Coronary Lesions: A Pragmatic Approach

579_Stenting_prels 16/8/2001 10:29 Page i CORONARY LESIONS A PRAGMATIC APPROACH 579_Stenting_prels 16/8/2001 10:2...

Author: Patrick W. Serruys | Martin B. Leon | Antonio Colombo | Michael J B Kutryk

65 downloads 1309 Views 6MB Size Report

This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form

DOWNLOAD PDF

579_Stenting_prels

16/8/2001 10:29

Page i

CORONARY LESIONS A PRAGMATIC APPROACH

579_Stenting_prels

16/8/2001 10:29

Page ii

579_Stenting_prels

16/8/2001 10:29

Page iii

CORONARY LESIONS A PRAGMATIC APPROACH Edited by

Patrick W Serruys MD PHD FACC FESC Head, Interventional Cardiology Thoraxcenter Academic Hospital Rotterdam-Dijkzigt Rotterdam The Netherlands

Antonio Colombo MD Director Cardiac Catheterization Laboratory EMO Centro Cuore Columbus Milan Italy

Martin B Leon MD Director and CEO Cardiovascular Research Foundation Lenox Hill Heart and Vascular Institute New York NY USA

Michael JB Kutryk MD Department of Cardiology St Michael’s Hospital Toronto ON Canada

MARTIN DUNITZ

© 2002 Martin Dunitz Ltd, a member of the Taylor & Francis group First published in the United Kingdom in 2002 by Martin Dunitz Ltd, The Livery House, 7–9 Pratt Street, London NW1 0AE Tel: Fax: E-mail: Webiste:

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

This edition published in the Taylor & Francis e-Library, 2003. 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 0-203-21327-0 Master e-book ISBN

ISBN 0-203-27030-4 (Adobe eReader Format) ISBN 1-85317-936-1 (Print Edition) Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. Distributed in the USA by Fulfilment Center Taylor & Francis 7625 Empire Drive Florence, KY 41042, USA Toll Free Tel.: +1 800 634 7064 E-mail: cserve@routledge_ny.com Distributed in Canada by Taylor & Francis 74 Rolark Drive Scarborough, Ontario M1R 4G2, Canada Toll Free Tel.: +1 877 226 2237 E-mail: [email protected] Distributed in the rest of the world by ITPS Limited Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel.: +44 (0)1264 332424 E-mail: [email protected] Composition by Wearset Ltd, Boldon, Tyne and Wear

579_Stenting_prels

16/8/2001 10:29

Page v

Contents

Preface Contributors 1

2

vii ix

Intracoronary brachytherapy: a new treatment for the prevention of restenosis 1 Alexander J Wardeh, Ken Kozuma, Arie HM Knook, Manel Sabaté, I Patrick Kay, Patrick W Serruys Therapeutic angiogenesis for coronary artery disease 21 Michael JB Kutryk, Saleem A Kassam, Duncan J Stewart

3

Spot stenting 43 Antonio Colombo and Takahiro Nishida

4

Ostial and bifurcation disease 67 Alexander JR Black, Jean Fajadet, Jean Marco

5

Left main disease 83 Alexander JR Black, Jean Fajadet, Jean Marco

6

Small vessel stenting 95 Flavio Airoldi, Carlo Di Mario, Remo Albiero, Antonio Colombo

7

Direct stenting 107 Sanjay Prasad, Ameet Bakhai, Ulrich Sigwart

8

9

Treatment of chronic total coronary occlusions Christopher EH Buller, Jaap N Hamburger

121

In-stent restenosis Raluca Arimie, David P Faxon

131

10 Restenosis, a pragmatic approach David R Holmes

141

11 Percutaneous intervention in acute coronary syndromes Michael J Curran, Cindy L Grines

153

12 Pediatric coronary artery abnormalities and interventions 185 Peter R Koenig, Ziyad M Hijazi 13 Post-angioplasty dissection David Antoniucci

197

14 Alternative imaging J Ligthart, Pim J de Feyter

211

15 Calcified and fibrotic lesions 237 Stefan Verheye, Glenn Van Langenhove, Mahomed Y Salame 16 Ablative techniques 255 Glenn Van Langenhove, Stefan Verheye, David P Foley

v

579_Stenting_prels

16/8/2001 10:29

Page vi

CONTENTS

17 Direct myocardial revascularization: surgical and catheter-based approaches 269 Shmuel Fuchs, Ran Kornowski, Martin B Leon 18 Stent retrieval 283 Antonio Colombo, Goran Stankovic 19 Adjunctive therapies in percutaneous coronary interventions 291 Thaddeus R Tolleson, Eric J Topol, Robert A Harrington

vi

20 Local drug delivery using drug-eluting stents 319 Yanming Huang, Eric Verbeken, Etienne Schacht, Ivan De Scheerder 21 The significance of biochemical markers for myocardial damage in interventional procedures 337 Nicholas M Robinson, Martin T Rothman Index

359

579_Stenting_prels

16/8/2001 10:29

Page vii

Preface

Since the first coronary balloon angioplasty was performed in 1977, enormous progress has been made in the field of interventional cardiology. The concerted efforts of the interventional community have advanced our understanding of the pathophysiology of coronary artery disease and restenosis, and have led to the implementation of new invasive technologies, the introduction of adjunct therapies, improvements in the design of interventional devices, and enhanced operator expertise. With the maturation of interventional cardiology into a discipline, advances in the field have progressed at an accelerated rate. This has resulted in an immense amount of new information, and keeping abreast of new developments can be daunting even for the most well read specialist. Coronary Lesions: A Pragmatic Approach was conceived to provide a comprehensive overview of the field of interventional cardiology. Each chapter focuses on a single important interventional subject, and the book is arranged to provide a practical, user-friendly

reference source for the busy specialist. The chapters were designed to provide a concise review of each topic and are written with a distinct how-to flavor. We hope that this unique format will provide the reader with essential background information with necessary practical tips on all facets of interventional cardiology. The editors are indebted to the contributing authors. They are each leading authorities in interventional techniques, and have done an extraordinary job in synthesizing basic science and clinical information to provide balanced reviews on each topic. The editors would also like to thank Mr Alan Burgess, our commissioning editor, and Ms Charlotte Mossop, project editor, at Martin Dunitz Ltd for their patience, encouragement and expertise. Patrick W Serruys Antonio Colombo Martin B Leon Michael JB Kutryk

vii

579_Stenting_prels

16/8/2001 10:29

Page viii

579_Stenting_prels

16/8/2001 10:29

Page ix

Contributors

Flavio Airoldi, MD

Christopher EH Buller, MD

Cardiac Catheterization Laboratory EMO Centro Cuore Columbus 20145 Milan Italy

Vancouver Hospital and Health Sciences Center Department of Medicine Vancouver BC V5Z 1L8 Canada

Remo Albiero, MD

Antonio Colombo, MD

EMO Centro Cuore Columbus 20145 Milan Italy

Director, Cardiac Catheterization Laboratory EMO Centro Cuore Columbus 20145 Milan Italy

David Antoniucci, MD Division of Cardiology Ospedale di Careggi 85-50134 Florence Italy

Michael J Curran, MD, FACC

Raluca Arimie, MD

Jean Fajadet, MD

University of Southern California Los Angeles CA USA

Unité de Cardiologie Interventionelle Clinique Pasteur 31076 Toulouse France

National Naval Medical Center Bethesda MD 20889–5600 USA

Ameet Bakhai, MBBS, MRCP Clinical Trials and Evaluations Unit Imperial College School of Medicine Royal Brompton Hospital London SW3 6NP UK

David P Faxon, MD

Alexander JR Black, MD

Pim J de Feyter, MD

Department of Cardiology The Geelong Hospital Geelong 3220 Australia

University Hospital-Dijkzigt Thoraxcenter 3000 CA Rotterdam The Netherlands

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

ix

579_Stenting_prels

16/8/2001 10:29

Page x

CONTRIBUTORS

David P Foley

Yanming Huang, MD


Katholieke Universiteit Leuven Campus Gasthuisberg BE-3000 Leuven Belgium

Shmuel Fuchs, MD

Saleem A Kassam, MD, MCE

Director, Interventional Myocardial Angiogenesis Cardiovascular Research Institute Washington Hospital Center Washington DC 20010 USA

Division of Cardiology Terence Donnelly Heart Center St Michael’s Hospital Toronto ON M5B 2W8 Canada

Cindy L Grines, MD, FACC

Department of Interventional Cardiology Thoraxcenter Academic Hospital Rotterdam-Dijkzigt Rotterdam The Netherlands

Division of Cardiology William Beaumont Hospital Royal Oak MI 48073-6769 USA

Jaap N Hamburger, MD, PhD, FESC Director of Research Interventional Cardiology Program St Paul’s Hospital Vancouver BC V6Z 1L7 Canada

Robert A Harrington, MD

I Patrick Kay, MBChB

Arie HM Knook, MD Department of Interventional Cardiology Thoraxcenter Academic Hospital Rotterdam-Dijkzigt Rotterdam The Netherlands

Peter R Koenig, MD

Duke Clinical Research Institute Durham NC 27707 USA

Assistant Professor of Clinical Pediatrics University of Chicago Children’s Hospital Chicago IL 60637 USA

Ziyad Hijazi, MD

Ran Kornowski, MD, FACC

Chief, Section of Pediatric Cardiology The University of Chicago Children’s Hospital Chicago IL 60637 USA

Director, Interventional Cardiology Rabin Medical Center Petach Tikva 49100 Israel

David R Holmes Jr, MD

Ken Kozuma, MD

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


x

579_Stenting_prels

16/8/2001 10:29

Page xi

CONTRIBUTORS

Michael JB Kutryk, MD, PhD

Sanjay Prasad, BSc, MBChB, MRCP, MD


Royal Brompton Hospital London SW3 6NP UK

Glenn van Langenhove, MD Middelheim Hospital 2020 Antwerp Belgium

Martin B Leon, MD

Nicholas M Robinson, MA, MD, MRCP Consultant Cardiologist London Chest Hospital London E2 9JX UK

Martin T Rothman, MB, ChB, FRCP, FACC, FESC

Director and CEO, Cardiovascular Research Foundation Lenox Hill Heart and Vascular Institute New York NY 10021 USA

Consultant Cardiologist London Chest Hospital London E2 9JX UK

J Ligthart



Jean Marco, MD Unité de Cardiologie Interventionelle Clinique Pasteur 31076 Toulouse France

Carlo Di Mario, MD Director of Research EMO Centro Cuore Columbus 20145 Milan Italy

Manel Sabaté, MD

Mahomed Y Salame, MRCP Andreas Grüntzig Cardiovascular Center Emory University Hospital Atlanta GA 30322 USA

Etienne Schacht, PhD Department of Organic Chemistry University of Ghent BE-9000 Ghent Belgium

Ivan De Scheerder, MD, PhD Takahiro Nishida, MD Research Fellow EMO Centro Cuore Columbus 20145 Milan Italy

Professor, Invasive Cardiology Katholieke Universiteit Leuven Campus Gasthuisberg BE-3000 Leuven Belgium

xi

579_Stenting_prels

16/8/2001 10:29

Page xii

CONTRIBUTORS

Patrick W Serruys, MD, PhD, FACC, FESC Head, Interventional Cardiology Catheterization Laboratory Thoraxcenter Academic Hospital Rotterdam-Dijkzigt 3015 GD Rotterdam The Netherlands

Ulrich Sigwart, FRCP, FESC, FACC Consultant Cardiologist Royal Brompton National Heart & Lung Hospital London SW3 6NP UK

Eric J Topol, MD Department of Cardiology The Cleveland Clinic Foundation Cleveland OH 44195-0001 USA

Eric Verbeken, MD, PhD Department of Histopathology Katholieke Universiteit Leuven Campus Gasthuisberg BE-3000 Leuven Belgium

Stefan Verheye, MD

Research Fellow EMO Centro Cuore Columbus 20145 Milan Italy

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

Duncan J Stewart, MD

Alexander J Wardeh, MD



Goran Stankovic

Thaddeus R Tolleson, MD Division of Cardiology Duke University Medical Center Durham NC 27715 USA

xii

579_Stenting_ch.01

14/8/2001 13:48

Page 1

1 Intracoronary brachytherapy: a new treatment for the prevention of restenosis Alexander J Wardeh, Ken Kozuma, Arie HM Knook, Manel Sabaté, I Patrick Kay, Patrick W Serruys

Introduction Percutaneous transluminal coronary angioplasty (PTCA) is an accepted treatment for coronary artery disease.1 However, angiographical restenosis is reported in 30–60% of patients after a successful PTCA.1–3 The main mechanisms of restenosis include acute elastic recoil of the vessel, late constriction of the arterial wall (negative remodeling), and neointimal hyperplasia.4–8 Neointimal hyperplasia develops by migration and proliferation of smooth muscle cells and myofibroblasts after balloon-induced trauma of the arterial wall and by deposition of an extracellular matrix by the smooth muscle cells.7,9–11 The restenosis rate has been reduced to 15–20% by stent implantation,3,12 by preventing elastic recoil and negative remodeling.13 However, the occurrence of restenosis after stent implantation remains unresolved, especially in small vessels and long lesions, where it may take place in more than 30% of the cases.14 It is primarily caused by neointimal hyperplasia, which occurs due to trauma of the arterial wall by the stent struts.6 The treatment of in-stent restenosis with conventional techniques (balloon angioplasty or debulking) is rather disappointing, with restenosis rates of 27–63%, which increase with the number of re-interventions.15–19 The term brachytherapy is used to describe intracavitary or interstitial radiation therapy.20 Recently, the term vascular brachytherapy has been introduced to describe endovascular radiation therapy. Vascular brachytherapy with a radio-

active source after PTCA or stent implantation is a promising treatment that might reduce restenosis by inhibition of neointimal hyperplasia21–23 and constrictive remodeling24,25 after percutaneous intervention.

Rationale Radiotherapy can successfully treat hypertrophic scars, keloids, heterotopic bone formation after total hip replacement, ophthalmic pterygia and solid malignancies. Usually, radiation doses of 7–10 Gy are used to treat these benign diseases, thereby efficiently inhibiting fibroblastic activity without influencing the normal healing process, and without causing significant morbidity during long-term follow-ups of up to 20 years.26–28 Vascular brachytherapy, using radiation doses of 12–20 Gy, appears to be efficacious in preventing restenosis by inhibiting neointimal formation22,29–31 and by increasing lumen diameters (positive remodeling).22,32–34

History In 1964, Friedman35 reported on the first in vivo use of intravascular radiotherapy. The first clinical trial, treating 30 patients with gamma (192Ir) endovascular radiotherapy for the treatment of in-stent restenosis of femoropopliteal arteries, was started in 1990 by Liermann.23 A reduced restenosis rate was observed without short- or long-term (5-year follow-up) complications. In

1

579_Stenting_ch.01

14/8/2001 13:48

Page 2

INTRACORONARY BRACHYTHERAPY

1995, Popowski36 reported on the first centering catheter, used in vascular brachytherapy with beta radiation to give a more homogeneous dose distribution to the vessel wall. In 1997, Condado37 treated 21 patients with de novo coronary lesions with angioplasty followed by intracoronary brachytherapy, using 192Ir. A restenosis rate of 27% was observed at 6-month follow-up. Also, due to the high prescribed dose, the first occurrence of a pseudoaneurysm after vascular brachytherapy was reported. Later in 1997, Teirstein38 reported on the first randomized double-blind placebo-controlled intracoronary brachytherapy trial, showing safety and efficacy of gamma (192Ir) radiation for the treatment of in-stent restenosis. Currently, multiple brachytherapy trials are either completed, ongoing or will be started shortly. An overview of brachytherapy trials is given in Table 1.1.

Physics Radioactivity is the process in which an unstable nucleus, which has either too many or too few neutrons, changes to a stable state (ground state). When it reaches the stable state, the basic element itself has changed, and this is known as radioactive disintegration or radioactive decay. The stable state is reached by -particle emission, -particle emission or electron capture (Figure 1.1). -Particles are heavyweight charged particles which can travel very short distances within tissues. -Particles are lightweight highenergy electrons, with either positive or negative charge. When -particles, which can travel only finite distances within tissues, are slowed down by nuclear interactions, they give rise to highpenetration X-rays, called Bremsstrahlung. -Rays are photons originating from the center of the nucleus, and take the form of electromagnetic radiation. Most often, an unstable nucleus will emit an - or -particle followed by -radiation. Only a few radioisotopes, e.g. phosphorus32 (a pure -emitter) emit particles without -radiation. -Rays may have either one or two

2

discrete energy values or a broad spectrum of many energy values. They penetrate deeply within tissues.39–41 When reaching a stable state by electron capture, the nucleus captures an electron from the innermost (closest to the nucleus) orbit, thereby making the outer shell with electrons unstable. To fill the gap left by the captured electrons, electrons from the outer orbit jump to the innermost orbit, which also leads to the emission of photons, called X-rays, which take the form of electromagnetic waves. -Rays and X-rays are both high-energy photons, without charge or mass. The only difference between -rays and X-rays is in their origin. Visible light waves and radiowaves are low-energy photons.39

Radiobiology When radiation is absorbed in a tissue, it can either cause direct damage to a critical target by ionization or it can indirectly damage a critical target by interacting with other molecules to produce free radicals, which will subsequently damage the critical target. Approximately 80% of the radiation damage is caused by these free radicals. Clearly, the most critical target that could be damaged by radiation is DNA. A consequence of this damage is that the cell will lose its ability to proliferate, which will ultimately lead to its death. Early and late toxic effects in normal tissue are mainly caused by cell death.39,42 There are several hypotheses explaining how radiation therapy could inhibit neointimal proliferation and thereby prevent restenosis: • Radiation might cause the inactivation of all target smooth muscle cells and myofibroblasts, while the surviving endothelial cells would repopulate and reline the artery. If this is true, smooth muscle cells should be more radiosensitive than endothelial cells. However, experimental evidence suggests no differences in the radiosensitivity of smooth muscle cells and endothelial cells.31,43

579_Stenting_ch.01

14/8/2001 13:48

Page 3

RADIOBIOLOGY

Study

No. of patients

Dose (Gy)

Lesion criteria

Lesion length (mm)

Source

Sponsor

ARREST ARTISTIC BERT BERT 1.5 Betacath BetaWRIST BETTER BRIDGE BRIE Compassionate use Rotterdam CURE Dose Finding GAMMA-1 GAMMA-2 GAMMA-3 Geneva GRANITE INDIRA

50 50 20 31 1456 50 150 100 13 22

8, 35a 12, 15, 18b 12, 14, 16c 12, 14, 16b 0, 14, 18b 20.6d 20d 0, 20c 14, 18b 16, 20b

De novo In-stent restenosis De novo De novo De novo, restenotic In-stent restenosis De novo, restenotic De novo De novo, restenotic In-stent restenosis

25 25 15 20 20 47 25 15 20 30

192

Ir Ir Sr/90Y Sr/90Y Sr/90Y 90 Y 32 P 32 P Sr/90Y Sr/90Y

Vascular therapies Vascular therapies Novoste Novoste Novoste Boston Scientific Radiance Guidant Novoste Novoste

30 181 252 125 280 15 100 800

20e 9, 12, 15, 18d 0, 8–30f 14b 14b 18d 14b 0, 11g

22 15 45 45 45 29 45 30

188

Re Y Ir 192 Ir 192 Ir 90 Y 192 Ir 192 Ir

Columbia University Schneider Cordis Cordis Cordis Schneider Cordis Cordis

INHIBIT IRIS LongWRIST MARS PERTH PREVENT

360 37 120 35 100 37

0, 20c 5–12h 0, 15b 20 Gyc 18d 0, 28, 35, 42c

44 28 80 20 20–80 22

32

P P Ir 188 Re 188 Re 32 P

Guidant Isostent Cordis Mallinckrodt Royal Perth Hospital Guidant

P32 Dose Response P32 Dose Response Cold Ends P32 Dose Response Hot Ends Radiation Stent Safety Trial RENO

162

45–92h

28

32

Isostent

50

h

22–92

De novo De novo In-stent restenosis In-stent restenosis In-stent restenosis De novo In-stent restenosis De novo, in-stent restenosis In-stent restenosis De novo, restenotic In-stent restenosis De novo In-stent restenosis De novo, restenotic in-stent restenosis De novo, restenotic, in-stent restenosis De novo, restenotic

15

32

Isostent

50

71–126h

De novo, restenotic

15

32

Isostent

30

52–106h

De novo, restenotic

13

32

SCRIPPS-1 SCRIPPS-2 SCRIPPS-3 SMARTS START START 40/20 SVG WRIST Venezuela WRIST

1000 55 100 500 180 476 206 120 21 130

b

14–20 16–22b 0, 8–30f 0, 8–30f 0, 14b 12b 0, 16, 20b 16, 20b 0, 15b 19–55i 0, 15b

De novo, restenotic, In-stent restenosis Restenotic In-stent restenosis In-stent restenosis De novo In-stent restenosis In-stent restenosis SVG De novo, restenotic In-stent restenosis

192

90

192

32

192

P P

P

P

ACS 90

Not limited

Sr/ Y

Novoste

30 65 81 25 20 20 45 30 47

192

Cordis Cordis Cordis Vascular therapies Novoste Novoste Cordis Non-commercial Cordis

Ir Ir Ir 192 Ir Sr/90Y Sr/90Y 192 Ir 192 Ir 192 Ir 192 192

a With intravascular ultrasound guidance. b At 2 mm from the source. c At 0.5 mm into the vessel wall. d At 1 mm from balloon surface. e At media. f To EEM. g At 3 mm from the source.h Cumulative dose over 100 days delivered to 1-mm depth outside the stent surface. i At 1.5 mm from the source.

Table 1.1 Intracoronary brachytherapy trials.

3

579_Stenting_ch.01

14/8/2001 13:48

Page 4


-particle

241

Am

237

Np

A

Electron (-particle)

3

H

3

He

B

Photon (-particle)

3

He

3

He

C

Figure 1.1 Production of radioactivity. (A) Example of -radiation: unstable nuclear core (left illustration) turns into a stable core by emitting an -particle (right illustration). (B) Example of -radiation: unstable nuclear core (left illustration) turns into a stable core by emitting a -particle (right illustration). (C) Example of -radiation: unstable nuclear core (left illustration) turns into a stable core by emitting a -particle (right illustration).

previous trials is that doses of more than 20 Gy are required to completely eliminate the smooth muscle cell population, which could result in late complications (e.g. the development of aneurysms).31,37,38 • Lower doses (20 Gy) are less likely to result in late complications. Consequently, restenosis may only be delayed for the period of time necessary for the population of smooth muscle cells to regenerate. If this were true, a delayed restenosis of 1–3 years would be expected.31 Additional evidence for this theory comes from a clinical trial23 where 12 Gy was prescribed to prevent restenosis in femoral arteries. No stenoses were seen after 3–27 months of follow-up;45 however, 16% restenosis was seen after prolonged followup.46

Brachytherapy devices and used isotopes Vascular brachytherapy can be performed by catheter-based systems, radiation balloons (both high dose rate) or radioactive stents (low dose rate). Among high-dose--emitting rate devices are (192Ir) or -emitting (32P, 90Sr, 90Y) seeds or wires and temporary filling of a dilatation balloon catheter with a high-activity -emitting solution (radionuclide liquid 188Re or 186Re, or 133 xenon gas.40 For an overview of the brachytherapy devices currently used in patients, see Table 1.2. For an overview of the used isotopes, see Table 1.3.

