What have we learned from the large outcomes trials of COX-2 selective inhibitors? The rheumatologist's perspective

The cyclooxygenase (COX)-2 selective inhibitors celecoxib and rofecoxib have been found to be more effective than placebo and comparably effective to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of patients with osteoarthritis and rheumatoid arthritis. Two large outcome studies, the Celecoxib Long-term Arthritis Safety Study (CLASS) and Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, were conducted to test the hypothesis that patients receiving a COX-2 selective inhibitor would have significantly fewer clinically important upper gastrointestinal events than patients taking nonselective NSAIDs. This article critically reviews the design and results of these trials. Both trials found that arthritis patients not taking low-dose aspirin (325 mg/day or less) who were randomized to receive COX-2 selective inhibitors had significantly fewer symptomatic and complicated ulcers than patients randomized to nonselective NSAIDs. A significant risk reduction was not demonstrated, however, in patients in the CLASS trial who were taking low-dose aspirin, itself an independent risk factor for the endpoint. These data validate the COX-2 hypothesis and support recommendations that a COX-2 selective inhibitor should be used in the treatment of patients at increased risk for symptomatic and complicated ulcers. Further studies are needed to determine whether COX-2 selective inhibitors are safer than nonselective NSAIDs when used in patients receiving low-dose aspirin. The COX-2 selective inhibitors have a similar profile of renal adverse events to nonselective NSAIDs. The increased rate of cardiovascular thromboembolic adverse events among patients randomized to rofecoxib compared to those randomized to naproxen in the VIGOR trial is consistent with the lack of an anti-platelet effect for this COX-2 selective inhibitor. This emphasizes the need for the use of low-dose aspirin in patients at risk for such events, especially myocardial infarction.