Risk of upper gastrointestinal injury and events in patients treated with cyclooxygenase (COX)-1/COX-2 nonsteroidal antiinflammatory drugs (NSAIDs), COX-2 selective NSAIDs, and gastroprotective cotherapy - An appraisal of the literature

Numerous studies using varying methodologies and outcome measures have examined the gastrointestinal risks of aspirin and nonaspirin nonsteroidal anti inflammatory drug (NSAID) use. Despite the large volume of literature, clarity regarding the key risk factors and their quantitative importance is lacking. We performed a comprehensive review of the literature to summarize the incidence of gastrointestinal injury in populations with varying risk characteristics using agents that inhibit both isoforms of cyclooxygenase and those that selectively inhibit only cyclooxygenase-2 (COX-2). Although risk estimates vary, the risk of serious gastrointestinal complications in NSAID users is approximately 2.5 to 4.5 times that of nonusers. The risk of NSAID-related gastrointestinal bleeding is augmented by concomitant low-dose aspirin and could approach double the risk of NSAID use alone. The preponderance of evidence shows that the risk of NSAID-related gastrointestinal bleeding is reduced approximately 50% with a coxib as compared with traditional NSAID. The relative risk of hospitalization resulting from upper gastrointestinal bleeding for patients treated with a nonselective NSAID was 4.4 (95% confidence interval [CI], 2.3-8.5) and 1.9 (95% CI, 1.0-3.5) when compared with celecoxib and rofecoxib, respectively. Aspirin increases the risk of NSAID-related gastrointestinal bleeding in patients taking COX-2 selective inhibitors, with odds ratios ranging from 5.8 to 7.7; however, it is unknown whether this risk is greater than the risk from aspirin alone. The risks from both traditional NSAIDs and COX-2 inhibitors are increased in the elderly, patients on anticoagulation, and patients with prior gastrointestinal events. Gastroprotective agents have been found to significantly reduce the risk for gastrointestinal injury in patients receiving NSAID therapy, especially those receiving concurrent low-dose cardioprotective doses of aspirin. Proton pump inhibitors (PPIs) and misoprostol both reduce the incidence of gastric and duodenal ulcers, as well as recurrence of ulcer complications in patients receiving NSAIDs. The relative risk for gastric ulcers ranged from 0.17 to 0.38, whereas for duodenal ulcers, the range was 0.11 to 0.28. Although misoprostol is slightly more effective in preventing gastric ulcers in these patients, PPIs are better tolerated. Although NSAIDs appear safe in "low-risk" populations, our review suggests that the use of gastroprotective cotherapy should be considered in patients at higher risk of NSAID-related upper gastrointestinal bleeding.