More research into proton pump inhibitors and dual antiplatelet therapy needed

January 15, 2015 – A meta-analysis led by the DCRI’s Chiara Melloni, MD, MHS, suggests more randomized clinical trials are needed to better understand how the therapies interact in cardiac patients.

A meta-analysis of studies examining the concomitant use of proton pump inhibitors (PPIs) and dual antiplatelet therapy (DAPT) in heart patients reveals conflicting results and suggests that additional research is needed to better understand how the two therapies interact.

chiara-melloni-newsThe analysis, conducted by the DCRI’s Chiara Melloni, MD, MHS (pictured); W. Schuyler Jones, MD; Sharif Halim, MD; Victor Hasselblad, PhD; Brooke Heidenfelder, PhD; and Rowena Dolor, MD, MHS; and Duke’s Jeffrey B. Washam, PharmD; and Stephanie B. Mayer, MD; was published this week in the online version of the journal Circulation: Cardiovascular Quality and Outcomes.

PPIs are drugs that reduce stomach acid; they are often prescribed alongside antiplatelet therapies to reduce gastrointestinal side effects. Studies have shown that the antiplatelet drug clopidogrel becomes less effective when administered with the PPI omeprazole. It is unclear, however, how dual administration of clopidogrel and omeprazole affects overall clinical outcomes. Some observational studies have reported an increased risk of major cardiovascular events, while others have found no difference. In this study, Melloni and her colleagues conducted a systematic literature review to evaluate the safety and effectiveness of PPIs when administered in concert with clopidogrel in patients with unstable angina and non-ST-segment elevation myocardial infarction.

The researchers searched the MEDLINE, EMBASE, and Cochrane Systematic Reviews databases from 1995 to 2012. They identified 35 relevant studies—four randomized controlled trials (RCTs) and 31 observational studies. Five of these studies (the four RCTs and one observational study) examined the clinical effect of omeprazole when used with DAPT; the remaining 30 studies assessed the effects of PPIs as a class when used with DAPT. The researchers’ meta-analysis found that the observational studies analyzing PPIs as a class consistently reported higher rates of heart attack, stroke, revascularization, stent thrombosis, and death among patients who received PPIs with DAPT. The four RCTs of omeprazole, however, showed no difference in clinical outcome.

The researchers noted the possibility of selection bias in the observational studies of PPIs as a class. Sicker patients, already at greater risk for adverse outcomes, are more likely to be treated with PPIs. The observational studies also lacked details about patients’ PPI regimens, including dosage and frequency of administration, the duration of treatment, concomitant medications, new prescription versus chronic therapy, and patients’ medication adherence.

Although the researchers attempted to control for these issues in their meta-analysis, they concluded that confounding effects might still be present and that the existing studies failed to provide enough evidence to make conclusions about the effects of PPIs as a class. Additional research, specifically in the form of RCTs, is needed to determine whether the higher rate of adverse events reported in the observational studies is caused by comorbidities among the patient population, the specific PPI agent used, or a genetic predisposition for reduced clopidogrel responsiveness.