Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer.
BACKGROUND
Selective cyclooxygenase inhibitors may retard the progression of cancer, but they have enhanced thrombotic potential. We report on cardiovascular adverse events in patients receiving rofecoxib to reduce rates of recurrence of colorectal cancer.


METHODS
All serious adverse events that were cardiovascular thrombotic events were reviewed in 2434 patients with stage II or III colorectal cancer participating in a randomized, placebo-controlled trial of rofecoxib, 25 mg daily, started after potentially curative tumor resection and chemotherapy or radiotherapy as indicated. The trial was terminated prematurely owing to worldwide withdrawal of rofecoxib. To examine possible persistent risks, we examined cardiovascular thrombotic events reported up to 24 months after the trial was closed.


RESULTS
The median duration of active treatment was 7.4 months. The 1167 patients receiving rofecoxib and the 1160 patients receiving placebo were well matched, with a median follow-up period of 33.0 months (interquartile range, 27.6 to 40.1) and 33.4 months (27.7 to 40.4), respectively. Of the 23 confirmed cardiovascular thrombotic events, 16 occurred in the rofecoxib group during or within 14 days after the treatment period, with an estimated relative risk of 2.66 (from the Cox proportional-hazards model; 95% confidence interval [CI], 1.03 to 6.86; P=0.04). Analysis of the Antiplatelet Trialists' Collaboration end point (the combined incidence of death from cardiovascular, hemorrhagic, and unknown causes; of nonfatal myocardial infarction; and of nonfatal ischemic and hemorrhagic stroke) gave an unadjusted relative risk of 1.60 (95% CI, 0.57 to 4.51; P=0.37). Fourteen more cardiovascular thrombotic events, six in the rofecoxib group, were reported within the 2 years after trial closure, with an overall unadjusted relative risk of 1.50 (95% CI, 0.76 to 2.94; P=0.24). Four patients in the rofecoxib group and two in the placebo group died from thrombotic causes during or within 14 days after the treatment period, and during the follow-up period, one patient in the rofecoxib group and five patients in the placebo group died from cardiovascular causes.


CONCLUSIONS
Rofecoxib therapy was associated with an increased frequency of adverse cardiovascular events among patients with a median study treatment of 7.4 months' duration. (Current Controlled Trials number, ISRCTN98278138 [controlled-trials.com].).
Kerr
David J
DJ
Oncology Clinical Trials Office, University of Oxford, Oxford, United Kingdom. david.kerr@clinpharm.ox.ac.uk
Dunn
Janet A
JA
Langman
Michael J
MJ
Smith
Justine L
JL
Midgley
Rachel S J
RS
Stanley
Andrew
A
Stokes
Joanne C
JC
Julier
Patrick
P
Iveson
Claire
C
Duvvuri
Ravi
R
McConkey
Christopher C
CC
D000236:Adenoma / Q000517:prevention & control* / Q000601:surgery; D000368:Aged; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000453:epidemiology / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000517:prevention & control* / Q000601:surgery; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007783:Lactones / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D012306:Risk; D013450:Sulfones / Q000009:adverse effects* / Q000627:therapeutic use
D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib