A final peer-review of the COGENT study confirms preliminary results that the combination of clopidogrel and proton pump inhibitors (PPIs) does not cause cardiovascular (CV) events. The latest results, however, also show a significant reduction in the rate of upper gastrointestinal (GI) bleeding, according to the study published Oct. 6 in the New England Journal of Medicine.
The finding that PPIs do not interfere with the antiplatelet effects of clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) still holds now that the study has been verified by two academic statisticians using the full adjucated data set, Deepak L. Bhatt, MD, from the Veterans Affairs Boston Healthcare System and Brigham & Women's Hospital in Boston, told Cardiovascular Business News.
"What was not emphasized when we presented those preliminary findings at TCT.09 and not fully apparent until now was the substantial reduction in the primary composite of GI event rates, but, more importantly, the stand alone GI bleeding rate as an endpoint," he said.
"This is the first randomized trial to demonstrate that prophylactic PPI administration reduces clinical intestinal tract bleeding in patients with low or average risk of bleeding," said Bhatt, adding that other studies have shown a reduction at endoscopically-defined endpoints.
Previous data are conflicting regarding the effects of PPIs to decrease the risk of GI complications associated with antithrombotic therapy, particularly in patients receiving dual-antiplatelet therapy. Some data also suggest that PPIs reduce the efficacy of clopidogrel.
To help clarify the matter, Bhatt and others initiated the COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) study. Investigators had intended to enroll 5,000 patients, but settled for 3,761 in the final analysis because the trial's sponsor, Cogentus Pharmaceuticals, filed for bankruptcy in January 2009. Patients were enrolled at 393 sites in 15 countries from January 2008 to December 2008.
The randomized double-blind, double-dummy, placebo-controlled parallel group phase III study evaluated the efficacy and safety of CGT-2168, a fixed-dose once-daily combination of clopidogrel (75 mg) and omeprazole (20 mg) (Prilosec, AstraZeneca) compared with clopidogrel alone. All patients received aspirin. There were 1,876 in the omeprazole arm and 1,885 in the placebo arm.
The primary GI endpoint was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction or perforation. The primary cardiovascular endpoint was a composite of death from CV causes, non-fatal MI, revascularization or stroke.
Researchers found no significant differences between the two arms in primary or secondary endpoints. Overall, 51 patients had a GI event: 1.1 percent with omeprazole and 2.9 percent with placebo at 180 days. The hazard ratio (HR) with omeprazole was 0.34, with a good confidence interval. The rate of overt upper GI bleeding was also reduced with omeprazole compared with placebo (HR 0.13).
"Despite COGENT being terminated prematurely, we still found reductions in GI bleedings that were highly statistically significant and if the trial had gone its full duration, that result would have been even more statistically significant," Bhatt said.
"The GI findings are remarkable and have the potential to be practice changing," he said. "If one interprets these data honestly, it shows that more patients should be on PPIs, and not less. That message is a correct one."
While COGENT investigators did not conduct a formal cost-effectiveness analysis, Bhatt said there is room for that debate. "Is it worthwhile to prescribe PPIs to everyone getting aspirin and clopidogrel, or for that matter, more potent antiplatelet therapy such as aspirin and prasugrel or aspirin and ticagrelor, where the benefits could be even larger because the bleeding risks are higher?" he asked.
"We've opened the door pretty wide to this concept of GI protection and its importance in patients with cardiovascular disease," Bhatt said, adding that companies might now realize there is an unmet need for this vulnerable patient population.
In COGENT, Bhatt and colleagues found that 109 patients had a cardiovascular event, with event rates