NEW YORK (Reuters Health) – Patients taking clopidogrel because of their high risk for cardiovascular events are more likely to have a major event if they carry the cytochrome P450 loss-of-function allele CYP2C19*2, or are taking a proton pump inhibitor (PPI).

These findings come from a meta-analysis of 23 studies, conducted by Dr. Gilles Montalescot, at Hopital Pitie-Salpetriere, Paris, and colleagues. “Metabolic activation by cytochrome P450 2C19 (CYP2C19) has emerged as a crucial determinant of clopidogrel pharmacodynamic response and clinical efficacy”, they note in their paper in the Journal of the American College of Cardiology for July.

The loss-of-function CYP2C19*2 allele, present in about 30% of Caucasians and up to 50 % of East Asians, can reduce the conversion of clopidogrel to its active metabolite. Also, some PPIs are CYP2C19 inhibitors.

“Our objective was to perform a quantitative review of the relationship between the reduced-function allele or the use of PPIs and major adverse cardiovascular events (MACE) and mortality in patients with long-term exposure to clopidogrel,” the team explains.

Pooled data from 10 studies involving nearly 12,000 subjects showed that those with the CYP2C19*2 allele had a 30% increased risk of MACE compared to noncarriers. Absolute rates were 9.7% vs. 7.8% (OR, 1.29; p<0.001). “This increased risk was apparent in both heterozygotes and homozygotes and was independent of the baseline cardiovascular risk,” the investigators found. The data were not strong enough to identify a statistically significant effect in heterozygotes alone, Dr. Montalescot explained in an email to Reuters Health. “It is indeed crucial to ascertain a gene-dose effect as CYP2C19*2 heterozygotes represent 20% to 25% of the general population,” he said. In 13 studies involving over 48,000 subjects, PPI users had a 21.8% rate of MACE compared to 16.7% among nonusers (OR, 1.41; p<0.001). Omeprazole was the most frequently prescribed PPI. “One of the major contributions of our analysis is to provide an explanation for the high heterogeneity among studies in the estimate of PPI influence in clopidogrel-treated patients,” Dr. Montalescot continued. “We were unable to find any significant interaction in low-risk patients so that there is no obvious reason to restrain PPI use in these patients. However, in a high-risk patient, PPI use will have a higher thrombotic risk than in a similar high-risk patient not taking PPI.” High-risk patients include those with a prior MI or episode of stent thrombosis, for example, or history of bleeding. “H2 antagonists are still an option instead of PPIs,” Dr. Montalescot pointed out. All-cause mortality odds ratios were 1.79 for CYP2C19*2 carriers versus noncarriers, and 1.18 for PPI users compared to nonusers. Asked if genotyping should be considered for patients being treated with clopidogrel, Dr. Montalescot said, “CYP2C19 genotyping is currently available through a number of laboratories but you usually have to wait several days to get the result.” However, a rapid and low-cost test is needed in order to incorporate genetic information into clinical management. “Rapid genetic testing should allow us to get the genetic profile as fast as we get a troponin level,” he concluded. Reference:
J Am Coll Cardiol 2010;56:134-143.