Expert Review: Thrombosis

Clopidogrel with aspirin in acute minor stroke or transient ischemic attack

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.
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.
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.
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 number, NCT00979589.).

The remarkable benefit of a three-week course of dual antiplatelet therapy with clopidogrel and low-dose aspirin versus aspirin alone, started within 24 hours (mean, 13 hours) after the onset of symptoms of a minor ischemic stroke or high-risk TIA, in reducing by one-third the risk of stroke (ischemic or hemorrhagic) at 90 days without increasing the risk of bleeding, as reported by the CHANCE Investigators (Wang Y et al, N Engl J Med 2013; 369:11-19), is probably surprising to stroke neurologists who saw a completely different movie in the MATCH trial (Diener HC et al, Lancet 2004;364:331-7)

However, it probably does not come as a surprise to interventional cardiologists that if you select the right population, ie, patients at particularly high risk for recurrent ischemia and low risk for hemorrhage (as in most trials of dual antiplatelet therapy in acute coronary syndromes
[ACS]), and start therapy early after the onset of symptoms (as in ACS), you can demonstrate a clinically important benefit by reducing the early recurrence of ischemia, at a time when the underlying atherothrombotic process is likely to be most sensitive to pharmacologic down-regulation of platelet activation by two agents (clopidogrel and aspirin) working through
complementary mechanisms of action (permanent inactivation of platelet P2Y12 and COX-1, respectively), and yielding additive protective effects.

Corresponding author from original paper
Wang Y, Beijing Tiantan Hospital, Capital Medical University, Beijing, China, e-mail

Citation: N Engl J Med 2013 ;369(1):11-9

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