Advances in Stroke Prevention Plenary Symposium at the 11th European Stroke Conference Geneva, Switzerland, May 29–June 1, 2002 Supported by an Educational Grant from Sanofi-Synthelabo
Editors
Julien Bogousslavsky, Lausanne Marie-Germaine Bousser, Paris
13 figures and 6 tables, 2003
Basel 폷 Freiburg 폷 Paris 폷 London 폷 New York 폷 Bangalore 폷 Bangkok 폷 Singapore 폷 Tokyo 폷 Sydney
S. Karger Medical and Scientific Publishers Basel 폷 Freiburg 폷 Paris 폷 London New York 폷 Bangalore 폷 Bangkok Singapore 폷 Tokyo 폷 Sydney
Fax + 41 61 306 12 34 E-Mail
[email protected] www.karger.com
Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2003 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–7583–1
Vol. 16, Supplement 1, 2003
Contents
1 Introduction Bousser, M.-G. (Paris); Bogousslavsky, J. (Lausanne) 3 Long-Term Outcome after Stroke due to Atrial Fibrillation Mattle, H.P. (Bern) 9 Outcome after Brain Haemorrhage Dennis, M.S. (Edinburgh) 14 Long-Term Outcome after Ischaemic Stroke/Transient Ischaemic Attack Hankey, G.J. (Perth) 20 Evidence with Antiplatelet Therapy and ADP-Receptor Antagonists Easton, J.D. (Providence, R.I.)
© 2003 S. Karger AG, Basel Fax + 41 61 306 12 34 E-Mail
[email protected] www.karger.com
Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/ced_issues
Cerebrovasc Dis 2003;16(suppl 1):1–2 DOI: 10.1159/000069933
Introduction
Stroke is the principal cause of disability, dependency and loss of social competence in the western world. The majority of strokes are of ischaemic origin, and most ischaemic strokes are due to atherothrombosis. Clearly, a thorough knowledge of prognosis and effective secondary prevention strategies are of paramount importance for clinicians who care for stroke patients. At the 11th European Stroke Conference, held in Geneva, Switzerland, between May 29 and June 1, 2002, delegates had the opportunity to attend two important symposia – an Educational Symposium entitled Longterm outcome after different stroke subtypes and a Satellite Symposium entitled Future trends in long-term prevention of ischaemic stroke – the role of atherothrombosis management. This supplement to Cerebrovascular Diseases is based on key presentations made during these sessions. In the first article of this supplement, Dr Heinrich Mattle provides an overview of long-term outcome after stroke due to atrial fibrillation (AF). AF, which is the most common cardiac arrhythmia and whose prevalence increases with age, places the patient at risk for left atrial thrombus formation, distal embolism and associated ischaemic stroke. AF is associated with substantial cardiovascular mortality and morbidity. Indeed, long-term survival data from the Framingham Heart Study indicates that AF is independently associated with an approximate doubling in mortality in both men and women. Moreover, in the European Atrial Fibrillation Trial, the annualized rate of vascular death, nonfatal stroke, nonfatal myocardial infarction or systemic embolism in patients who received placebo was 12%. There is clear evidence that antithrom-
ABC
© 2003 S. Karger AG, Basel 1015–9770/03/0165–0001$19.50/0
Fax + 41 61 306 12 34 E-Mail
[email protected] www.karger.com
Accessible online at: www.karger.com/ced
botic therapy reduces the risk of serious vascular ischaemic events in AF patients. Oral anticoagulation reduces the risk of stroke recurrence by approximately 60% compared with placebo. Acetylsalicylic acid (ASA) is less effective than anticoagulation, reducing the risk of stroke by around 20%. Thus, the use of ASA as first-line antithrombotic therapy in AF patients is limited to those at low risk. An important topic for future investigation is whether dual antiplatelet therapy, for example clopidogrel in addition to ASA, is a suitable alternative to warfarin for the reduction of thromboembolism in high- or intermediate-risk AF patients. This will be the topic of the planned ACTIVE trial. Dr Martin Dennis then describes our current knowledge on outcome after primary intracerebral haemorrhage (PICH). Dr Dennis highlights the methodological difficulties that hamper the study of PICH prognosis, including the small proportion of all strokes that are due to PICH, the need for brain imaging (or autopsy) to arrive at a reliable diagnosis of PICH, differences in definition of PICH according to imaging method and its timing, and the heterogeneity of haemorrhage aetiologies and types. Although individual estimates of 1-month case fatality have wide confidence intervals, pooled data from unselected PICH cohorts provide a more precise estimate of about 42%. After PICH, greater age and stroke severity are both associated with increased case fatality and poorer functional outcomes. Currently, there is no definite evidence to indicate that the risk of recurrent stroke after PICH differs from that after ischaemic stroke of equivalent clinical severity. Generation of more precise data on progno-
sis after PICH will require pooling of data from community-based studies that have used consistent definitions and methodology. It is already well established that bloodpressure lowering dramatically reduces the risk of recurrent intracerebral haemorrhage. In the first of two articles relating to the generalized nature of atherothrombosis and its consequences, Dr Graeme Hankey reviews the evidence from high-quality studies on short- and long-term predictors of post-stroke outcome and studies on prognosis in patients with transient ischaemic attack (TIA) or ischaemic stroke. This article demonstrates that the most consistent predictor of short-term (1-month) mortality is stroke severity, whereas over the longer term (1–5 years), the strongest predictor of death is increasing age, closely followed by cardiac failure. Additional predictive factors for death over this time period include a history of previous symptomatic atherothrombosis and risk factors for atherothrombotic disease. Furthermore, over time, the annual risk of recurrent cerebrovascular events decreases but the risk of cardiovascular events increases, emphasizing that patients with TIA and ischaemic stroke are at risk of recurrent ischaemic events of both the brain and the heart. On the basis of these findings, Dr Hankey concludes that strategies for secondary prevention after TIA or stroke should include removal of symptomatic disease, control of risk factors for atherogenesis, and prevention of atherothrombosis in all vascular beds. Finally, Dr J. Donald Easton provides an overview of current evidence and future prospects for ADP-receptor antagonist therapy for the prevention of vascular ischaemic events in atherothrombotic patients, with a particular focus on patients with symptomatic cerebrovascular disease. As shown in meta-analyses by the Antithrombot-
2
Cerebrovasc Dis 2003;16(suppl 1):1–2
ic Trialists’ Collaboration and the Cochrane Stroke Group, the ADP-receptor antagonists clopidogrel and ticlopidine are associated with superior protection against major atherothrombotic events (stroke, MI or vascular death) compared with ASA. The Cochrane Group also confirmed that compared with ticlopidine, clopidogrel offers a more favourable safety/tolerability profile. The CURE trial, which provided ‘proof of principle’ for the use of clopidogrel on top of ASA to provide incremental benefit in high-risk atherothrombtic patients, has stimulated interest in advanced antiplatelet strategies in patients with ischaemic stroke. Since Geneva, this interest has been reinforced by publication of the results of the CREDO trial, which showed that long-term use of clopidogrel on top of ASA provides sustained, incremental benefit in patients who undergo percutaneous coronary intervention. The ongoing MATCH study is comparing clopidogrel on top of ASA versus clopidogrel alone in an international, randomized, double-blind trial in patients with recent TIA or ischaemic stroke who are at high risk of atherothrombotic recurrence. The ongoing CHARISMA trial compares clopidogrel and placebo on top of usual treatment based on low-dose ASA in high-risk atherothrombotic patients. Additional trials of clopidogrel on top of standard therapy including ASA are planned in neurology, including SPS3, in patients with small subcortical strokes, and ATARI, in patients who have recently recovered from a TIA. The articles assembled here represent a current reference source on outcome after stroke and its management. We hope that you find them useful and informative. Marie-Germaine Bousser, MD Julien Bogousslavsky, MD
Introduction
Cerebrovasc Dis 2003;16(suppl 1):3–8 DOI: 10.1159/000069934
Long-Term Outcome after Stroke due to Atrial Fibrillation Heinrich P. Mattle Department of Neurology, Inselspital, University of Bern, Bern, Switzerland
Key Words Atrial fibrillation W Prognosis W Stroke
Abstract Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF is paroxysmal or persistent and becomes permanent when it does not convert to sinus rhythm spontaneously or when attempted cardioversion fails. The prevalence of AF is 0.4% in the general population and increases with age up to 6–8% in octogenarians. In men, the age-adjusted prevalence is generally higher than in women. During AF, synchronous mechanical atrial activity is disturbed, resulting in haemodynamic impairment. This can give rise to thrombus formation and embolism to the systemic circulation. Thrombus associated with AF arises most frequently in the left atrial appendage. Cerebrovascular emboli in AF patients most often manifest as transient ischaemic attacks or ischaemic strokes. The overall rate of ischaemic stroke among patients with nonrheumatic AF averages 5% per year, but the rate increases with age. Patients with AF are at higher risk of cerebrovascular events from all causes. Of all strokes, one in every six occurs in patients with AF. Including transient ischaemic attacks and silent strokes detected radiographically, the overall rate of all cerebro-
vascular events in AF patients rises to more than 7% per year, although approximately one third of these are due to causes that are only secondarily or incidentally associated with AF or related anticoagulant therapy. Antiarrhythmic therapy is useful to improve cardiac rate and function in AF. However, to reduce first or recurrent emboli, antithrombotic therapy is of paramount importance. Results from several randomized clinical trials of antithrombotic therapies have shown that adjusted-dose warfarin reduces first or recurrent stroke by about 60% compared with placebo. When patients with nonvalvular AF are anticoagulated, the odds against ischaemic stroke and intracranial bleeding favour an INR between 2.0 and 3.0. Acetylsalicylic acid is less efficacious than warfarin in AF patients, reducing the risk of stroke by about 20%. Therefore, this antiplatelet agent should be used only for AF patients at low risk. Anticoagulation is the current treatment modality in AF patients at high or intermediate risk, i.e. patients with history of transient ischaemic attack or stroke, those aged 1 65 years, those with a history of hypertension, diabetes, heart failure or structural heart disease, valvular disease or significant systolic dysfunction. The benefit of dual antiplatelet regimens in AF patients is unknown, and combining antiplatelet agents with different mechanisms of action is an important topic for future investigation. Copyright © 2003 S. Karger AG, Basel
ABC
© 2003 S. Karger AG, Basel 1015–9770/03/0165–0003$19.50/0
Fax + 41 61 306 12 34 E-Mail
[email protected] www.karger.com
Accessible online at: www.karger.com/ced
Heinrich Mattle, MD Department of Neurology Inselspital, University of Bern CH–3010 Bern (Switzerland) Tel. +41 31 6329784, Fax +41 31 6320321, E-Mail
[email protected] 12 Women Men
Prevalence (%)
10 8 6 4 2 0
