Gastroenterology

Gastroenterology

Volume 131, Issue 6, December 2006, Pages 1674-1682
Gastroenterology

Clinical–alimentary tract
A Randomized Trial of Rofecoxib for the Chemoprevention of Colorectal Adenomas

https://doi.org/10.1053/j.gastro.2006.08.079Get rights and content

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.

Section snippets

Materials and Methods

The Adenomatous Polyp PRevention On Vioxx (APPROVe) trial was a randomized, double-blind, placebo-controlled trial of the efficacy of oral rofecoxib, 25 mg/day, to prevent colorectal adenomas. For regulatory purposes, the main study hypothesis was that 3 years of treatment with rofecoxib would reduce the adenoma risk among higher-risk subjects, that is, those with at least one of the following at baseline: an adenoma 1 cm or greater in estimated diameter, an adenoma with villous or

Results

Overall, 3260 patients were screened for study; 2587 were randomized to rofecoxib 25 mg or placebo (Figure 1). Seventeen subjects found not to have at least 1 colorectal adenoma on uniform pathology review were dropped from efficacy analyses, leaving 1277 subjects randomized to rofecoxib and 1293 randomized to placebo. There were no substantial differences between treatment groups in demographic, lifestyle, or clinical characteristics (Table 1). Overall, 2015 (78.4%) subjects met the criteria

Discussion

In this large, randomized, double-blind clinical trial, we found that rofecoxib significantly reduced the 3-year risk of recurrent adenomas among patients with a recent adenoma history. Risk reduction for advanced lesions was similar to that for all adenomas. There was a suggestion that subjects presenting with advanced adenomas may experience less benefit in terms of relative risk than those with small tubular adenomas only. The chemopreventive effect did not appear to differ according to

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  • Cited by (0)

    Supported by Merck Research Laboratories.

    The authors are indebted to the study subjects for their cooperation and enthusiasm.

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