The Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial demonstrated that the addition of clopidogrel to low-dose ASA in Chinese patients with acute minor stroke or transient ischemic attack provided better protection against subsequent stroke compared to ASA alone (Wang et al. N Engl J Med 2013;369:11-19).
Subjects in that study (n=5,170) were randomized within 24 hours of minor ischemic stroke/high-risk TIA to ASA 75 mg/day x 90 days, or ASA 75 mg/day x 21 days + clopidogrel at a loading dose of 300 mg, followed by 75 mg/day x 90 days. All subjects received ASA at a dose determined by the clinician (75-300 mg) on day 1. The rate of subsequent stroke at 90 days was 8.2% in the ASA-clopidogrel group versus 11.7% in the ASA alone group (hazard ratio 0.68). The rate of moderate/severe hemorrhage (0.3%) and hemorrhagic stroke (0.3%) were the same with the two regimens.
A subsequent meta-analysis of 15 studies (n=97,692) reported a 21% reduction in stroke risk with the clopidogrel-ASA combination in high-risk vascular patients (Chen et al. PLoS One 2014;9:e104402). The risk of a major bleeding complication with dual antiplatelet therapy was not increased in the short term (relative risk 1.1), but was higher with long-term use (RR 1.76 for intracranial bleeding).
The CHANCE investigators have now published a number of updates. At one year, the stroke rate was 10.6% in the clopidogrel-ASA group compared to 14.0% with ASA alone (HR 0.78) (Wang et al. Circulation 2015;132:40-60). The rate of moderate or severe hemorrhage remained low (combination 0.3%; ASA 0.4%). There was a similar incidence of cerebral microbleeds with the combination versus ASA alone (Wang et al. Neurol Res 2015;37:993-997).
Poor functional outcome occurred in 9.9% of patients receiving dual antiplatelet therapy compared to 11.6% of patients on ASA alone. The clopidogrel-ASA combination also resulted in a somewhat greater improvement in 90-day functional outcomes and patient quality of life compared to ASA alone (Wang et al. Neurology 2015;85:573-579).
Most recently, the association between three CYP2C19 alleles (*2, *3, *17) and cerebrovascular outcomes was analysed (Wang et al. JAMA 2016;316:70-78). There was no reduction in the rate of new stroke at 90 days with clopidogrel-ASA in carriers of loss-of-function alleles (*2, *3); a benefit was only seen in non-carriers, indicating a significant role of the CYP2C19 genotype in treatment response.