Association Between CYP2B6 Polymorphisms and Efficacy of Clopidogrel in Minor Stroke or Transient Ischemic Attack

Abstract

BACKGROUND: CYP2B6 (cytochrome P450 subfamily IIB polypeptide 6), encoded by the CYP2B6 gene, is a critical enzyme involved in clopidogrel metabolism. However, the association between CYP2B6 polymorphisms and the efficacy of clopidogrel in minor stroke or transient ischemic attack for secondary stroke prevention remains unclear. METHODS: Based on CHANCE (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) randomized clinical trial of aspirin plus clopidogrel versus aspirin alone, we investigated the role of CYP2B6 polymorphisms and the efficacy of clopidogrel in patients with minor stroke or transient ischemic attack in China from October 2009 to July 2012. A total of 2853 patients were successfully genotyped for CYP2B6 -516G>T, rs3745274 and CYP2B6 -1456 T>C, rs2054675. The primary efficacy and safety outcomes were new stroke and any bleeding within 90 days. RESULTS: Among the 2853 patients, 32.8% were identified as the carriers of the CYP2B6 -516 GT/TT or -1456 TC/CC genotype. The incidences of 90-day new stroke in aspirin plus clopidogrel and aspirin alone groups were 7.1% versus 11.3% among noncarriers, respectively; and 9.7% versus 12.2% among carriers, respectively. The efficacy of aspirin plus clopidogrel versus aspirin alone was not significantly different ( P interaction=0.29) in noncarriers (adjusted hazard ratio, 0.61 [95% CI, 0.45–0.83]) compared to carriers (adjusted hazard ratio, 0.80 [95% CI, 0.54–1.18]). The incidence (n=51) of 90-day any bleeding in aspirin plus clopidogrel and aspirin alone groups were 2.2% (21 bleeds) versus 1.9% (18 bleeds) among noncarriers (adjusted hazard ratio, 1.11 [95% CI, 0.59–2.09]) and 1.9% (9 bleeds) versus 0.7% (3 bleeds) among carriers (adjusted hazard ratio, 3.23 [95% CI, 0.86–12.12]). Similar findings were observed during the 1-year follow-up. CONCLUSIONS: In this post hoc analysis of the CHANCE trial, we did not observe a significant difference in the efficacy of aspirin plus clopidogrel compared with aspirin in carriers versus noncarriers of CYP2B6 -516 GT/TT or -1456 TC/CC genotype. Our results suggest that both carriers and noncarriers suffering from a minor stroke are likely to benefit from aspirin plus clopidogrel treatment over aspirin monotherapy for secondary prevention. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00979589.