NEW YORK (Reuters Health) – An analysis of “real-life” data from a French myocardial infarction (MI) registry fails to show any clinically relevant interaction between clopidogrel and proton pump inhibitor (PPI) therapy.

Among 3,670 MI patients, coadministration of clopidogrel and a PPI was not associated with an increased risk for major cardiovascular events during hospitalization or during the one-year follow-up in either the overall population or any of the subgroups tested.

This was true regardless of CYP2C19 genotype. This is the “interesting and new point in our paper,” Dr. Tabassome Simon, from Saint Antoine Hospital, Paris, noted in an e-mail to Reuters Health.

“Therefore, the results do not support the avoidance of PPI use for those patients receiving clopidogrel who are at increased risk of gastrointestinal bleeding; particularly for those patients with no or one CYP2C19 loss-of-function allele (representing 97% of the patients),” Dr. Simon wrote. However, patients with two loss-of-function alleles may be a greater risk.

Clopidogrel is metabolized to its active form by cytochrome P450 enzymes, including CYP2C19. Because many PPIs are metabolized by or inhibit CYP2C19, there is intense debate about whether or not PPIs interfere with the antiplatelet effect of clopidogrel enough to impact clinical outcomes.

A number of conflicting reports on this topic have helped fuel the debate. Some studies have suggested an increased risk of cardiovascular events in patients receiving a PPI and clopidogrel concomitantly compared with clopidogrel alone. Other studies have shown no significant effect of concomitant PPI use on the clinical efficacy of clopidogrel.

Studies have also shown that genetic polymorphisms that naturally confer reduced CYP2C19 enzyme activity are associated with an increased risk of cardiovascular events in clopidogrel-treated patients.

In the February 8 issue of Circulation, available online now, Dr. Simon and colleagues report that they failed to find evidence of clinical interaction between PPIs and clopidogrel in 3,670 patients in the French Acute ST-Elevation and Non-ST-Elevation MI (FAST-MI) Registry.

A total of 2,353 patients received clopidogrel 48 hours after being hospitalized for definite MI and 1,453 of these patients also received a PPI.

After multivariate analysis, concomitant use of clopidogrel and a PPI was not associated with an increased risk of in-hospital death, reinfarction, stroke, bleeding or transfusion (adjusted hazard ratio, 0.90). Likewise, continued PPI treatment was not an independent predictor of the overall one-year survival (hazard ratio 0.97) or one-year MI, stroke, or death in clopidogrel-treated patients (hazard ratio, 0.98).

The specific PPI didn’t seem to alter the results, the investigators report. In a linked commentary, Dr. Michelle L. O’Donoghue of Brigham and Women’s Hospital in Boston notes that more than a significant number of patients were taking omeprazole, which is believed to be one of the stronger CYP2C19 inhibitors.

Similarly, no significant change in risk of cardiovascular events or death was evident for patients with no or one CYP2C19 loss-of-function allele. However, patients carrying two CYP2C19 loss-of-function variants and treated with a PPI had a numerically higher incidence of in-hospital major ischemic events than those with no PPI treatment (3 of 25 or 12% versus 1 of 19 or 5%).

“Because of the low number of patients (3%) and resultant large confidence interval ranges, the possibility that a higher early risk (during hospitalization) may exist in patients with 2 CYP2C19 variant alleles cannot be totally excluded and needs further clinical studies,” Dr. Simon told Reuters Health.

Overall, Dr. O’Donoghue concludes, “the weight of the evidence suggests that clopidogrel can be administered safely in combination with a PPI for patients at risk of gastrointestinal complications.”

Circulation 2011;123:468-470,474-482.