By Jeffrey Zimmet, MD, PhD

Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center

Dr. Zimmet reports no financial relationships relevant to this field of study.

SYNOPSIS: A dedicated analysis of the COGENT trial involving coronary artery disease patients on dual antiplatelet therapy shows comparable risks of gastrointestinal and cardiovascular events between low- and high-dose aspirin, and similar benefits of prophylactic proton pump inhibitor therapy.

SOURCE: Vaduganathan M, Bhatt DL, Cryer BL, et al. Proton-pump inhibitors reduce gastrointestinal events regardless of aspirin dose in patients requiring dual antiplatelet therapy. J Am Coll Cardiol 2016;67:1661-1671.

Much of cardiology therapeutics deal with balancing the benefits of antiplatelet and antithrombotic agents against the risks of bleeding. Dual antiplatelet therapy (DAPT) is the normal course of treatment for patients who present with acute coronary syndromes or post percutaneous coronary intervention (PCI), but it exposes patients to well-recognized risks of gastrointestinal (GI) bleeding. Although available data support a protective effect of proton pump inhibitors (PPIs) in this arena, these agents are generally underused, at least in part due to an underestimation of risk posed by low-dose aspirin.

The COGENT trial, originally published in 2010, randomized patients with an acute indication for DAPT to concurrent therapy with omeprazole or placebo. Although the study ended prematurely due to loss of funding, it showed that omeprazole reduced the risk of composite upper GI events (1.1% vs. 2.9%; P < 0.001) as well as symptoms of dyspepsia at 180 days, without increasing ischemic events. Researchers examined whether the protective effect of PPIs was consistent across different doses of aspirin, and to determine the cardiovascular safety and GI efficacy of PPI therapy in patients on low-dose vs. high-dose aspirin.

COGENT was a multinational trial that randomized 3,761 patients from 393 sites across 15 countries. Based on available aspirin dosing data from 99.8% of the intention-to-treat cohort, patients were divided into low-dose (< 100 mg, most commonly 81 mg; n = 2,480; 66.1%) and high-dose (> 100 mg, most commonly 325 mg; n = 1,272; 33.9%) aspirin groups. Low-dose aspirin users were more likely to be older and female, and to present with a history of hypertension, stroke, and established peripheral artery disease. Unsurprisingly, high-dose aspirin users were more likely, compared with the low-dose group, to have undergone recent PCI (91.3% vs. 61.6%) and to be enrolled from U.S. sites (80.4% vs. 39.8%).

At a mean follow-up of 110 days, PPI use reduced the incidence of the primary GI endpoint significantly in both the low-dose (1.2% vs. 3.1%; P = 0.003) and high-dose (0.9% vs. 2.6%; P = 0.05) aspirin groups. There was no apparent effect of aspirin dose on PPI efficacy in reducing the primary GI endpoint (P for interaction = 0.80). PPI use did not significantly increase the incidence of major adverse cardiovascular events in low-dose (5.6% vs. 5.5%; P = 0.95) or high-dose (4.2% vs. 5.5%; P = 0.92; interaction P = 0.91) aspirin groups. After adjustment for baseline risk, high-dose aspirin did not influence the risk for adjudicated composite upper GI events, gastroesophageal reflux disease, or major adverse cardiac events compared with low-dose aspirin.

In this large randomized trial of PPI use in cardiac patients on DAPT, the authors concluded that low-dose aspirin was associated with similar risks of GI and cardiovascular events compared with high-dose aspirin, and that prophylactic PPI therapy consistently reduced the rates of GI events and GI symptoms out to 180 days.

COMMENTARY

PPI therapy has long demonstrated efficacy in reducing GI events and symptoms, so why is it so consistently underused in treatment of coronary artery disease (CAD) patients on DAPT? One answer is that clinicians underestimate the risk of bleeding when using low-dose aspirin. In the COGENT trial, approximately two-thirds of the 3,752 patients were treated with low-dose aspirin. The trial confirmed that patients on low-dose aspirin did not have an increased risk of cardiovascular events, but conversely demonstrated that adverse GI events were similar between low- and high-dose groups. Notably, this second point is in contrast to data from the HORIZONS AMI and CURRENT-OASIS 7 trials, which previously reported elevated GI event rates with high-dose aspirin. Moreover, in this trial the magnitude of the measured benefit of prophylactic PPI use was similar regardless of aspirin dose. In the low-dose aspirin group, PPI use was associated with a nearly 2% absolute risk reduction (number needed to treat = just over 50) in primary upper GI events at 180 days. The limited follow-up of the COGENT trial is clearly a weakness, and yet one might have predicted an even greater degree of benefit with more time.

The other issue is the persistent debate over potential adverse interactions between PPIs and clopidogrel. COGENT is by far the largest randomized, clinical trial of PPI therapy in patients with CAD on aspirin and clopidogrel, and very clearly demonstrated no adverse effect of omeprazole on cardiac endpoints. Here again, the limited term of follow-up is of some concern, and yet ischemic event rates are consistently highest in the early months post acute coronary syndrome and post PCI. A recent meta-analysis of 10 randomized trials similarly showed that PPIs decrease the risk of low-dose aspirin–associated upper GI bleeding in patients treated with DAPT without an increase in the risk of major cardiovascular events. Notably, the newer and more-potent P2Y12 agents were not used in COGENT and are lacking data on PPI efficacy.

The argument for PPI use in a majority of CAD patients on DAPT is strong, particularly insofar as these patients typically present with other risk factors for GI bleeding, which brings this recommendation in accordance with current guidelines. This study demonstrates that the shift toward low-dose aspirin in the DAPT equation should not provide a false sense of security, and that these patients benefit significantly from GI prophylaxis with PPIs.