Objective To compare the antiplatelet effects of vicagrel and clopidogrel in patients with different cytochrome P450(CYP)2C19 genotypes.Methods This is a post-hoc analysis of a phase Ⅱ clinical trial of vicagrel,which included patients with coronary heart disease who underwent percutaneous coronary intervention from August 2018 to June 2019 in 18 centers.Patients were categorized based on the presence of CYP 2C19*2 or*3 loss-of-function(LOF)alleles into LOF carrier group(n=111)and non-LOF carrier group(n=90).Each group included patients received vicagrel 5 mg,6 mg,7.5 mg,or clopidogrel 75 mg for 28 days per study protocol.P2Y12 reaction units(PRU)were measured using VerifyNow at baseline,6 to 8 hours after loading dose,7 to 10 days after randomization,and 28 days after randomization and the percentage inhibition of platelet aggregation(％IPA)was calculated.The primary endpoint was％IPA on day 28.Within the patients from the General Hospital of Northern Theater Command,8 to 12 patients in each study arms were enrolled in a prespecified pharmacokinetic sub-study,measuring the time to reach maximum plasma concentration(Tmax),peak plasma concentration(Cmax),and area under the plasma concentration-time curve(AUC).Results Among 201 patients,the age was(58.8±8.5)years,and 139(69.2％)were male.In non-LOF carriers,there was no significant differences in PRU values and％IPA between the vicagrel 5 mg,6 mg,7 mg,and clopidogrel groups at all time points(all P＞0.05).In LOF carriers,％IPA was significantly higher in the vicagrel-treated groups than in the clopidogrel group at 6-8 hours after loading dose(22.9(14.2,31.5)％vs.19.8(11.0,28.6)％vs.29.5(20.9,38.0)％vs.12.9(3.9,21.9)％,P=0.038)and 7-10 days after randomization(22.4(14.2,30.5)％vs.34.4(26.1,42.6)％vs.39.8(31.8,47.9)％vs.24.7(16.3,33.2)％,P=0.001),with a trend towards higher％IPA in the vicagrel-treated groups at day 28(30.4(21.3,39.6)％vs.36.5(27.2,45.7)％vs.40.8(31.8,49.8)％vs.30.7(21.2,40.2)％,P=0.056).Pharmacokinetic results of 35 patients showed that the Cmax and AUC of the active metabolite M15-2 of vicagrel was similar to that of clopidogrel in non-LOF carriers,but AUC between vicagrel 5 mg,6 mg,7 mg and clopidogrel were significantly different in LOF carriers((5.6±0.6)h·μg-1·L-1 vs.(6.8±2.7)h·μg-1·L-1 vs.(9.2±3.3)h·μg-1·L-1 vs.(4.2± 1.9)h·μg-1·ml-1,P=0.020).Conclusion Vicagrel and clopidogrel have similar antiplatelet effects in non-LOF carriers,but vicagrel exhibits superior antiplatelet effects in LOF carriers.
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