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Until the recent outcome studies comparing the COX-2-specific inhibitors with traditional NSAIDs were completed, the only prospective data regarding the risk of serious complications caused by NSAIDs were from the Misoprostol Ulcer Complications Outcomes Safety

Assessment (MUCOSA) trial (16), which studied the outcome of rheumatoid arthritis patients taking nonaspirin NSAIDs plus misoprostol or placebo. In the trial, 0.95% of patients on nonaspirin NSAIDs plus placebo developed serious GI complications within 6 months compared with 0.57% of patients on NSAIDs plus misoprostol. This is consistent with the frequently quoted 2-4% risk placed on the NSAID label by the Food and Drug Administration. The CLASS and Vioxx Gastrointestinal Outcomes Research (VIGOR) studies, comparing celecoxib and rofecoxib with traditional NSAIDs, confirmed these rates—approximately 2%/yr for complicated ulcers and 4% for symptomatic ulcers (2,3).

Patients with a history of ulcer complications and those taking concomitant anticoagulant therapy have the highest risk of developing NSAID-associated serious GI complications. Moderate risk factors include advanced age, concomitant corticosteroid use, underlying major organ impairment, the use of high-dose or multiple NSAIDs, and arthritis-related disability. Gender and symptoms do not appear to predict increased risk (17).

The past occurrence of an NSAID-associated serious GI complication is unequivocally associated with an increased likelihood (relative risk, 4.76) of another complication with recurrent NSAID use (17). Not surprisingly, the concomitant use of NSAIDs and anticoagulants markedly exacerbates the risk of GI bleeding and increases the risk of hospitalization by 2.2-fold (18). Although corticosteroids do not increase the risk of peptic ulcer disease when used alone, their use with NSAIDs leads to a nearly twofold increase in complication risk and a greater than tenfold risk of death (19).

Increasing age is an independent predictor of experiencing an NSAID-associated GI complication. Clinically significant major organ impairment, particularly cardiovascular disease, was identified as an independent risk factor in the MUCOSA trial. Patients with cardiovascular disease were at a nearly twofold increased risk for GI complications caused by NSAID therapy, independent of aspirin use (16).

Symptoms or the lack thereof, are not good predictors of NSAID complication risk. In one study, 58% of patients admitted with an NSAID complication had no antecedent dyspeptic symptoms, compared with the presence of symptoms in 75% of those with non-NSAID-compli-cated ulcers (20).

A metaanalysis assessed the effect of different types and dosages of NSAIDs on serious GI complications, using ibuprofen as the reference medication. NSAIDs with increasing COX-1 activity were associated with increasing risks of serious GI complications. The relative risk was more than twofold higher with high- versus low-dose NSAID therapy.

The data indicated a trend for ibuprofen being less likely to cause serious GI complications than naproxen or indomethacin. This metaanalysis also concluded that the low occurrence of serious GI complications associated with ibuprofen in previous individual studies was probably owing to the low dosages of ibuprofen frequently used by patients (21).

Several studies have evaluated agents that bypass gastric absorption (e.g., salsalate, nabumetone) or agents that are less potent COX-1 inhibitors (e.g., etodolac, nabumetone, and meloxicam). These trials demonstrated a significant reduction in endoscopic gastric ulcers and erosions with salsalate, etodolac, and nabumetone. Meloxicam and nabumetone have also been associated with a low rate of symptomatic ulcers in analyses of their respective clinical trial programs. However, the results of these studies should be interpreted cautiously for several reasons, including variability in the assessment of NSAID-associated endoscopic damage. Most importantly, these agents have not been subjected to large-scale outcome trials designed to examine the incidence of serious GI complications (e.g., bleeding, perforation, hospitalization, or death) (5).

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