Dosimetry • Radiation could cause a large amount of potentially proliferating and migrating smooth muscle cells to either lose their ability to proliferate or to perish. In this way, the remaining proliferating cells are too few to cause restenosis, especially when taking into account the fact that cells have a finite proliferative capacity.44 What can be learned from

4

Vascular brachytherapy requires accurate knowledge of the dose delivered at 0.5–5 mm from the radioactive source. The treated coronary artery segment is usually 2–5 cm in length, with a diameter of 3–5 mm and a vessel wall thickness of 0.5–3 mm. The radiation dose given to the vessel wall should probably target the media as well as the adventitia.40,47,48

Wire Liquid-filled balloon Seeds Wire Wire Liquid-filled balloon Stent

X-ray device Stent Balloon Seeds Liquid-filled balloon

Ir Re

Sr/90Y P 32 P 188 Re 32

90

Y

X-ray 32

Novoste Nucletron/Guidant Guidant Radiant ACS Schneider/Boston Scientific Interventional Innovations Corporation Isostent Radiance Cordis Mallinckrodt

Table 1.2 Brachytherapy devices.

Beta-stent RDX Radiation Delivery System Gamma IRT Delivery System Liquid-filled balloon 32

P P 192 Ir 186 Re

P

32

188

192

Wire

Seed ribbon

Manual Manual Manual Manual

Automated

Afterloader

Manual

Hydraulic Afterloader Afterloader Manual

Manual Manual

Manual

Delivery

Yes Yes No Yes

No

Yes

Yes

Yes Yes Yes Yes

No Yes

No

Centering

14/8/2001 13:48

Angiorad System Solution-Applied Beta Emitting Radioisotope (SABER) System Beta-Cath System Nucletron Coronary System Galileo System Isolated Liquid Beta Source Balloon Radiation Delivery System Multi-link RX Radiation Coronary Stent System Schneider–Sauerwein Intravascular Radiation System Soft X-ray System

Ir

192

Best Medical International/Cordis Vascular Therapies Columbia University

The 192Ir Radioactive seed ribbon

Source information

Manufacturer

Radiation device

579_Stenting_ch.01 Page 5

5

579_Stenting_ch.01

14/8/2001 13:48

Page 6


Isotope

Emission

Maximum energy

Half-life

192

Ir Sr/90Y 90 Y 32 P 188 Re 186 Re 188 W/Re 133 Xe 131 I

,

74 days 28.6 years 64 h 14.3 days 17 h 90.6 h 69.4 days 5.25 days 8.04 days

99m

612 keV 2.28 MeV 2.28 MeV 1.71 MeV 2.12 MeV 1.08 MeV 2.12 MeV 0.35 MeV 0.81 MeV () 723 keV () 140 keV

90

Tc

6.02 days

Table 1.3 Isotopes used for intracoronary brachytherapy.

Ideally, the dose distribution should be given to the area injured by balloon angioplasty, while keeping the dose to the surrounding tissues as low as possible. Irradiation times should be less than 10 min to minimize the risk of acute thrombosis and other coronary complications during treatment. This would require either highactivity -sources (100 mCi activity), introducing safety issues for both patient and personnel, or -sources of 10–100 mCi. The radiation source should have dimensions, stiffness and flexibility compatible for use in complex coronary lesions. From a cost-effectiveness point of view, the used radioisotope, when using a catheter-based system, should have a sufficiently long half-life so that it may be used during several treatments over a long period of time.39,40 Not only the total radiation dose, but also the dose rate, is important, since damage caused by radiation can be repaired between fractionated doses or during low-dose-rate exposure. Therefore, the dose rate effect should be accounted for when comparing results of treatments using high dose rates with those of treatments using low dose rates. Cell death is markedly demonstrated in vitro at dose rates between 1 and 100 cGy/min.49,50 Curiously, an in vitro experi-

6

ment with human cells has shown that a dose rate of 0.6 cGy/min causes more cell death than 0.2 or 2.6 cGy/min. The explanation given for this inverse dose rate effect is that continuous irradiation at a dose rate of approximately 0.6 cGy/min effectively blocks cells in the mitosis (G2) phase of the cell cycle, which is known to be more radiosensitive, thereby causing more cell death.39

Centering versus noncentering A more homogeneous dose distribution is obtained by centering the radiation source with a balloon catheter (Figure 1.2). However, even with a centered source, eccentric intraluminal positioning (caused by, for example, an angulated lesion or a heavily calcified plaque) will result in areas of both relative underdose and overdose. Another example: if an artery has a curvature radius of 1 cm, the dose along the concave curvature of the artery will be 10–15% higher compared to the convex curvature, since the source will be closer to the concave curvature.39,51 This could become clinically important,

579_Stenting_ch.01

14/8/2001 13:48

Page 7

-RADIATION VERSUS -RADIATION

A

B

Figure 1.2 Dose distribution differences in centered versus non-centered sources. A centered source (A) delivers a more homogenous dose to the vessel wall compared to a non-centered source (B).

since low doses may stimulate neointimal proliferation,32,52 and high doses can give rise to the development of aneurysms.37

-Radiation versus -radiation From a radiobiological point of view, it is unimportant whether -radiation, -radiation or X-radiation is used. An equal dose, given to the same location at an equal dose rate, will lead to an equal biological effect.53 -Radiation has the following advantages. It deeply penetrates into the tissue, making it ideal for the treatment of large vessels (Figure 1.3). -Radiation is not shielded by stents, making it ideal for the treatment of in-stent restenosis. The most important advantage of -therapy is that it is the first treatment showing a reduction of restenosis in several large randomized, doubleblind, placebo-controlled trials (Table 1.4). The disadvantages of -therapy are as follows.

-Rays penetrate through normally used lead shields. A 1-inch lead shield is required to block the -rays. When high-energy -radiation is used, all ‘unnecessary’ personnel must leave the catheterization laboratory in order to limit their exposure to radiation. Overall, the patient and personnel receive higher radiation doses from a -radiation procedure in comparison to a -radiation procedure. This problem of radiation exposure limits the maximal specific activity used for -therapy. Lower specific activities, however, result in longer dwell times (8–20 min) to achieve the same therapeutic doses, making total procedure times longer, which in turn increases the risk of cardiac events.40,54 The advantages of -radiation are as follows. Thick plastic is able to shield -energy. Since -radiation only penetrates a few millimeters into the surrounding area, exposure to -energy is limited. Therefore, higher specific activities can be used, making dwell times shorter (3–10 min) and total procedure times shorter. Additional radiation exposure to the patient and personnel

7

579_Stenting_ch.01

14/8/2001 13:48

Page 8


16 Gy

8Gy

A

recently reported55 (JJ Popma ACC2000 presentation, stent versus directional coronary atherectomy randomized (START) trial), its efficacy for de novo or restenotic lesions remains to be proven by a randomized, double-blind, placebocontrolled trial. Owing to the steeper depth–dose fall-off curve, -energy will probably not be able to treat vessels with diameters 4 mm and/or will require centering devices to ensure homogenicity of the dose (Figures 1.2 and 1.3). -Energy has also been shown to be partially shielded by stents and calcified plaques, which may require an increase in the prescribed dose of up to 20%. Finally, dose distribution calculations of -emitters are more complicated than those of -emitters.40,54,56 While working with -radiation is obviously easier, -radiation has been used for several years without causing significant problems.40,54

Radioactive stents

B

8Gy

16Gy

Figure 1.3 Example of the differences of isodose contours of - and -radiation. With -radiation (B) the minimum effective dose of 8 Gy (dark grey arrow), inhibiting neointimal proliferation, extends further into the surrounding tissue, compared to -radiation (A). Therefore, -radiation is preferable to -radiation in large coronary vessels.

is negligible. Healthcare personnel can therefore remain in the catheterization laboratory. -Therapy also has disadvantages. While results from clinical trials (Table 1.5) are encouraging, and its efficacy for in-stent restenosis has been

8

One of the advantages of a -particle-emitting radioactive stent is that the radioactive source is centered and in close contact with the vessel wall. Another advantage is the short procedure time, since the implantation time of a radioactive stent is equal to that of a non-radioactive stent. The dose distribution, however, will not be uniform, given the gridded structure of the stent and the concomitant inhomogeneous distribution of the radioactive source.39 This might not be a problem if the concept of an electron-beam fence is true.57 According to this concept, the radiation emitted by the stent generates a fence at the endoluminal surface, which prevents smooth muscle cells and myofibroblasts from migrating into the stent.58 The results of the clinical data so far are rather disappointing, with restenosis rates of up to 52% (Table 1.6).59–61 While strict in-stent restenosis is observed to decrease with increasing levels of radiation doses, edge restenosis is the main cause of target lesion revascularization at high dose levels (Figure 1.4).60,61 This edge restenosis is probably caused by a combination

579_Stenting_ch.01

14/8/2001 13:48

Page 9

RADIOACTIVE STENTS

Study

No. of patients

SCRIPPS

Gy

8–30a

53

Lesion length (mm)

Source

Restenosis rate

MACE

30

192

17 54 22 60 46 78 33 55 34

15 48 35 68 NA NA 28 44 30

WRIST

130

15b

47

Long WRIST

120

15b

36–80

GAMMA-1

252

GAMMA-2

125

8–30a

Ir Placebo 192 Ir Placebo 192 Ir Placebo 192 Ir Placebo 192 Ir

45 45

14b

MACE, major cardiac events; NA, not available. a To EEM. b Dose at 2 mm from the source.

Table 1.4 Results of placebo-controlled -radiation trials at 6-month follow-up.

Study

Geneva BERT BERT 1.5 Beta WRIST

No. of patients 15 20 35 50

Gy

Lesion length (mm)

Source length (mm)

Source

Restenosis rate

MACE

18a 12, 14, 16b 12, 14, 16b 20.6c

20 15 20 47

29 30 30 29

90

14, 18b 20 9, 12, 15, 18c 15

30 29

16, 20, 24d

22

27

40 15 11 34 71 34 9 26 22 50 29 45 53

33 15 9 34 76 34 16 13 26 32 18 25.9 47

BRIE Dose Finding Study PREVENT

149 181

START

396

18, 20b

20

30

18

16, 20b

30

30

Compassionate use Rotterdam

96

Y Sr/90Y Sr/90Y 90 Y Placebo Sr/90Y 90 Y 9 Gy 90 Y 18 Gy 32 P Placebo Sr/90Y Placebo Sr/90Y

MACE, major cardiac events. a Dose at the inner arterial surface. b Dose at 2 mm from the source. c Dose at 1 mm from balloon. d Dose at 1 mm into vessel wall. 50 placebo patients from WRIST.

Table 1.5 Results of -radiation trials at 6-month follow-up.

9

579_Stenting_ch.01

14/8/2001 13:48

Page 10


Study

No. of patients

IRIS 1A IRIS 1B IRIS Heidelberg IRIS Rotterdam P32 Dose Response Rotterdam P32 Dose Response Milan

32 25 11 26 40 23 29 30 40

Stent activity (µCi)

Lesion length (mm)

Restenosis rate

TLR

0.5–1.0 0.75–1.5 1.5–3.0 0.75–1.5 6.0–12

15 15 15 28 28

31 50 54 17 44

21 32 NA 12 25

0.75–3.0 3.0–6.0 6.0–12 12–21

28

52 41 50 30

52 41 50 30

NA, not available; TLR, target lesion revascularization.

Table 1.6 Results of 32P radioactive stents at 6-month follow-up.

of balloon trauma and low-dose radiation at the stent edge, so geographical miss occurs in all cases. Since geographical miss has been shown to be one of the determinants of edge restenosis,62 future therapies will concentrate on the prevention of geographical miss by minimizing trauma and/or increasing radiation dose at the edges. Several new therapies are currently under investigation. Square-shouldered balloons, used for stent deployment, in which the entire balloon remains within the stent, will minimize barotrauma at the proximal and distal edges. Cold end stents, in which the center of the stent is made radioactive, while the proximal and distal 5 mm of the stent edges are non-radioactive, may decrease edge restenosis, if this restenosis is caused by negative remodeling. Another option is the implantation of hot end stents, in which the stent edges are made more radioactive compared to the center of the stent, thereby decreasing the chance of geographical miss.

Limitations of brachytherapy Unfortunately, vascular brachytherapy has its limitations, which include the following:

10

• Low radiation doses (4–8 Gy) may stimulate neointimal proliferation.52,63 This could be due to the fact that growth factors are synthesized de novo and secreted by surviving cells.64 These growth factors promote the proliferation of smooth muscle cells.65 • Delayed depletion of some cells (adventitial cells, fibroblasts) could lead to subsequent repopulation, whereby smooth muscle cells from the media could be progressively replaced by fibroblasts and extracellular matrix, leading to fibrosis, as has been previously described in animal experiments.22,29 • Persisting dissections after -radiation have been observed at 6-month angiographical follow-up66,67 (Figure 1.5). • Geographical miss, where the injured area is not completely covered by the irradiated area, is a major cause of edge restenosis (Figure 1.6). The incidence of geographical miss ranges from 18% to 34%. In cases of geographical miss, a restenosis rate of 39% was seen, versus 9% when there was no geographical miss.68 Geographical miss increases the chance of restenosis rate up to four fold. Edge restenosis has been observed at the edges of

579_Stenting_ch.01

14/8/2001 13:49

Page 11

LIMITATIONS OF BRACHYTHERAPY

A

Figure 1.4 Example of edge restenosis. At 6-month angiographic follow-up, a radioactive stent (proximal and distal ends marked by the dotted lines) shows an excellent result. However, at the proximal edge, a severe edge restenosis (arrow) is observed.

B the treated area. It appears to occur when the area injured by the balloon is larger than the irradiated area69 (Figure 1.7). • Mid-term (2–3-year) follow-up indicates signs of delayed rather than inhibited restenosis70–72 (Figures 1.8 and 1.9) • Black holes are observed in 22–39% of cases at 6-month intravascular ultrasound (IVUS) follow-up of the cases at the Thoraxcenter. They are called black holes because they are

Figure 1.5 Example of a persisting dissection. (A) Post-procedure, a dissection (arrow) is observed by intravascular ultrasound. (B) At 2-year follow-up, the dissection (arrow) remains unhealed.

11

579_Stenting_ch.01

14/8/2001 13:49

Page 12


Proximal gold marker

Distal gold marker 30-mm RST

A Fully irradiated segment B

C D E

Injured area

Injured area Injured area Injured area

Geographical miss segments

Figure 1.6 Explanation of geographical miss. (A) A radiation source train (RST) of 30-mm length. Because of the dose fall-off at both ends, the fully irradiated segment is smaller than the total length of the source train. (B) No geographical miss: the injured area is fully covered by the RST. (C) Proximal geographical miss: the injured area is proximal and not covered by the RST. (D) Distal geographical miss: the injured area is distal and not covered by the RST. (E) Proximal and distal geographical miss: the injured area is both proximal and distal, and not covered by the RST.

echolucent on IVUS. Pathology reveals smooth muscle cells in the extracellular matrix containing abundant proteoglycans and an absence of elastin and mature collagen. Sixty per cent of the black hole cases have angiographic restenosis. Whether these limitations will reduce the use of brachytherapy remains unknown.

12

Figure 1.7 Example of proximal and distal geographical miss, resulting in a candy wrapper edge restenosis (arrows) at 6-month follow-up.

Safety issues of brachytherapy Work with radiation therapy must be performed with extreme care, because of the following safety issues: • The risk of perforation will probably be small, especially when keeping the dose delivered to the adventitia low.30 • Aneurysm formation (Figure 1.10) seems to be dose related and has been observed in patients receiving high radiation doses of up to 92 Gy.37 However, in other trials,30,46,73–75 using lower doses of up to 30 Gy, no excessive aneurysm formation has been observed. • A dose-dependent delay in endothelialization of the stent has been shown, which might increase the chance of subacute thrombo-

579_Stenting_ch.01

14/8/2001 13:49

Page 13

SAFETY ISSUES OF BRACHYTHERAPY

Change in MLD 3 2.68 2.49

2.5

2.12 1.97

mm

2

1

1.68

1.77

1.5 1.14 0.98

0.5 0 Pre

Post

6-month

Condado

3-year

SCRIPPS

A

A Long-term follow-up WRIST Trial 70

63.1

63.1

63.1

60 50 40 % 30 20

23.1

26.2

13.8

10 0 6-month

2-year

1-year 192

Ir

Placebo

B Figure 1.8 Indications of delayed, rather than inhibited, restenosis after intracoronary brachytherapy. (A) Both the Condado and the SCRIPPS trial show a continuing loss of MLD, after 6-month followup. (B) During 2-year follow-up, the restenosis rate remains stable at 65.1% in the placebo group, while it increases from 13.8% to 26.2% in the irradiated group.

B Figure 1.9 Example of delayed restenosis. (A) Good angiographic result, 6 months after intracoronary brachytherapy. (B) In the same patient, 16 months after treatment, a severe candy wrapper edge restenosis is observed.

13

579_Stenting_ch.01

14/8/2001 13:49

Page 14


• High doses of radiation (35 Gy) applied to larger tissue areas, used for the treatment of neoplasms, result in accelerated coronary artery disease.79–81 Intermediate doses (30–40 Gy) have shown a low risk of cardiac disease during long-term follow-up (mean 11 years).82 • Radiation-induced carcinogenesis is of great concern; however, since irradiation delivers an extremely low dose beyond the immediate lesion, and the exposed tissues (e.g. arteries, veins, cardiac muscle, and pericardium) have a low spontaneous carcinogenicity rate, this risk appears to be extremely low.30,75 The safety of radiation therapy for benign diseases has been confirmed for periods of more than 20 years.26 Also, the safety of peripheral vascular brachytherapy during a 6-year followup has been reported.46 Recently, the 2-year follow-up of patients treated with intracoronary brachytherapy has shown no signs of late clinical effects.30

Figure 1.10 Example of a coronary aneurysm (arrow), 6 months after intracoronary brachytherapy.

sis.29,76 Also, in patients treated by catheterbased brachytherapy, with and without stent implantation, late thrombotic occlusions, with an incidence of up to 11%, have been observed.77 Therefore, all patients treated with coronary brachytherapy should receive either ticlopidine or clopidogrel for at least 6 months and aspirin indefinitely. • Vessel enlargement (positive remodeling) due to brachytherapy can induce late stent malapposition, which may result in late stent thrombosis,78 which is another reason for prolonged, or even lifelong, antiplatelet therapy.

14

Indications Intracoronary brachytherapy should be given to patients at high risk of developing restenosis. Therefore, brachytherapy should be given to patients with: • in-stent restenosis • long lesions • multivessel disease • saphenous vein graft lesions • small coronary artery lesions • diabetic disease • renal insufficiency.

Contraindications Intracoronary brachytherapy should not be given if the patient has a high risk of receiving a toohigh cumulative dose at the vessel wall. This is

579_Stenting_ch.01

14/8/2001 13:49

Page 15

CONCLUSION

possible in patients with: • previous radiotherapy of the chest • previous intracoronary brachytherapy, in case of previous -irradiation, or previous brachytherapy of the treated vessel segment, in case of previous -irradiation.

Conclusion Intracoronary brachytherapy is a promising new therapy for the treatment of in-stent restenosis. Whether it may also prevent restenosis after balloon angioplasty for de novo or restenotic lesions will be known by the end of the year 2000, when the 6-month angiographical followup data of current ongoing trials will be available. Long-term clinical and angiographical follow-up is also necessary, to ensure long-term safety and efficacy.

15

579_Stenting_ch.01

14/8/2001 13:49

Page 16


References

1. Holmes DR Jr, Vliestra 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(12):77C–81C. 2. Serruys PW, Luijten 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(2):361–371. 3. 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. Benestent Study Group. N Engl J Med 1994; 331(8):489–495. 4. Mintz GS, Pichard AD, Kent KM et al. Intravascular ultrasound comparison of restenotic and de novo coronary artery narrowings. Am J Cardiol 1994; 74(12): 1278–1280. 5. Currier JW, Faxon DP. Restenosis after percutaneous transluminal coronary angioplasty: have we been aiming at the wrong target? J Am Coll Cardiol 1995; 25(2):516–520. 6. Mintz GS, Popma JJ, Pichard AD et al. Arterial remodeling after coronary angioplasty: a serial intravascular ultrasound study. Circulation 1996; 94(1):35–43. 7. Nobuyoshi M, Kimura T, Ohishi H et al. Restenosis after percutaneous transluminal coronary angioplasty: pathologic observations in 20 patients. J Am Coll Cardiol 1991; 17(2):433–439. 8. Serruys PW, Emanuelsson H, van der Giessen W et al. Heparin-coated Palmaz–Schatz stents in human coronary arteries. Early outcome of the Benestent-II Pilot Study. Circulation 1996; 93(3):412–422. 9. MacLeod DC, Strauss BH, de Jong M et al. Proliferation and extracellular matrix synthesis of smooth muscle cells cultured from human

16

10.

11. 12.

13.

14.

15.

16.

17.

18.

coronary atherosclerotic and restenotic lesions. J Am Coll Cardiol 1994; 23(1): 59–65. Guarda E, Katwa LC, Campbell SE et al. Extracellular matrix collagen synthesis and degradation following coronary balloon angioplasty. J Mol Cell Cardiol 1996; 28(4): 699–706. Hamon M, Bauters C, McFadden EP et al. Restenosis after coronary angioplasty. Eur Heart J 1995; 16(suppl I):33–48. 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. Stent Restenosis Study Investigators. N Engl J Med 1994; 331(8):496–501. Haude M, Erbel R, Issa H, Meyer J. Quantitative analysis of elastic recoil after balloon angioplasty and after intracoronary implantation of balloon-expandable Palmaz–Schatz stents. J Am Coll Cardiol 1993; 21(1):26–34. Dussaillant GR, Mintz GS, Pichard AD et al. Small stent size and intimal hyperplasia contribute to restenosis: a volumetric intravascular ultrasound analysis. J Am Coll Cardiol 1995; 26(3):720–724. Lau KW, Ding ZP, Johan A et al. Angiographic restenosis rate in patients with chronic total occlusions and subtotal stenoses after initially successful intracoronary stent placement. Am J Cardiol 1999; 83(6):963–965, A9–A10. Sharma SK, Duvvuri S, Dangas G et al. Rotational atherectomy for in-stent restenosis: acute and long-term results of the first 100 cases. J Am Coll Cardiol 1998; 32(5):1358–1365. Eltchaninoff H, Koning R, Tron C et al. Balloon angioplasty for the treatment of coronary in-stent restenosis: immediate results and 6-month angiographic recurrent restenosis rate. J Am Coll Cardiol 1998; 32(4):980–984. Dauerman HL, Baim DS, Cutlip DE et al. Mechanical debulking versus balloon angioplasty for the treatment of diffuse in-stent restenosis. Am J Cardiol 1998; 82(3):277–284.

579_Stenting_ch.01

14/8/2001 13:49

Page 17

REFERENCES

19. Bauters C, Banos JL, Van Belle E et al. Sixmonth angiographic outcome after successful repeat percutaneous intervention for in-stent restenosis. Circulation 1998; 97(4):318–321. 20. Hall EJ. Radiobiology for the radiologist, 4th edn. Philadelphia: JB Lippincott Company, 1994. 21. 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(10):3025–3031. 22. Wiedermann JG, Marboe C, Amols H et al. Intracoronary irradiation markedly reduces neointimal proliferation after balloon angioplasty in swine: persistent benefit at 6-month follow-up. J Am Coll Cardiol 1995; 25(6):1451–1456. 23. Liermann D, Bottcher HD, Kollath J et al. Prophylactic endovascular radiotherapy to prevent intimal hyperplasia after stent implantation in femoropopliteal arteries. Cardiovasc Intervent Radiol 1994; 17(1):12–16. 24. Waksman R, Rodriguez 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 1997; 96(6): 1944–1952. 25. Sabate M, Serruys PW, van der Giessen WJ et al. Geometric vascular remodeling after balloon angioplasty and beta-radiation therapy: a three-dimensional intravascular ultrasound study. Circulation 1999; 100(11):1182–1188. 26. Kovalic JJ, Perez CA. Radiation therapy following keloidectomy: a 20-year experience. Int J Radiat Oncol Biol Phys 1989; 17(1):77–80. 27. Walter WL. Another look at pterygium surgery with postoperative beta radiation. Opthal Plast Reconstr Surg 1994; 10(4):247–252. 28. Blount LH, Thomas BJ, Tran L et al. Postoperative irradiation for the prevention of heterotopic bone: analysis of different dose schedules and shielding considerations. Int J Radiat Oncol Biol Phys 1990; 19(3):577–581. 29. Hehrlein C, Gollan C, Donges K et al. Lowdose radioactive endovascular stents prevent smooth muscle cell proliferation and neointi-

30.

