The use of clopidogrel combined with proton pump inhibitors (PPI) has been the subject of an immeasurably controversial area of debate over the last 2 years. We've seen this to the point of product labeling changes by the makers of clopidogrel, and we've seen this by advisories at a number of major organizations, including the US Food and Drug Administration (FDA), suggesting that the two should not be combined, specifically because of potential harm that resulted in increased cardiovascular poor outcomes.
I'm happy to report to you that a consensus document[1] has just been published in the December issues of the publications from the American College of Cardiology, the American College of Gastroenterology, and the American Heart Association.
What the writing group determined in a very extensive and exhaustive review of the literature was the following. There was pharmacologic suggestion of potential interactions between particularly omeprazole and clopidogrel, which would decrease some of the effectiveness of clopidogrel.
But it did not seem to translate to cardiovascular harm, and the studies that were suggesting cardiovascular harm were all observational and retrospective studies, with very nominal odds ratios, all of which were less than 2. The only prospective trial, which was just published in November in The New England Journal of Medicine, was the COGENT trial.[2] It looked at a prospective evaluation of omeprazole plus clopidogrel and showed no demonstrable cardiovascular harm. In fact, it showed a demonstrable gastrointestinal (GI) protective benefit in the patients who were prescribed with the activation omeprazole plus clopidogrel.
The consensus document determined that, at present, there's no evidence to suggest a significant cardiovascular harm, and there may be potential GI benefit, as suggested by the only randomized prospective trial we have.
They did look at the effect of adding an H2 blocker instead of a PPI and suggested that first we know that between H2 blockers and PPIs, as a result of prophylaxis in patients on nonsteroidal agents, PPIs are better.
And the H2 blockers are better than placebo, so perhaps in patients at low risk, H2 blockers could be substituted. But again, in patients who need the PPIs -- for example, patients with moderate to severe reflux disease or patients deemed at high risk for GI outcomes -- clearly the PPIs are still the way to go.
In patients who you feel are at risk for GI injury, I think the present data, based on the consensus recommendations from the 3 organizations and endorsed by their boards, put us back on the appropriate tact of: if they're defined to be at risk, the risk/benefit ratio should be determined, and if the patients are determined to be at significant GI risk, a PPI seems most reasonable.
Final answer: I think we can recommend that if patients are defined at GI risk, moderate-severe risk, they should be coprescribed with a PPI, and, we hope, that will put the patient back on the safest pathway that we have at present day.
