Key result
CYP polymorphisms affecting clopidogrel metabolism are associated with increased 1-year mortality after AMI, with CYP2C19*2 increasing risk in whites (HR 1.70) and CYP2C19*17 in blacks (HR 8.97).
Why the study?
Do specific CYP polymorphisms affect 1-year mortality in white and black patients treated with clopidogrel after acute myocardial infarction?
Cohort (n=2,732)
Yes
Do specific CYP polymorphisms affect 1-year mortality in white and black patients treated with clopidogrel after acute myocardial infarction?
Hazard Ratio: 1.7 (95% CI 1.01–2.86)
p-value: p=0.046
CYP polymorphisms affecting clopidogrel metabolism are associated with increased mortality after acute myocardial infarction, with the specific risk alleles and putative mechanisms varying significantly between white and black patients.
Does not support routine CYP genotyping to guide clopidogrel post-AMI; extends race-specific associations but remains hypothesis-generating.
BACKGROUND: Clopidogrel is recommended after acute myocardial infarction but has variable efficacy and safety, in part related to the effect of cytochrome P450 (CYP) polymorphisms on its metabolism. The effect of CYP polymorphisms on cardiovascular events among clopidogrel-treated patients after acute myocardial infarction remains controversial, and no studies to date have investigated the association of CYP variants with outcomes in black patients. METHODS AND RESULTS: Subjects (2732: 2062 whites; 670 blacks) hospitalized with acute myocardial infarction enrolled in the prospective, multicenter TRIUMPH study were genotyped for CYP polymorphisms. The majority of whites (79%) and blacks (64.4%) were discharged on clopidogrel. Among whites, carriers of the loss-of-function CYP2C19*2 allele had significantly increased 1-year mortality (adjusted hazards ratio [HR]: 1.70; confidence interval [CI]: 1.01-2.86; P=0.046) and a trend toward increased rate of recurrent MI (adjusted HR: 2.10; CI: 0.95-4.63; P=0.066). Among blacks, increased 1-year mortality was associated with the gain-of-function CYP2C19*17 allele (adjusted HR for *1/*17 versus *1/*1: 2.02; CI: 0.92-4.44; *17/*17 versus *1/*1: 8.97; CI: 3.34-24.10; P<0.0001) and the CYP1A2*1C allele (adjusted HR for *1/*1C versus *1/*1: 1.89; CI: 0.85-4.22; *1C/*1C versus *1/*1: 4.96; CI: 1.69-14.56; P=0.014). Bleeding events were significantly more common among black carriers of CYP2C19*17 or CYP1A2*1C. CONCLUSIONS: Both loss-of-function and gain-of-function CYP polymorphisms affecting clopidogrel metabolism are associated with increased mortality among clopidogrel-treated patients after acute myocardial infarction; the specific polymorphism and the putative mechanism vary according to race.
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Cresci et al. (2014) conducted a cohort in acute myocardial infarction (n=2,732). CYP polymorphisms (CYP2C19*2, CYP2C19*17, CYP1A2*1C) vs. Non-carriers / wild-type (*1/*1) was evaluated on 1-year mortality (HR 1.70, 95% CI 1.01-2.86, p=0.046). CYP polymorphisms affecting clopidogrel metabolism are associated with increased 1-year mortality after AMI, with CYP2C19*2 increasing risk in whites (HR 1.70) and CYP2C19*17 in blacks (HR 8.97).
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