Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.
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.
Bresalier
Robert S
RS
Department of Gastrointestinal Medicine and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston 77030-4009, USA. rbresali@mdanderson.org
Sandler
Robert S
RS
Quan
Hui
H
Bolognese
James A
JA
Oxenius
Bettina
B
Horgan
Kevin
K
Lines
Christopher
C
Riddell
Robert
R
Morton
Dion
D
Lanas
Angel
A
Konstam
Marvin A
MA
Baron
John A
JA
D018256:Adenomatous Polyps / Q000517:prevention & control*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000401:mortality; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D015994:Incidence; D007783:Lactones / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012306:Risk; D055502:Secondary Prevention; D016037:Single-Blind Method; D013450:Sulfones / Q000009:adverse effects* / Q000627:therapeutic use; D013927:Thrombosis / Q000139:chemically induced* / Q000453:epidemiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D001241:Aspirin