Many clinicians are concerned about a possible interaction between the proton pump inhibitor omeprazole (Prilosec) and the antiplatelet drug clopidogrel (Plavix), which is often given to patients as part of dual antiplatelet therapy after an acute coronary syndrome or a percutaneous coronary intervention. Indeed, the US Food and Drug Administration (FDA) has warned that omeprazole reduces the antiplatelet effect of clopidogrel.
Although we should not take such warnings lightly, we also should not be alarmed. The data on which the FDA warning was based came mostly from laboratory assays of platelet function. Preliminary results from a randomized, controlled clinical trial with hard end points show that, for the time being, we should not change the way we manage patients.
PROTON PUMP INHIBITORS DECREASE GASTROINTESTINAL BLEEDING
Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after an acute coronary syndrome or a percutaneous coronary intervention compared with aspirin alone.1 However, it also increases the risk of gastrointestinal bleeding. A recent analysis determined that dual antiplatelet therapy was the most significant risk factor associated with serious or fatal gastrointestinal bleeding in high-risk survivors of myocardial infarction.2
Given the risks of significant morbidity and death in patients on dual antiplatelet therapy who develop gastrointestinal bleeding, an expert consensus panel recommended the use of proton pump inhibitors in patients on dual antiplatelet therapy who have risk factors for gastrointestinal bleeding.3 Accordingly, these drugs are commonly used for gastrointestinal protection in patients requiring dual antiplatelet therapy.
A POSSIBLE CYP450 INTERACTION
Clopidogrel is metabolized from a prodrug to its active metabolite by the cytochrome P450 (CYP450) system. Proton pump inhibitors also are metabolized by the CYP450 system.4 Proton pump inhibitors are thought to diminish the activity of clopidogrel via inhibition of the CYP2C19 isoenzyme. However, the clinical significance of this inhibition is not clear. Different drugs of this class inhibit the CYP450 system to varying degrees.
The potential interaction between proton pump inhibitors and clopidogrel is worrisome for many physicians, since adverse cardiovascular outcomes are more common in patients in whom the antiplatelet response to clopidogrel is impaired.1 This interaction led to the publication of numerous articles, and prompted the FDA to carefully analyze the potential clinical implications.
In several randomized trials, omeprazole diminished the response to clopidogrel (measured via platelet function assays).5,6 It is unclear if this is a class effect, as proton pump inhibitors other than omeprazole have not consistently been shown to have this effect.6,7 Observational studies of the effect of co-administration of a proton pump inhibitor and clopidogrel on cardiovascular outcomes following acute coronary syndromes have had conflicting findings.8–11
THE FDA ISSUES AN ADVISORY
Given the reports of an impaired platelet response to clopidogrel with omeprazole, the FDA asked the manufacturer for data on this potential interaction. The data showed diminished platelet inhibition when clopidogrel was co-administered with omeprazole or when the two were taken 12 hours apart.
On November 17, 2009, the FDA issued a patient advisory and updated the patient safety information on the package insert for clopidogrel about this drug interaction.12 Specifically, the FDA warns that omeprazole reduces the antiplatelet effect of clopidogrel by about 50%. The FDA warning sparked debate in the medical community, as the decision was based in part on ex vivo data.
POST HOC ANALYSES FROM RANDOMIZED CONTROLLED TRIALS
Several post hoc analyses of large randomized clinical trials have studied the potential interaction between proton pump inhibitors and clopidogrel.
In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, clopidogrel reduced the incidence of death, myocardial infarction, or stroke to a similar extent regardless of baseline use of a proton pump inhibitor.13
In patients undergoing percutaneous coronary intervention, the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation—Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) trial found that those taking a proton pump inhibitor had significantly less platelet inhibition with clopidogrel compared with those not on one.14 However, patients taking prasugrel (Effient) and a proton pump inhibitor only had a slight trend towards diminished platelet inhibition.14
The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) found that proton pump inhibitors did not influence the long-term outcome of cardiovascular death, myocardial infarction, or stroke for patients on clopidogrel or prasugrel after an acute coronary syndrome.14 A subanalysis did not reveal any differences between omeprazole or other drugs of this class as to an effect on the primary outcome.
Though informative, the results of these post hoc analyses need to be validated with data from randomized clinical trials.