Objective: To compare the effectiveness and tolerability of three misoprostol dosing regimens for the prevention of gastric and duodenal ulcers associated with long-term nonsteroidal anti-inflammatory drug (NSAID) therapy.
Design: A multicenter, 12-week, randomized, double-blind, placebo-controlled, parallel, four-limb study.
Patients: Eligibility criteria included upper gastrointestinal symptoms during NSAID therapy and no endoscopic evidence of gastric or duodenal ulcers. A total of 1623 patients was enrolled; 1197 of these met major accession and regimen-compliance criteria and completed the trial. These 1197 patients composed the evaluable group.
Interventions: Patients were randomly assigned to one of four regimens: placebo four times daily; 200 µg of misoprostol twice daily and placebo twice daily; 200 µg of misoprostol three times daily and placebo once daily; and 200 µg of misoprostol four times daily.
Measurements: Upper gastrointestinal endoscopic examinations for ulcers were done after 4, 8, and 12 weeks of therapy. Tolerability and safety of the regimens were assessed by adverse-event monitoring.
Results: In the placebo group, the incidence of gastric ulcers was 15.7% and the incidence of duodenal ulcers was 7.5%. The incidence of gastric ulcers was significantly lower in the groups receiving misoprostol twice daily (8.1%; difference, 7.6% [95% CI, 2.7% to 12.5%]; P = 0.002), three times daily (3.9%; difference, 11.8% [CI, 7.4% to 16.3%]; P < 0.001), and four times daily (4%; difference, 11.7% [CI, 6.7% to 16.8%]; P < 0.001) compared with placebo. The gastric ulcer rate was significantly higher in patients receiving misoprostol twice daily compared with those receiving misoprostol three times daily (difference, 4.2% [95% CI, 0.7% to 7.7%]; P = 0.02). A significant (P = 0.02) misoprostol dose-response effect was noted in the prevention of gastric ulcers. The incidence of duodenal ulcers was significantly lower in the groups receiving misoprostol twice daily (2.6%; difference, 4.9% [CI, 1.5% to 8.2%]; P = 0.004), three times daily (3.3%; difference, 4.2% [CI, 0.6% to 7.7%]; P = 0.019), and four times daily (1.4%; difference, 6.1% [CI, 2.6% to 9.6%]; P = 0.007) compared with placebo. No significant difference was detected between patients receiving misoprostol twice daily and those receiving misoprostol three times daily, and no dose-response effect was noted with duodenal ulcers. The incidence of withdrawals for adverse events was significantly lower in the groups receiving misoprostol twice daily (12%) and three times daily (12%) than in the group receiving it four times daily (20%). The incidence of gastrointestinal adverse events was significantly higher in the group receiving misoprostol four times daily (74%) than in the placebo group (62%).
Conclusion: Misoprostol, 200 µg twice or three times daily, offers substantial protection against gastric and duodenal ulcers in patients receiving long-term NSAID therapy. These dosages were better tolerated than the currently approved regimen of 200 µg four times daily.