31. 32.

33.

34.

35.

36.

37.

38.

39. 40.

mal hyperplasia in rabbits. Circulation 1995; 92(6):1570–1575. Teirstein PS, Massullo V, Jani S et al. Twoyear follow-up after catheter-based radiotherapy to inhibit coronary restenosis. Circulation 1999; 99(2):243–247. Brenner DJ, Miller RC, Hall EJ. The radiobiology of intravascular irradiation. Int J Radiat Oncol Biol Phys 1996; 36(4):805–810. 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(4):767–775. 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 histopathologic analyses. Int J Radiat Oncol Biol Phys 1996; 36(4):777–788. Sabaté M, Serruys PW, van der Giessen WJ et al. Geometric vascular remodeling after balloon angioplasty and beta-radiation therapy: a threedimensional intravascular ultrasound study. Circulation 1999; 100: 1182–1188. Friedman M, Felton L, Byers S. The antiatherogenic effect of iridium192 upon the cholesterol-fed rabbit. J Clin Invest 1964; 43:185–192. Popowski Y, Verin V, Papirov I et al. Intraarterial 90Y brachytherapy: preliminary dosimetric study using a specially modified angioplasty balloon. Int J Radiat Oncol Biol Phys 1995; 33(3):713–717. 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(3):727–732. Teirstein PS, Massullo V, Jani S et al. Catheterbased radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med 1997; 336(24):1697–1703. Waksman R. Vascular brachytherapy, 2nd edn. New York: Futura Publishing Company, 1999. Waksman R. Intracoronary brachytherapy in the Cath Lab. Physics dosimetry, technology and safety considerations. Herz 1998; 23(6):401–406.

17

579_Stenting_ch.01

14/8/2001 13:49

Page 18


41. Simpkin DJ, Cullom SJ, Mackie TR. The spatial and energy dependence of bremsstrahlung production about beta point sources in H2O. Med Phys 1992; 19(1): 105–114. 42. Munro TR. The relative radiosensitivity of the nucleus and cytoplasm of Chinese hamster fibroblasts. Radiat Res 1970; 42(3):451–470. 43. Hall EJ, Marchese M, Rubin J, Zaider M. Low dose rate irradiation. Front Radiat Ther Oncol 1988; 22:19–29. 44. Hayflick L. Aging, longevity, and immortality in vitro. Exp Gerontol 1992; 27(4):363–368. 45. 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(1):183–186. 46. Schopohl B, Liermann D, Pohlit LJ et al. 192Ir endovascular brachytherapy for avoidance of intimal hyperplasia after percutaneous transluminal angioplasty and stent implantation in peripheral vessels: 6 years of experience. Int J Radiat Oncol Biol Phys 1996; 36(4):835–840. 47. Reidy MA, Fingerle J, Lindner V. Factors controlling the development of arterial lesions after injury. Circulation 1992; 86(6 suppl):III43–III46. 48. Wilcox JN, Waksman R, King SB, Scott NA. The role of the adventitia in the arterial response to angioplasty: the effect of intravascular radiation. Int J Radiat Oncol Biol Phys 1996; 36(4):789–796. 49. Mitchell JB, Bedford JS, Bailey SM. Dose-rate effects in mammalian cells in culture III. Comparison of cell killing and cell proliferation during continuous irradiation for six different cell lines. Radiat Res 1979; 79(3):537–551. 50. Hehrlein C, Stintz M, Kinscherf R et al. Pure beta-particle-emitting stents inhibit neointima formation in rabbits. Circulation 1996; 93(4):641–645. 51. Waksman R, Robinson KA, Crocker IR et al. Endovascular low-dose irradiation inhibits neointima formation after coronary artery balloon injury in swine. A possible role for radiation therapy in restenosis prevention. Circulation 1995; 91(5):1533–1539. 52. Schwartz RS, Koval TM, Edwards WD et al.

18

53.

54. 55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

Effect of external beam irradiation on neointimal hyperplasia after experimental coronary artery injury. J Am Coll Cardiol 1992; 19(5):1106–1113. Silber S, von Rottkay P, Gielow A et al. Intracoronary brachytherapy with strontium/ yttrium-90. Initial experiences in Germany. Herz 1998; 23(6):380–393. Teirstein PS. Gamma versus beta radiation for the treatment of restenosis. Herz 1998; 23(6): 335–336. Waksman R, Bhargava B, White L et al. Intracoronary beta-radiation therapy inhibits recurrence of in-stent restenosis. Circulation 2000; 101(16):1895–1898. Amols HI, Trichter F, Weinberger J. Intracoronary radiation for prevention of restenosis: dose perturbations caused by stents. Circulation 1998; 98(19):2024–2029. Fischell TA, Carter AJ, Laird JR. The betaparticle-emitting radioisotope stent (isostent): animal studies and planned clinical trials. Am J Cardiol 1996; 78(3A):45–50. 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(3):529–536. Wardeh AJ, Kay IP, Sabate M et al. Betaparticle-emitting radioactive stent implantation. A safety and feasibility study. Circulation 1999; 100(16):1684–1689. Albiero R, Nishida T, Adamian M et al. Edge restenosis after implantation of high activity (32)P radioactive beta-emitting stents. Circulation 2000; 101(21):2454–2457. Albiero R, Adamian M, Kobayashi N et al. Short- and intermediate-term results of (32)P radioactive beta-emitting stent implantation in patients with coronary artery disease: The Milan Dose–Response Study. Circulation 2000; 101(1):18–26. Sabate M, Kay IP, Gijzel AL et al. Compassionate use of intracoronary beta-irradiation for treatment of recurrent in-stent restenosis. J Invasive Cardiol 1999; 11:582–588. Dorr W, Emmendorfer H, Haide E, Kummermehr J. Proliferation equivalent of ‘accelerated repopulation’ in mouse oral mucosa. Int J Radiat Biol 1994; 66(2): 157–167. Witte L, Fuks Z, Haimovitz-Friedman A et al.

579_Stenting_ch.01

14/8/2001 13:49

Page 19

REFERENCES

65.

66.

67.

68.

69.

70.

71.

72.

73.

Effects of irradiation on the release of growth factors from cultured bovine, porcine, and human endothelial cells. Cancer Res 1989; 49:5066–5072. Bertrand OF, Mongrain R, Lehnert S et al. Intravascular radiation therapy in atherosclerotic disease: promises and premises. Eur Heart J 1997; 18(9):1385–1395. Kay IP, Sabate M, Van Langenhove G et al. Outcome from balloon induced coronary artery dissection after intracoronary beta radiation. Heart 2000; 83(3):332–337. Meerkin D, Joyal MJV, Bonan R. Long-term morphological effects of post angioplasty betaradiation: an IVUS study. JACC 2000; 35(2):1A. Sabate M, Costa MA, Kozuma K et al. Geographic miss: a cause of treatment failure in radio-oncology applied to intracoronary radiation therapy. Circulation 2000; 101(21): 2467–2471. Albiero R, Di Mario C, van der Giessen WJ et al. Procedural results and 30-day clinical outcome after implantation of beta-particle emitting radioactive stents in human coronary arteries. Eur Heart J 1998; 19:457. 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(4):360–365. Waksman R, White LR, Mehran R et al. Two years follow-up after intracoronary gamma radiation therapy for in-stent restenosis: results from a randomized clinical trial. JACC 2000; 35(2):10A. Condado JA, Lansky AJ, Saucedo JF et al. Three year clinical and angiographic follow-up after intracoronary 192-iridium radiation therapy. Circulation 1998; 98(17):3422. King SB 3rd, Williams DO, Chougule P et al. Endovascular beta-radiation to reduce restenosis after coronary balloon angioplasty: results

74.

75.

76.

77.

78.

79.

80.

81.

82.

of the beta energy restenosis trial (BERT). Circulation 1998; 97(20):2025–2030. Meerkin D, Bonan R, Crocker IR et al. Efficacy of beta radiation in prevention of postangioplasty restenosis. An interim report from the beta energy restenosis trial. Herz 1998; 23(6):356–61. 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(5): 1138–1144. Carter AJ, Laird JR. Experimental results with endovascular irradiation via a radioactive stent. Int J Radiat Oncol Biol Phys 1996; 36(4):797–803. Costa MA, Sabate M, van der Giessen WJ et al. Late coronary occlusion after intracoronary brachytherapy. Circulation 1999; 100(8): 789–792. Kozuma K, Costa MA, Sabate M et al. Late stent malapposition occurring after intracoronary beta-irradiation detected by intravascular ultrasound. J Invasive Cardiol 1999; 11(10):651–655. Savage DE, Constine LS, Schwartz RG, Rubin P. Radiation effects on left ventricular function and myocardial perfusion in long term survivors of Hodgkin’s disease. Int J Radiat Oncol Biol Phys 1990; 19(3):721–727. King V, Constine LS, Clark D et al. Symptomatic coronary artery disease after mantle irradiation for Hodgkin’s disease. Int J Radiat Oncol Biol Phys 1996; 36(4):881–889. Kleikamp G, Schnepper U, Korfer R. Coronary artery and aortic valve disease as a long-term sequel of mediastinal and thoracic irradiation. Thorac Cardiovasc Surg 1997; 45(1):27–31. Glanzmann C, Kaufmann P, Jenni R et al. Cardiac risk after mediastinal irradiation for Hodgkin’s disease. Radiother Oncol 1998; 46(1):51–62.

19

579_Stenting_ch.01

14/8/2001 13:49

Page 20

579_Stenting_ch.02

14/8/2001 13:50

Page 21

2 Therapeutic angiogenesis for coronary artery disease Michael JB Kutryk, Saleem A Kassam, Duncan J Stewart

Introduction Ischemic heart disease is the major cause of death in adults in most developed and many developing countries, and is now the commonest cause of death worldwide. Effective treatments of coronary artery disease involve the percutaneous revascularization techniques of balloon angioplasty and stenting or coronary artery bypass grafting (CABG). The long-term success of both of these approaches is limited by the development over time of native vessel restenosis and graft occlusions. In addition, despite continued advances in the prevention and treatment of coronary artery disease, there are still many patients who are not candidates for conventional treatments. Therapeutic angiogenesis is a strategy designed to restore blood supply to the myocardium by the administration of growth factors to augment native angiogenesis.

Angiogenesis The term angiogenesis, first used by Hertig in 1935 to describe the growth of blood vessels in the placenta, was reintroduced by Folkman in 1972 to describe neovascularization accompanying solid tumor growth.1 Angiogenesis is the process by which new capillaries sprout and differentiate from pre-existing microvascular networks. This process results in newly developed microvessels, most of which resemble capillaries (diameter of 5–8 µm). Although the exact

mechanisms are not fully understood, angiogenesis is thought to involve a series of events including: (1) activation of endothelial cells within a pre-existing vessel and vasodilatation of the parent vessel; (2) degradation of the basement membrane and extracellular matrix; (3) migration of activated endothelial cell from the parent vessel directed by chemotactic factors liberated from fibroblasts, monocytes, platelets, mast cells and neutrophils, towards the site where angiogenesis is required; (4) proliferation of endothelial cells in the newly forming vessels; (5) differentiation of these endothelial cells back to a quiescent phenotype with lumen formation; (6) recruitment of pericytes along the newly formed vascular structures; (7) formation of a new basement membrane by the newly organized endothelial cells and pericytes; and (8) remodeling of the neovascular network, with maturation and stabilization of the blood vessels (Figure 2.1). Angiogenesis is rapidly initiated in response to hypoxia or ischemia, and endothelial cell activation is the first process to take place in physiological or pathophysiological angiogenesis. The expression of several endothelial genes initiates a cascade of reactions, which then involve neutrophils and smooth muscle cells. Hypoxia induces increased levels of a family of hypoxiainducible transcription factors (HIFs), including HIF-1 (or the aryl hydrocarbon receptor nuclear translocator, ARNT), HIF-1, and HIF-2. They mediate the response to hypoxia by binding to specific DNA sequences, the

21

579_Stenting_ch.02

14/8/2001 13:51

Page 22

THERAPEUTIC ANGIOGENESIS FOR CORONARY ARTERY DISEASE

Activation

Differentiation

1. BM dissolution (MMP act.) – TNF, IL-8, etc. – VEGF, bFGF – ET-1

4. Tube formation – VEGF, bFGF, etc. – NO – angiopoietin 1

2. Migration of ECs – cytokines – angiogenic GFs – ET-1, NO

5. Pericyte recruitment – angiopoietin1 – NO

3. Proliferation of ECs – VEGF, bFGF, etc. – ET-1

6. BM deposition – angiopoietin 1 – NO Vessel stabilization – angiopoietin 1

Figure 2.1 Sequential events in angiogenesis. (1) Basement membrane disintegration opens the way for (2) endothelial cell migration. (3) Cords of cells proliferate and (4) define a new vascular channel. (5) Cessation of cell migration and proliferation coincides with the recruitment of perivascular support cells (6) with the formation of a new basement membrane and vessel maturation and stabilization.

hypoxia-response promoter elements, which regulate the transcription of an array of genes critical to the cellular response to hypoxia, including several genes that regulate angiogenesis.2 Leukocytes and platelets are potent producers of angiogenic growth factors, and several adhesion, chemoattractant and activator molecules govern their emigration from the bloodstream. Integral membrane proteins, including integrins, play an important role in the process of angiogenesis. Integrins are heterodimeric cell surface receptors composed of two non-covalently associated transmembrane glycoproteins ( and ) that mediate attachment of cells to their foundation but are also involved in intracellular signal

22

transduction.3–5 Endothelial cells express a number of different integrins, and of these v3 has been shown to be particularly important during angiogenesis. v3 is a receptor for many proteins with an exposed Arg–Gly–Asp (RGD) tripeptide component, including vitronectin, fibronectin, fibrinogen, laminin, collagen, thrombospondin, osteopontin and von Willebrand factor. Although the v3 receptor is not widely expressed, it is prominent on cytokine-activated endothelial cells or smooth muscle cells, suggesting its relevance in angiogenesis.6 A number of angiogenic cytokines have been shown to increase the expression of the v and 3 subunits on endothelial cells,7,10 and it has been

579_Stenting_ch.02

14/8/2001 13:51

Page 23

ANGIOGENESIS

demonstrated that v3 antagonists (antibodies and cyclic RGD peptides) inhibit angiogenesis.11–14 Newer data suggest that endothelial cell survival and proliferation in response to vascular endothelial growth factor (VEGF) may require the association of one of its receptors with v3 (Figure 2.2). Basement membrane degradation, extracellular matrix invasion and capillary lumen formation are also essential components of the angiogenic process, all of which are dependent on a cohort of proteases and protease inhibitors. Although a number of enzymatic systems have been implicated in extracellular proteolysis, many of the enzymes belong to one of two famil-

ies, the serine proteases, in particular the plasminogen activator (PA)/plasmin system, and the matrix metalloproteases (MMPs). Plasminogen activators u-PA and t-PA convert the ubiquitous plasma protein plasminogen to plasmin. Plasmin activates certain MMPs, has a broad trypsin-like activity and degrades proteins such as fibronectin, laminin and the protein core of proteoglycans.15–17 Subsequent steps in angiogenesis, including endothelial cell migration, proliferation, new vessel formation and maturation, result in a functional vascular conduit.4,18–20 Nitric oxide (NO) appears to play a crucial role in mediating various processes, including terminating the

VEGF PIGF VEGF-B

VEGF VEGF-C VEGF-D VEGF-E

VEGF-C VEGF-D

VEGFR-1

VEGFR-2

VEGFR-3

Complement to C1r/s homology domain

ssss

Homology to coagulation factors V and VII

3 NRP-1

VEC

Ig-like domain

Tyrosine kinase domain MAM domain Angiogenesis

Lymphangiogenesis

Figure 2.2 The currently known growth factors and receptors of the VEGF family. The three signaling tyrosine kinase receptors of the VEGF family (VEGFR-1, VEGFR-2 and VEGFR-3), the soluble VEGFR-1 receptor, the accessory isoform-specific receptor neurolipin-1 (NRP-1), the integrin receptor v3 and VE-cadherin are displayed with their major structural features. Ligand binding induces receptor signal transduction, leading to various responses. VEGFR-1 and VEGFR-2 mediate angiogenesis, whereas VEGFR-3 is also involved in lymphangiogenesis. NRP-1 (and neurolipin-2) binds to specific C-terminal sequences present only on VEGFs that bind to VEGFR-1 and/or VEGFR-2. v3 integrin and VE-cadherin have been found complexed with activated VEGFR-2. VE-cadherin also associates with an activated VEGFR-3 complex. VEC, VE-cadherin; NRP-1, neurolipin-1; MAM, meprin, A5, mu. See Chan et al123 for explanations of the various structural motifs of the neurolipins. Modified from Veikkola et al.124

23

579_Stenting_ch.02

14/8/2001 13:51

Page 24


proliferative actions of growth factors, and promoting the formation of vascular tubes.20–22 In the setting of coronary ischemia, NO is required for VEGF to function23 which may, in turn, be mediated by endothelin release.24 Secretion of platelet-derived growth factor (PDGF) helps attract other elements to the neovascular platform. Cell-to-cell contact, and the presence of transforming growth factor-beta (TGF-) are thought to spur the differentiation and maturation of pericytes and smooth muscle cells.20 The glycoprotein angiopoietin-1 (Ang-1) and its tyrosine receptor kinase Tie-2 help the immature endothelial cell network to establish biochemical interactions and vessel integrity.20

Vasculogenesis The process of angiogenesis is distinct from that of vasculogenesis. The term vasculogenesis is strictly reserved for the formation of new blood vessels during embryogenesis. Initially, mesenchymal cells differentiate in situ into early hemangioblasts that form cellular aggregates (blood islands), in which the inner cell population differentiates into hematopoetic precursors, and the outer cell population gives rise to the primitive endothelial cells that generate a functioning vascular network.25–27 The primitive vascular plexus subsequently develops into a complex, interconnecting network of mature blood vessels.

Arteriogenesis The importance of the collateral coronary circulation has long been known,18,28–33 and the mechanisms governing the growth and proliferation of pre-existing collateral vessels differ from those regulating angiogenesis and vasculogenesis. The growth and proliferation of collaterals is called arteriogenesis. The clinical significance of collateral arteries is based on their ability to proliferate into large conductance arteries, which can efficiently restore bloodflow to ischemic

24

territories. Adequate development of these collaterals may take days to weeks, in order to compensate for critical stenoses of the nutrient branches of the coronary tree. Genetic factors are responsible for the variable number of preexisting intracoronary connections and their capacity to grow, and lead to marked inter- and intraspecies variability.34,35 An important stimulator of arteriogenesis is increased shear stress that leads to changes within the newly recruited artery. The most important change is the activation of the endothelium. The result is an increased expression of a number of genes, partially via a protein that binds to the shear stress responsive element (SSRE) that is present in the promoter of many of these genes, including nitric oxide synthase (NOS), PDGF and monocyte chemoattractant protein (MCP-1). Adhesion molecules are also upregulated, allowing for the adhesion and invasion of monocytes and platelets, which are also potent producers of growth factors. The process of arteriogenesis does not require hypoxia as a physical stimulus. Neovascularization depends on two distinct processes; cell proliferation and vessel differentiation. These processes must occur in proper timing and proportion in order for functioning vessels to arise. It is likely that cell proliferation and differentiation occur in concert, and growth modulators may preferentially promote one process over the other in response to specific signaling mechanisms. Indeed, most angiogenically active factors are present in normal resting conditions, and up- and downregulation of these substances is determined by physiological and pathophysiological moderators.21,36,37 Growthpromoting factors are generated and active to varying degrees in response to the local environment and, depending on the local milieu, may be capable of promoting neovascularization. While VEGF and fibroblast growth factor (FGF) may regulate basement membrane disintegration, the presence of Ang-1 may be required for leukocyte and precursor cell adhesion, recruitment and proliferation, cell differentiation, maturation and the establishment of a mature vessel. The inter-

579_Stenting_ch.02

14/8/2001 13:51

Page 25

OVERVIEW OF VASCULAR GROWTH FACTORS

dependence of angiogenic factors is exemplified by FGF and NO. In the presence of NO, the action of FGF may switch from one that causes endothelial proliferation to one responsible for differentiation.22 Finally, such a paradigm would suggest that therapeutic angiogenesis would require the provision of several factors at appropriate points in the process to allow for the desired product.38

Overview of vascular growth factors The existence of biological mediators of vascular growth was hypothesized more than three decades ago, with the discovery of a tumor factor that was found to be mitogenic for endothelial cells.39 This factor was subsequently identified as a member of the FGF family.40 It soon became evident that tumor biology could be applied in a practical way to common disease processes like peripheral vascular and coronary artery diseases. Many angiogenic proteins have now been identified (Table 2.1). The most extensively studied and best characterized angiogenic growth factors are members of the VEGF and FGF families. More recently, attention has focused on the angiopoietin family, which includes angiopoietins 1–4.

Fibroblast growth factor The fibroblast growth factor family consists of 19 structurally similar compounds, of which FGF-1 (acidic, aFGF) and FGF-2 (basic, bFGF) are best described.20,36,41 The members of the FGF family possess a high degree of homology and share important features, including: (1) an ability to bind heparin with high affinity; (2) an ability to bind high-affinity receptors possessing tyrosine kinase activity, which subsequently initiates intracellular signaling pathways responsible for inducing cell division (modulated by attachment to the low-affinity receptor); and (3) an ability to bind to a low-affinity, high-capacity

receptor that represents a site that modulates the activity and function of the high-affinity receptor with cell surface heparin sulfate proteoglycans.42–44 The aFGF and bFGF proteins are single-chain, heparin-binding polypeptides of 154 and 146 amino acids respectively.40,45 Unlike other members of the FGF family, which have signal sequences and are secreted through standard secretory pathways, aFGF and bFGF do not have signal sequences and are not secreted by classical mechanisms. The FGFs have been shown to modulate many intra- and extracellular activities that are necessary for angiogenesis, including: (1) the upregulation of proteases that are essential in the modulation of the extracellular matrix; (2) the activation of kinases that regulate intracellular signaling pathways that are important to cell replication; and (3) the signaling of molecules involved in cell–cell interactions and interactions related to capillary tubule formation. Their particular affinity for the smooth muscle cell has led to the hypothesis that FGF compounds are more active in larger-vessel formation.4,20,46

Vascular endothelial growth factor The VEGF family of mitogens and their tyrosine kinase receptors play a central role in both physiological and pathological angiogenesis. The VEGF family currently includes six known members, VEGF (VEGF-A, VEGF-1), placental growth factor (PlGF), VEGF-B, VEGF-C (VEGF-2), VEGF-D, and orf virus VEGF (VEGF-E). The family members are all secreted dimeric glycoproteins, and they all contain characteristic regularly spaced eight-cysteine residues, the cystine knot motif. The first identified and the best-studied member of the group is VEGF (VEGF-A), a soluble mitogen mapped to chromosome 6p21.3, which plays a role in all major angiogenic events.47–51 VEGF was described independently by a number of different groups using a variety of different assays. For a number of years the protein was variably referred to as vascular permeability factor (VPF)

25

579_Stenting_ch.02

14/8/2001 13:51

Page 26


Angiogen

Endothelial cell specific

Acidic fibroblast growth factor (aFGF) Basic fibroblast growth factor (bFGF) Fibroblast growth factor 3 (FGF-3) Fibroblast growth factor 4 (FGF-4) Fibroblast growth factor 5 (FGF-5) Fibroblast growth factor 6 (FGF-6) Fibroblast growth factor 7 (FGF-7) Fibroblast growth factor 8 (FGF-8) Fibroblast growth factor 9 (FGF-9) Angiogenin 1 Angiogenin 2 Hepatocyte growth factor/scatter factor (HGF/SF) Platelet-derived growth factor (PDE-CGF) Transforming growth factor- (TGF-) Transforming growth factor- (TGF-) Tumor necrosis factor- (TNF-) Vascular endothelial growth factor 121 (VEGF 121) Vascular endothelial growth factor 145 (VEGF 145) Vascular endothelial growth factor 165 (VEGF 165) Vascular endothelial growth factor 189 (VEGF 189) Vascular endothelial growth factor 206 (VEGF 206) Vascular endothelial growth factor B (VEGF-B) Vascular endothelial growth factor C (VEGF-C) Vascular endothelial growth factor D (VEGF-D) Vascular endothelial growth factor E (VEGF-E) Vascular endothelial growth factor F (VEGF-F) Placental growth factor Angiopoietin-1 Angiopoietin-2 Thrombospondin (TSP) Proliferin Ephrin-A1 (B61) E-selectin Chicken chemotactic and angiogenic factor (cCAF) Leptin Heparin affinity regulatory peptide (HARP) Heparin Granulocyte colony-stimulating factor Insulin-like growth factor Interleukin-8 Thyroxine

No No No No No No No No No Yes Yes No Yes No No No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No No Yes Yes Yes No Yes No No No No No No

Modified from Hamaway et al.122

Table 2.1 List of angiogenic proteins.

