title: Pooled analysis of rofecoxib placebo-controlled clinical trial data: lessons for postmarket pharmaceutical safety surveillance.
abstract: 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  In September 2004, rofecoxib was voluntarily withdrawn from the worldwide market. Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal as an example to inform future postmarket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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Geriatrics and Palliative Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1070, New York, NY 10029, USA. joseph.ross@mssm.edu
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Ross
authors.forename: David
authors.initials: D
authors.lastname: Madigan
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Hill
authors.forename: David S
authors.initials: DS
authors.lastname: Egilman
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Wang
authors.forename: Harlan M
authors.initials: HM
authors.lastname: Krumholz
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D002319:Cardiovascular System / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D004345:Drug Industry / Q000592:standards; D006801:Humans; D015994:Incidence; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects*; D009203:Myocardial Infarction / Q000139:chemically induced* / Q000401:mortality; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D056737:Safety-Based Drug Withdrawals; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors; D014481:United States / Q000453:epidemiology; D014486:United States Food and Drug Administration
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib