• Robert S Bresalier, Robert S Sandler, Hui Quan, James A Bolognese, Bettina Oxenius, Kevin Horgan, Christopher Lines, Robert Riddell, Dion Morton, Angel Lanas, Marvin A Konstam, John A Baron, and Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators.
• Department of Gastrointestinal Medicine and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston 77030-4009, USA. rbresali@mdanderson.org
• N. Engl. J. Med. 2005 Mar 17; 352 (11): 109211021092-102.

BackgroundSelective inhibition of cyclooxygenase-2 (COX-2) may be associated with an increased risk of thrombotic events, but only limited long-term data have been available for analysis. We report on the cardiovascular outcomes associated with the use of the selective COX-2 inhibitor rofecoxib in a long-term, multicenter, randomized, placebo-controlled, double-blind trial designed to determine the effect of three years of treatment with rofecoxib on the risk of recurrent neoplastic polyps of the large bowel in patients with a history of colorectal adenomas.MethodsA total of 2586 patients with a history of colorectal adenomas underwent randomization: 1287 were assigned to receive 25 mg of rofecoxib daily, and 1299 to receive placebo. All investigator-reported serious adverse events that represented potential thrombotic cardiovascular events were adjudicated in a blinded fashion by an external committee.ResultsA total of 46 patients in the rofecoxib group had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95 percent confidence interval, 1.19 to 3.11; P=0.008). The increased relative risk became apparent after 18 months of treatment; during the first 18 months, the event rates were similar in the two groups. The results primarily reflect a greater number of myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. There was earlier separation (at approximately five months) between groups in the incidence of nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure (hazard ratio for the comparison of the rofecoxib group with the placebo group, 4.61; 95 percent confidence interval, 1.50 to 18.83). Overall and cardiovascular mortality was similar in the two groups.ConclusionsAmong patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk.Copyright 2005 Massachusetts Medical Society.

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