Is clopidogrel (Plavix) plus aspirin better than aspirin alone in stroke and TIA?

Wang Y, Wang Y, Zhao X, et al. “Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.” New England Journal of Medicine. 2013 Jul 4;369(1):11-9.

BACKGROUND:

Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke. Combination therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone.

METHODS:

In a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China, we randomly assigned 5170 patients within 24 hours after the onset of minor ischemic stroke or high-risk TIA to combination therapy with clopidogrel and aspirin (clopidogrel at an initial dose of 300 mg, followed by 75 mg per day for 90 days, plus aspirin at a dose of 75 mg per day for the first 21 days) or to placebo plus aspirin (75 mg per day for 90 days). All participants received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischemic or hemorrhagic) during 90 days of follow-up in an intention-to-treat analysis. Treatment differences were assessed with the use of a Cox proportional-hazards model, with study center as a random effect.

RESULTS:

Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group, as compared with 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-aspirin group and in eight (0.3%) in the aspirin group (P=0.73); the rate of hemorrhagic stroke was 0.3% in each group.

CONCLUSIONS:

Among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage. (Funded by the Ministry of Science and Technology of the People`s Republic of China; CHANCE ClinicalTrials.gov number, NCT00979589.).

Comments from clinical reviewers

  • Emergency Medicine: CHANCE trial provides convincing evidence of direct relevance to emergency physicians to support benefit of dual antiplatelet therapy in a subset (~12%) of acute (<24 hours) minor stroke (NIHSS <4) or TIA (ABCD2 >3) patients providing reduced stroke risk with NNT 29 (95% CI 19-54). Although biologically plausible that these benefits could be attained without increased CNS bleeding events, it is unlikely that dual antiplatelet therapy would not increase overall bleeding complications as is observed in ACS trials (increased risk of major bleeding by 38%, as noted in the accompanying editorial). Nonetheless, CHANCE provides compelling evidence to alter emergency medicine management of acute stroke/high-risk TIA in a subset of patients by implementing dual antiplatelet therapy.
  • General Internal Medicine-Primary Care(US): It is very useful to know that dual anti-platelet therapy is effective for preventing stroke after TIA or acute minor stroke. The fact that only around 12% of the population of stroke patients qualified for the therapy, and that follow-up was only 90 days, limits generalizability. Nonetheless, this may be very helpful to patients, particularly in low-resource healthcare settings.
  • Internal Medicine There is pre-existing data that clopidogrel is somewhat superior to aspirin in this setting, and I believe that clopidogrel/aspirin combination was not shown to be superior to clopidogrel alone. Perhaps I’m missing something important, but I’m not sure how new this is.
  • Neurology: This is the first RCT evidence for early dual anti-platelet therapy for preventing stroke after TIA or acute ischemic stroke. The design of the study differs from most previous stroke prevention studies in that this study focuses on early risk within the first 90 days, whereas most stroke prevention studies in the past focused on long-term chronic prevention. The redemonstration of early stroke risk after ischemic stroke or TIA previously observed in observational data and the ability to reduce the early risk are important aspects of the study.
  • Neurology: The paper has good methodology and enough power to answer an important question that is directly relevant to clinical practice. Congratulations!
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