26

579_Stenting_ch.02

14/8/2001 13:51

Page 27

OVERVIEW OF VASCULAR GROWTH FACTORS

or vasculotropin, but has come to be predominantly known as VEGF. Alternative splicing from a single gene gives rise to five different isoforms of VEGF composed of 121, 145, 165, 189 and 206 amino acids. The 165 and 121 isoforms are the predominant forms. The 165 variant is the most potent stimulator of endothelial cell division, 50–100-fold more potent than the 121 isoform, while the latter lacks heparin-binding ability and, as a consequence, is not anchored to the extracellular matrix when secreted, which allows for a paracrine effect. The greater mitogenic potency of VEGF165 may be conferred by its neurolipin-1-binding region, which is encoded by exon 7 of the VEGF gene (Figure 2.2).52 Targeted inactivation of a single VEGF allele in the mouse results in haplo-insufficiency with embryonic lethality due to abnormal blood vessel development at around 9 days of gestation, attesting to its importance in embryonic development.53,54 The VEGF homologs are ligands for a set of tyrosine kinase receptors, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (FLT-4) (Figure 2.2). In adult tissues, VEGFR-1 and VEGFR-2 localize to vascular endothelial cells, whereas VEGFR-3 is expressed mainly in the lymphatic endothelium. The ligand specificities of the VEGF receptors differ: VEGFR-1 binds VEGF, VEGF-B and P1GF, VEGFR-2 binds VEGF, VEGF-C, VEGF-D and the orf virus VEGF, while VEGFR-3 binds VEGF-C and VEGF-D. Ligand binding induces receptor dimerization and subsequent auto- and transphosphorylation. Hypoxia is one of the main stimuli driving angiogenesis, and the expression of VEGF is highly regulated by oxygen tension, providing a physiological feedback mechanism to accommodate insufficient tissue oxygenation by promoting blood vessel formation. The transcription of the VEGF gene under hypoxic conditions is mediated by a family of hypoxia-inducible factors (HIF-1, HIF-1 and HIF-2), which bind to hypoxia-responsive elements in the VEGF promoter. In addition, hypoxia also

induces the upregulated expression of a ribonucleic acid-binding protein (HuR). HuR stabilizes the VEGF mRNA through interaction with sequences in the 3 untranslated region.55–57 Many other stimuli, which do not promote angiogenesis, can also modulate angiogenesis indirectly by regulating VEGF expression in specific cell types. These include cytokines, growth factors, endotoxins, adenosine derivatives and transcriptional factors such as c-fos and c-jun. VEGF is expressed by macrophages and leukocytes and, although VEGFR-1 and VEGFR-2 are both activated by the same ligand, their downstream signaling pathways lead to different cellular responses. VEGFR-2 activation is required for the determination of the fate of endothelial and hemopoietic cells, their migration and proliferation.58,59 VEGFR-1 activation is more important for proper regulation of endothelial cell migration and adhesion and blood vessel organization.60,61 In general, adult VEGF expression is low.62 One exception is the female reproductive organ, and the ovarian follicle, where it may be involved in embryo implantation, endometrial vascularization and the development of the corpus luteum.63 Expression is increased in pathological states dependent on increased vascularity, such as myocardial ischemia, arthritis and tumor growth.41 Among patients with coronary artery disease (CAD), VEGF concentrations have been found to be elevated in atherosclerotic lesions, particularly in those with increased collaterals.28,64 There are two features of VEGF that distinguish it from the FGF compounds. First, receptors for VEGF are found predominantly on vascular endothelial cells, resulting in a specific target organ effect. Second, the terminal amino acid sequence allows for secretion from cells. This feature allows for the delivery of the DNA sequence encoding VEGF, with its subsequent transcription and translation, which leads to greater and more sustained tissue concentrations when compared to protein delivery alone.65 The effects of FGF and VEGF on neovascularization may be synergistic.38

27

579_Stenting_ch.02

14/8/2001 13:51

Page 28


Recent animal data have identified a potential negative effect of recombinant human VEGF (rhVEGF) protein. When administered via a single intraperitoneal injection to apolipoprotein-E-deficient cholesterol-fed mice, rhVEGF enhanced atherosclerotic plaque progression.66 Similar results were reported with the administration of rhVEGF to cholesterol-fed rabbits. Whether this applies to angiogenic agents other than VEGF is currently not known; however, these findings have clinical implications and will impact on the design of future clinical trials.

The angiopoietins The angiopoietins represent a new family of angiogenic growth factors that bind a receptor tyrosine kinase that is primarily restricted to endothelial cells, Tie-2.67 The angiopoietins include a receptor activator, angiopoietin-1 (Ang-1), and a putative endogenous receptor antagonist, angiopoietin-2 (Ang-2). Ang-1 is a 70-kDa protein that induces tyrosine phosphorylation of Tie-2 in endothelial cells. Ang-1 binding induces endothelial cell chemotaxis but is not mitogenic for endothelial cells. In this regard, knockout mice lacking either Tie-2 or its activating ligand Ang-1 exhibit embryonic lethality; however, the early stages of VEGF-dependent vascular development still occur normally in these mice, resulting in the formation of a primitive vascular plexus. Morphological evaluation of these Tie-2 / and Ang-1 / mice demonstrates deficiencies in vessel branching, with fewer and simpler vessels, poorly organized subendothelial matrix, loosening of endothelial cell contacts with the basement membrane, and generalized lack of perivascular cells.68–71 Transgenic overexpression of Ang-2 during embryogenesis also leads to a lethal phenotype similar to that seen in embryos lacking either Ang-1 or Tie2, consistent with a role for Ang-2 as a natural antagonist for Tie-2.72 These transgenic phenotypes imply a function for Tie-2 in the expansion of the primitive endothelial tubules to a network of mature vessels composed of endothelial and

28

adventitial cells. The angiopoietins appear to act in a complementary and coordinated fashion with VEGF, increasing the complexity and maturity of the vasculature.73 The angiopoietins also appear to play an important role in postnatal neovascularization. In the adult, Ang-1 and Tie-2 appear to be widely expressed in the quiescent adult vasculature, while Ang-2 is highly expressed only at sites of vascular remodeling.72 In vitro studies have shown that hypoxia upregulates Ang-2 expression and downregulates Ang-1.74–76 In a corneal micro-pocket model of angiogenesis, Asahara et al77 showed that exogenous coadministration of Ang-1 and VEGF produced larger and more numerous blood vessels than VEGF alone. Ang-2 acts as a natural antagonist of Ang-1, blocking its stabilizing function. It may loosen capillary structure, render endothelial cells more responsive to angiogenic stimuli, and allow the activation of endothelial cells to a more plastic state where they are responsive to the sprouting signal provided by VEGF78 (Figure 2.3). Recent evidence has suggested that Ang-2 might also have biphasic actions under circumstances of low oxygen tension, initially blocking Ang-1 activity by acting as a Tie-2 antagonist, allowing endothelial cell activation in response to VEGF and other cytokines, and later contributing directly to the stabilization and maturation of newly formed blood vessels, as a partial or full Tie-2 agonist.79 Other members of the angiopoietin family have been described (Ang-3 and Ang-4), but their properties have not been fully described.

Therapeutic angiogenesis Preclinical studies Numerous animal experiments have demonstrated the link between growth factors and new vessel formation. Initial studies with FGF demonstrated accelerated wound healing in diabetic mice, leading to the first indicated use of topical growth factors for debrided diabetic

579_Stenting_ch.02

14/8/2001 13:51

Page 29

THERAPEUTIC ANGIOGENESIS

VEGF VEGF-R2 (Flk1)

VEGF-R1 (Flt1)

Basement membrane

Ang-1

Ang-2

Tie-2

Tie-2

VEGF VEGF-R1/2

Peri-endothelial cells

Endothelial cells

Birth, migration and proliferation of endothelial cells

Tube formation and cell-cell interaction

Recruitment of and interaction with pericytes. Maintains vessel integrity and quiescence.

Matrix contacts and support cell interactions loosen. Allows access to angiogenic inducers.

Vessel maturation

Figure 2.3 Coordinated and complementary angiogenic activities of VEGF and the angiopoietins. VEGF, angiopoietin-1, and angiopoietin 2 bind to receptor thymidine kinases (RTKs) that have similar cytoplasmic signaling domains. Binding of the ligands to their receptors elicits downstream signals with distinctive cellular responses. Only VEGF binding to the VEGF-R2 receptor sends a classical proliferative signal. VEGF binding to VEGF-R1 elicits endothelial cell–cell interactions and capillary tube formation. Ang-1 binding to the Tie2 RTK recruits and likely maintains association of peri-endothelial support cells (pericytes, smooth muscle cells, myocardiocytes), thus stabilizing a newly formed blood vessel. One property of Ang-2 is that it binds and blocks kinase activation in endothelial cells. The Ang2 negative signal causes vessel structures to become loosened, reducing endothelial cell–cell contacts with matrix and disassociating peri-endothelial support cells. This loosening likely renders the endothelial cells more accessible and responsive towards the angiogenic inducers like VEGF. Modified from reference 125.

ulcers.80–82 Animal studies of therapeutic angiogenesis have centered around two models: the rabbit hind limb model of peripheral ischemia, and the porcine model of myocardial ischemia.83–87 Both VEGF and FGF, administered by either an intra-arterial or an intramuscular route, can promote collateral blood vessel development after ligation of the rabbit femoral artery. In these studies, treated animals had more angiographically and histologically visible collat-

eral vessels, greater hind limb bloodflow, higher distal perfusion pressure, and enhanced muscle performance. Models of ischemic porcine myocardium, induced by placement of an ameroid constriction of a coronary artery, have also demonstrated augmentation of myocardial vascularization after both protein and gene treatment administered via intracoronary or perivascular injection.88–92 These preclinical studies supported the proof of principle that vascular

29

579_Stenting_ch.02

14/8/2001 13:51

Page 30


growth factors can promote angiogenesis to improve bloodflow to ischemic muscle.

Human studies Until recently, human angiogenic experiments have been predominantly limited to small series in which VEGF or FGF, protein or gene, have been administered.46,93–108 Delivery strategies have included intracoronary, epicardial or direct myocardial injection of either VEGF or bFGF protein, or genetic material. The latter can be delivered as naked plasma DNA or in a viral vector. Preliminary human trials in peripheral vascular disease have demonstrated improvements in ankle–brachial index, enhancements of angiographically visible collaterals, improvements in rest pain and analgesic medication use, ulcer healing and diminished critical limb ischemia.93,94 Schumacher and colleagues were the first to report on therapeutic angiogenesis in human myocardium. Among 40 patients undergoing CABG with a left internal mammary artery (LIMA) graft and a left anterior descending artery (LAD) stenosis distal to the anastomosis, they randomly assigned patients to direct intramyocardial injection of aFGF or denatured protein control near the distal non-grafted segment.95 At 3 months, they described significantly increased angiographic collaterals among FGF-injected patients compared to placebo. This effect persisted for 3 years, and was associated with improved echocardiographic ejection fraction and functional class.96 Sellke et al reported on a series of eight patients with ischemic heart disease who received bFGF as an adjunct to CABG.97 These patients had at least one major arterial distribution that was not amenable to revascularization but were otherwise candidates for CABG. The growth factor was delivered by sustained-release microcapsules that were implanted around the ischemic territory during surgery. At 12 week follow-up, three patients showed clear enhancement of perfusion to the unrevascularized

30

myocardium, three patients had minimal overall change, and one patient had a new fixed defect on stress nuclear perfusion imaging. Similarly, Laham and colleagues studied the effects of bFGF. They randomly assigned patients undergoing CABG to receive 10 or 100 µg of bFGF, or placebo via perivascular microcapsular delivery, into an artery serving an ischemic territory that was not grafted.46,98 Although only 24 patients were studied, promising trends were observed with respect to angina, perfusion scores and MRI-imaged ischemic areas between placebo and treated groups at 3 months, particularly in the higher-dose group. Intracoronary injection of bFGF protein was performed in patients with stable coronary artery disease by Unger and his colleagues.99 Doses greater than 30 µg/kg were associated with hypotension and bradycardia. Compared to placebo, patients receiving bFGF had similar exercise treadmill times at 1 month. Udelson’s group delivered escalating doses of intravenous or intracoronary bFGF to 59 patients with CAD that was unsuitable for revascularization.100 They reported improved scintigraphic perfusion scores reflecting decreased inducible ischemia. An overview of the clinical trials of FGF is shown in Table 2.2. Six small studies have evaluated VEGF delivery to ischemic myocardium (Table 2.3). Protein therapy performed with varying doses of intracoronary rhVEGF was studied by Henry et al in a series of 15 patients who were suboptimal candidates for conventional revascularization techniques.101 Nuclear perfusion imaging was performed at 30 and 60 days, and seven patients underwent angiographic assessment. The investigators reported an overall improvement in perfusion in seven patients and minimal changes in the patients who had received the lowest doses. Collateralization was improved in five of the seven patients who had undergone angiography. Hendel’s group also evaluated the intracoronary administration of VEGF protein. In their study, 14 patients received various doses of rhVEGF protein. The investigators reported a significant

Yes bFGF protein Heparin/alginate microcapsules 10/100 µg Epicardial fat implantation Clinical/MPI Positive

Yes aFGF protein None 70 mg Intramyocardial DSA Positive

Dose Delivery

Endpoint Result

GXT Safe

3–100 µg/kg Intracoronary

No bFGF protein None

25 RDB Yes

Unger et al99

MPI Positive

0.33–48 µg/kg IC/IV


59 Observational No

Udelson et al100

Yes bFGF protein Heparin/alginate microcapsules 10/100 µg Epicardial fat implantation MPI Safe

8 Observational No

Sellke et al97

GXT/MPI/QOL Negative

200 µg Intracoronary


337 RDB Yes

FIRST

Table 2.2 Clinical trials of FGF delivery

14/8/2001 13:51

GXT, graded exercise stress test; RDB, randomized, double blind; MPI, myocardial perfusion imaging; IC, intracoronary; IV, intravascular; DSA, digital subtraction angiography; QOL, quality of life.

24 RDB No

40 RDB Yes

N Design Placebo controlled Thoracotomy Agent Vector

Laham et al98

Schumacher et al95

Parameter


31

579_Stenting_ch.02

14/8/2001 13:51

Page 32


improvement in resting (but not stress) perfusion as assessed by nuclear scintigraphy.102 Gene therapy, using either naked plasmid DNA or adenovirus as a vector for VEGF, has been tested in several early clinical trials. Losordo et al performed a phase I study of five patients with refractory angina who received intramyocardial injections of naked plasmid DNA encoding for VEGF165 as sole therapy via mini-thoracotomy (no CABG).103 All patients were found to have improved perfusion scores as assessed by nuclear imaging at 30 and 60 days and had radiographic evidence of improved collateral flow into ischemic areas on angiography. In addition, the patients reported improvements in anginal class and a reduction in nitroglycerin use. Similar results were reported by Vale et al.104 Their study employed three doses of naked plasmid DNA encoding the 165 isoform of vascular endothelial growth factor (phVEGF165), which was injected into the myocardium as sole therapy in patients with symptomatic myocardial ischemia. Thirty patients who were not candidates for conventional revascularization were treated with a total dose of either 125 µg (n 10), 250 µg (n 10) or 500 µg (n 10) of phVEGF165. Twenty-six (87%) of the 30 patients reported clinical improvement. Exercise tolerance (Bruce protocol) increased significantly up to 360 days post gene delivery. Stress SPECT-Sestamibi myocardial imaging was performed in 29 patients followed for 60 days. Mean perfusion-defect scores for both stress and rest images were significantly decreased (improved) at day 60. Left ventricular ejection fraction (LVEF) was either unchanged (n 16) or improved (n 14, mean increase in LVEF 5%) following gene therapy. Hendel et al and Fortuin et al have reported results of a dose-ranging trial examining gene transfer of VEGF-C (VEGF-2).105,106 VEGF-C shows 30% homology to VEGF165 and is a specific ligand for the endothelial receptor tyrosine kinases VEGFR-2 and VEGFR-3 (Figure 2.2).52 Three doses of VEGF-C were delivered via intramyocardial injection after mini-

32

thoracotomy in 30 patients. Stress SPECT-Sestamibi myocardial imaging was performed at baseline, and at 4 and 12 weeks after VEGF injection. In the 27 patients who were available for follow-up perfusion imaging, improvement was seen in 15 and 12 of the rest and stress scans respectively, with evidence for a dose-dependent effect. Canadian Cardiovascular Society (CCS) class decreased from 3.6 0.5 at baseline to 1.3 1.0 (p < 0.005) at 12 week follow-up, and average exercise times increased from 5:55 3:20 min to 7:56 3:24 min (p < 0.005). At 12 weeks after treatment, endocardial electromechanical mapping demonstrated a significant improvement in myocardial contractile function without an improvement in myocardial viability, suggesting rescue of hibernating myocardium.107 Rosengart and colleagues injected adenovirus vector containing VEGF121 directly into the myocardium of 21 patients as an adjunct to CABG (15 patients) or as sole therapy via minithoracotomy (6 patients).108 Coronary angiography and nuclear perfusion scans after 30 days suggested improvement in both groups. In addition, patients reported symptomatic improvement after therapy. Collectively, these phase 1 and 2 studies describe an experience of 291 patients without blinded outcome assessment. Although data from these studies cannot be used to draw conclusions concerning efficacy, they firmly established the feasibility and safety of different methods of gene transfer, and have set the stage for larger randomized trials. Also being tested is percutaneous catheter-mediated injection of vector. Trials are currently underway to assess the efficacy of this approach. Only two relatively large, randomized, double-blind, placebo-controlled studies have been performed in humans. The FIRST Study (FGF-2 Initiating Revascularization Support Trial) recruited 337 patients with angina considered to be suboptimal for traditional revascularization. In a double-blind, placebo-controlled manner, participants were randomized to three

30 Observational No

N

Design

Placebo

0.2/0.8/2.0 mg Intramyocardial IC Clinical/GXT/

Dose

Delivery

Endpoint

Positive

Plasmid

Positive

MPI

0.167 µg/kg

Positive

GXT/MPI

Clinical/

Intramyocardial

500 µg

0.005/0.017/0.05/ 125/250/

None

DNA

VEGF165

Yes

No

Observational

30

Vale et al104

Positive

angiography

Clinical/MPI/

Intramyocardial

125 µg

Plasmid

DNA

VEGF165

Yes

No

Observational

20

Symes et al108A

Positive

MPI

IC

0.167 µg/kg

0.005/0.017/0.05/

None

protein

rhVEGF

No

No

Observational

14

Hendel et al102

Positive

GXT

angiography/

Clinical/MPI/

Intramyocardial

1000 µg

Adenovirus

DNA

VEGF121

Yes

No

Observational

21

Rosengart et al108

Safety

angiography

Clinical/MPI/

Intramyocardial

125 µg

Plasmid

DNA

VEGF165

Yes

No

Observational

5

Losordo et al103

Negative

angiography

Clinical/GXT/

IC/IV

Table 2.3 Clinical trials of VEGF delivery.

min

17/50 ng/kg/

None

protein

rhVEGF

No

Yes

RDB

178

VIVA

GXT, graded exercise stress test; RDB, randomized, double blind; MPI, myocardial perfusion imaging; NOGA, NOGA electromechanical mapping; IC, intracoronary; IV, intravascular.

Result

Plasmid

Vector

MPI/NOGA

VEGF-C

Agent protein

No rhVEGF

Thoracotomy No

No

Observational

15

Henry et al101

14/8/2001 13:51

controlled

Hendel et al102

Parameter


33

579_Stenting_ch.02

14/8/2001 13:51

Page 34


doses of intracoronary bFGF protein (0.3, 3 and 30 µg/kg). At 90 days, there was no difference between groups in the primary endpoint of exercise treadmill times, or in the secondary endpoints of nuclear perfusion parameters (p 0.64), and quality of life indices (Seattle Angina Questionnaire (SAQ) or short-form 36 (SF-36)). On post hoc analysis, there was a suggestion that the greatest reduction in anginal score was at the 3 µg/kg dose, among older patients (>65 years) and those with the most severe angina (p 0.06). The VIVA Trial (VEGF in Ischemia for Vascular Angiogenesis) involved a patient cohort similar to that of the FIRST Trial with nuclear evidence of a reversible perfusion defect; the patients were assigned randomly to two doses of growth factor (17 or 50 ng/kg) or placebo. VEGF protein was administered during coronary angiography via intracoronary injection, followed by three intravenous doses on days 3, 6 and 9. Although no improvement in treadmill scores was seen at 60 days, mean CCS anginal class was significantly lower for the high-dose group compared to placebo at 120 days (1.6 0.1 versus 2.1 0.1, p 0.04). No safety concerns were raised in either of these landmark trials. Although both trials were unable to demonstrate efficacy, several factors may account for the lack of effect. In the two randomized human trials, growth factor delivery was accomplished via an intracoronary or intravenous route. It is unclear if this method provides adequate tissue levels to stimulate and maintain angiogenesis. This is particularly true for bFGF, given the poor specificity for target endothelium. In fact, doseranging studies for both FGF and VEGF suggest a graded effect at higher doses.99,102 In addition, injection into myocardium or pericardial fat may be necessary for clinically relevant dose delivery and transfection rates, as suggested by several studies.98,109,110 In planning controlled trials to assess the effectiveness of gene therapies, investigators must consider a number of significant factors.

