Effect of clopidogrel plus ASA vs. ASA early after TIA and ischaemic stroke: a substudy of the CHARISMA trial

Authors


  • Search terms: Cerebrovascular disease/stroke, infarction, and stroke prevention.

  • Conflict of interest: Graeme J. Hankey: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: consulting fees from Sanofi-Aventis, Bristol-Myers Squibb, Bayer and Boehringer Ingelheim and lecture fees from Sanofi-Aventis, Bristol-Myers Squibb, Bayer and Boehringer Ingelheim; S. Claiborne Johnston: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: None; J. Donald Easton: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: consulting fees from Sanofi-Aventis and Bristol-Myers Squibb; Werner Hacke: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: Member of the executive Committee of CHARISMA, Consulting fees from Sanofi-Aventis and Bristol-Myers Squibb; Jean-Louis Mas: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: Consulting fees from Sanofi-Aventis and Bristol-Myers Squibb; Danielle Brennan: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: None; Koon-Hou Mak: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: research support from Sanofi-Aventis and Bristol-Myers Squibb; Deepak L. Bhatt: I declare that I participated in the design, execution of the study, the data analysis and review of the manuscript. I have seen and approved the final version. Dr. Bhatt discloses the following relationships: research grants (directly to the institution) – Astra Zeneca, Bristol Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi Aventis, The Medicines Company; Honoraria (donated to non-profits for >2 years) – Astra Zeneca, Bristol Myers Squibb, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, Glaxo Smith Kline, Millennium, Paringenix, PDL, Sanofi Aventis, Schering Plough, The Medicines Company, tns Healthcare; Speaker's bureau (>2 years ago) – Bristol Myers Squibb, Sanofi Aventis, The Medicines Company; Consultant/Advisory Board (any honoraria donated to non-profits) – Astra Zeneca, Bristol Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, Glaxo Smith Kline, Johnson & Johnson, McNeil, Medtronic, Millennium, Otsuka, Paringenix, PDL, Philips, Portola, Sanofi Aventis, Schering Plough, The Medicines Company, tns Healthcare, Vertex; Expert testimony regarding clopidogrel (the compensation was donated to a non-profit organisation); Cleveland Clinic Coordinating Center currently receives or has received research funding from: Abraxis, Alexion Pharma, AstraZeneca, Atherogenics, Aventis, Biosense Webster, Biosite, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardionet, Centocor, Converge Medical Inc., Cordis, Dr. Reddy's, Edwards Lifesciences, Esperion, GE Medical, Genentech, Gilford, GSK, Guidant, J&J, Kensey-Nash, Lilly, Medtronic, Merck, Mytogen, Novartis, Novo Nordisk, Orphan Therapeutics, P&G Pharma, Pfizer, Roche, Sankyo, Sanofi-Aventis, Schering-Plough, Scios, St. Jude Medical, Takeda, TMC, VasoGenix, Viacor; Keith A.A. Fox: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: consulting fees from Sanofi-Aventis; lecture fees from Sanofi-Aventis and Bristol-Myers Squibb; and grant support from Sanofi-Aventis. Eric J. Topol: I declare that I participated in the design and execution of the study, analysis of the data and reviewing of the manuscript. I have seen and approved the final version. I have the following conflicts of interest: research support from Sanofi-Aventis and Bristol-Myers Squibb.

Professor Graeme J. Hankey*, Consultant Neurologist and Head of Stroke Unit, Royal Perth Hospital, 197 Wellington St, Perth 6000, Australia.
E-mail: gjhankey@cyllene.uwa.edu.au

Abstract

Background The Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilisation, Management and Avoidance (CHARISMA) trial reported no statistically significant benefit of adding clopidogrel to acetylsalicylic acid in the long-term management of a broad population of patients with stable vascular disease. However, a subanalysis raised the hypothesis that dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid may be more effective than aspirin in patients with prior ischaemic stroke, myocardial infarction of symptomatic peripheral arterial disease. We aimed to determine whether the possible benefits of clopidogrel plus acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke may be ‘front-loaded’, and maximal within the first 30-days of randomisation, without being unduly hazardous.

Methods This was a subanalysis of a randomised, double-blind, placebo-controlled trial of clopidogrel vs. placebo, in addition to background therapy with low-dose acetylsalicylic acid (CHARISMA trial), restricted to all patients with transient ischaemic attack or ischaemic stroke. The primary efficacy outcome was stroke, and safety outcome severe bleeding, during the follow-up period.

Results Among all transient ischaemic attack and ischaemic stroke patients randomised to placebo (n=2163), 131 (6·1%) experienced a stroke during follow-up compared with 105 (4·9%) of 2157 patients assigned clopidogrel (hazard ratio: 0·80, 95% confidence intervals: 0·62–1·03). There was no significant difference in severe bleeding (1·7% placebo vs. 1·9% clopidogrel, hazard ratio: 1·11, 95% confidence intervals: 0·71–1·73). Among all patients randomised within 30-days of their qualifying transient ischaemic attack or ischaemic stroke to placebo (n=667), 46 (6·9%) experienced a stroke compared with 34 (5·1%) of 664 patients assigned clopidogrel (hazard ratio: 0·74, 0·46–1·16). There was no significant difference in severe bleeding (1·6% placebo vs. 1·4% clopidogrel, hazard ratio: 0·83, 95% confidence intervals: 0·34–2·01).

Conclusion The data are consistent with, but do not prove the hypothesis that early addition of clopidogrel to acetylsalicylic acid in patients with transient ischaemic attack and ischaemic stroke of arterial origin may be more effective and acceptably safe compared with acetylsalicylic acid alone. Adequately powered clinical trials that are dedicated to exploring this hypothesis are needed.

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