Omeprazole and Clopidogrel — Is There a Clinically Meaningful Interaction?

Abstract & Commentary

By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study.This article originally appeared in the January 2011 issue of Clinical Cardiology Alert. It was edited by Michael H. Crawford, MD, and peer reviewed by Ethan Weiss, MD. Dr. Crawford is Professor of Medicine, Chief of Cardiology, University of California, San Francisco, and Dr. Weiss is Assistant Professor of Medicine, Division of Cardiology and CVRI, University of California, San Francisco. Dr. Crawford is on the speaker for Astra-Zeneca, and Dr. Weiss reports no financial relationships relevant to this field of study.

Source: Bhatt, DL et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010:363:1909-1917.

Gastrointestinal (GI) bleeding is a major complication of dual anti-platelet therapy (DAPT) with aspirin and clopidogrel. Omeprazole reduces the risk of GI bleeding in this setting. However, studies of platelet function have suggested that omeprazole also may reduce the efficacy of clopidogrel-mediated platelet inhibition. Whether this translates into an increase in ischemic events is controversial. Clinical-trial data are conflicting, with some studies showing increased cardiovascular events in patients on DAPT who also take omeprazole, compared to those who do not take omeprazole, but other studies are failing to show any association. However, to date, these studies have all been retrospective. Bhatt and colleagues report the first prospective, randomized, placebo-controlled trial to address this issue.

The study aimed to enroll approximately 5,000 patients with coronary artery disease who were prescribed DAPT with aspirin and clopidogrel but, due to withdrawal of sponsor funding, the trial stopped early. Only 3,873 patients were randomized to receive either omeprazole 20 mg daily vs. placebo, and the trial had both a GI primary endpoint and a cardiovascular primary endpoint. The GI primary endpoint was a combination of upper GI bleeding and reduction in hemoglobin of at least 2g/dL (or decrease of hematocrit by 10%), presumed to be due to upper GI bleeding, gastric or duodenal ulcer, gastric or duodenal erosions, obstruction, or perforation. The primary cardiovascular endpoint was a composite of cardiovascular death, myocardial infarction, coronary revascularization, or ischemic stroke. Inclusion criteria were patients over 21 years of age with coronary artery disease who were receiving aspirin and clopidogrel after presenting with either acute coronary syndrome or placement of a coronary stent. Exclusion criteria included prolonged hospitalization, the need for either shorter- or longer-term proton pump inhibitor (PPI) therapy, use of H2 blockers, misoprostol or sucralfate, pre-existing erosive esophagitis, varices or previous gastric surgery, oral anticoagulation, recent fibrinolytic, or prior clopidogrel use for > 21 days.

Results: Baseline characteristics were well-matched in the placebo and omeprazole groups, with mean age 69 years, two-thirds male, approximately 50% positive for Helicobacter pylori, and 9% using NSAIDS. The omeprazole group had a significantly lower rate of the primary GI endpoint (1.1% vs. 2.9%; p < 0.001); this included lower rates of GI bleeding. Importantly, the presence or absence of H. pylori and the use of NSAIDs made no difference to this outcome. All the components of the composite GI primary outcome were numerically higher in the placebo group. There was no difference between the placebo and omeprazole in the cardiovascular primary endpoint (54 events vs. 55 events; p = 0.98). This was consistent across all subgroups and all components of the composite endpoint. The rate of serious adverse events also did not differ between groups (10.1% vs. 9.4% in omeprazole and placebo groups, respectively; p = 0.48). The only difference in adverse events was a higher rate of diarrhea with omeprazole (3.0% vs. 1.8%; p = 0.01). The authors conclude that among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper GI bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but they add that their results do not rule out a clinically meaningful difference in cardiovascular events due to the use of a PPI.

Commentary

There has been much discussion about the risks of GI bleeding with DAPT and the potential interactions between clopidogrel and PPIs. Platelet-function studies have suggested that PPIs interfere with the anti-platelet effect of clopidogrel. However, the clinical-event rates from post-hoc analyses of clinical trials have been conflicting about whether there is a clinically relevant interaction between these drugs. This prospective trial reassures us that omeprazole does indeed reduce GI bleeding in patients on DAPT. Furthermore, it does not suggest a clinically meaningful interaction between these two drugs, in terms of cardiovascular events. However, the authors point out that the observed event rate was lower than expected, and this reduces the power of the study. Thus, they do not consider this definitive proof of a lack of interaction. This sentiment is echoed by the upcoming ACCF/AHA/ACG 2010 Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines (in press). This document highlights the lack of evidence of a clinical outcome from such a proposed interaction, but also acknowledges the biological plausibility that such an interaction may exist, particularly in some subgroups, such as poor metabolizers of clopidogrel. They recommend individualizing the risks of GI bleeding vs. ischemic events in every patient before deciding on the use of PPIs, rather than prescribing them to everyone. In those patients taking aspirin and clopidogrel who are at high risk for GI bleeding, it is reasonable to prescribe PPIs.

It is important to note that there may be important differences between PPIs in terms of their effects on cytochrome p-450 and, therefore, they may have different effects on clopidogrel metabolism. The results of the current study may not be generalizable to all PPIs. Conversely, there may be differences between clopidogrel and the newer P2Y12 inhibitors, such as prasugrel, and the current results may not necessarily apply to these new agents. Decisions regarding anti-platelet and PPI agents will need to be individualized for each patient.