NEW YORK (Reuters Health) – The concern about proton pump inhibitors (PPIs) possibly interfering with the efficacy of clopidogrel may be misdirected, according to a new report. It seems that PPIs themselves are associated with increased cardiovascular risk, independent of clopidogrel use, Danish investigators report.

In the Annals of Internal Medicine for September 21, Dr. Mette Charlot, at Copenhagen University Hospital Gentofte in Hellerup, and colleagues note the ongoing controversy over a putative drug interaction between PPIs and clopidogrel in which the conversion of clopidogrel to its active metabolite is inhibited.

“We sought to examine the risk for adverse cardiovascular outcomes related to concomitant use of PPIs and clopidogrel compared with that of PPIs alone in a large, unselected cohort of patients hospitalized with first-time myocardial infarction,” the authors explain.

Using Denmark’s National Patient Registry, the researchers identified all 56,406 patients with an acute MI between 2000 and 2006 who survived at least 30 days. Of these, 24,704 were prescribed clopidogrel and 6753 were also prescribed a PPI; among the 31,704 individuals not given clopidogrel, 8889 received a PPI.

During the first year post-MI, there were 9137 cardiovascular deaths or rehospitalizations for MI or stroke — the primary endpoint.

Analysis of the data showed that the hazard ratio for the primary endpoint was 1.29 (p<0.001) for patients who received both clopidogrel and a PPI compared with those who did not receive a PPI. Among patients who did not receive clopidogrel, the use of a PPI therapy was associated with the same hazard ratio of 1.29. Why might PPI use be a linked to increased cardiovascular risk? The authors suspect it can be explained by differences in baseline comorbid conditions that were not measured, such as smoking, lipid levels or BMI. “Such unmeasured confounders would have to elevate the risk 2.5- to 3-fold to explain the observed increased risk for cardiovascular events. This is a large but potentially plausible amount of risk elevation for a confounder or a mix of confounders.” That said, Dr. Charlot and colleagues conclude, “These results seem to refute concerns about increased risk for ischemic events during concomitant PPI and clopidogrel therapy.” Ann Intern Med 2010; 153:378-386.