Risk of cardiovascular events and rofecoxib: cumulative meta-analysis.
BACKGROUND
The cyclo-oxygenase 2 inhibitor rofecoxib was recently withdrawn because of cardiovascular adverse effects. An increased risk of myocardial infarction had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to cardioprotection of naproxen rather than a cardiotoxic effect of rofecoxib. We used standard and cumulative random-effects meta-analyses of randomised controlled trials and observational studies to establish whether robust evidence on the adverse effects of rofecoxib was available before September, 2004.


METHODS
We searched bibliographic databases and relevant files of the US Food and Drug Administration. We included all randomised controlled trials in patients with chronic musculoskeletal disorders that compared rofecoxib with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo, and cohort and case-control studies of cardiovascular risk and naproxen. Myocardial infarction was the primary endpoint.


RESULTS
We identified 18 randomised controlled trials and 11 observational studies. By the end of 2000 (52 myocardial infarctions, 20742 patients) the relative risk from randomised controlled trials was 2.30 (95% CI 1.22-4.33, p=0.010), and 1 year later (64 events, 21432 patients) it was 2.24 (1.24-4.02, p=0.007). There was little evidence that the relative risk differed depending on the control group (placebo, non-naproxen NSAID, or naproxen; p=0.41) or trial duration (p=0.82). In observational studies, the cardioprotective effect of naproxen was small (combined estimate 0.86 [95% CI 0.75-0.99]) and could not have explained the findings of the VIGOR trial.


CONCLUSIONS
Our findings indicate that rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarise the accumulating evidence need to be clarified.
Jüni
Peter
P
Department of Social and Preventive Medicine, University of Berne, Berne, Switzerland.
Nartey
Linda
L
Reichenbach
Stephan
S
Sterchi
Rebekka
R
Dieppe
Paul A
PA
Egger
Matthias
M
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D016022:Case-Control Studies; D015331:Cohort Studies; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D007783:Lactones / Q000009:adverse effects* / Q000627:therapeutic use; D009288:Naproxen / Q000009:adverse effects / Q000627:therapeutic use; D010003:Osteoarthritis / Q000188:drug therapy; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D013450:Sulfones / Q000009:adverse effects* / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D009288:Naproxen