34

These include: (1) selection of the appropriate means of delivery of therapeutic material; (2) determination of appropriate endpoints to be studied; (3) quantification and resultant objectification of the results; (4) assurance of adequate controls; (5) selection of patients to be included; (6) determination of the mechanisms of any observed clinical effects; and (7) assessment of complications—potential, actual, local, systemic, immediate and long term. Delivery of growth factors has been accomplished using two means—through the use of single or multiple doses of recombinant protein, or by a gene transfer approach—and each strategy has its limitations. Factors that favor the use of proteins include the ability to regulate their dose and thus to define a therapeutic window between efficacy and toxicity. This would allow withdrawal of treatment if and when necessary. Factors arguing against the use of protein for therapeutic angiogenesis are: (1) the considerable cost involved in producing significant quantities of pyrogen-free materials; (2) the appearance of secondary effects (prolonged administration of bFGF is associated with a decrease in arterial pressure, moderate thrombocytopenia, and moderate anemia); and (3) the requirement for repeated or prolonged administration of protein. Local perivascular delivery via myocardial injection, pericardial fat implantation of coated microspheres or pericardial instillation has been attempted in order to address the latter limitation.111–113 In contrast, gene therapy results in the prolonged secretion of growth product by host cells, offering sustained protein levels with a single administration. However, the potential for extralesional uptake of the gene or vector and distant, unwanted effects in non-target tissues, related either to the vector or the gene product that it encodes, is of concern. There are many means to deliver genes coding for angiogenic products. The simplest is through the delivery of naked plasmid DNA. Injection of naked DNA into myocardium has been shown to result in growth factor expression for a considerable period of time, without incorporation into

579_Stenting_ch.02

14/8/2001 13:51

Page 35

THERAPEUTIC ANGIOGENESIS

host DNA.110,114 Many facilitated means of delivery have also been studied. Liposomal encapsulation has been tested; however, current techniques are associated with a low transfection efficiency. Retrovirus encapsulation and delivery allows for effective and long-term gene expression through DNA incorporation into the genome; however, the potential for activation of retroviral genes in the host DNA is of concern. Encapsulation of gene in adenoviral vectors is an effective means of delivery; however, it is associated with an immune response that can lead to destruction of the vector or a significant systemic inflammatory response.115 The choice of efficacy endpoints for clinical trials remains an area of controversy. The ideal endpoint for angiogenesis trials should have the following characteristics: (1) it should address the primary hypothesis and represent a direct marker of efficacy; (2) it should be clinically meaningful; (3) it should be easily measured and not be prohibitively costly to perform or analyze; (4) it should provide insight into mechanisms; and (5) it should lend itself to statistical analysis. The endpoints for trials of angiogenesis can be considered either clinical (angina status, functional capacity, or quality of life) or physiological (improved myocardial perfusion, improvement in vessel collateralization, improvement in global or regional wall motion). One of the clinical assessments which has been considered as an endpoint for angiogenesis trials is exercise stress testing. The advantages of employing exercise testing as a clinical endpoint for angiogenesis trials is that it is often used in phase 1 and 2 studies, and the results are quantitative and semi-objective (rate pressure product, time to ST depression) and fairly reproducible. The disadvantages of using exercise testing as an endpoint are that comorbidities (peripheral vascular disease, chronic obstructive lung disease, arthritis) may limit exercise performance, day-today variability exists, and the reasons for test termination may still be subjective. Changes in CCS score or response to the SAQ have also been used as clinical endpoints in

angiogenesis trials. The advantages of these types of assessments are that they are highly relevant to patients and easy to interpret (especially CCS), are sensitive to change, are fairly reproducible (especially SAQ), and are familiar to most clinicians (CCS used in clinical practice). The disadvantages of these assessments are that they are more subjective than exercise stress testing (double-blinding necessary), the CCS score requires observer input (the SAQ does not), changes in SAQ are not easily interpreted (lack of familiarity by clinicians), and the placebo effects are substantial (~40% in the DIRECT DMR study). The advantages of using the MOS SF-36 or Utility Index (HUI) are that they are both broadly applicable, they are sensitive to change, and normal values have been established for various disease states. Disadvantages of these types of analyses as endpoints are that they are considered to be softer endpoints, they are more subjective, and the changes are not easily interpreted (lack of familiarity by clinicians). One of the problems common to all clinical endpoints is that they are prone to placebo effects. One solution to this problem is to look for objective endpoints that can explain the subjective outcomes such as reduction in CCS class. In this regard, ‘angiogenesis-specific’ quality of life or symptom assessment tools may be necessary. An additional problem with clinical endpoints is that small changes may be undetected, but still clinically meaningful (basement effect). Although clinical endpoints are employed in trials of myocardial angiogenesis, physiological assessments are preferred as primary endpoints. Several physiological endpoints have been considered, including SPECT myocardial perfusion imaging, MRI, and PET. The advantages of nuclear scintigraphy are that it is sensitive to changes after revascularization, it is reproducible, and wall motion can be assessed. There are concerns, however, over the adequacy of the spatial resolution obtainable with nuclear imaging. MRI has enormous potential, and is

35

579_Stenting_ch.02

14/8/2001 13:51

Page 36


able to provide excellent spatial resolution and information on structure, function and flow. Although MRI is gaining greater acceptance with time, prohibitive cost and restrictive availability limits its use. PET scanning is more sensitive than SPECT in measuring coronary flow reserve. It remains the only way to measure absolute bloodflow. The limitations of PET imaging are the poor spatial resolution, the lack of widespread availability and its cost. There may be several reasons for the disparate results of the reported clinical trials of angiogenesis and the results from animal models. In addition to the issues of dose, mechanism of delivery, and endpoint, the choice of patient cohort to study may have confounded the clinical trials, making positive results unattainable. Unlike animal populations, the patient population of interest has demonstrated an inability to form or recruit adequate collateral vessels prior to inclusion in the trials. In addition, the response to simple growth factor delivery may differ in the presence of diffuse atherosclerosis and endothelial dysfunction, compared with the response in experimental ischemic models.116 Also, various cardiac medications and health states, including aspirin, captopril, lovastatin, furosemide, hypercholesterolemia, smoking, diabetes and age, inhibit negatively impact on the angiogenic response.32,112,117–121 Also impacting on the generalization of the results of the clinical trials is the recognition that patients enrolled in clinical trials of angiogenesis are highly selected on the basis of anatomy, symptoms, left ventricular function, concurrent disease and motivation.

36

Future research Current animal studies are focusing on the mechanisms of angiogenesis, examining in particular the roles of different compounds and the local and host factors that govern their effectiveness. The action of angiogenic factors in the mileu of CAD is also an area of active research. The results of animal studies and early results of clinical trials suggest that delivery of a cocktail of angiogenic factors might be more effective than delivery of a single agent, and may more closely mimic the physiological angiogenic response. Finally, stem cell transplantation may allow for the development of all components required for new myocardium and functioning vascular network, and may provide a feasible therapy in the future.

Summary Exciting and promising options are being explored for the treatment of CAD. Over the past decade, the discovery and study of vascular growth factors has shed much light on the complex mechanistic processes of vascular development cogent to a wide variety of disease processes. This research has pooled resources from many disciplines, including molecular sciences, oncology and vascular biology. While this field is still in its infancy, advances in the understanding of the endothelial organ, and the insights gained from clinical studies, will provide a wealth of therapeutic options for modern diseases.

579_Stenting_ch.02

14/8/2001 13:51

Page 37

REFERENCES

References

1. Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 1972; 175:409–416. 2. Wang GL, Semonza GI. Purification and characterization of hypoxia inducible factor 1. J Biol Chem 1995; 270:1230–1237. 3. Brooks PC, Montgomery AM, Rosenfeld M et al. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 1994; 79:1157–1164. 4. Tomanek RJ, Schatteman GC. Angiogenesis: new insights and therapeutic potential. Anat Rec 2000; 261:126–135. 5. Hynes RO, Bader BL, Hodivala-Dilke K. Integrins in vascular development. Braz J Med Biol Res 1999; 32(5):501–510. 6. Varner AJ, Brooks PC, Cheresh DA. The integrin v3: angiogenesis and apoptosis. Cell Adhes Commun 1996; 3:367–374. 7. Basson CT, Kocher O, Basson MD et al. Differential modulation of vascular cell integrin and extracellular matrix expression in vitro by TGF-1 correlates with reciprocal effects on cell migration. J Cell Physiol 1992; 153: 118–128. 8. Swerlick RA, Brown EJ, Xu Y et al. Expression and modulation of the vitronectin receptor on human dermal microvascular endothelial cells. J Invest Dermatol 1992; 99:715–722. 9. Sepp NT, Li L-J, Lee KH et al. Basic fibroblast growth factor increases expression of the v3 integrin complex on human microvascular endothelial cells. J Invest Dermatol 1994; 103:295–299. 10. Senger DR, Ledbetter SR, Claffey KP et al. Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the v3 integrin, osteopontin, and thrombin. Am J Pathol 1996; 149:293–305. 11. Brooks PC, Clark RAF, Cheresh DA. Requirement of vascular integrin v3 for

angiogenesis. Science 1994; 264:569–571. 12. Brooks PC, Strömblad S, Klemke R et al. Antiintegrin v3 blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest 1995; 96:1815–1822. 13. Drake CJ, Cheresh DA, Little CD. An antagonist of integrin v3 prevents maturation of blood vessels during embryonic neovascularization. J Cell Sci 1995; 108:2655–2661. 14. Hammes H-P, Brownlee M, Jonczyk A et al. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nature Med 1996; 2:529–533. 15. Dvorak HF. Tumours: wounds that do not heal. Similarities between tumour stroma generation and would healing. N Engl J Med 1986; 315:1650–1659. 16. Haas TL, Madri JA. Extracellular matrixdriven matrix metalloproteinase production in endothelial cells: implications for angiogenesis. Trends Cardiovasc Med 1999; 9: 70–77. 17. Mignatti P, Rifkin DB. Plasminogen activators and matrix metalloproteinases in angiogenesis. Enzyme Protein 1996; 49:117–137. 18. Buschmann I, Schaper W. The pathophysiology of the collateral circulation. J Pathol 2000; 190:338–342. 19. Henry TD. Therapeutic angiogenesis. BMJ 1999; 318:1536–1539. 20. Griffioen A, Molema G. Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharm Rev 2000; 52:237–268. 21. Jang J, Ho HV, Kwan H et al. Angiogenesis is impaired by hypercholesterolemia: role of assymmetric dimethylarginine. Circulation 2000; 102:1414–1419. 22. Babaei S, Teichert-Kuliszewska K, Monge JC et al. Role of nitric oxide in the angiogenic response in vitro to basic fibroblast growth factor. Circ Res 1998; 82:1007–1015. 23. Matsunaga T, Warltier DC, Weihrauch DW

37

579_Stenting_ch.02

14/8/2001 13:51

Page 38


24.

25.

26.

27. 28.

29. 30.

31.

32.

33.

34.

38

et al. Ischemia-induced coronary collateral growth is dependent on vascular endothelial growth factor and nitric oxide. Circulation 2000; 102:3098–3103. Goligorsky MS, Budzikowski AS, Tsukahara H, Noiri E. Co-operation between endothelin and nitric oxide in promoting endothelial cell migration and angiogenesis. Clin Exp Pharmacol Physiol 1999; 26:269–271. Flamme I, Frolich T, Risau W. Molecular mechanisms of vasculogenesis and embryonic angiogenesis. J Cell Physiol 1997; 173: 206–210. Risau W, Sariola H, Zerwes HG et al. Vasculogenesis and angiogenesis in embryonicstem-cell-derived embryoid bodies. Development 1988; 102:471–478. Nicosia RF, Villaschi S. Autoregulation of angiogenesis by cells of the vessel wall. Int Rev Cytol 1999; 185:1–43. Fleisch M, Billinger M, Eberli FR et al. Physiologically assessed coronary collateral flow and intracoronary growth factor concentrations in patients with 1- to 3-vessel coronary artery disease. Circulation 1999; 100: 1945–1950. Sasayama S, Fujita M. Recent insights into coronary collateral circulation. Circulation 1992; 85:1197–1204. Charney R, Cohen M. The role of the coronary collateral circulation in limiting myocardial ischemia and infarct size. Circulation 1993; 126:937–945. Ito W, Arras M, Scholz D. Angiogenesis but not collateral growth is associated with ischemia after femoral artery occlusion. Am J Physiol 1997; 273:H2155–H2165. Jones MK, Wang H, Peskar BM. Inhibition of angiogenesis by nonsteroidal antiinflammatory drugs; insight into mechanisms and implications for cancer growth and ulcer healing. Nature Med 1999; 5:1418–1423. Cohen M, Rentrop KP. Limitations of myocardial ischemia by collateral circulation during sudden controlled coronary artery occlusion in human subjects: a prospective study. Circulation 1986; 74:469. Marcus ML, Chilian WM, Kanatsuka H et al. Understanding the coronary circulation through studies at the microvascular level.

Circulation 1990; 82:1–7. 35. Schaper W. Control of coronary angiogenesis. Eur Heart J 1995; 16(suppl C):66–68. 36. Nugent MA, Iozzo RV. Fibroblast growth factor-2. Int J Biochem Cell Biol 2000; 32:115–120. 37. Nakagawa K, Chen YX, Ishibashi H et al. Angiogenesis and its regulation: roles of vascular endothelial cell growth factor. Semin Thromb Hemost 2000; 26:61–66. 38. Asahara T, Bauthers C, Zheng LP. Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo. Circulation 1995; 92: 365–371. 39. Folkman J, Merier E, Abernathy C, Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133:275–288. 40. Burgess WH, Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Annu Rev Biochem 1989; 58:575–606. 41. Gerwins P, Skoldenberg E, Claesson-Welsh L. Function of fibroblast growth factors and vascular endothelial growth factors and their receptors in angiogenesis. Crit Rev Oncol Hematol 2000; 34:185–194. 42. Yayon A, Klagsbrun M, Esko J et al. Cell surface heparin-like molecules required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 1991; 64: 841–848. 43. Moscatelli D. Metabolism of receptor-bound and matrix-bound basic fibroblast growth by bovine capillary endothelial cells. J Cell Biol 1988; 107:753–759. 44. Brown KJ, Hendry IA, Parish CR. Acidic and basic fibroblast growth factor bind with differing affinity to the same heparin sulfate proteoglycan on BALB/c3T3 cells: implications for potentiation of growth factor action by heparin. J Cell Biochem 1995; 58:6–14. 45. Slavin J. Fibroblast growth factors: at the heart of angiogenesis. Cell Biol Int 1995; 19:431–444. 46. Sellke FW, Laham RJ, Edelman ER et al. Therapeutic angiogenesis with basic fibroblast growth factor: technique and early results. Ann Thorac Surg 1998; 65: 1540–1544. 47. Neufeld G, Cohen T, Gengrinovitch S,

579_Stenting_ch.02

14/8/2001 13:51

Page 39

REFERENCES

48.

49.

50. 51. 52. 53.

54.

55. 56.

57.

58.

59.

Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999; 13:9–22. Tischer E, Mitchell R, Hartman T et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 1991; 266:11947–11954. Keyt BA, Berleau LT, Nguyen HV et al. The carboxyl-terminal domain (111–165) of vascular endothelial growth factor is critical for its mitogenic potency. J Biol Chem 1996; 271:7788–7795. Zachary I. Vascular endothelial growth factor. Int J Biochem Cell Biol 1998; 30: 1169–1174. Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med 1999; 77:527–543. Veikkola T, Alitalo K. VEGFs, receptors and angiogenesis. Semin Cancer Biol 1999; 9: 211–220. Carmeliet P, Ferreira V, Breier G et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996; 380:435–439. Ferrara N, Carver-Moore K, Chen H et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380:439–442. Dor Y, Keshet E. Ischemia driven angiogenesis. Trends Cardiovasc Med 1997; 7: 289–294. Levy AP, Levy NS, Goldberg MA. Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem 1996; 271:2746–2753. Levy NS, Chung S, Furneaux H, Levy AP. Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. J Biol Chem 1998; 273:6417–6423. Waltenberger J, Claesson-Welsh L, Siegbahn A et al. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 1994; 269:26988–26995. Gerber HP, McMurtrey A, Kowalski J et al. Vascular endothelial growth factor regulates endothelial cell survival through the phos-

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

phatidylinositol 3 -kinase/Akt signal transduction pathway. Requirement for Flk1/KDR activation. J Biol Chem 1998; 273:30336–30343. Fong Gh, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 1995; 376:66–70. Fong GH, Klingensmith J, Wood CR et al. Regulation of flt-1 expression during mouse embryogenesis suggests a role in the establishment of vascular endothelium. Dev Dyn 1996; 207:1–10. Shalaby F, Rossant J, Yamaguchi TP et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995; 376(6535):62–66. Shweiki D, Itin A, Neufeld G et al. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest 1993; 91:2235–2243. Inoue M, Itoh H, Ueda M et al. Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation 1998; 98:2108–2116. Isner JM, Pieczek A, Schainfield R. Clinical evidence of angiogenesis following arterial gene transfer of phVEGF165. Lancet 1996; 348:370–374. Celletti FL, Waugh JM, Amabile PG et al. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nature Med 2001; 7:425–429. Davis S, Aldrich TH, Jones PF et al. Isolation of angiopoietin-1, a ligand for the Tie2 receptor by secretion-trap expression cloning. Cell 1996; 87:1161–1169. Dumont DJ, Gradwohl G, Fong GH et al. Dominant–negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev 1994; 8:1897–1909. Sato TN, Tozawa Y, Deutsch U et al. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 1995; 376:70–74.

39

579_Stenting_ch.02

14/8/2001 13:51

Page 40


70. Suri C, Jones PF, Patan S et al. Requisite role of angiopoietin-1, a ligand for the Tie2 receptor, during embryonic angiogenesis. Cell 1996; 87:1171–1180. 71. Puri MC, Rossand J, Alitalo K et al. The receptor tyrosine kinase TIE is required for the integrity and survival of vascular endothelial cells. EMBO J 1995; 376:70–74. 72. Maisonpierre PC, Suri C, Jones PF et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 1997; 277:55–60. 73. Thurston G, Suri C, Smith K et al. Leakageresistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 1999; 286:2511–2514. 74. Mandriota SJ, Pepper MS. Regulation of angiopoietin-2 mRNA levels in bovine microvascular endothelial cells by cytokines and hypoxia. Circ Res 1998; 83:852–859. 75. Enholm B, Paavonen K, Ristimaki A et al. Comparison of VEGF, VEGF-B, VEGF-C and Ang-1 mRNA regulation by serum, growth factors, oncoproteins and hypoxia. Oncogene 1997; 14:2475–2483. 76. Oh H, Takagi H, Suzuma K et al. Hypoxia and vascular endothelial growth factor selectively up-regulate angiopoietin-2 in bovine microvascular endothelial cells. J Biol Chem 1999; 274:15732–15739. 77. Asahara T, Chen D, Takahashi T et al. Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2 modulate VEGF-induced postnatal neovascularization. Circ Res 1998; 83:233–240. 78. Hanahan D. Signaling vascular morphogenesis and maintenance. Science 1997; 277: 48–50. 79. Teichert-Kuliszewska K, Maisonpierre PC, Jones N et al. Biological action of angiopoietin-2 in a fibrin matrix model of angiogenesis is associated with activation of Tie2. Cardiovasc Res 2001; 49:659–670. 80. Broadley KN, Aquino AM, Hicks B et al. Growth factors bFGF and TGB beta accelerate the rate of wound repair in normal and in diabetic rats. Int J Tissue React 1988; 10: 345–353. 81. Greenhalgh DG, Sprugel KH, Murray MJ, Ross R. PDGF and FGF stimulate wound

40

82.

83.

84.

85.

86.

87.

88.

89.

90.

healing in the genetically diabetic mouse. Am J Pathol 1990; 136:1235–1246. Thompson DW, Li WW, Maragoudakis M. The clinical manipulation of angiogenesis: pathology, side-effects, surprises, and opportunities with novel therapies. J Pathol 2000; 190:330–337. Baffour R, Berman J, Garb JL et al. Enhanced angiogenesis and growth of collaterals by in vivo administration of recombinant basic fibroblast growth factor in a rabbit model of acute lower limb ischemia: dose–response effect of basic fibroblast growth factor. J Vasc Surg 1992; 16(2):181–191. Isner JM, Kaufman J, Rosenfield K et al. Combined physiologic and anatomic assessment of percutaneous revascularization using a Doppler guidewire and ultrasound catheter. Am J Cardiol 1993; 14:70D–86D. Pu LQ, Sniderman AD, Brassard R et al. Enhanced revascularization of the ischemic limb by angiogenic therapy. Circulation 1993; 88:208–215. Takeshita S, Pu LQ, Stein LA et al. Intramuscular administration of vascular endothelial growth factor induces dose-dependent collateral artery augmentation in a rabbit model of chronic limb ischemia. Circulation 1994; 90:II228–II234. Takeshita S, Zheng LP, Brogi E et al. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest 1994; 93:662–670. Harada K, Friedman M, Lopez JJ et al. Vascular endothelial growth factor administration in chronic myocardial ischemia. Am J Physiol 1996; 270:H1791–H1802. Lazarous DF, Shou M, Stiber JA et al. Adenoviral-mediated gene transfer induces sustained pericardial VEGF expression in dogs: effect on myocardial angiogenesis. Cardiovasc Res 1999; 44:294–302. Lopez JJ, Edelman ER, Stamler A et al. Basic fibroblast growth factor in a porcine model of chronic myocardial ischemia: a comparison of angiographic, echocardiographic and coronary flow parameters. J Pharmacol Exp Ther 1997; 282:385–390.

579_Stenting_ch.02

14/8/2001 13:51

Page 41

REFERENCES

91. Lopez JJ, Edelman ER, Stamler A et al. Angiogenic potential of perivascularly delivered aFGF in a porcine model of chronic myocardial ischemia. Am J Physiol 1998; 274:H930–H936. 92. Shou M, Thirumurti V, Rajanayagam S et al. Effect of basic fibroblast growth factor on myocardial angiogenesis in dogs with mature collateral vessels. J Am Coll Cardiol 1997; 29:1102–1106. 93. Baumgartner I, Pieczek A, Manor O et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. Circulation 1998; 97: 1114–1123. 94. Lazarous DF, Unger EF, Epstein SE et al. Basic fibroblast growth factor in patients with intermittent claudication: results of a phase I trial. J Am Coll Cardiol 2000; 36: 1239–1244. 95. Schumacher B, Pecher P, von Specht BU, Stegmann T. Induction of neoangiogenesis in ischemic myocardium by human growth factors. First clinical results of a new treatment for coronary heart disease. Circulation 1998; 97:645–650. 96. Pecher P, Schumacher BA. Angiogenesis in ischemic human myocardium: clinical result after 3 years. Ann Thorac Surg 2000; 69: 1414–1419. 97. Sellke FW, Laham RJ, Edleman ER et al. Therapeutic angiogenesis with basic fibroblast growth factor: technique and early results. Ann Thorac Surg 1998; 65: 1540–1544. 98. Laham RJ, Selke FW, Edelman ER et al. Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: results of a phase I randomized, double-blind, placebo-controlled trial. Circulation 1999; 100:1865–1871. 99. Unger EF, Goncalves L, Epstein SE et al. Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris. Am J Cardiol 2000; 85:1414–1419. 100. Udelson JE, Dilsizian V, Laham RJ et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 improves stress and rest myocardial perfusion abnormalities

101.

102.

103.

104.

105.

106.

107.

108.

in patients with severe symptomatic chronic coronary artery disease. Circulation 2000; 102:1605–1610. Henry TD, Rocha-Singh K, Isner JM et al. Results of intracoronary recombinant human vascular endothelial growth factor (rhVEGF) administration trial. J Am Coll Cardiol 1998; 31(suppl A):65A (abstract). Hendel RC, Henry TD, Rocha-Singh K et al. Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dosedependent effect. Circulation 2000; 101: 118–121. Losordo DW, Vale PR, Symes JF et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 1998; 98:2800–2804. Vale PR, Symes JF, Esakof DD et al. Direct myocardial gene transfer of VEGF165 in patients with end-stage coronary artery disease: 12-month results of a phase I/II clinical trial. J Am Coll Cardiol 2001; 37(suppl A):285A (abstract). Hendel RC, Vale PR, Losordo DW et al. The effects of VEGF-2 gene therapy on rest and stress myocardial perfusion: results of serial SPECT imaging. Circulation 2000; 102(suppl):II-769 (abstract). Fortuin FD Jr, Vale P, Losordo DW et al. Direct myocardial gene transfer of vascular endothelial growth factor-2 (VEGF-2) naked DNA via thoracotomy relieves angina pectoris and increases exercise time: one-year follow-up of a completed dose-escalating phase 1 study. J Am Coll Cardiol 2001; 37(suppl A):285A–286A. Vale PR, Milliken CE, Fortuin D et al. Correlation of NOGA left ventricular electromechanical mapping and radionuclide perfusion imaging demonstrating augmented perfusion of ischemic myocardium in patients undergoing direct myocardial VEGF-2 gene transfer. J Am Coll Cardiol 2001; 37(suppl A):370A. Rosengart TK, Lee LY, Patel SR et al. Sixmonth assessment of a phase I trial of angiogenic gene therapy for the treatment of

41

579_Stenting_ch.02

14/8/2001 13:51

Page 42


coronary artery disease using direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA. Ann Surg 1999; 230:466–470. 108A. Symes JF, Losardo DW, Vale PR et al. Genen therapy with vascular endothelial growth factor for inoperable coronary artery disease. Am Thorac Surg 1999; 68:830–836. 109. Rosengart TK, Lee LY, Patel SR et al. Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 1999; 100:468–474. 110. Li K, Welikson RE, Vikstrom KL, Leinwand LA. Direct gene transfer into the mouse heart. J Mol Cell Cardiol 1997; 29:1499–1504. 111. Rosengart TK, Patel SR, Crystal RG. Therapeutic angiogenesis: protein and gene therapy delivery strategies. J Cardiovasc Risk 1999; 6:29–40. 112. Simons M, Bonow RO, Chronos NA et al. Clinical trials in coronary angiogenesis: issues, problems, consensus: an expert panel summary. Circulation 2000; 102:E73–E86. 113. Laham RJ, Garcia L, Baim DS et al. Therapeutic angiogenesis using basic fibroblast growth factor and vascular endothelial growth factor using various delivery strategies. Curr Interv Cardiol Rep 1999; 1: 228–233. 114. Anderson ED, Mourich DV, Leong JA. Gene expression in rainbow trout (Oncorhynchus mykiss) following intramuscular injection of DNA. Mol Mar Biol Biotechnol 1996; 5: 105–113. 115. McElvaney NG. Is gene therapy in cystic fibrosis a realistic expectation? Curr Opin Pulmonary Med 1996; 2:466–471. 116. Schultz A, Lavie L, Hochberg I et al. Interindividual heterogeneity in the hypoxic regulation of VEGF: significance for the

42

117.

