Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial.
Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis.
                We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers).
                Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups.
                In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor. Gastrointestinal (GI) toxicity mediated by dual cyclooxygenase (COX)-1 and COX-2 inhibition of nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious alterations of mucosal integrity or, more commonly, intolerable GI symptoms that may necessitate discontinuation of therapy. Unlike NSAIDs, rofecoxib targets only the COX-2 isoform.
                To assess the tolerability of rofecoxib compared with naproxen for treatment of osteoarthritis.
                Randomized, controlled trial.
                600 office and clinical research sites.
                5557 patients (mean age, 63 years) with a baseline diagnosis of osteoarthritis of the knee, hip, hand, or spine.
                Rofecoxib, 25 mg/d, or naproxen, 500 mg twice daily. Use of routine medications, including aspirin, was permitted.
                Discontinuation due to GI adverse events (primary end point) and use of concomitant medication to treat GI symptoms (secondary end point). Efficacy was determined by patient-reported global assessment of disease status and the Australian/Canadian Osteoarthritis Hand Index, as well as discontinuations due to lack of efficacy. Patients were evaluated at baseline and at weeks 6 and 12.
                Rates of cumulative discontinuation due to GI adverse events were statistically significantly lower in the rofecoxib group than in the naproxen group (5.9% vs. 8.1%; relative risk, 0.74 [95% CI, 0.60 to 0.92]; P = 0.005), as were rates of cumulative use of medication to treat GI symptoms (9.1% vs. 11.2%; relative risk, 0.79 [CI, 0.66 to 0.96]; P = 0.014]). Subgroup analysis of patients who used low-dose aspirin (13%) and those who previously discontinued using arthritis medication because of GI symptoms (15%) demonstrated a relative risk similar to the overall sample for discontinuation due to GI adverse events (relative risk, 0.56 [CI, 0.31 to 1.01] and 0.53 [CI, 0.34 to 0.84], respectively). No statistically significant difference was observed between treatments for efficacy in treating osteoarthritis or for occurrence of other adverse events.
                In patients with osteoarthritis treated for 12 weeks, rofecoxib, 25 mg/d, was as effective as naproxen, 500 mg twice daily, but had statistically significantly superior GI tolerability and led to less use of concomitant GI medications. Benefits of rofecoxib in subgroup analyses were consistent with findings in the overall sample.
In patients with RA, rofecoxib demonstrates a greater degree of efficacy than placebo, while having a comparable safety profile. Rofecoxib demonstrates a similar degree of efficacy as naproxen, but with a significantly lower rate of ulceration and gastrointestinal bleeding. Rofecoxib was associated with a greater risk for MI, but the exact significance and pathophysiology of this possible relationship is unclear.
Rofecoxib was voluntarily withdrawn from global markets in October 2004. It cannot therefore be prescribed and therefore there are no implications for practice concerning its use. None the less when considering which NSAID to use, it must be borne in mind that the toxicity of NSAIDs is variable amongst patients and drugs and it tends to be dose related and associated with variation in the mode of action, absorption, distribution and metabolism.There remains a number of questions over both the benefits and risks associated with Cox II selective agents and further work is ongoing. It is likely that this issue will not be resolved until research has enabled a fuller understanding of the complex mechanism by which the Cox system operates.