BACKGROUND: In September 2004, rofecoxib was voluntarily withdrawn from the 
worldwide market. Our objective was to determine whether and when analysis of 
published and unpublished placebo-controlled trials could have revealed 
cardiovascular risk associated with rofecoxib before its withdrawal as an 
example to inform future postmarket pharmaceutical safety surveillance efforts.
METHODS: We conducted a cumulative subject-level pooled analysis of data from 
all randomized, placebo-controlled trials of rofecoxib conducted by the 
manufacturer before September 2004. Our main outcome measurement was incidence 
of any investigator-reported death from any cause or cardiovascular 
thromboembolic (CVT) adverse event.
RESULTS: We identified 30 randomized, placebo-controlled trials of rofecoxib 
that enrolled a combined 20 152 subjects. Trial duration ranged from 4 weeks to 
4 years; enrollment ranged from 17 to 2586 subjects prescribed either rofecoxib 
or placebo; and rofecoxib dose ranged from 12.5 mg to 50 mg. As of December 
2000, 21 of these trials had been completed (70%), and the risk of a CVT adverse 
event or death was greater among subjects assigned to the rofecoxib group (rate 
ratio [RR], 2.18; 95% confidence interval [CI], 0.93-5.81) (P = .07), raising 
concerns from a safety standpoint. Subsequently collected data through June 2001 
showed that rofecoxib was associated with a 35% increased risk of a CVT adverse 
event or death (RR, 1.35; 95% CI, 1.00-1.96) (P = .05). Analyzing data available 
as of April 2002, we found a 39% increased risk (RR, 1.39; 95% CI, 1.07-1.80) (P 
= .02), and using data available as of September 2004, we found a 43% increased 
risk (RR,1.43; 95% CI, 1.16-1.76) (P < .001).
CONCLUSION: Cumulative pooled analysis of all randomized, placebo-controlled 
trials demonstrates a trend toward increased cardiovascular risk associated with 
rofecoxib compared with placebo as early as December 2000, the comparison 
reaching a P value of .05 by June 2001, nearly 3(1/2) years before the 
manufacturer's voluntary market withdrawal.