A multicenter, randomized, double-blind, placebo-controlled trial of high-dose rebamipide treatment for low-dose aspirin-induced moderate-to-severe small intestinal damage.

Toshio Watanabe,Masatsugu Shiba,Tetsuo Arakawa,Osamu Handa,Kazuma Fujimoto,Toshikazu Yoshikawa,Yasuhisa Sakata,Toshihisa Takeuchi,Yuji Naito,Kazuhide Higuchi,Tetsuya Tanigawa,John Green

doi:10.1371/journal.pone.0122330

Abstract

BackgroundLow-dose aspirin (LDA) frequently causes small bowel injury. While some drugs have been reported to be effective in treating LDA-induced small intestinal damage, most studies did not exclude patients with mild damage thought to be clinically insignificant.AimWe conducted a multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy of a high dose of rebamipide, a gastroprotective drug, for LDA-induced moderate-to-severe enteropathy.MethodsWe enrolled patients who received 100 mg of enteric-coated aspirin daily for more than 3 months and were found to have more than 3 mucosal breaks (i.e., erosions or ulcers) in the small intestine by capsule endoscopy. Eligible patients were assigned to receive either rebamipide 300 mg (triple dose) 3 times daily or placebo for 8 weeks in a 2:1 ratio. Capsule endoscopy was then repeated. The primary endpoint was the change in the number of mucosal breaks from baseline to 8 weeks. Secondary endpoints included the complete healing of mucosal breaks at 8 weeks and the change in Lewis score (an endoscopic score assessing damage severity) from baseline to 8 weeks.ResultsThe study was completed by 38 patients (rebamipide group: n = 25, placebo group: n = 13). After 8 weeks of treatment, rebamipide, but not placebo, significantly decreased the number of mucosal breaks (p = 0.046). While the difference was not significant (p = 0.13), the rate of complete mucosal break healing in the rebamipide group (32%, 8 of 25) tended to be higher than that in the placebo group (7.7%, 1 of 13). Rebamipide treatment significantly improved intestinal damage severity as assessed by the Lewis score (p = 0.02), whereas placebo did not. The triple dose of rebamipide was well tolerated.ConclusionsHigh-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy.Trial RegistrationUMIN Clinical Trials Registry UMIN000003463

Highlights

While it is prescribed widely for the primary or secondary prevention of cardiovascular or cerebrovascular disease [1,2,3], low-dose aspirin (LDA) increases the risk of gastrointestinal ulceration and bleeding
The study was completed by 38 patients
High-dose rebamipide is effective for the treatment of Low-dose aspirin (LDA)-induced moderate-tosevere enteropathy

Summary

Introduction

While it is prescribed widely for the primary or secondary prevention of cardiovascular or cerebrovascular disease [1,2,3], low-dose aspirin (LDA) increases the risk of gastrointestinal ulceration and bleeding. Several clinical trials were performed with the aim of overcoming this adverse effect of LDA on the small intestine, and some drugs were shown to effectively heal LDA-induced small intestinal damage [4, 7, 8]. These studies did not exclude patients with mild damage thought to be clinically insignificant. While some drugs have been reported to be effective in treating LDA-induced small intestinal damage, most studies did not exclude patients with mild damage thought to be clinically insignificant

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Results

Conclusion