Adding a proton pump inhibitor to dual antiplatelet therapy significantly reduced the risk of gastrointestinal bleeding without raising the risk of cardiovascular events, according to a report published online Oct. 6 in the New England Journal of Medicine.
Dr. Deepak L. Bhatt
The finding that PPIs don’t appear to blunt the effect of antiplatelets is reassuring in view of the results of several previous studies that found a possible adverse drug interaction, said Dr. Deepak L. Bhatt of Harvard Medical School and the Veterans Affairs Boston Healthcare System, and his associates in the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT).
“Our trial, in which the study population was at least 10 times as large as those in previous randomized studies and was not selected to represent high-risk patients, showed a significant reduction in clinically manifested gastrointestinal bleeding events, including overt bleeding, with a PPI as compared with placebo,” they noted.
COGENT, an international, randomized, double-blind phase III study, assessed the safety and efficacy of omeprazole in 3,761 patients with coronary heart disease who were already taking clopidogrel plus aspirin. The study subjects were enrolled at 393 sites in 15 countries, randomly assigned to add either omeprazole 20 mg (1,876 patients) or placebo (1,885 patients) to their treatment regimen, and followed for a median of 106 days (341 days maximum). The median age was 69 years in both groups; 67% and 70% of patients were male in the omeprazole and placebo groups, respectively.
The study was halted prematurely when the sponsor, Cogentus Pharmaceuticals, suddenly lost its financial backing; the company has since become defunct. The study’s statistical power is limited because the number of adverse events that developed was smaller than had been anticipated when it was designed.
At 180 days, there were 55 gastrointestinal bleeding events, with 47 patients having 1 such event and 4 patients having 2 events. The GI bleeding event rate was 1.1% with omeprazole, significantly lower than the 2.9% rate with placebo. Similarly, the rates of overt gastroduodenal bleeding, overt upper GI bleeding of unknown origin, and a composite of all overt and occult GI bleeding events also were significantly lower with the active drug.
“The number of patients who would need to be treated for 6 months to prevent one occurrence of an event that was part of the primary gastrointestinal end point was 55, and the number needed to treat to prevent one occurrence of overt GI bleeding was 98,” Dr. Bhatt and his colleagues said (N. Engl. J. Med. 2010 Oct. 6 [doi 10.1056/NEJMoa1007964]).
In addition, at 180 days the percentage of participants with symptoms of gastroesophageal reflux disease was only 0.2% in the omeprazole group, compared with 1.2% in the placebo group.
There were 109 cardiovascular adverse events (55 in the omeprazole group and 54 in the placebo group). The two groups were not significantly different in their rates of the primary cardiovascular end point, a composite of death from CV causes, nonfatal MI, coronary revascularization, or ischemic stroke.
“Although previous observational studies have yielded conflicting results in this regard, [our] study reveals no signal of harm from concomitant clopidogrel and PPI use,” the investigators said.
The rates of serious adverse events did not differ significantly between the two study groups (10% with omeprazole and 9% with placebo). Similarly, the rates of overall diverse events did not differ significantly (41% and 43%, respectively). None of the patients had diarrhea due to Clostridium difficile infection.
This study was supported by Cogentus Pharmaceuticals, which is now defunct. Dr. Bhatt reported receiving grants from AstraZeneca, Bristol-Myers Squibb, Eisai, Sanofi Aventis, and the Medicines Company, and his associates reported ties to numerous drug and device manufacturers.