118.

119.

120.

121.

122.

123.

124.

125.

development of the coronary artery collateral circulation. Circulation 1999; 100:547–552. Volpert OV, Ward WF, Lingen MW. Captopril inhibits angiogenesis and slows the growth of experimental tumours in rats. J Clin Invest 1996; 98:671–679. Felesko W, Balkowiec EZ, Sieberth E. Lovastatin and tumour necrosis factor-alpha exhibit potentiated antitumour effects against Ha-ras-transformed murine tumour via inhibition of tumour-induced angiogenesis. Int J Cancer 1999; 81:560–567. Panet R, Markus M, Atlan H. Bumetanide and furosemide inhibited vascular endothelial cell proliferation. J Cell Physiol 1994; 158: 121–127. Van Belle E, Bauters C, Bertrand ME. From the angiogenic response to ischemia to the validation of the concept of ‘therapeutic angiogenesis’. Arch Mal Coeur Vaiss 1998; 91:1159–1170. Rivard A, Silver M, Chen D et al. Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adenoVEGF. Am J Pathol 1999; 154:355–363. Hamaway AH, Lee LY, Crystal RG, Rosengart TK. Cardiac angiogenesis and gene therapy: a strategy for myocardial revascularization. Curr Opin Cardiol 1999; 14: 515–522. Chen H, Chedotal A, He Z et al. Neurolipin2 a novel member of the neurolipin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron 1997; 19:547–559. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 2000; 60:203–212. Hanahan D. Signaling vascular morphogenesis and maintenance. Science 1997; 277: 48–50.

579_Stenting_ch.03

14/8/2001 13:52

Page 43

3 Spot stenting Antonio Colombo and Takahiro Nishida

Introduction and background The treatment of long lesions has historically yielded poor immediate and long-term results when approached with traditional balloon angioplasty.1,2 The length of a coronary lesion is a predictor of procedural failure3–5 and balloon dilatation has been associated with a higher risk of vessel dissection, occlusion, and late restenosis.6–10 The application of new devices such as long balloons11 and rotational atherectomy12,13 increased procedural success but did not improve restenosis rate. Old studies using directional atherectomy (DCA) in long lesions (20 mm) reported high procedural failure (74% success rate) and an increase in complication rate (10.8%).14 In one study, in de novo lesions 10 mm in length, major complication rates were 12.5%, with a success rate of 84%.15 An early report by Robertson et al showed a restenosis rate of 62.5% in lesions 20 mm treated with DCA.16 Randomized device trials performed in long lesions, comparing excimer laser (ELCA) to percutaneous transluminal coronary angioplasty (PTCA) (AMRO trial: Amsterdam Rotterdam trial) and ELCA versus PTCA and versus rotablator in the ERBAC trial (Excimer Laser Rotablator Balloon Angioplasty Comparison), failed to show that any particular device has any advantage, with better follow-up results.17,18 The AMRO trial showed that there were more acute closures (8% versus 0.8%) and a trend towards more restenosis in the ELCA group (52% versus

41%). In the ERBAC trial, both rotablator and ECLA resulted in a better immediate lumen enlargement, but there was no benefit in 6-month restenosis rates. The introduction of coronary stents improved the immediate success in the treatment of long lesions.19 There are now numerous reports on the use of coronary stenting in long lesion. These studies indicate improved immediate outcome, as compared to balloon angioplasty, in terms of low incidence of occlusion.20–22 Despite this advancement, the restenosis rate increases with the length of the lesion23 and with the length of the stent used.24

Intravascular ultrasound guidance and the basis for spot stenting The concept at the basis of spot stenting is to try to obtain the best possible result with balloon angioplasty and to utilize a stent to improve the result where the balloon produced an insufficient lumen or caused an occlusive dissection. A number of studies employing the concept of intravascular ultrasound (IVUS)-guided PTCA in the treatment of coronary lesions produced promising results.25–27 Stone et al reported the early angiographic and clinical results of IVUS-guided PTCA in the Clinical Outcomes with Ultrasound Trial (CLOUT). On the basis of the vessel size and extent of plaque burden in the

43

579_Stenting_ch.03

14/8/2001 13:52

Page 44

SPOT STENTING

reference segment evaluated by IVUS, 73% of the lesions needed upsized balloons (final balloon-to-artery ratio 1.30 0.17) even after achieving an acceptable angiographic result. The success rate of IVUS-guided PTCA was 99%. This angiographic oversized balloon angioplasty, IVUS-guided, resulted in a large final minimal lumen diameter without increased rates of significant dissections or ischemic complications. The Washington Hospital Center reported pilot work on IVUS-guided balloon angioplasty utilizing balloons sized according to the mediato-media diameter as determined by IVUS. The endpoint used in this study was quite ambitious. The authors aimed to achieve a minimal lumen cross-sectional area 70% of the average vessel cross-sectional area, with no lumencompromising dissections. Crossover to stenting was needed in 61% of lesions. Final lumen area in the PTCA group was 6.0 2.0 mm2, with no incidence of abrupt vessel closure. Target lesion revascularization was needed in 17% of lesions. Frey et al reported on a total of 269 patients (358 lesions) who were randomized to IVUS-guided intervention and angiographyguided intervention in the SIPS trial.27 Stenting was performed in about 50% of lesions in both groups. Major adverse cardiac events (MACE) (myocardial infarction, urgent revascularization, death) during hospitalization were fewer with the IVUS-guided interventions. Based on these concepts, we modified the IVUS-guided PTCA approach to include the spot stenting technique. The basis of this approach is that it is quite common, in a long lesion, for balloon angioplasty not to achieve an optimal result throughout the entire length of the lesion. Stents may be utilized to treat the segment where an optimal angioplasty result was not achieved. This approach allows achieving the best lumen enlargement while utilizing the shortest possible stent. A stent will be deployed where lumen dimensions do not meet prespecified IVUS criteria. In contrast to traditional stenting, where a lesion is covered from a proximal normal segment to a distal normal segment, the concept

44

behind this approach tends to minimize stent length. Avoiding the treatment of long lesions with long stents has the goal of minimizing two potential problems: the high restenosis rates associated with long stents, and the pattern of diffuse in-stent restenosis. This technique does not depart from the aim of optimizing the final lumen and covering dissections with a stent. The concept of optimizing inflow and outflow is still valid. The only difference compared to the past is that dissections and results following balloon angioplasty are evaluated by IVUS. The lumen measurements based on IVUS will allow us to determine if a result is adequate or not, without the need to place a stent on any segment lacking a perfect angiographic result. IVUS-guided PTCA with spot stenting is a synergistic strategy utilizing PTCA, stents and IVUS for the treatment of long lesions, particularly if located in small vessels. This is not a method which seeks to compare the results of lesions treated with PTCA against those which receive a stent. It is a technique combining PTCA and stenting, with the objective of achieving a predetermined IVUS luminal result while restricting stent length. This approach is based on the premise that IVUS guidance for the coronary intervention will allow us to: (1) maximize the probability of achieving a prespecified criterion of lumen enlargement with balloon angioplasty, therefore minimizing or removing the need for stenting; and (2) identify the particular segment or segments of a lesion where the luminal result is not optimal, so as to be able to focally implant a stent only at that specific site. One assumption of this strategy is that the late loss following an optimal angioplasty will be lower compared to the one following implantation of a long stent. This approach allows a reduction in restenosis by the attainment of an optimal minimum luminal diameter (MLD) with angioplasty while limiting the stent length.

579_Stenting_ch.03

14/8/2001 13:52

Page 45

OUR EXPERIENCE

Our experience We tested this approach in a prospective study performed between April 1997 and June 1999, which included 146 consecutive patients with 173 lesions. The flow chart for this study is shown in Figure 3.1. The operator evaluates by visual estimate if the lesion to be treated is a long lesion which needs this approach. In general, this decision is taken if the lesion is too long to be treated with a single inflation of a 20 mm long balloon. Long lesions (15 mm) are initially approached with PTCA, utilizing a balloon-toartery ratio of 1 : 1. At the discretion of the operator, IVUS is performed prior to balloon dilatation, and the size of the first balloon is selected according to the IVUS media-to-media measurements. This means that the first step is to perform a preintervention IVUS evaluation. If this initial IVUS assessment is not possible or the operator prefers to defer this first IVUS evaluation, the lesion is first dilated with a balloon sized according to angiography. If extensive calcium is present, rotational atherectomy (Rotablator) can be performed before PTCA. If during balloon dilatation the balloon does not completely expand at 10–12 atm, a cutting balloon can be used. A cutting balloon is indicated if the IVUS study shows a fibrotic or moderately calcified lesion. If, after initial PTCA balloon dilatation, the IVUS criteria are met in all segments of the lesion, the procedure is considered complete. Criteria for success based on IVUS evaluation are: (1) achievement of a lumen cross-sectional area 50% of the vessel crosssectional area at the lesion site; or (2) a minimum true lumen cross-sectional area

5.5 mm2. These success criteria are defined independently of the presence of a dissection, as long as the true lumen cross-sectional area is adequate and meets our prespecified lumen cross-sectional area criterion, and thromolysis in myocardial infarction (TIMI) grade 3 flow is present. If the IVUS criteria are not met, the operator may consider using a bigger balloon or higher pressure, according to lesion morphology

and the IVUS vessel diameters. If balloon upsizing is not possible, a stent is implanted focally only in the segment or segments of the lesion where the IVUS criterion has not been achieved, taking care to use the shortest stent length necessary to obtain an optimal result. IVUS is performed at the end of the procedure to ensure achievement of IVUS success criteria and to document final lumen dimensions. Clinical, angiographic and procedural characteristics of the lesions treated with this approach are shown in Tables 3.1 and 3.2. Measurements were performed with quantitative angiography (QCA) using the QCA-CMS (Medis, Leiden, The Netherlands) by operators not involved in the procedure. These lesions had an average reference vessel diameter of 2.96 0.50 mm and a lesion length of 25.8 8.2 mm. Ninety-one per cent of the

Long lesion

PTCA with B/V ratio 1 :1 by IVUS (media to media)

IVUS criteria: CSA 5.5 mm2 or lumen area 50% of target lesion VA

Criteria not met Criteria met: procedure is complete Larger balloon or higher pressure

Criteria not met

Place a stent only in segments where IVUS criteria not met

Figure 3.1 Flow diagram of IVUS-guided PTCA with spot stenting.

45

579_Stenting_ch.03

14/8/2001 13:52

Page 46

SPOT STENTING

Number of patients Age (years) Male gender Hypertension Diabetes mellitus Hypercholesterolemia Current and previous smoker LVEF (%) Previous MI Multivessel disease Unstable angina pectoris

146 62 10 134 (92%) 82 (56%) 16 (11%) 83 (57%) 86 (59%) 61 12 75 (51%) 109 (75%) 46 (32%)

LVEF, left ventricular ejection fraction; MI, myocardial infarction.

Table 3.1 Baseline characteristics.

lesions approached were complex (type B2 and C). Of the 173 lesions treated, 63 lesions achieved IVUS criteria of success with PTCA alone, while 110 lesions required spot stenting. The vessels involved and the location of the lesion within the vessel had no influence upon whether a stent would eventually be required. Type B1 lesions were more likely to be treated with PTCA alone. The rotablator was adjunctively utilized in 16% of cases overall. The average final balloon-to-artery ratio used was 1.2 0.2, with an average pressure of 14 3.7 atm. The average stent length utilized in the lesions which did not meet IVUS criteria following PTCA (n 110) was 16.9 6.5 mm. This aggressive balloon sizing produced an acute gain of 2.03 0.76 mm. The acute gain was 1.60 0.64 mm for the lesions which were treated with PTCA alone, and 2.28 0.71 mm for the lesions which received a stent. This strategy of IVUS-guided PTCA allowed us to maximize the gain with simple balloon dilatation. It is interesting to note that the acute gain of 1.60 mm achieved with IVUS guidance in the group treated with PTCA alone was similar to

46

the acute gain achieved in the stent arms of the BENESTENT28 and STRESS trials,29 1.40 mm and 1.72 mm, respectively, which used angiographic-guided stenting. In the group of patients requiring additional stenting, we were able to maintain a total stent length much shorter than the lesion length measured with QCA (Figure 3.2).

Case examples We would like to illustrate the spot stenting approach by presenting and discussing two typical cases, which were treated according to this strategy. An example of a typical lesion approached with IVUS-guided PTCA and spot stenting is shown in Figure 3.3. This is a 36.4 mm long lesion located in an obtuse marginal branch. The initial balloon of 3.0 mm was selected according to the visual estimate of an operator with extensive IVUS experience. We used the statement ‘extensive IVUS experience’ in order to help understand why the first balloon selected was oversized compared to the usual practice of angiographic guidance; QCA measurement of this artery showed a reference vessel size of 2.17 mm. This decision shows how frequently

Percentiles plot 100 80 Percentile

Patients

Lesion length

60

Length of stented segment

40 20 0 5 10 15 20 25 30 35 40 45 50 55 Length (mm)

Figure 3.2 Frequency–distribution curve of lesion length versus stented segment length. Contrary to most trials, the final stent length is shorter than the angiographic lesion length.

579_Stenting_ch.03

14/8/2001 13:52

Page 47

CASE EXAMPLES

Number of lesions RCA LAD LCx Proximal Mid Distal Modified ACC/AHA class: B1 B2 C Reference diameter (mm) MLD (mm) Diameter stenosis (%) Lesion length (mm) DCA Rotablator Balloon-to-artery ratio Maximal inflation pressure (atm) Post-MLD (mm) Post-diameter stenosis (%) Number of deployed stents Total deployed length of stents (mm) Slotted tube stent Coil stent

Total

Stent

Balloon

p

173 54 (31%) 88 (51%) 31 (18%) 66 (38%) 86 (50%) 21 (12%)

110 28 (26%) 62 (56%) 20 (18%) 42 (38%) 60 (55%) 8 (7%)

63 26 (41%) 26 (41%) 11 (18%) 24 (38%) 26 (41%) 13 (21%)

0.041 0.06 1.00 1.00 0.11 0.014

10 (16%) 6 (10%) 47 (75%) 2.91 0.53 0.79 0.40 74 14 26.0 8.1 1 (2%) 9 (14%) 1.2 0.2 13 4.0 2.37 0.54 22 13 – – – –

0.030 1.00 0.10 0.34 0.85 0.95 0.83 0.42 0.67 0.62 0.004 0.001 0.001 – – – –

16 (9%) 6 (6%) 16 (9%) 10 (9%) 141 (82%) 94 (86%) 2.96 0.50 2.99 0.48 0.78 0.44 0.77 0.47 74 15 74 15 25.8 8.2 25.7 8.2 6 (4%) 5 (5%) 28 (16%) 19 (17%) 1.2 0.2 1.2 0.2 14 3.7 15 3.4 2.80 0.66 3.04 0.59 11 15 4.2 12 – 1.1 0.4 – 16.9 6.5 – 101 (92%) – 8 (7%)

RCA, right coronary artery; LAD, left anterior descending artery- LCx, left circumflex artery; ACC, American College of Cardiology; AHA, American Heart Association.

Table 3.2 Baseline angiographic characteristics and procedural data.

angiography may underestimate the vessel size. In fact, the IVUS media-to-media measurements (Figure 3.4) indicated a vessel diameter of 2.7 mm. This means that the operator oversized the balloon even according to IVUS measurements. Following the initial balloon dilatation, the angiographic result seen in Figure 3.4 appears acceptable. The IVUS evaluation pointed out that at the center of the lesion the criteria for success were not met (b). A decision to implant a

3.0 mm stent 18 mm long was then taken. Stenting produced an acceptable result in segment (b), while the proximal and distal areas could be safely left with an optimal PTCA result (Figure 3.5). Of note is a small dissection only demonstrated by IVUS in Figure 3.5a. The mean stent length utilized in this 36 mm long lesion demonstrates the concept of spot stenting utilizing a combination of PTCA and stenting during the treatment of the same

47

579_Stenting_ch.03

14/8/2001 13:52

Page 48

SPOT STENTING

Figure 3.3 Case 1. Baseline angiogram. A long lesion is present in an obtuse marginal branch with an angiographic reference size of 2.17 mm.

lesion. Another illustrative example is shown in Figure 3.6. We see a 34.3 mm long lesion in the mid left anterior descending (LAD) on a vessel 3.28 mm in reference size by QCA. The operator initially performed angioplasty utilizing a 3.5 mm cutting balloon with multiple overlapping inflations throughout the lesion length. The subsequent angiogram, shown in Figure 3.7, shows an acceptable angiographic result with small extraluminal dissections. At this time, IVUS evaluation was performed in order to confirm or disprove that this angiographic result was acceptable. Figure 3.7a–d summarize the most relevant IVUS images of the pull-back. The first information listed refers to the size of the vessel. Proximally, this artery had a reference size by IVUS of over 4 mm in diameter; the mid and distal parts of the vessel had sizes slightly less than 3.5 mm. Aware of this information, the operator could have used a larger balloon proximally if this result was not acceptable. As shown in Figure 3.7a, the area stenosis proximally is only 45%. This result is therefore acceptable,

48

and no bigger balloon or stenting is necessary at this level. Slightly more distally, there is a 68% area stenosis despite the use of a balloon of appropriate size (Figure 3.7b). This means that this residual lesion should be stented. The IVUS evaluation allowed placement of a 4.0 mm stent 15 mm long. It may be asked why the operator did not use a 4.0-mm balloon before deciding to proceed with a stent. The answer to this question is that the residual area stenosis and the plaque burden at the lesion site were quite large and unlikely to suggest that a simple angioplasty with a 0.5-mm larger balloon would have made much difference. In addition, the threshold for performing stent implantation in a vessel with a reference size over 3.5 mm is quite low, due to the low restenosis rate in large vessels. The same line of reasoning applies to the other segment shown Figure 3.7c. The final result is shown in Figure 3.8. Figure 3.2 summarizes the frequency–distribution curve depicting the relationship between lesion length and stent length with the spot stenting approach. These curves are not overlapping. This finding is different from our usual experience, in which stent length matches lesion length. In previous studies such as the BENESTENT I and II and STRESS trials28–30 and in many other stent trials, stent length almost always exceeds lesion length. With the spot stenting approach, stent length is actually less than the lesion length (16.9 6.5 mm versus 25.7 8.2 mm). This is an important concept to consider, since there is now evidence to support the view that the length of the deployed stent and the number of stents implanted are implicated as contributing factors to increased restenosis rates.23,24 Based on these notions, stents were limited to the shortest length that allowed the achievement of an adequate lumen. This strategy was not associated with a higher risk of complications. The procedural success rate was 92%. Acute and subacute thrombosis occurred in 0.7% and 1.4% of cases respectively, Q-wave myocardial infarction in 1.4%,

579_Stenting_ch.03

14/8/2001 13:52

Page 49

CASE EXAMPLES

a

a

b

b c

c

Figure 3.4 Case 1. Post balloon angioplasty. 3.0 mm 10 atm. (a) Lumen CSA 2.7 mm2. Vessel CSA 5.4 mm2. Area stenosis 50%. Media-to-media diameter 2.4 2.7 mm. (b) Lumen CSA 2.0 mm2. Vessel CSA 4.6 mm2. Area stenosis 57%. Media-tomedia diameter 1.9 2.7 mm. (c) Lumen CSA 2.9 mm2. Vessel CSA 4.0 mm2. Area stenosis 28%. Media-to-media diameter 2.3 2.3 mm.

49

579_Stenting_ch.03

14/8/2001 13:53

Page 50

SPOT STENTING

a

a

b

b

c

c

Figure 3.5 Case 1. Final angiogram and IVUS images. Crossflex LC 3.0 mm 18 mm, 20 atm. (a) Lumen CSA 2.9 mm2. Vessel CSA 5.7 mm2. Area stenosis 50%. Media-to-media diameter 2.7 2.7 mm. (b) Lumen CSA 5.0 mm2. Strut-to-strut diameter 2.7 2.7 mm. (c) Lumen CSA 2.9 mm2. Vessel CSA 3.6 mm2. Area stenosis 21%. Media-to-media diameter 1.9 2.5 mm.

50

579_Stenting_ch.03

14/8/2001 13:53

Page 51

PROCEDURAL SAFETY

Figure 3.6 Case 2. Baseline angiogram. LAD mid. Reference vessel diameter: 3.28 mm. Lesion length: 34.3 mm.

and emergency and in-hospital CABG in 0.7%; no patient died during the hospital stay.

Selected lesion examples The lesions presented in Figures 3.9 to 3.12 are typical examples of long stenosis which are best suited for the approach of spot stenting.

Procedural safety Historically, balloon angioplasty performed with ‘oversized balloons’ without IVUS guidance has been reported to be associated with poor outcome.31,32 In addition, placing a stent without fully ‘covering’ the lesion has been viewed as dangerous because of the risk of acute and suba-

cute stent thrombosis due to the potential flow disturbance. However, when IVUS is used to guide the intervention, any flow-limiting dissection can be more accurately assessed and a more educated decision can be made regarding this particular segment should be left untreated. The rate of major procedural complications in this study does not differ significantly from what has been reported with traditional coronary stenting in simpler and more focal lesions. In the STRESS trial, Q-wave myocardial infarction occurred in 2.9% of patients, and emergency bypass surgery was done in 2% of patients.29 Therefore, it seems that this approach does not increase the incidence of major procedural complications or subacute events, despite treating a more complex lesion subset.

51

579_Stenting_ch.03

14/8/2001 13:53

Page 52

SPOT STENTING

a

b a b

c

d

c

d

Figure 3.7 Case 2. Post cutting balloon. 3.5 mm 12 atm. (a) Lumen CSA 9.7 mm2. Vessel CSA 17.4 mm2. Area stenosis 45%. Media-to-media diameter 4.3 5.2 mm. (b) Lumen CSA 3.3 mm2. Vessel CSA 10.2 mm2. Area stenosis 68%. Mediato-media diameter 3.6 3.8 mm. (c) Lumen CSA 4.4 mm2. Vessel CSA 13.6 mm2. Area stenosis 68%. Media-to-media diameter 3.9 4.5 mm. (d) Lumen CSA 5.8 mm2. Vessel CSA 8.8 mm2. Area stenosis 34%. Media-to-media diameter 3.2 2.6 mm.

