Clopidogrel-PPI Interaction Questioned in Meta-analysis

January 27, 2015

DURHAM, NC — There is a disconnect between results derived from observational studies examining the safety of using proton-pump inhibitors (PPIs) with dual antiplatelet therapy and the results obtained from randomized, controlled clinical trials, according to a new meta-analysis[1].

Among 30 observational studies, investigators report that patients treated with aspirin and clopidogrel for unstable angina/NSTEMI who received concomitant treatment with a PPI had a significantly increased risk of adverse cardiovascular outcomes compared with patients who received dual antiplatelet therapy alone.

In contrast, there was no significant difference in ischemic outcomes in patients treated with dual antiplatelet therapy and omeprazole compared with dual antiplatelet therapy and placebo in four randomized clinical trials. Treatment with omeprazole, the only PPI tested in randomized trials, did result in a significant reduction in gastrointestinal bleeding.

"Although a net-clinical-benefit analysis was not performed, these data suggest that omeprazole and clopidogrel can be safely coadministered," according to lead investigator Dr Chiara Melloni (Duke University Medical Center, Durham, NC) and colleagues. "These findings, all based on randomized trials, call into question the Food and Drug Administration warning against the concomitant use of clopidogrel and omeprazole."

In 2009, the FDA issued a public-health warning about the possible interaction between clopidogrel and omeprazole. The alert stated that when the two drugs are taken together, the effectiveness of clopidogrel is reduced. "Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole," according to the FDA.

Boxed Warning Should Be Removed, Says Editorialist

While the researchers say the results of the meta-analysis, which are published in the January 2015 issue of Circulation: Cardiovascular Quality and Outcomes, warrant another randomized, controlled clinical trial to determine whether there truly is an interaction between clopidogrel and omeprazole or other PPI inhibitors, Dr Peter Berger (Geisinger Medical Center, Danville, PA) doesn't believe such study is needed.

In an editorial[2], Berger makes the case that the observational studies are "hopelessly confounded" and that physicians should accept the randomized trial evidence. He points out there were concerns about an interaction between clopidogrel and statins, as well as concerns about clopidogrel and calcium-channel blockers, based on observational studies. These concerns were alleviated when randomized trials were performed. Regarding the PPI-clopidogrel interaction, Berger points out that the ischemic-event curves in the randomized trials are "virtually superimposable."

"What does seem clear, however, is that warnings about the coadministration of PPIs with clopidogrel ought be removed," he writes.

As reported by heartwire at the time, cardiologists were surprised, even "shocked," by the 2009 FDA warning. The warning was based on mechanistic in vitro studies showing a significant interaction between clopidogrel and omeprazole on the amount of clopidogrel active metabolite formed and the degree of platelet aggregation. These studies showed that pantoprazole had less of an interaction with clopidogrel.

In 2010, however, the COGENT randomized clinical trial was published in the New England Journal of Medicine. As reported by heartwire at that time, investigators observed no clinical interaction between omeprazole and clopidogrel. Treatment with omeprazole significantly reduced the risk of gastrointestinal bleeding, but there was no increased risk of cardiac events, including MI or need for coronary revascularization, among patients treated aspirin, clopidogrel, and omeprazole.

Systematic Review of Published Studies

In their review of the data, Melloni and colleagues graded the strength of the evidence and estimated the effect on various clinical end points, including all ischemic events, all-cause mortality, cardiovascular mortality, MI, coronary revascularization, and stroke.

Regarding the composite ischemic end point at one year, the randomized-trial data showed no signal of harm in patients treated with omeprazole and dual antiplatelet therapy, while the observational data suggested that patients treated with omeprazole had a 35% increased risk of ischemic events. The strength of the evidence was rated low, with investigators stating, "The discrepancy between the randomized clinical trials and observational studies makes it difficult to draw a firm conclusion about the effect."

Regarding all-cause mortality at one year, the randomized trials showed no effect when omeprazole was added to therapy, but the observational data suggested there was a trend toward increased risk. When MI and all-cause mortality were assessed, the observational data showed a significant 27% increased risk in events among patients taking omeprazole. For nonfatal MI at one year, the observational data suggested a significant 33% higher risk among omeprazole-treated patients, while the randomized data showed no effect. The data were graded as low or moderate in strength.

Berger agrees that certain PPIs block the ex vitro inhibition of aggregation and reduce clopidogrel's active metabolite, but the data do not suggest they reduce the efficacy of clopidogrel in terms of preventing ischemic outcomes.

In the editorial, Berger says another important message is being lost amid the confusion. Clinical trials testing PPIs with aspirin or aspirin and clopidogrel have shown fewer gastrointestinal adverse effects with the PPIs and fewer patients stopping their antiplatelet therapy. The more appropriate concern might be that PPIs are too infrequently administered with these drugs rather than prescribed too much or at all.

Melloni reports no relevant financial relationships; disclosures for the other coauthors are listed in the paper. Berger reports research grants from Lilly, Sanofi, and Bristol-Myers Squibb.

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