Chan F, Ching J, Hung L, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352:238-44.
The optimal choice of antiplatelet therapy for patients with coronary heart disease who have had a recent upper gastrointestinal hemorrhage has not been well studied. Clopidogrel has been shown to cause fewer episodes of gastrointestinal hemorrhage than aspirin, but it is unknown whether clopidogrel monotherapy is in fact superior to aspirin plus a protonpump inhibitor. In this prospective, randomized, doubleblind trial, Chan and colleagues hypothesize that clopidogrel monotherapy would “not be inferior” to aspirin plus esomeprazole in a population of patients who had recovered from aspirin-induced hemorrhagic ulcers.
The study population was drawn from patients taking aspirin who were evaluated for an upper gastrointestinal bleed and had ulcer disease documented on endoscopy. Patients with documented Helicobacter pylori infection were treated with a 1-week course of a standard triple-drug regimen. All subjects, regardless of H. pylori status, were treated with an 8-week course of proton-pump inhibitors (PPI). Inclusion criteria included endoscopic confirmation of ulcer healing and successful eradication of H. pylori, if it was present. The location of the ulcers was not specified in the study.
Exclusion criteria included use of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, anticoagulant drugs, corticosteroids, or other anti-platelet agents; history of gastric surgery; presence of erosive esophagitis; gastric outlet obstruction; cancer; need for dialysis; or terminal illness.
Subjects who met the inclusion criteria were randomized to receive either 75 mg of clopidogrel and placebo or 80 mg of aspirin daily plus 20 mg of esomeprazole twice a day for a 12 months. Patients returned for evaluation every 3 months during the 1-year study period. The primary endpoint was recurrence of ulcer bleeding, which was predefined as clinical or laboratory evidence of gastrointestinal hemorrhage with a documented recurrence of ulcers on endoscopy. Lower gastrointestinal bleeding was a secondary endpoint.
Of 492 consecutive patients who were evaluated, 320 met inclusion criteria and were evenly divided into the clopidogrel plus placebo or the aspirin plus esomeprazole arms. Only 3 patients were lost to followup. During the study period, 34 cases of suspected gastrointestinal hemorrhage (defined as hematemesis, melena, or 2 g/dL decrease of hemoglobin) were identified. During endoscopy,14 cases were confirmed to be due to recurrent ulcer bleeding. Of these, 13 ulcers were in the clopidogrel arm (6 gastric ulcers, 5 duodenal, and 2 both) and 1 ulcer (duodenal) in the aspirin plus esomeprazole arm, a statistically significant difference (p=.001).
Fourteen patients were determined to have a lower gastrointestinal hemorrhage. Interestingly, these cases were evenly divided between the clopidogrel group (7 cases) and the aspirin plus esomeprazole (7 cases). This finding suggests the effect of esomeprazole in this study may be specific in preventing recurrent upper gastrointestinal ulcer formation and hemorrhage. The 2 groups had equivalent rates of recurrent ischemic events.
This study addresses an important clinical question, frequently encountered by hospitalists. The recommendation that clopidogrel be used instead of aspirin in patients who require antiplatelet therapy but have a history of upper gastrointestinal hemorrhage is based on studies using high-dose (325 mg) aspirin and excluded patients on acid-suppressing therapy. However, this study failed to prove noninferiority of clopidogrel to aspirin and esomeprazole for this indication. Although this study was not designed to show superiority of aspirin and esomeprazole over clopidogrel, these results indicate that this may be the case, and such a study would be timely. (CG)