52

579_Stenting_ch.03

14/8/2001 13:53

Page 53

PROCEDURAL SAFETY

a

b

a b c

c d

d

Figure 3.8 Case 2. Final angiogram and IVUS images. 2 Crown 4.0 mm 15 mm, 12 atm (a) Lumen CSA 10.6 mm2. Vessel CSA 17.8 mm2. Area stenosis 41%. Media-to-media diameter 4.4 5.2 mm. (b) Lumen CSA 10.0 mm2. Strut-to-strut diameter 3.4 3.6 mm. (c) Lumen CSA 9.2 mm2. Strut-to-strut diameter 3.2 3.8 mm. (d) Lumen CSA 6.7 mm2. Vessel CSA 10.4 mm2. Area stenosis 36%. Media-to-media diameter 3.5 3.8 mm.

53

579_Stenting_ch.03

14/8/2001 13:53

Page 54

SPOT STENTING

Figure 3.9 Case 3. Baseline. A diffuse diseased lesion located in the proximal and mid right coronary artery.

Figure 3.10 Case 3. Final result following implantation of 4 mm NIR stent 16 mm long in the proximal right coronary artery. All the other segments of the lesions were successfully dilated with PTCA. The haziness present distally to the implanted stent when evaluated with IVUS did not represent a reduction in lumen to suggest the implantation of an additional stent.

(a)

b a

Haziness (b)

Minimal intimal tear

54

579_Stenting_ch.03

14/8/2001 13:53

Page 55

LONG-TERM OUTCOME

Baseline

Figure 3.11 Case 4. Baseline. A distal left anterior descending coronary artery with diffuse disease.

Implications for management of dissections after coronary interventions Traditionally, dissections after PTCA have been considered a risk factor for acute closure. This concept applies also to coronary stenting, where even small edge dissections are usually stented because of the fear of subacute stent thrombosis. However, inducing a dissection is an integral part of lumen enlargement with PTCA, and not all dissections should be judged to be equally

malignant events. A dissection may predispose to an adverse event when it compromises the lumen, leading to subsequent vessel closure. There is no doubt that if a dissection is associated with a decrease in TIMI flow, stenting becomes mandatory. However, when a dissection is associated with a TIMI 3 flow, further evaluation beyond angiographic assessment should be considered. IVUS interrogation or coronary flow measurements are tools useful for this evaluation. A recent study that compared the degree of agreement between angiography and IVUS reported a large discrepancy between these two modalities, particularly when dissections are present.33 With the IVUS-guided PTCA with spot stenting strategy, residual dissections, which were evaluated by IVUS, were present and left untreated in 29% of lesions (82% type B), both in the angioplasty-alone group and in the spot stenting group. These dissections, which were mostly type B, were all associated with TIMI 3 flow, and met the IVUS criterion to leave at the dissection site a residual lumen at least 50% of the vessel area. These dissections, which were left without additional stenting, did not produce an increased risk of acute or subacute adverse events.

Long-term outcome The lesions treated with the IVUS-guided spot stenting approach had a mean vessel diameter of 2.96 mm and a mean length of 25.8 mm, an incidence of binary restenosis of 29%, a target lesion revascularization (TLR) rate of 29%, and a late MACE rate of 33% (11 7.9-month follow-up interval); these are encouraging outcome data compared to what have been reported in the literature with PTCA or stenting long lesions.10,19,21 This approach allows lumen optimization while limiting stent length. This goal is achieved without an increase in procedural complications such as acute or subacute vessel closure. The long-term outcome appears favorable, thanks to the combination of a large lumen achieved with simple balloon dilatation

55

579_Stenting_ch.03

14/8/2001 13:53

Page 56

SPOT STENTING

(b)

(a)

a b Dissection

(a)

(b) Dissection

Figure 3.12 Case 4. IVUS evaluation following angioplasty with 3.0-mm balloon (10 atm).

and with a minimal usage of long stents which may lead to excessive intimal hyperplasia. The major procedural and clinical findings utilizing this technique of IVUS-guided balloon angioplasty assisted by spot stenting are as follows: (1) treatment of long lesions with this technique is associated with a higher procedural success rate than that of the historical controls treated with PTCA, and a similar success rate to those reported with stenting;34–36 (2) complication rates do not increase; and (3) long-term follow-up data suggest that the angiographic

56

restenosis rate and the need for TLR with this approach are better compared to PTCA alone or stenting applied to these types of lesion. Studies which reported a favorable long-term outcome with a strategy of stenting the full lesion length dealt with vessels with a large reference diameter37,38 or used only TLR, myocardial infarction or death as the long-term endpoint. The large reference vessel diameter is known to be an important factor that counteracts the negative effect of lesion length or stent length.39,40 An evaluation limited to TLR or

579_Stenting_ch.03

14/8/2001 13:54

Page 57

PATTERN OF RESTENOSIS

i)

ii)

other major cardiac events without an angiographic follow-up are known to give an optimistic assessment of the long-term results of coronary interventions.41

Pattern of restenosis a b

Figure 3.13 Case 4. Final result following implantation of two stents. (a) ACS RX Duet 3.0 13 mm. (b) ACS RX Duet 3.0 8 mm.

A

One of the main problems following the implantation of long stents is the pattern of restenosis. Diffuse in-stent restenosis and total occlusion are known to be associated with a high incidence of target vessel revascularization following a second intervention.42 Studies have reported that the use of a long stent was associated with a pattern of diffuse in-stent restenosis.24,43 For this reason, it is important not only to try to minimize the restenotic events but also, if restenosis occurs, to try to avoid the pattern of diffuse restenosis or total occlusion.

B

Figure 3.14 (A) Case 5. Baseline. A total occlusion of a right coronary artery with diffuse disease. (B) Case 5. IVUS-guided balloon sizing. After balloon angioplasty. PTCA + cutting balloon (final procedure before stenting). 3.75 mm, 10 atm. 57

579_Stenting_ch.03

14/8/2001 13:54

Page 58

SPOT STENTING

(i)

(ii)

(iii)

C

Figure 3.14 continued After balloon angioplasty. (C) Case 5. Lumen evaluation with IVUS. (i) Lumen CSA 6.7 mm2. Vessel CSA 13.2 mm2. (ii) Lumen CSA 4.0 mm2. Vessel CSA 13.2 mm2. (iii) Lumen CSA 4.5 mm2. Vessel CSA 8.8 mm2.

58

579_Stenting_ch.03

14/8/2001 13:54

Page 59

PATTERN OF RESTENOSIS

3.75 mm

16 atm

D

E

Figure 3.14 continued (D) Case 5. Implantation of a single 15-mm long stent. Final result. (E) Case 5. Follow-up result. Six-month follow-up.

59

579_Stenting_ch.03

14/8/2001 13:55

Page 60

Preintervention angiogram i)

ii)

QCA

iv)

IVUS

iii)

Figure 3.15 Case 6. A long lesion in mid right coronary artery. Notice the large discrepancy between the IVUS and angiographic reference vessel size. QCA: Ref 2.67 mm; MLD 0.98 mm; lesion length 49.2 mm. IVUS: media-to-media 4.1 mm; balloon size 3.75 mm.

(a)

(c)

a b

c (b)

Dissection

Figure 3.16 Case 6. Result following IVUS-guided PTCA. (a) Lumen 3.5 mm2. (b) Lumen 7.3 mm2. (c) LCSA 5.6 mm2.

60

579_Stenting_ch.03

14/8/2001 13:56

Page 61

Stent

Stent: DART 16 mm

After balloon angioplasty

After spot stenting

Figure 3.17 Case 6. Following a single 16-mm stent implantation with a 4-mm balloon.

(a)

Stent

(c)

a

b

c

LCSA 8.1 mm2

LCSA 6.6 mm2

(b)

Dissection LCSA 10.2 mm2

Figure 3.18 Case 6. Final result with IVUS evaluation.

61

579_Stenting_ch.03

14/8/2001 13:56

Page 62

SPOT STENTING

Lesion Stent restenosis Focal (10 mm) Diffuse (10 mm) Total occlusion

27 12 (44%) 15 (56%) 0

Table 3.3 Pattern of stent restenosis.

The 27 restenotic lesions in our experience of spot stenting had a diffuse pattern in 15 lesions (56%). The other 12 restenotic lesions (44%) had a focal pattern and, interestingly, no total occlusion occurred (Table 3.3). This is the reason why we expect that the long-term outcome of patients treated with this modality will be superior among patients who reach an endpoint. The incidence of a further restenotic event is likely to be less for the group of patients with a lower incidence of diffuse in-stent restenosis.

Contraindications There are formal or technical contraindications to this technique. We do not see the advantage of the more complex approach of spot stenting when the long lesion is located on a vessel with an angiographic reference size of 3.5 mm or larger. The restenosis rate of long stents implanted on vessels with a large reference diameter is low, and the difference compared to a

62

short stent is not large enough to justify a more complex and expensive approach.39,40 The most practical strategy for a long lesion located on a vessel with a reference diameter of 3.5 mm or larger is direct stenting with full lesion coverage. An area of concern is when the operator is not confident with the interpretation of the IVUS images. The need to rely on the judgment concerning the evaluation of IVUS findings is a key element for the success of this procedure. In particular, the decision not to stent a dissection depends on the correct measurement of the true residual lumen. A mistake in this evaluation may leave untreated an occlusive dissection which may cause late stent thrombosis. In a situation of uncertainty or inadequate IVUS image quality, such as the one related to the presence of nonuniform rotational artifacts, the operator may use doppler coronary flow reserve or measurement of pressure gradients with calculation of the fractional flow reserve to evaluate if a final result is adequate.

Conclusions IVUS-guided balloon angioplasty assisted by spot stenting allows safe treatment of long lesions. This strategy requires utilization of stents in the majority of cases; most of the stents utilized are shorter than the original length of the lesion. Procedural complications are low, and long-term outcome appears to be superior to the results achieved in historical controls, which utilize PTCA alone, or stenting where the lesion is covered from normal segment to normal segment.

579_Stenting_ch.03

14/8/2001 13:56

Page 63

REFERENCES

References

1. Ellis S, Roubin G, King SI et al. Importance of stenosis morphology in the estimation of restenosis risk after elective percutaneous transluminal coronary angioplasty. Am J Cardiol 1989; 63:30–34. 2. Tenaglia A, Zidar J, Jackman J et al. Treatment of long coronary artery narrowings with long angioplasty balloon catheters. Am J Cardiol 1993; 71:1274–1277. 3. Meier B, Gruentzig AR, Hollman J et al. Does length or eccentricity of coronary stenoses influence the outcome of transluminal dilatation? Circulation 1983; 67:497–499. 4. Ellis SG, Roubin GS, King SB 3rd et al. Angiographic and clinical predictors of acute closure after native vessel coronary angioplasty. Circulation 1988; 77:372–379. 5. Detre KM, Holmes DR Jr, Holubkov R et al. Incidence and consequences of periprocedural transluminal coronary angioplasty registry. Circulation 1990; 82:739–750. 6. Serruys PW, Luijten HE, Beatt KJ et al. Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. Circulation 1988; 77:361–371. 7. Bourassa MG, Lesperance J, Eastwood C et al. Clinical, physiologic, anatomic and procedural factors predictive of restenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1991; 18:368–376. 8. Pepine CJ, Hirshfeld JW, MacDonald RG et al. A controlled trial of corticosteroids to prevent restenosis after coronary angioplasty. Circulation 1990; 81:1753–1761. 9. Ryan TJ, Bauman WB, Kennedy JW et al. Guidelines for percutaneous transluminal angioplasty: a report of the American College of Cardiology/American Heart Association task force on assessment of diagnostic and therapeutic cardiovascular procedures (Subcommittee on percutaneous transluminal coronary angioplasty). J Am Coll Cardiol 1993; 22:2033–2054. 10. Hirshfeld JW Jr, Schwartz JS, Jugo R et al.

11.

12.

13.

14.

15.

16.

17.

18.

19.

Restenosis after coronary angioplasty: a multivariate statistical model to relate lesion and procedure variables to restenosis. The M-HEART Investigators. J Am Coll Cardiol 1991; 18:647–656. Cannon AD, Roubin GS, Hearn JA et al. Acute angiographic and clinical results of long balloon percutaneous transluminal coronary angioplasty and adjuvant stenting for long narrowings. Am J Cardiol 1994; 73:635–641. Bertrand ME, Lablanche JM, Leroy F et al. Percutaneous transluminal coronary rotary ablation with Rotablator (European experience). Am J Cardiol 1992; 69:470–474. Warth DC, Leon MB, O’Neill 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. Baim D, Hinohara T, Holmes D et al. Results of directional coronary atherectomy during multicenter preapproval testing. Am J Cardiol 1993; 72:6E–11E. Hinohara T, Rowe MH, Tcheng JE et al. Effect of lesion characteristics on outcome of directional coronary atherectomy. J Am Coll Cardiol 1991; 17:1112–1120. Robertson G, Selmon M, Hïnohara T et al. The effect of lesion length on outcome of directional coronary atherectomy. Circulation 1990; 82:III-623. Appleman YE, Piek J, Redekop WK et al. Excimer laser angioplasty versus balloon angioplasty in longer coronary lesions: a multivariate analysis. Circulation 1995; 92:I-74. Foley DP, Appleman YE, Piek JJ. Comparison of angiographic restenosis propensity of excimer laser coronary angioplasty and balloon angioplasty in the Amsterdam Rotterdam (AMRO) trial. Circulation 1995; 92: I-477. Kobayashi Y, De Gregorio J, Kobayashi N et al. Comparison of immediate and follow-up results of the short and long NIR stent with

63

579_Stenting_ch.03

14/8/2001 13:56

Page 64

SPOT STENTING

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

64

the Palmaz–Schatz stent. Am J Cardiol 1999; 84:499–504. Roguin A, Grenadier E, Peled B et al. Acute and 30-day results of the serpentine balloon expandable stent implantation in simple and complex coronary arterial narrowings. Am J Cardiol 1997; 80:1155–1162. Williams IL, Thomas MR, Robinson NM et al. Angiographic and clinical restenosis following the use of long coronary Wallstents. Cathet Cardiovasc Interv 1999; 48:287–293. Antoniucci D, Valenti R, Santoro GM et al. Preliminary experience with stent-supported coronary angioplasty in long narrowings using the long Freedom Force stent: acute and sixmonth clinical and angiographic results in a series of 27 consecutive patients. Cathet Cardiovasc Diagn 1998; 43:163–167. Kastrati A, Elezi S, Dirschinger J et al. Influence of lesion length on restenosis after coronary stent placement. Am J Cardiol 1999; 83:1617–1622. Kobayashi Y, De Gregorio J, Kobayashi N et al. Stented segment length as an independent predictor of restenosis. J Am Coll Cardiol 1999; 34:651–659. Stone GW, Hodgson JM, St Goar FG et al. Improved procedural results of coronary angioplasty with intravascular-ultrasound guided balloon sizing. Circulation 1997; 95:2044–2052. Abizaid A, Mehran R, Pichard AD et al. Results of high pressure ultrasound-guided ‘over-sized’ balloon PTCA to achieve ‘Stentlike’ results. J Am Coll Cardiol 1997; 29(suppl A):280A. Frey AW, Muller Ch, Hodgson J, Roskamm H. Fewer acute major adverse cardiac events (MACE) by ultrasound guided interventions: findings from the strategy of intracoronary ultrasound guided PTCA and stenting (SIPS) trials Eur Heart J 1997; 18(suppl):862 (abstract). 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. Benestent Study Group. N Engl J Med. 1994; 331:489–495. Fischman DL, Leon MB, Baim DS et al. A ran-

30.

31.

32. 33.

34.

35.

36.

37.

38.

domized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N Engl J Med. 1994; 331:496–501. Serruys PW, van Hout B, Bonnier H et al. Randomised comparison of implantation of heparin-coated stents with balloon angioplasty in selected patients with coronary artery disease. Lancet 1998; 352:673–681. Roubin GS, Douglas JS, King SB et al. Influence of balloon size on initial success, acute complications, and restenosis after percutaneous transluminal coronary angioplasty. Circulation 1988; 78:557–565. Nichols AB, Smith R, Berke AD et al. Importance of balloon size in coronary angioplasty. J Am Coll Cardiol 1989; 13:1094–1100. Ozaki Y, Violaris A, Kobayashi T et al. Comparison of coronary luminal quantitation obtained from intracoronary ultrasound and both geometric and videodensitometric quantitative angiography before and after balloon angioplasty and directional atherectomy. Circulation 1997; 96:491–499. Ozaki Y, Violaris AG, Hamburger J et al. Short- and long-term clinical and quantitative angiographic results with the new, less shortening Wallstent for vessel reconstruction in chronic total occlusion: a quantitative angiographic study. J Am Coll Cardiol 1996; 28:354–360. Gambhir DS, Sudha R, Trehan V et al. Immediate and six-month outcome of self-expanding Wallstent for long lesions in native coronary arteries. Indian Heart J 1997; 49:53–59. De Scheerder IK, Wang K, Kostopoulos K et al. Treatment of long dissections by use of a single long or multiple short stents: clinical and angiographic follow-up. Am Heart J 1998; 136:345–351. Mehran R, Hong M, Lansky A et al. Vessel size and lesion length influence late clinical outcomes after native coronary artery stent placement. Circulation 1997; 96:1520 (abstract). Kornowski R, Bhargava B, Fuchs S et al. Procedural results and late clinical outcomes after percutaneous interventions using long ( or 25 mm) versus short (20 mm) stents. J Am

579_Stenting_ch.03

14/8/2001 13:56

Page 65

REFERENCES

Coll Cardiol 2000; 35:612–618. 39. Hong MK, Park SW, Mintz GS et al. Intravascular ultrasonic predictors of angiographic restenosis after long coronary stenting. Am J Cardiol 2000; 85:441–445. 40. Rozenman Y, Mereuta A, Schechter D et al. Long-term outcome of patients with very long stents for treatment of diffuse coronary disease. Am Heart J 1999; 138:441–445. 41. Baim DS, Kuntz RE. Appropriate uses of angiographic follow-up in the evaluation of

new technologies for coronary intervention. Circulation 1994; 90:2560–2563. 42. Mehran R, Dangas G, Abizaid AS et al. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. Circulation 1999; 100:1872–1878. 43. Lee SG, Lee CW, Hong MK et al. Predictors of diffuse-type in-stent restenosis after coronary stent implantation. Cathet Cardiovasc Intervent 1999; 47:406–409.

65

579_Stenting_ch.03

14/8/2001 13:56

Page 66

579_Stenting_ch.04

14/8/2001 14:01

Page 67

4 Ostial and bifurcation disease Alexander JR Black, Jean Fajadet, Jean Marco

Overview Advances in angioplasty equipment and adjunctive medical therapy have been associated with improved immediate and long-term outcomes. However, the treatment of ostial and bifurcation lesions continues to be problematic, with reduced procedural success rates and an increased need for repeat procedures during long-term follow-up. With the exception of aorto-ostial disease, which presents its own unique challenges in terms of accurate visualization and precise instrumentation, these situations share a common pathologic basis, largely related to the likelihood of plaque shift with resultant axial redistribution, which results in the so-called ‘snow-plough’ effect.1,2 A systematic approach to management in these situations requires an understanding of the different possible ‘permutations’ of lesion morphologic type and the likely outcomes after intervention according to these anatomic subtypes. Ideally, a clear rationale for therapeutic decision-making will be based on this kind of information, indicating the need for side-branch protection, the appropriateness of debulking, and whether to deploy one, two (or more) stents. As well as requiring more attention to overall strategic considerations, bifurcation and aorto-ostial lesions commonly pose greater technical challenges, with the potential need to use two guidewires, balloons or stents demanding a higher degree of technical skill in the case of bifurcation disease, and difficulties in guide catheter manipulation

and stent positioning adding to the complexity of aorto-ostial intervention. The likelihood of a higher rate of in-hospital major adverse coronary events (MACE) and a higher restenosis rate when compared to non-bifurcation/ostial lesions must be taken into account if percutaneous intervention is chosen ahead of alternative treatment strategies.

Classification systems for bifurcation/ostial lesions Bifurcation lesions These can be classified according to the angulation of the bifurcation and the specific location of the plaque burden (Figures 4.1–4.7). Angulation between the branches of the bifurcation is an important issue in terms of side-branch access and the likelihood of significant plaque shift, and the relationship of the amount of plaque material with respect to the proximal main, distal main and side-branches will dictate the likely consequences of any plaque shift which occurs. Both of these issues will influence the resultant treatment strategy and must be consciously considered in every case. Notwithstanding these issues, we are currently using a reasonably standard algorithm in the majority of cases (Table 4.1): • Y-shaped lesions—The angulation between the side-branch and distal main branch is less than 70°. Access to the side-branch is usually

67

579_Stenting_ch.04

14/8/2001 14:01

Page 68

OSTIAL AND BIFURCATION DISEASE

Figure 4.1 Type 1 lesion involving main branch and side-branch.

Figure 4.2 Type 2 lesion sparing ostium of side-branch.

Figure 4.3 Type 3 lesion proximal to branch.

Figure 4.4 Type 4 lesion involving both distal with sparing of main branch proximally.

Figure 4.5 Type 4a lesion involving main branch distal to side-branch only.

Figure 4.6 Type 4b lesion with sparing of main branch and involvement of side-branch ostium only.

Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7 Step 8 Step 9 Step 10

Wire all side-branches 2.25 mm in diameter Dilate the side-branch before the main branch is stented Kissing balloon inflation is always performed after main branch stenting, and again if the side-branch is stented Stent the main branch Use the T-technique, stenting into the main branch first ‘Jail’ the side-branch wire with the main branch stent The side-branch may be stented first (see text) Side-branch stenting should be provisional ‘Modified’ Y-technique?—only in cases of type 4b lesions Never use the ‘culotte’ or ‘V’ techniques

Table 4.1 Suggested scheme for bifurcation stenting.

68

579_Stenting_ch.04

14/8/2001 14:01

Page 69

APPROACH TO TREATMENT

easy, but plaque shifting is also more pronounced. • T-shaped lesions—The angulation between the side-branch and distal main branch is more than 70°. Access to the side-branch is usually more difficult, and plaque shifting is less important. This angulation is usually reduced after both branches of the bifurcation have been wired, possibly changing the properties of a T-shaped lesion to those of a Y-shape (Figure 4.7). The distribution of plaque material around the point of bifurcation may predict the response to balloon/stent instrumentation and enable more appropriate selection of treatment strategy: • Type 1 lesions—These are defined as ‘true’ bifurcation lesions involving the main branch proximal and distal to the bifurcation and the ostium of the side-branch (Figure 4.1).

• Type 2 lesions involve the main branch at the bifurcation site but not the ostium of the sidebranch (Figure 4.2). • Type 3 lesions are located in the main branch, proximal to the bifurcation. These are also considered ‘bifurcation’ lesions, because they are frequently associated with a deterioration of the ostium of one or both distal branches after balloon percutaneous transluminal coronary angioplasty (PTCA) and coronary stenting due to the ‘snow-plough’ effect (Figure 4.3). • Type 4 lesions are located at the ostium of each branch of the bifurcation in the absence of lesions in the proximal part of the bifurcation (Figure 4.4). If only one branch is involved, they can be subclassified as follows; the treatment of ‘branch vessel ostial lesions’ is discussed in the appropriate section. Type 4a: ‘Main branch ostial lesion’ (Figure 4.5). Type 4b: ‘Side-branch ostial lesion’ (Figure 4.6).

Ostial lesions These can be divided into three categories, with differing pathologies and behaviour according to site:

90°

• aorto-ostial native coronary • aorto-ostial graft • branch vessel ostial disease.

90°

70°

The last category shares some of the properties of bifurcation disease, with the possibility of plaque shift (types 4a and 4b above), whereas aorto-ostial disease presents unique challenges, with difficult visualization and resistance to dilatation.

Approach to treatment Figure 4.7 A ‘T’-shaped lesion (>70° between branch and distal main vessel) may become ‘Y’-shaped (70°) after wiring.

