Prevention of NSAID-induced gastroduodenal ulcers

Non-steroidal anti-inflammatory drugs (NSAIDs) are important agents in the management of arthritic and inflammatory conditions, and are among the most frequently prescribed medications in North America and Europe. However, there is overwhelming evidence linking these agents to a variety of gastrointestinal (GI) toxicities.

To review the effectiveness of common interventions for the prevention of NSAID induced upper GI toxicity.

A literature search was conducted, according to the Cochrane methodology for identification of randomized controlled trials in electronic databases, including MEDLINE from 1966 to June 2002, Current Contents for 6 months prior to June 2002, EMBASE to February 2002, and a search of the Cochrane Controlled Trials Register from 1973 to 2002. Biosis Previews(R), ADIS LMS Drug Alerts, Pharmaceutical News Index (PNI)(R) were searched to June 2002. New articles since the last search update were evaluated. Recent conference proceedings were reviewed and content experts and companies were contacted.

Randomized controlled clinical trials (RCTs) of prostaglandin analogues (PA), H2-receptor antagonists (H2RA) or proton pump inhibitors (PPI) for the prevention of chronic NSAID induced upper GI toxicity were included.

Two independent reviewers extracted data regarding population characteristics, study design, methodological quality and number of patients with endoscopic ulcers, ulcer complications, symptoms, overall drop-outs, drop outs due to symptoms. Dichotomous data was pooled using RevMan V4.1. Heterogeneity was evaluated using a chi square test.

Forty RCTs met the inclusion criteria. All doses of misoprostol significantly reduced the risk of endoscopic ulcers. Misoprostol 800 ug/day was superior to 400 ug/day for the prevention of endoscopic gastric ulcers (RR=0.17, and RR=0.39 respectively, p=0.0055). A dose response relationship was not seen with duodenal ulcers. Misoprostol caused diarrhea at all doses, although significantly more at 800 ug/day than 400 ug/day (p=0.0012). Misoprostol was the only prophylactic agent documented to reduce ulcer complications. Standard doses of H2RAs were effective at reducing the risk of endoscopic duodenal (RR=0.36; 95% CI: 0.18-0.74) but not gastric ulcers(RR=0.73; 95% CI:0.50-1.09). Both double dose H2RAs and PPIs were effective at reducing the risk of endoscopic duodenal and gastric ulcers (RR=0.44; 95% CI:0.26-0.74 and RR=0.40;95% CI;0.32-0.51 respectively for gastric ulcer), and were better tolerated than misoprostol.

Misoprostol, PPIs, and double dose H2RAs are effective at preventing chronic NSAID related endoscopic gastric and duodenal ulcers. Lower doses of misoprostol are less effective and are still associated with diarrhea. Only Misoprostol 800ug/day has been directly shown to reduce the risk of ulcer complications such as perforation hemorrhage or obstruction.