In the study by Jean-Philippe Collet & colleagues, published in the Lancet, 259 young patients (aged <45 years) who survived a first myocardial infarction and were exposed to clopidogrel treatment for at least a month, were enrolled in a multicentre registry and underwent CYP2C19*2 determination. The primary endpoint was a composite of death, myocardial infarction, and urgent coronary revascularisation occurring during exposure to clopidogrel. The primary endpoint occurred more frequently in carriers than in non-carriers (15 vs. 11 events; hazard ratio [HR] 3.69 [95% CI 1.69–8.05], p=0.0005), as did stent thrombosis (eight vs. four events; HR 6.02 [1.81–20.04], p=0.0009). The detrimental effect of the CYP2C19*2 genetic variant persisted from 6 months after clopidogrel initiation up to the end of follow-up (HR 3.00 [1.27–7.10], p=0.009). After multivariable analysis, the CYP2C19*2 genetic variant was the only independent predictor of cardiovascular events (HR 4.04 [1.81–9.02], p=0.0006).
Authors concluded that “the CYP2C19*2 genetic variant is a major determinant of prognosis in young patients who are receiving clopidogrel treatment after myocardial infarction”.
Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study.
Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G.
Lancet. 2008 Dec 22. [Epub ahead of print]
Cumulative Kaplan-Meier estimates of the rates of first cardiovascular event (death, non-fatal myocardial infarction, or urgent revascularisation) during the follow-up period (A) and from 6 months after clopidogrel initiation (B)HR=hazard ratio.
Simultaneously, two independent papers published online in the New England Journal of Medicine confirmed that carriers of at least one loss-of-function allele CYP2C19 display blunted response to clopidogrel which expose them to higher risk for adverse cardiovascular events.
In particular, Mega and colleagues tested the association between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite, and platelet inhibition in response to clopidogrel in 162 healthy subjects. Authors also examined the association between these genetic variants and cardiovascular outcomes in a separate cohort of 1477 subjects with acute coronary syndromes who were treated with clopidogrel in the “Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction” (TRITON–TIMI) 38.
Authors found that, in healthy subjects who were treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele (approximately 30% of the study population) had a relative reduction of 32.4% in plasma exposure to the active metabolite of clopidogrel, as compared with noncarriers (P<0.001). Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was 9 percentage points less than that seen in noncarriers (P<0.001). Among clopidogrel-treated subjects in TRITON–TIMI 38, carriers had a relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers (12.1% vs. 8.0%; hazard ratio for carriers, 1.53; 95% confidence interval [CI], 1.07 to 2.19; P = 0.01) and an increase by a factor of 3 in the risk of stent thrombosis (2.6% vs. 0.8%; hazard ratio, 3.09; 95% CI, 1.19 to 8.00; P = 0.02).
The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or stroke. The primary efficacy outcome was assessed in 1477 patients who were assigned to treatment with clopidogrel and who provided a genetic sample.
Finally, in the FAST-MI studies investigators report on 2208 patients presenting with an acute myocardial infarction in a nationwide French registry who received clopidogrel therapy. Authors then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up.
Unlike all other tested genetic variants patients carrying any two CYP2C19 loss-of function alleles had a higher event rate than patients with none (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51).