A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas

BACKGROUND & AIMS: In human and animal studies, nonsteroidal anti-inflammatory drugs have been associated with a reduced risk of colorectal neoplasia. Although the underlying mechanisms are unknown, inhibition of cyclooxygenase (COX), particularly COX-2, is thought to play a role. We conducted a randomized, placebo-controlled, double-blind trial to assess whether use of the selective COX-2 inhibitor rofecoxib would reduce the risk of colorectal adenomas. METHODS: We randomized 2587 subjects with a recent history of histologically confirmed adenomas to receive daily placebo or 25 mg rofecoxib. Randomization was stratified by baseline use of cardioprotective aspirin. Colonoscopic follow-up evaluation was planned for 1 and 3 years after randomization. The primary end point was all adenomas diagnosed during 3 years' treatment. In a modified intent-to-treat analysis, we computed the relative risk of any adenoma after randomization, using Mantel-Haenszel statistics stratified by low-dose aspirin use at baseline. RESULTS: Adenoma recurrence was less frequent for rofecoxib subjects than for those randomized to placebo (41% vs 55%; P < .0001; relative risk [RR], 0.76; 95% confidence interval [CI], 0.69-0.83). Rofecoxib also conferred a reduction in risk of advanced adenomas (P < .01). The chemopreventive effect was more pronounced in the first year (RR, 0.65; 95% CI, 0.57-0.73) than in the subsequent 2 years (RR, 0.81; 95% CI, 0.71-0.93). As reported previously, rofecoxib was associated with increased risks of significant upper gastrointestinal events and serious thrombotic cardiovascular events. CONCLUSIONS: In this randomized trial, rofecoxib significantly reduced the risk of colorectal adenomas, but also had serious toxicity.     

Risks of clinically significant upper gastrointestinal events with etodolac and naproxen: a historical cohort analysis

BACKGROUND AND AIMS: Etodolac is a generic nonsteroidal anti-inflammatory drug (NSAID). Previous in vitro studies have shown that etodolac is a selective inhibitor of cyclooxygenase (COX)-2 with selectivity in between that of other COX-2 inhibitors such as celecoxib and rofecoxib. However, there are no outcomes data assessing clinically significant upper gastrointestinal (CSUGI) events with etodolac. METHODS: A historical cohort study was performed at the Dallas Veterans Affairs Medical Center in which 16,286 veteran patients (5596 patient-years) received etodolac or naproxen during a 3-year period without concurrent use of other ulcerogenic drugs other than low-dose aspirin. The primary outcome was the CSUGI event rate of the etodolac and naproxen groups without concomitant low-dose aspirin. RESULTS: The incidence of CSUGI events was .78% and .24% for naproxen and etodolac, respectively. In the NSAID-naive subset, the incidence of CSUGI events was .99% and .24% for naproxen and etodolac, respectively. Compared with naproxen, etodolac was associated with a reduction in upper gastrointestinal events, corresponding to an odds ratio of .39 (95% confidence interval, .20-.76; P = .006). Concomitantly used low-dose aspirin increased event rates with naproxen 2-fold and etodolac 9-fold. Hence, there was no significant difference in gastrointestinal event rates between etodolac and naproxen when low-dose aspirin was taken concomitantly. CONCLUSIONS: Etodolac is a generic COX-2 selective inhibitor that reduces CSUGI events compared with the nonselective NSAID naproxen. However, concomitant use of low-dose aspirin negates the gastrointestinal safety advantages of etodolac.