Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.
Level 2 - randomized trial
Individual randomized double-blind placebo-controlled trial
PubMed 15713943 · doi:10.1056/NEJMoa050493
What was done
In a multicenter, randomized, double-blind, placebo-controlled trial, 2586 patients with a history of colorectal adenomas were assigned to receive either 25 mg of rofecoxib daily (n = 1287) or placebo (n = 1299) for up to three years. The trial evaluated adenoma recurrence while investigator-reported potential thrombotic cardiovascular serious adverse events were adjudicated by a blinded external committee.
What was found
Confirmed thrombotic cardiovascular events occurred in 46 patients in the rofecoxib group (1.50 events per 100 patient-years over 3059 patient-years) compared with 26 patients in the placebo group (0.78 events per 100 patient-years over 3327 patient-years), yielding a relative risk of 1.92 (95% CI, 1.19 to 3.11; P = 0.008). The increased risk emerged after 18 months of treatment and was primarily driven by myocardial infarctions and ischemic cerebrovascular events. Nonadjudicated investigator-reported congestive heart failure, pulmonary edema, or cardiac failure diverged earlier around 5 months (hazard ratio 4.61, 95% CI 1.50 to 18.83). Overall and cardiovascular mortality did not differ significantly between groups.
Why it matters
This trial provided definitive randomized evidence that long-term selective COX-2 inhibition with rofecoxib increases serious thrombotic cardiovascular events, fundamentally changing clinical practice and the regulatory status of COX-2 inhibitors.
Limits
The study was designed and powered primarily for colorectal adenoma recurrence rather than cardiovascular endpoints. Heart failure and pulmonary edema outcomes were investigator-reported without external adjudication. The population was limited to individuals with prior colorectal adenomas receiving a single fixed dose (25 mg daily).
Cited by
- context Vioxx was removed from the market after research by Dr. Steven Nissen at the Cleveland Clinic demonstrated an increased risk of heart attacks.