What Drug Should Not Be Combined with Clopidogrel?

The U.S. Food and Drug Administration issued a black box warning in 2009 to warn against the combining the dual antiplatelet therapy (DAPT) clopidogrel with which proton pump inhibitor?

a. omeprazole

b. esomeprazole

c. lansoprazole

d. dexlansoprazole

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Answer: a

The U.S. Food and Drug Administration (FDA) warned against co-prescribing omeprazole and clopidogrel amid concerns that omeprazole reduced clopidogrel’s anti-clotting effect by half. Patients at risk for heart attack or stroke who use clopidogrel to prevent blood clots would not get the full effect of the medicine if they were also taking omeprazole, said the FDA at the time. Since the FDA’s black box warning, which was mainly based on pharmacodynamics data rather than clinical outcomes, many physicians have avoided giving gastroprotective agents that significantly reduce risk of GI bleeding to patients with unstable angina/non–ST-segment–elevation myocardial infarction (UA/NSTEMI), according to Dr. Chiara Melloni, an assistant professor of medicine at the Duke Clinical Research Institute in Durham, N.C.

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A study she published in January 2015 appeared to contradict the FDA’s alert. Dr. Melloni and colleagues reviewed randomized controlled trials published between 1995 and 2012 to determine what effect if any the addition of omeprazole had on patients who were being treated with aspirin and clopidogrel for UA/NSTEMI. According to 4 randomized controlled trials (RCTs), adding omeprazole to DAPT did not increase risk of adverse ischemic outcomes. On the other hand, 30 observational trials that compared PPI use to non-PPI use demonstrated the drugs increased risk of all-cause mortality or non-fatal heart attack at 1 year and non-fatal heart attack, all-cause mortality, and revascularization beyond 1 year. Data from RCTs involving omeprazole and clopidogrel interaction have consistently raised no safety concerns, pointed out Dr. Melloni. She also said PPIs have a clearly demonstrated efficacy in reducing bleeding risk, in particular reducing the risk of GI bleeding, so the decision to administer the medications to patients treated with clopidogrel should be individualized based on the patient's bleeding and cardiovascular risk.