Carriers of CYP2C19 variant at increased risk for cardiac events

Non-functioning allele may inhibit metabolism of clopidogrel.

Among patients with acute coronary syndromes who were taking clopidogrel, carriers of non-functioning alleles of the CYP2C19 gene were 53% more likely than non-carriers to die from cardiovascular causes, or have a myocardial infarction or stroke.

Two articles involving the interaction between these alleles and clopidogrel were recently published in The New England Journal of Medicine. The researchers from both studies concluded that reduced-functioning alleles of the CYP2C19 gene prevented metabolism of clopidogrel and led to cardiovascular events.

European population

The first study was conducted by researchers from several institutions in France. It involved 2,208 patients with acute MI who were being treated with clopidogrel. The researchers tested associations of allelic variants of genes involved in clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19) and biologic activity (P2RY12 and ITGB3) with all-cause mortality risk, nonfatal stroke or MI within one year of treatment initiation.

During the study period, 225 patients died and 94 patients had nonfatal MI or stroke. There were four loss-of-function alleles of CYP2C19 (*2, *3, *4 or *5). Patients carrying any two of these alleles had a 21.5% chance of a cardiovascular event, compared with a 13.3% chance for patients with no reduced-function alleles (HR=1.98; 95%CI, 1.10-3.58). The chance of cardiac event was 3.58 times higher in patients with two non-functioning CYP2C19 alleles than in those with functioning alleles among 1,535 patients who underwent percutaneous coronary artery intervention during hospitalization (95% CI, 1.71-7.51).

Results from Boston

The second study explored associations between functional genetic variants in CYP genes, plasma concentrations of active drug metabolite and platelet inhibition in 162 healthy participants who were taking clopidogrel. The same associations were then explored in a separate cohort of 1,477 patients with acute coronary syndromes from the TRITON-TIMI 38 trial who were taking clopidogrel.

Healthy carriers of one or more non-functioning CYP2C19 allele had a 32.4% lower plasma exposure to the active metabolite of clopidogrel than non-carriers (P<.001). Carriers also had an absolute reduction in maximal platelet aggregation in response to clopidogrel that was nine absolute percentage points lower than noncarriers (or approximately 25% less platelet inhibition).

The rate of mortality from cardiovascular causes, MI or stroke was 12.1% among carriers of the variant with acute coronary syndromes vs. 8.0% among non-carriers (HR=1.53; 95% CI, 1.07-2.19). The risk of stent thrombosis in carriers of the variant with acute coronary syndromes was 2.6% compared with 0.8% among non-carriers in the same group (HR=3.09; 95% CI, 1.19-8.00).

In both studies, the average loading dose of clopidogrel was 300 mg per day, and the maintenance dose upon hospital discharge was 75 mg per day.

For more information:

N Engl J Med. 2009;doi:10.1056/NEJMoao808227.

N Engl J Med. 2009;doi:10.1056/NEJMoao809171.