Toronto, ON - A review of medical claims from managed-care plans in US suggests that clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Aventis) is frequently contributing to gastrointestinal complications, particularly to increased risks in developing an ulcer or gastrointestinal bleeding [1]. Investigators report that 6.2% of patients prescribed clopidogrel filed at least one insurance claim for ulcer or gastrointestinal bleeding, with women more likely than men to develop these adverse effects from the antiplatelet medication.

One expert, however, urges caution in interpreting the new report. Dr Robert Harrington (Duke Clinical Research Institute, Durham, NC) says that insurance-claims data are "notoriously incomplete" and that little is known about the study. Harrington told heartwire that the study, presented here at the International Society for Pharmacoeconomics and Outcomes Research 2008 International Meeting this week, is nonrandomized and the comparator arm is unknown. Moreover, it is not clear whether or not adjustments for comorbidities associated with an increased risk of bleeding have been made.

"Bottom line," said Harrington, "these data are raising an interesting hypothesis: clopidogrel is associated with gastrointestinal bleeding that leads to discontinuation of the therapy and therefore a possible increase in ischemic events. But it is just that, an interesting hypothesis."

The retrospective study tracked insurance claims for gastrointestinal adverse events among approximately 368 000 patients in the first year following their prescription for clopidogrel. In the review, 72% were 60 years of age and older. Information about concurrent aspirin use was not available. Overall, 6.2% of patients filed a medical claim for ulcer or gastrointestinal complications, with more women than men filing claims (7.2% vs 5.4%, respectively).

Lead investigator Dr Pablo Lapuerta, chief medical officer and senior vice president at Cogentus Pharmaceuticals, conducted the study. In a press releases issued by Cogentus, Lapuerta states that the "inhibition of normal platelet function by clopidogrel likely contributed to gastrointestinal complications, particularly in such a real-world setting in which patients often have multiple risk factors. While it is important for patients to stay on clopidogrel to prevent the progression of coronary heart disease, ulcers and bleeding can result in patients not taking their heart-disease medicine."

Cogentus is sponsoring a phase 3 study testing its product CGT-2168, a drug that combines clopidogrel with the proton-pump inhibitor omeprazole. The hope is that the combination drug maintains the benefits of clopidogrel while reducing these gastrointestinal side effects. Among patients participating in the 4000-patient study, known as Clopidogrel and the Optimization of Gastrointestinal Events Trials (COGENT-1), half will be randomized to clopidogrel and aspirin, and half to clopidogrel and omeprazole. The first patient was enrolled in January 2008.

Harrington notes that the study will be needed to determine whether the combination is able to preserve the antithrombotic benefit of clopidogrel. One study, for example, reported by heartwire, showed that omeprazole reduced the antiplatelet effect of clopidogrel, although researchers prominent in the antiplatelet field warned about attaching too much significance to the ex vivo study [2].