis prevention 98–100, 109f thrombus formation, pathophysiology of restenosis 9–10 ticlopidine, for restenosis prevention 98t, 100–101, 109f tirofiban, for restenosis prevention 98t, 102 TOSCA trial 150–151 tranilast, for restenosis prevention 103–104 transluminal extraction catheter, for debulking 172 trapidil, for restenosis prevention 104, 109f ultrasound see intravascular ultrasound (IVUS)

INDEX

vapiprost, for restenosis prevention 98–100 vascular radiation therapy animal models 221–222 clinical trials 205–206 beta radiation therapy 209t, 212–213, 227–229 gamma radiation therapy 206, 207–208t, 210–212, 224–227 for in-stent restenosis 197–198, 213–215 delivery techniques 204, 226f, 227f, 231–235 dosimetric calculations 205 history 203 intravascular ultrasound imaging 86–88, 89f late thrombosis 234 limitations of technique 216 long-term safety and efficacy 228–229 mechanism of action 203–204

peripheral arterial disease 265–267 radiation physics 204–205, 227–228 radioisotope stents see radioisotope stents vasodilators, for restenosis prevention 106–107 vectors, for gene transfer choice of 132–133 nonviral vectors 133–134 viral vectors 134–135, 136f VENESTENT trial 149 vessel size measurement, using intravascular ultrasound 77–81 warfarin, for restenosis prevention 98t, 102 WRIST trial (Washington Radiation for In-Stent Restenosis Trial) 207t, 210, 226–227 Zwolle trial 147–148

279

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