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

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