SAN FRANCISCO—Despite highly publicized observational studies that prematurely lead to societal warnings and regulatory changes regarding proton pump inhibitors (PPIs), the first randomized, placebo-controlled trial, COGENT, found that the combination of proton pump inhibitors (PPI) and clopidogrel did not lead to adverse events. The results were presented during the late breaking clinical trials session at the 2009 Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium.
Over the past several years, there have been a series of observational studies and smaller trials, published in high-profile peer-reviewed journals, such as JACC and JAMA, which suggested that omeprazole (Prilosec; AstraZeneca) and other PPIs diminished the platelet inhibitory effect of clopidogrel (Plavix; Bristol-Myers Squibb) and led to adverse events.
These early studies prompted the FDA to initiate a probe into the matter, recommending that healthcare professionals “re-evaluate the need for starting or continuing treatment with a PPI, including Prilosec OTC [over-the-counter], in patients taking clopidogrel.”
However, lead investigator Deepak Bhatt, MD, chief of cardiology at VA Boston Healthcare System and director of integrated interventional cardiovascular program at Brigham and Women’s Hospital in Boston, said that there has been a “lack of data” to suggest that PPIs can adversely effect patients also taking Plavix.
COGENT is the first trial truly powered to answer this question for both GI and cardiovascular events.
Enrolling 3,627 patients at 393 sites, the researchers sought to determine whether PPI versus placebo reduced GI events in patients on dual-antiplatelet therapy, and if there was any cardiovascular interaction between clopidogrel and PPI.
The gastrointestinal (GI) endpoint was upper GI bleeding, symptomatic upper GI bleeding, pain of presumed GI origin with underlying multiple erosive disease confirmed by endoscopy, obstruction, or perforation. The cardiovascular endpoint was the composite of cardiovascular death, non-fatal MI, CABG or PCI, or ischemic stroke.
The initial planned sample size was 3,200 patients, an accrual period of one year and a maximum follow up of two years. As a low rate of GI events was observed when the trial was ongoing, the sample size target was increased to 4,200 and then about 5,000 (143 GI events). However, the study ended somewhat prematurely when the sponsor, Cogentus, declared bankruptcy. Ultimately, as a result, there was no specific funding for the presented analyses.
Bhatt reported that the survival rates for PCI versus placebo for composite cardiovascular events, MI events and revascularization were virtually identical.
This means that “there is no harm or excess risk with concomitant administration of PPI and clopidogrel at a 95 percent confidence interval,” Bhatt said.
The researchers also broke out the data for various subgroups, such as body mass index, age, race, gender or the use of non-steroidal anti-inflammatory pain medicines—none of which indicated any evidence of cardiovascular risks.
For GI events, there was a significant reduction in favor of the PPI arm over the placebo arm.
“These data provide strong reassurance that there is no clinically relevant adverse cardiovascular interaction between clopidogrel and PPIs,” Bhatt noted.
The results “call into question the exact relationship between ex vivo platelet assays and clinical outcomes, especially with respect to assessing drug interactions,” Bhatt said, adding that, “platelet assays and observational data are not a substitute for randomized controlled data.”
However, Bhatt concluded that, “further research is needed to define the optimal strategy to reduce GI events in patients on antithrombotic therapy, though, based on this trial, prophylactically-administered PPIs seem very promising.”
He added that even though Prilosec was the only PPI investigated in the trial, the data can be extrapolated out to other PPIs.
In the trial's commentary, Shamir R. Mehta, MD, from the department of cardiology at McMaster University in Hamilton, Ontario, said that, "these findings show how people can be completely mislead by observational data. The initial studies were blown way out of proportion to the point where health authorities [issued warnings against] these agents without randomized evidence. Now, we have a randomized trial in COGENT that shows that this was not the case."