Among patients with a history of aspirin-induced ulcer bleeding, aspirin plus esomeprazole was shown to be superior to clopidogrel for the prevention of recurrent bleeding. The results of a 12-month, prospective, randomized, double-blind trial do not support current American College of Cardiology/American Heart Association guidelines recommending that clopidogrel be used as an alternative antiplatelet agent in patients who have a major gastrointestinal intolerance to aspirin, according to the authors of the study.
"Our results raise doubts about the gastrointestinal safety of clopidogrel even in the absence of active ulcers," the authors stated.
The study, conducted in Hong Kong, enrolled 320 patients who had been taking low-dose aspirin (≤325 mg/d) to prevent vascular diseases and who presented with upper gastrointestinal (GI) bleeding. Patients with Helicobacter pylori infection were treated for 1 week with a 3-drug regimen that included a proton pump inhibitor (PPI). During this period, aspirin was withheld. All patients received PPIs to promote the healing of ulcers. Patients were considered eligible for study inclusion if, after 8 weeks, an endoscopy confirmed that their ulcers had healed and they tested negative for H pylori.
The end point of recurrent ulcer bleeding occurred in 13 patients (8.6%; 6 gastric ulcers, 5 duodenal ulcers, 2 both) (95% CI, 4.1%–13.1%) who received clopidogrel, compared with 1 patient (0.7%; 1 duodenal ulcer) (95% CI, 0%–2.0%) who received aspirin plus esomeprazole (95% CI for the difference, 3.4–12.4; P=.001). Researchers regarded the recurrent ulcer bleeding in the clopidogrel recipients as "unacceptably high." In 10 of the 14 patients with recurrent bleeding (71.4%), the ulcers appeared at their previous locations.
Adverse events occurred in 9.4% of those who received clopidogrel (7.5% had dyspepsia and 1.9% had allergy) and in 4.4% of those who received aspirin plus esomeprazole (2.5% had dyspepsia and 1.9% had allergy). Recurrent ischemic events occurred in 9 patients who received clopidogrel (6 had unstable angina, 1 had a myocardial infarction [MI], and 2 had cerebrovascular insufficiency) and in 11 patients who received aspirin plus esomeprazole (7 had unstable angina, 1 had an MI, and 3 had cerebrovascular insufficiency).
In an accompanying editorial, Byron Cryer, MD, noted study limitations, including the fact that all of the patients were negative for or had been cured of H pylori infection, and none were taking anticoagulants or corticosteroids during the study, suggesting that the results cannot be applied with certainty to patients at risk for GI complications of aspirin therapy.
Dr Cryer, associate professor of Medicine at the University of Texas Southwestern Medical School, also commented: "Although clopidogrel and other agents that impair angiogenesis might not be the primary cause of gastrointestinal ulcers, their antiangiogenic effects may impair the healing of background ulcers; when combined with the propensity to increase bleeding, these agents may convert small, silent ulcers into large ulcers that bleed profoundly."
SOURCES Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352:238–244.
Cryer B. Reducing the risks of gastrointestinal bleeding with antiplatelet therapies. N Engl J Med. 2005;352:287–289.