Clopidogrel is now the second most commonly used prescription drug world wide, driven by its adjunctive use in interventional cardiology with aspirin as dual antiplatelet therapy (DAPT). Upper gastrointestinal (GI) bleeding is the most common serious complication associated with the long-term use of DAPT and some observational data have suggested that the prophylactic use of proton-pump inhibitors may ameliorate this risk, although this has not been specifically tested in trials. More recently, concerns have arisen about the potential for interaction between clopidogrel and proton-pump inhibitors, which may reduce clopidogrel’s antiplatelet efficacy and raises doubts over whether they should be co-prescribed. Again however, this information has been primarily observational and it is far from clear whether this interaction is of clinical significance.

In the double-blind, multicentre, placebo-controlled COGENT trial, patients with an indication for DAPT were randomised in a stratified strategy depending on Helicobacter pylori status and non-steroidal anti-inflammatory drug use either to DAPT+omeprazole or DAPT+placebo. Out of a planned enrolment of 5000, 3873 patients were recruited before the trial was prematurely halted owing to the financial collapse of the industry sponsor. The primary GI end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, non-fatal myocardial infarction, revascularisation, or stroke. GI events occurred in 51 patients in total; 1.1% with omeprazole and 2.9% with placebo at 180 days (HR with omeprazole, 0.34, 95% CI 0.18 to 0.63; p<0.001). In addition, the rate of overt upper GI bleeding was also reduced with omeprazole (HR=0.13; 95% CI 0.03 to 0.56; p=0.001). Using these figures, the number needed to be treated for 6 months to prevent one occurrence of the combined primary end point was 55, and the number needed to be treated to prevent one occurrence of overt GI bleeding was 98. Most importantly, of the 109 patients who had a cardiovascular event, there was no significant difference in event rate between omeprazole (4.9%) and placebo (5.7%) (HR with omeprazole, 0.99; 95% CI 0.68 to 1.44; p=0.96) and the only adverse effect that was significantly more common in the omeprazole group was diarrhoea.

Conclusions

Among patients receiving DAPT, prophylactic use of omeprazole reduced the rate of upper GI bleeding without causing any clinically apparent increase in cardiovascular events. Although the trial was stopped early, this study still provides excellent supportive evidence for this strategy, which was equally efficacious in high-risk groups.

▶ Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363:1909–17.