Clopidogrel (Plavix) shows increased risk of ulcers

Patients taking clopidogrel (Plavix) have a much higher risk of recurrent ulcer bleed than those treated with aspirin plus the protion-pump inhibitor esomeprazole (Nexium), according to a new study, published in the Jan. 20, 2005, issue of the New England Journal of Medicine.

The American College of Cardiology-American Heart Association guidelines recommend the use of clopidogrel for hospitalized patients with a coronary syndrome who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance, the researchers say. They wanted to assess whether clopidogrel was an alternative to aspirin plus a proton-pump inhibitor for patients at risk for ulcer.

The researchers studied 320 patients who took aspirin to prevent vascular diseases and who presented with ulcer bleeding. These patients had multiple risk factors, including a recent history of aspirin-induced ulcer bleeding, advanced age, and coexisting conditions, according to the study. After the ulcers had healed, the researchers randomly assigned patients who were negative for Helicobacter pylori to receive either 75 mg clopidogrel daily plus esomeprazole placebo twice daily (161 patients) or 80 mg aspirin daily plus 20 mg esomeprazole twice daily (159 patients) for 12 months. The endpoint was recurrent ulcer bleeding.

An independent, blinded, adjudication committee reviewed the data to determine which patients had reached the study endpoints. The committee identified 14 cases of recurrent ulcer bleeding, 13 in the clopidogrel group (8.6%) and one (0.7%) in the aspirin-plus-esomeprazole group.

Among these high-risk patients who received clopidogrel after their ulcers had healed, the incidence of recurrent ulcer bleeding was unacceptably high. The researchers concluded, "Our observations do not support the current recommendation that clopidogrel be used for patients who have major gastrointestinal intolerance of aspirin."

In an editorial accompanying the article in the journal, a physician also remarked about the "astonishing increase" in the rate of recurrent upper gastrointestinal bleeding from ulcers in the group receiving clopidogrel, as compared with those in the group taking aspirin plus esomeprazole.

Conventional wisdom suggests that clopidogrel should be a safer, nonulcerogenic alternative for patients at high risk for aspirin-induced ulcers, said Byron Cryer, MD, associate professor of internal medicine at the University of Texas Southwestern Medical School in Dallas. "The observations in regard to upper gastrointestinal bleeding in this study challenge conventional wisdom and suggest that there are novel mechanisms underlying the pathogenesis of ulcers."

The study also shows two additional points, he said. First, it confirms the capacity of proton-pump inhibitors to reduce recurrent upper gastrointestinal bleeding markedly in patients who take low-dose aspirin and are at high risk for gastrointestinal toxicity. The study also reinforces the need to focus on baseline gastrointestinal risk factors in patients being considered for any type of antiplatelet therapy.

A challenging question now is what therapy to provide for patients who already have had gastrointestinal complications while taking aspirin or other nonsteroidals anti-inflammatory medications, Cryer concluded. "The study by Chan, et al clearly indicates that the recommendation [of replacing aspirin with clopidogrel] is harmful and that such patients should be given aspirin plus a proton-pump inhibitor."