Clopidogrel is an antiplatelet agent indicated for the treatment of patients with recent MI, recent stroke, established peripheral arterial disease, acute coronary syndromes, or post-percutaneous coronary interventions.1 Clopidogrel prevents platelet aggregation that may lead to a blockage and a subsequent cardiovascular events. Therefore clopidogrel is a useful agent in primary and secondary prevention of cardiovascular events.2 Due to clopidogrel's efficacy in these patients, it has become the second most prescribed drug in the world.3 However, the risk for gastrointestinal (GI) bleeding is increased with use of an antiplatelet agent. Thus, a proton pump inhibitor (PPI) such as omeprazole is indicated in patients at high risk for GI bleeding taking clopidogrel alone or with aspirin therapy. Recent observational studies suggest that concomitant use of clopidogrel and a PPI leads to an increased risk of CV events.1
The investigators of the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) assessed the efficacy and safety of concomitant administration of clopidogrel plus aspirin and PPIs in patients with coronary artery disease (CAD). The trial was an international, randomized, double blind, double-dummy, placebo-controlled, parallel-group, phase 3 study of the efficacy and safety of a fixed-dose combination of clopidogrel (75 mg) and omeprazole (20 mg), as compared with clopidogrel alone. 4 Patients included in the study had to be 21 years of age or older and the use of clopidogrel therapy with concomitant aspirin was anticipated for at least the next 12 months. The primary GI efficacy end point was the time from randomization to the first occurrence of a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. Furthermore, the primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The study population represented patients at elevated risk for death from cardiovascular causes.
The investigators planned to enroll 5000 patients; however, a total of 3761 patients were included in the analyses. The median duration of follow-up was 106 days. The primary GI end point was reduced from 2.9% with placebo to 1.1% with omeprazole at 180 days after randomization (hazard ratio, 0.30; 95% CI, 0.13 to 0.66; P=0.001). The number needed to treat for 6 months to prevent one occurrence of the primary gastrointestinal end point was 55. For the cardiovascular outcomes, there was no significant difference in the rate of the primary cardiovascular end point between omeprazole and placebo (P=.98 by the log-rank test). The primary cardiovascular event rate was 5.7% in the placebo group and 4.9% in the omeprazole group at 180 days after randomization (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P=0.96). Furthermore, the rate of serious adverse events did not differ significantly between omeprazole (10.1%) and placebo (9.4%) (P=0.48).
The COGENT investigators found no apparent cardiovascular interaction between clopidogrel and omeprazole. Patients receiving aspirin and clopidogrel had a reduced rate of upper gastrointestinal bleeding when concurrently using a PPI.4 However, they do note limitations to the analysis. First, the trial’s power is limited due to ...