Bifurcation lesions Side-branch occlusion has long been recognised as a complication of coronary angioplasty,3,4 and

69

579_Stenting_ch.04

14/8/2001 14:01

Page 70


early strategies for dealing with this problem evolved into the double guidewire and balloon technique.5 Additional measures such as ‘debulking’ have been reported to improve outcome.6,7 With the advent and increased application of coronary stenting together with refinements in stent and delivery equipment design, a variety of technical approaches have been proposed to deal with this problem.8–11 When faced with such an array of possibilities, the interventionist must select the most appropriate management strategy for each individual case. Several issues must be addressed.

Does the side-branch need protection? In a study of 175 patients (182 lesions), Aliabadi et al12 reported side-branch occlusion in 43 of 223 side-branches, the majority (67%), following high-pressure balloon inflation. By multivariate analysis, the presence of >50% ostial narrowing of side-branches that arose from within or just beyond the diseased portion of the parent vessel was a powerful predictor (odds ratio 40, p < 0.0001) of subsequent closure, accounting for 80% of the observed cases. It is worth noting that at 9-month follow-up, there was no difference in combined clinical events between those patients with and without side-branch occlusion. Fischman et al13 evaluated the fate of side-branches 1 mm in diameter (n 66 of 57 stent placements in 167 consecutive lesions). Of 60 side-branches patent after initial balloon angioplasty, 3 subsequently occluded after stent placement; all 3 had 50% ostial stenosis at baseline. At 6-month follow-up, all were patent. Does the side-branch need balloon dilation? In general, this will depend on the size (>2–2.5 mm) and distribution of the branch, the initial angiographic result after stenting of the main vessel, and any ischemic consequences resulting from compromised flow. Does the side-branch need a stent? Al Suwaidi et al14 reported the results of stenting

70

for ‘true bifurcation’ (type 1) stenoses, where both parent and branch vessels were >2.0 mm diameter by visual estimate. Angiographic success occurred in 75 of 77 (97.4%) instances where the side-branch was dilated through the struts of the parent vessel stent and not stented, and 51 of 54 (94.4%, p NS) cases where the side-branch was stented (‘Y’ n 19, ‘T’, n 31). At 1-year follow-up, there were no significant differences between patients receiving one versus two stents with respect to survival, myocardial infarction (MI), coronary angioplasty bypass graft (CABG) or repeat revascularization; however, the authors noted a trend to better long-term outcome in patients receiving only a single stent. Moreover, MACE during 1 year of follow-up was significantly more frequent in patients who had undergone a ‘Y’-type bifurcation stenting strategy, occurring in 86.3% of this group compared with only 30.3% in those who had undergone ‘T’ stenting (p 0.004). Pan et al15 reported a series of 70 patients undergoing bifurcation stent implantation, 47 receiving a single stent in the parent vessel, and 23 receiving a stent to each branch in a ‘T’ configuration. There was no significant difference in procedural success (89% versus 91% respectively, p NS); however, major cardiac events at 18-month follow-up were more frequent in patients receiving stents to both branches (56% versus 25%, p < 0.05). A similar study by Yamashita et al16 reported a series of 92 patients undergoing bifurcation stenting, comparing those who received a stent to each branch (n 53) with those receiving a single stent to only the parent vessel with balloon angioplasty of the side-branch (n 39). In-hospital MACE were only reported in patients who received stenting to both vessels, with no events in the single-stent group (13% versus 0%, p < 0.05). Six-month angiographic restenosis (62% versus 48%), target lesion restenosis (TLR) (38% versus 36%) and MACE (51% versus 38%), although numerically greater for patients receiving stents to both vessels, were not significantly different.

579_Stenting_ch.04

14/8/2001 14:01

Page 71

PRACTICAL APPROACH

Ostial lesions True ostial lesions are less frequent but can be technically demanding, with a significantly increased complication rate after balloon angioplasty compared with non-ostial locations. A spectrum of different anatomic locations can be covered by this definition, including aorto-ostial lesions (native vessel or graft ostial location), as well as branch ostial lesions which can be further subdivided into major branch ostial lesions (ostial left anterior descending (LAD) or circumflex) and secondary branches such as diagonal or obtuse marginal branches. Initial attempts to deal with this problem by balloon dilation alone were marked by a high rate of primary failure in addition to increased rates of restenosis following successful procedures.17 The main technical advances which have been explored in an attempt to achieve an improvement in outcome have been debulking devices and coronary stents. The use of debulking, by either directional atherectomy, rotational atherectomy or laser, was compared with a historical series of balloon-only angioplasties by

Baseline

Sabri et al,18 who noted an improvement in acute gain following the use of debulking devices, and a suggestion of reduced immediate complication rates. This finding has been confirmed in other studies;19 however, restenosis rates have been unacceptably high.20,21 Rocha-Singh,22 in an early report of stenting for aorto-ostial disease, reported a favorable binary restenosis rate of 27.8% at 6-month follow-up in 42 patients receiving Palmaz–Schatz stents for aorto-ostial disease. More recently, the use of cutting balloon angioplasty has been advocated;23 however, is it likely that this technology will need to be used adjunctively with stenting except in anatomic situations where plaque shift into adjacent branches is undesirable (e.g. ostial left circumflex (LCX), proximal diagonal).24

Practical approach Case examples that illustrate some of the points of this chapter are included (Figures 4.8–4.13 (bifurcation angioplasty), Figures 4.14–4.19 (ostial disease)). It must be emphasized,

Final result

Figure 4.8 Case 1 The small sub-branch of the obtuse marginal is considered too small to warrant protection and is occluded after stenting the main branch (arrows) without clinical sequelae.

71

579_Stenting_ch.04

14/8/2001 14:01

Page 72


however, that each case encountered will need to be assessed according to its specific clinical and anatomic characteristics, within the framework of the general guidelines offered.

Bifurcation lesions If the side-branch is small in diameter or distribution, it may be reasonable to concentrate on the

main branch without specific attention to the side-branch (Figure 4.8). More significant sidebranches will require protection and probably balloon dilatation, for which we had previously practiced ‘provisional’ kissing inflation (Figures 4.9–4.11). Our current practice is to perform kissing balloon inflation in all cases of bifurcation disease (Figures 4.11–4.13), following stent implantation but also after initial branch vessel

A

Baseline Final result

B

Figure 4.9 Case 2 Stent to LAD with balloon to diagonal, no final kissing balloon inflation. Note plaque shift into diagonal ostium after stenting LAD (inset A) treated by balloon inflation through stent struts (inset B) followed by low pressure ‘non-kissing’ balloon inflation in LAD—final result in right panel.

Baseline

Final result

Figure 4.10 Case 3 Bifurcation left main disease predominantly involving ostium of LAD (type 2)—after left main LAD stenting, there is plaque shift into the ostium of the LCX (inset) which is corrected by balloon inflation in the LCX with alternate (‘non-kissing’) balloon inflation without stenting the LCX.

72

579_Stenting_ch.04

14/8/2001 14:01

Page 73

PRACTICAL APPROACH

A

B Baseline – Type 2 Y-shaped lesion

C Final result

Figure 4.11 Case 4 Stent to type 2 lesion LAD, with marked plaque shift into diagonal (inset A), with residual stenosis origin of diagonal after ‘non-kissing’ inflation diagonal (inset B), followed by kissing balloon inflation LAD/diagonal (inset C).

Baseline – Type 1 lesions D1 and D2 A

C

B

D

Final result

Figure 4.12 Case 5 Complex type 1 lesion involving proximal LAD and first and second diagonal branches. Both diagonal branches are wired first, followed by the LAD (inset A). The two diagonal branches are stented first in ‘T’ fashion (inset B), followed by ‘kissing balloon’ inflations to the LAD and each diagonal separately (inset C, D).

73

579_Stenting_ch.04

14/8/2001 14:01

Page 74


A

B

Baseline

C

D

Final result

Figure 4.13 Case 6 Kissing stent (T-type). Complex type 1 lesion. A dissection plane is noted in the ostial segment of the diagonal (inset A, arrowed) after stent implantation in the LAD. The diagonal is rewired through the LAD stent and dilated (inset B) and stented (inset C) before a final ‘kissing’ inflation (inset D). The final result is satisfactory in both branches.

dilation in most cases. As a general approach to the management of bifurcation lesions, we suggest the following 10 steps: 1. Wire all side-branches 2.25 mm in diameter or if there is ostial disease in significant side- branches 2 mm in diameter. Cross the most difficult part of the lesion first. 2. Dilate the side-branch before the main branch is stented, unless its ostium is completely normal and remains normal after balloon inflation in the main branch. 3. Kissing balloon inflation can be performed before main branch stenting, and is always performed after main branch stenting, and again if the side-branch is stented.

74

4. Stent the main branch even if the result of balloon dilatation is satisfactory. 5. Use the T-technique, stenting into the main branch first in most cases. 6. ‘Jail’ the side-branch wire with the main branch stent, unless a decision has been made to stent the side-branch first. 7. The side-branch may be stented first (modified T-technique) if the origin of the sidebranch remains 90° after wiring, with significant ostial disease or moderate–severe calcification, or if there is a significant dissection in the side-branch after main/sidebranch kissing inflation, which might compromise our ability to wire or stent the side-branch after the main branch has been stented.

579_Stenting_ch.04

14/8/2001 14:01

Page 75

PRACTICAL APPROACH

8. Side-branch stenting should otherwise be provisional, depending on the result after kissing inflation into the main/side-branch. 9. Consider a ‘modified’ Y-technique (stenting into the distal side and main branches only), only in cases of type 4b lesions where the proximal segment remains completely normal after balloon inflation. Avoid or minimize stenting back into the proximal segment. 10. Never use the ‘culotte’ or ‘V’ techniques, in view of increased adverse outcomes with these techniques and a lack of any benefit in terms of technical success.

Ostial lesions (Table 4.2) Native vessel aorto-ostial disease It is important to determine the degree of calcification, as this will impact on the likely success of balloon dilation and the choice of overall strat-

egy—if available, consider the use of intravascular ultrasound (IVUS) when calcification is not evident angiographically, and use rotational atherectomy if there is >90° circumferential calcification. When rotational atherectomy is used, we recommend a stepped-burr approach, aiming for a burr/artery ratio of 0.7–0.8. In general, vessels >2.5 mm in diameter will then be stented with a slotted tube stent. Positioning of the stent with respect to the aortic margin of the lesion is of critical importance, as distal placement will not cover the segment most at risk of recoil, and proximal placement will put the stent struts at risk of trauma from the guiding catheter. After stent implantation, we recommend flaring the proximal end of the stent with an oversized balloon. Given the need for a much more conservative strategy when dealing with left main than with right coronary disease, the overall strategy differs somewhat between the left and right coronary arteries:

Aorto-ostial Left main Always stent Rotational atherectomy if any calcification CABG if heavy calcification, multi-vessel disease or impaired left-ventricular function Right coronary Rotational atherectomy if > mild calcification CABG if heavy calcification or poor left ventricular function Graft Always stent Rotational atherectomy if severe calcification Branch vessel LAD DCA for ‘Y’ shaped lesions Rotational atherectomy if calcified Stent for ‘T’ shape Circumflex Avoid plaque shift into LAD—DCA if Y-shaped DCA, directional coronary atherectomy.

Table 4.2 Suggested scheme for ostial stenting.

75

579_Stenting_ch.04

14/8/2001 14:01

Page 76


• Ostial left main: if non-calcified, we suggest balloon and stent; may consider direct stent (Figure 4.14), DCA stent, or cutting balloon stent. If there is mild–moderate calcification, consider rotational atherectomy and stent; if heavily calcified or in the presence of multivessel coronary disease or impaired left ventricular (LV) function, consider CABG. • Ostial right coronary artery (RCA) lesions: if non-calcified or mildly calcified, treat as for non-calcified LCA, although stenting is less ‘mandatory’ if there is a good result following debulking. Consider a direct stent strategy for non-calcified lesions (Figure 4.15). If there is heavy calcification, consider rotational atherectomy for single-vessel disease, and CABG if there is multivessel disease with impaired LV function. • Guide catheters to consider for left main include a standard or short-tip left Judkins (if using femoral access), extra-backup shape or AL2. For RCA ostial disease, consider a shorttip right Judkins, AR1 or AR2, or AL1 if there is superior take-off. • Initial angiographic views suggested are either 10–20° LAO or shallow RAO with mild caudal angulation for the LCA, and 30° LAO or lateral for the RCA.

A

Bypass graft aorto-ostial disease Generally, these lesions are difficult to dilate and elastic, and are less calcified than native aortoostial lesions (Figure 4.16). Elastic recoil is a major problem, and stenting with or without prior debulking by rotational atherectomy will be needed. Our practice is to reserve atherectomy for cases with marked visible calcification. If the graft is diffusely diseased and anastamosed to the LAD or if there are other grafts in need of intervention, consider redo-CABG, especially if mammary conduits are available. Guide catheter selection will depend on the placement of the aortic anastamosis—the multipurpose catheter is useful if there is a downward take-off of the graft; otherwise consider a right Judkins or Hockey stick. Branch ostial disease This is a much more frequent problem, and is complicated by marked elastic recoil in the target vessel and also by the possibility of plaque shift into adjacent vessels. For ostial LAD lesions (Figures 4.17 and 4.18), consider atherectomy (rotational if mild–moderately calcified, directional if not) stenting, especially for Y-shaped lesions, where there is a higher risk of plaque shift into the ostium of the LCX. If the LAD is 40%, compared with 67% and 22% 12% respectively when LVEF was 40%) and distal bifurcation lesions involving the ostium of the left anterior descending artery (LAD) or the left circumflex artery (LCX). • Low-risk patients with good ventricular function who desire not to have bypass surgery. • Patients with preserved LV function, left main stem anatomically suitable for stenting and multivessel disease who are good candidates for CABG but have anatomic characteristics such as lack of calcium, short lesion length, location in large-caliber vessel and lack of involvement of a branching vessel which appear suitable for percutaneous interventions.

Contraindications These may be ‘relative’, depending on clinical need: • Patients with reduced LV function (LVEF < 40%). • Good candidates for CABG with distal bifurcation lesion and reduced LVEF. • Good candidates for CABG with distal bifurcation lesion and occluded right coronary artery. • Patients with multivessel disease with reduced LV function and anatomic characteristics suitable for coronary artery bypass surgery. • Heavily calcified left main disease. • Short (16 atm for 120 before wiring LM

Guide 8 Fr; IABP ready;c BP >120

Stent the RCA first, then left-sided lesions as right →→→

Wire

Distal LAD

Exchange rota wire for better support

Predilate

Undersized branch balloon, 15 s at 18 atm. Wait 1 min

Appropriatesize balloon (by 0.5 mm) at low (8 atm) pressure

Stentc

Ensure uninflated balloon passes freely before stenting, >16 atm for 16 atm for 15–20 mm) within moderately tortuous vessels with a diameter 5 cases

Level 3: requires >20 cases

Level 4: not recommended

Vessel

Proximal and mid LAD

Ostial LAD

Degenerated vein graft, unprotected left main

Angle of take-off Tortuosity Lesion length Vessel diameter Vessel dissection

Shallow None 10 mm 3.0 mm Absent

Shallow Mild 10 mm 3.0 mm Absent

Distal LAD, RCA, non-degenerated vein graft, RCX, protected left main Moderate Moderate 11–20 mm 2.5 mm Focal flap, not angulated

Lesion morphology

Eccentric, concentric Restenosis None

Ulcerated

Thrombus

De novo Mild

All Moderate

Lesion type Calcification

Severe Severe >20 mm 3 times normal was seen in 16% of DCA and 6% of PTCA patients, and elevation >5 times normal was seen in 9% of DCA and 4% of PTCA patients. One-year follow-up, however, revealed no overall relationship between the elevation of periprocedural CPK/CPK-MB and 1-year cumulative mortality rate.15

Perforation Coronary arterial perforation is rare and does not exceed 1% in the larger reported series. It is generally caused by a misdirected or overenthusiastic cut of normal arterial wall. Perforation can be treated by perfusion balloon, covered-stent placement and pericardiocentesis if necessary. In the BOAT trial, perforation was seen in 1.4% of patients in the DCA arm and led to clinical sequelae in 0.8%.15 Acute closure The incidence of abrupt closure of the coronary artery following atherectomy has been shown to depend on the number of procedures performed by the operator. Also, the newer and more dedicated devices seem to further reduce acute events. Abrupt closure is generally caused by thrombus or vessel dissection, and must be treated accordingly. Eventually, urgent CABG may be necessary. CAVEAT I reported incidences of urgent CABG in up to 3% of cases.30 Side-branch occlusion Directional atherectomy may result in ‘snowplowing’, thereby obstructing possibly important side-branches. As in other interventional procedures, this can be treated by wire cannulation and conventional balloon angioplasty. The use of a second guidewire to protect the side-branch should be discouraged, as possible cutting and distal embolization of the wire during atherectomy may occur. Epicardial vasospasm Vasospasm of the epicardial coronary artery may occur quite frequently during coronary 263

579_Stenting_ch.16

14/8/2001 14:38

Page 264

ABLATIVE TECHNIQUES

Figure 16.6 (A) Severe coronary artery spasm after single passage with the Rotablator in a midLAD lesion. (B) The spasm completely resolves after intracoronary nitrate administration.

atherectomy-related interventions (Figure 16.6). This may be caused by vibrations induced by the device, the presence of the guidewire, or both. Generally, this vasospasm is transient and responds quickly to intracoronary nitrates; sometimes, intracoronary calcium antagonists, low-pressure balloon inflation (1 atm) or removal of the guidewire are necessary.

No-reflow phenomenon The no-reflow phenomenon may be due to embolization of friable material and/or spasm of the coronary microcirculation, or may be due to dissection of the coronary artery. The incidence is higher in SVG lesions and in native lesions containing thrombus material. Although treatment with calcium antagonists may prove to be of value, this situation may be irreversible, with absence of flow restoration. Slow flow has been reported in up to 7.6% in rotational atherectomy trials.24 Distal embolization The incidence has been reported to be 0–13%.14,31,32 Usually, this phenomenon is 264

caused by dislodgement of friable material, loss of tissue stored in the collection chamber, or release of plaque material during rotational atherectomy, as suggested by an incidence of non-Q-wave myocardial infarctions of 9% in previous trials.33

Practical approach to the use of ablative techniques Perfect positioning of the guiding catheter before introducing the atherectomy device is crucial. Indeed, because of the caliber and rigidity of the different devices, a non-co-axial alignment of the guiding catheter may lead to injury to the ostium of the coronary vessel. Therefore, lesions in vessels not amenable for good guiding catheter positioning may not be fit for atherectomy.

Lesions amenable to ablation Eccentric lesions These lesions may be especially suited for directional atherectomy, since this technique provides

579_Stenting_ch.16

14/8/2001 14:38

Page 265

PRACTICAL APPROACH TO THE USE OF ABLATIVE TECHNIQUES

a directional approach which can be fully controlled by the operator. In 447 lesions in 382 procedures, Hinohara et al showed that the atherectomy success rate was greater than 80% and the combined atherectomy and angioplasty success rate was greater than 90% for complex morphologic features such as eccentric lesions, lengthy lesions, lesions with abnormal contour, angulated lesions, ostial lesions and lesions with branch involvement. In the presence of calcific deposition, the atherectomy success rate was 52% for primary lesions and 83% for restenosed lesions. Among angiographically complex lesions, calcium was the predictor for failed atherectomy (p 0.0001). They concluded that DCA is safe and effective for the treatment of obstructive lesions in coronary arteries in selected cases. In particular, it achieves a high success rate in lesions with complex morphologic characteristics, such as eccentricity, abnormal contour and ostial involvement.34

Ostial lesions These lesions are still a challenge in interventional cardiology. Not only do they tend to be very rigid, but they also easily restenose, and often a stable guiding catheter position is difficult to obtain. Although success rates up to 90% have been described, restenosis rates may reach 50% in native coronary arteries, and even 90% in restenotic vein graft lesions.35 TEC may also be used, but the cutter-to-artery ratio should be less than 0.7, and additional devices are usually needed to obtain optimal results.4 In an observational trial with 105 patients, rotational atherectomy could be performed with a high procedural success rate. Calcified lesions Lesions that contain over 180° of calcium may impose severe limitations on the application of atherectomy. Indeed, limited elasticity of segments with abundant calcium may prohibit smooth passage of the steel housing of atherectomy catheters. Also, the presence of superficial calcium may limit the ability of the device to

excise the lesion.4 In such cases, rotational atherectomy may reduce the superficial calcium load and allow the use of subsequent directional atherectomy.

Chronic total occlusions Transluminal extraction atherectomy may be used in the case of a total occluded coronary artery that can be passed with a guidewire. The smallest size of the catheter should be used initially, especially if the caliber of the distal vessel is unknown. In-stent restenosis Currently, no data support the use of atherectomy above that of plain balloon angioplasty for the treatment of in-stent restenosis. Left main lesions Laster et al analyzed the acute and long-term results following 24 DCA procedures in 22 patients with ‘protected’ left main lesions. Acute success (residual stenosis

Coronary Lesions: A Pragmatic Approach

Trade Finance: A Pragmatic Approach

Informal Logic: A Pragmatic Approach

Coronary Artery Stenting: A Case-Oriented Approach

Tips and Tricks in Interventional Therapy of Coronary Bifurcation Lesions

Rethinking Business Ethics: A Pragmatic Approach

Informal Logic: A Pragmatic Approach, 2nd edition

Informal Logic: A Pragmatic Approach, 2nd edition

The Ethics of Managed Care: A Pragmatic Approach

Risk Regulation at Risk: Restoring a Pragmatic Approach

Essentials of Insight Meditation Practice: A Pragmatic Approach to Vipassana

Normative Theory in International Relations: A Pragmatic Approach

Essentials of Insight Meditation Practice: A Pragmatic Approach to Vipassana

Atlas of Thyroid Lesions

Pragmatic Ajax. A Web 2.0 Primer, Pragmatic Bookshelf

Coronary Artery CTA: A Case-Based Atlas

Acute coronary syndromes

Acute Coronary Syndrome: Multidisciplinary and Pathway-Based Approach

Coronary Magnetic Resonance Angiography

MRI atlas of MS Lesions

Pragmatic Impairment

Pragmatic Power

A Pragmatic Conception of the A Priori

Coronary Disease in Women

Acute Coronary Syndromes

Coronary Magnetic Resonance Angiography

Rx Coronary Thrombosis

Pragmatic Guide to Subversion (Pragmatic Guides)

Cytologic Detection of urothelial lesions

Pathology of Vascular Skin Lesions

Coronary Lesions: A Pragmatic Approach

Trade Finance: A Pragmatic Approach

Informal Logic: A Pragmatic Approach

Coronary Artery Stenting: A Case-Oriented Approach

Tips and Tricks in Interventional Therapy of Coronary Bifurcation Lesions

Rethinking Business Ethics: A Pragmatic Approach

Informal Logic: A Pragmatic Approach, 2nd edition

Informal Logic: A Pragmatic Approach, 2nd edition

The Ethics of Managed Care: A Pragmatic Approach

Risk Regulation at Risk: Restoring a Pragmatic Approach

Essentials of Insight Meditation Practice: A Pragmatic Approach to Vipassana

Normative Theory in International Relations: A Pragmatic Approach

Essentials of Insight Meditation Practice: A Pragmatic Approach to Vipassana

Atlas of Thyroid Lesions

Pragmatic Ajax. A Web 2.0 Primer, Pragmatic Bookshelf

Coronary Artery CTA: A Case-Based Atlas

Acute coronary syndromes

Acute Coronary Syndrome: Multidisciplinary and Pathway-Based Approach

Coronary Magnetic Resonance Angiography

MRI atlas of MS Lesions

Pragmatic Impairment

Pragmatic Power

A Pragmatic Conception of the A Priori

Coronary Disease in Women

Acute Coronary Syndromes

Coronary Magnetic Resonance Angiography

Rx Coronary Thrombosis

Pragmatic Guide to Subversion (Pragmatic Guides)

Cytologic Detection of urothelial lesions

Pathology of Vascular Skin Lesions

Recommend Documents