Professor and Chair of Pharmacology, Catholic University School of Medicine, Rome, Italy
Stroke is common during the first few weeks after a transient ischemic attack (TIA) or minor ischemic stroke. Dual antiplatelet therapy with clopidogrel and aspirin may provide greater protection against subsequent stroke than aspirin alone. This hypothesis was tested by Wang Y et al. (N Engl J Med 2013;369:11-9) in a randomized, double-blind, placebo-controlled trial funded by the Ministry of Science and Technology of the People’s Republic of China (CHANCE ClinicalTrials.gov number, NCT00979589) conducted in 114 centres in China. In the study, 5170 patients were randomly assigned “within 24 hours after the onset of a 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)”. The administration of aspirin was on an open-label basis and left at the discretion of the managing physician (range: 75 to 300 mg on day 1). The main study end points was stroke (ischemic or hemorrhagic) during 90 days of follow-up and the statistical analysis was on an intention-to-treat basis. Stroke occurred in 8.2% of patients in the clopidogrel-aspirin group v. 11.7% in the aspirin only group (hazard ratio, 0.68; 95% confidence interval, 0.57 to 0.81; P<0.001). Moderate or severe hemorrhage occurred in a similar proportion of patients (0.3%) in the clopidogrel-aspirin group and the aspirin group (0.3%) (P=0.73); the rate of hemorrhagic stroke was also similar in both treatment groups (0.3%). Thus this study in patients with TIA or minor stroke, showed that combined treatment with clopidogrel and aspirin was superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of bleeding.
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 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.
