ACTIVE-Genetics - Clinical Trial Results：积极的遗传-临床试验结果.pptVIP

Effects of CYP2C19 genotypes on clopidogrel treatment in the CURE and ACTIVE trials Guillaume Pare MD Canada Research Chair in Genetic and Molecular Epidemiology Background Assumption that CYP2C19 poor metabolizers do not convert the pro-drug into the active metabolite and thus do not derive clinical benefit of treatment “Black box” warning from FDA of reduced effectiveness of clopidogrel in patients who are poor metabolizers Use of a higher dose of clopidogrel Use of an alternative antiplatelet agent CYP2C19 Alleles 3 allele classes - “Wild type” (*1): 63% - Loss-of-function (*2, *3): 13% - Gain-of-function (*17): 24% 5 metabolizer phenotypes - Poor: 2 loss-of-function alleles (2%) - Intermediate: 1 loss-of-function and 1wild type alleles (16%) - Extensive: 2 wild types alleles (39%) - Ultra: 1 or 2 gain-of-function alleles (37%) - Unknown: 1 gain-of-function and 1 loss-of-function alleles (6%) 2 carrier status - Loss-of-function carriers (1 or more *2, *3): 24% - Gain-of-function carriers (1 or more *17): 41% CURE Trial 12,562 ACS patients without ST-segment elevation Randomized to Clopidogrel (75mg) or Placebo On a background of ASA (75 mg to 325 mg) Average follow-up of 9 months Outcomes First Primary: CV death, MI, Stroke Second Primary: First primary, or recurrent ischemia, or UA Safety: Major bleed (life-threatening or not) Yusuf et al. NEJM 2001; 345: 494-502 CURE Genetics Baseline Characteristics Characteristic OVERALL CURE-Genetics Placebo Clopidogrel Total Placebo Clopidogrel Total N 6303 6259 12562 2510 2549 5059 Female (%) 38.3 38.7 38.5 40.9 41.2 41.0 Age 64.2 (11.3) 64.2 (11.3) 64.2 (11.3) 63.9 (11.1) 63.8 (11.0) 63.8 (11.0) BMI 27.4 (4.1) 27.4 (4.1) 27.4 (4.1) 27.6 (4.1) 27.7 (4.2) 27.6 (4.2) Diabetes (%) 22.8 22.4 22.6 21.5 20.7 21.1 Smoking (%) 22.7 23.4 23.0 21.6 23.1 22.4 SBP 134.1 (22.0) 134.4 (22.5) 134.2 (22.2) 134.6 (22.0) 135.5 (22.3) 135.0 (22.1) PCI without stent 4.0 3.7 3.9 3.9 3.2 3.5 PCI with stent 17.3 17.3 17.3 13.5 15.5 14.