Cardiovascular Events Associated With Rofecoxib in a Colorectal Adenoma Chemoprevention Trial

N Engl J Med. 2005 Mar 17;352(11):1092-102. doi: 10.1056/NEJMoa050493. Epub 2005 Feb 15.

Abstract

Background: Selective 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.

Methods: A 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.

Results: A 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.

Conclusions: Among patients with a history of colorectal adenomas, the use of rofecoxib was associated with an increased cardiovascular risk.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyps / prevention & control*
  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Aspirin / therapeutic use
  • Cardiovascular Diseases / chemically induced*
  • Cardiovascular Diseases / mortality
  • Colorectal Neoplasms / prevention & control*
  • Cyclooxygenase Inhibitors / adverse effects*
  • Cyclooxygenase Inhibitors / therapeutic use
  • Double-Blind Method
  • Female
  • Humans
  • Incidence
  • Lactones / adverse effects*
  • Lactones / therapeutic use
  • Male
  • Middle Aged
  • Proportional Hazards Models
  • Risk
  • Secondary Prevention
  • Single-Blind Method
  • Sulfones / adverse effects*
  • Sulfones / therapeutic use
  • Thrombosis / chemically induced*
  • Thrombosis / epidemiology

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Cyclooxygenase Inhibitors
  • Lactones
  • Sulfones
  • rofecoxib
  • Aspirin