Prevention of NSAID-related upper gastrointestinal toxicity: a meta-analysis of traditional NSAIDs with gastroprotection and COX-2 inhibitors

Abstract

Background: Traditional NSAIDs (tNSAIDs) and COX-2 inhibitors (COX-2s) are important agents for the treatment of a variety or arthritic conditions. The purpose of this study was to systematically review the effectiveness of misoprostol, H2-receptor antagonists (H2RAs), and proton pump inhibitors (PPIs) for the prevention of tNSAID related upper gastrointestinal (GI) toxicity, and to review the upper gastrointestinal (GI) safety of COX-2s.

Methods: An extensive literature search was performed to identify randomized controlled trials (RCTs) of prophylactic agents used for the prevention of upper GI toxicity, and RCTs that assessed the GI safety of the newer COX-2s. Meta-analysis was performed in accordance with accepted techniques.

Results: 39 gastroprotection and 69 COX-2 RCTs met inclusion criteria. Misoprostol, PPIs, and double doses of H2RAs are effective at reducing the risk of both endoscopic gastric and duodenal tNSAID-induced ulcers. Standard doses of H2RAs are not effective at reducing the risk of tNSAID-induced gastric ulcers, but reduce the risk of duodenal ulcers. Misoprostol is associated with greater adverse effects than the other agents, particularly at higher doses. COX-2s are associated with fewer endoscopic ulcers and clinically important ulcer complications, and have fewer treatment withdrawals due to GI symptoms than tNSAIDS. Acetylsalicylic acid appears to diminish the benefit of COX-2s over tNSAIDs. In high risk GI patients, tNSAID with a PPI or a COX-2 alone appear to offer similar GI safety, but a strategy of a COX-2 with a PPI appears to offer the greatest GI safety.

Conclusion: Several strategies are available to reduce the risk of upper GI toxicity with tNSAIDs. The choice between these strategies needs to consider patients' underlying GI and cardiovascular risk.

Keywords: COX-2 inhibitors; NSAID; gastrointestinal toxicity.

Figure 1

Misoprostol vs placebo for the prevention of gastric ulcers – efficacy by dose.

Figure 2

Misoprostol vs placebo – drop-outs due to side-effects by dose.

Figure 3

H2RAs compared to placebo for the prevention of gastric ulcer. Analysis by dose in studies of 12 weeks or longer duration.

Figure 4

H2RAs compared to placebo for the prevention of duodenal ulcer. Analysis by dose in studies of 12 weeks or longer duration.

Figure 5

Proton pump inhibitors compared to placebo for the prevention of gastric ulcer in studies of 8 weeks or longer duration.

Figure 6

Proton pump inhibitors compared to placebo for the prevention of duodenal ulcer in studies of 8 weeks or longer duration.

Figure 7

COX-2 vs tNSAID for endoscopic ulcers with any COX-2 dose.

Figure 8

Gastroduodenal ulcers analysed by individual COX-2 inhibitor compared to tNSAIDs.

Figure 9

POBs (perforation, obstruction or bleeding) with COX-2s vs tNSAIDs.

Figure 10

PUBs (POBs [perforation, obstruction or bleeding] or symptomatic ulcer) with COX-2s vs tNSAIDs.

Figure 11

Clinical ulcers (PUBs [perforation, obstruction, bleeding or the presence of a symptomatic ulcer]) with COX-2 + ASA vs tNSAID + ASA. Note: This is a non-randomized comparison.

Figure 12

Clinical ulcers (PUBs [perforation, obstruction, bleeding or the presence of a symptomatic ulcer]) with COX-2 + ASA vs COX-2 alone. Note: This is a non-randomized comparison.

Figure 13

Clinical ulcers (PUBs [perforation, obstruction, bleeding or the presence of a symptomatic ulcer]) with tNSAID + ASA vs tNSAID alone. Note: This is a non-randomized comparison.