title: Under-reporting of cardiovascular events in the rofecoxib Alzheimer disease studies.
abstract: BACKGROUND
  In September 2004, rofecoxib (Vioxx) was removed from the market after it was found to produce a near doubling of cardiovascular thrombotic (CVT) events in a placebo-controlled study. Its manufacturer stated that this was the first clear evidence of such risk and criticized previous analyses of earlier CVT risk for focusing on investigator-reported events. We studied contemporaneously adjudicated CVT events to assess the information on cardiovascular risk available while the drug was in widespread use.
  
  
  METHODS
  Using an intention-to-treat analysis of adjudicated CVT deaths, we analyzed detailed patient-level data collected during 3 randomized placebo-controlled trials of rofecoxib versus placebo that had been designed to define the drug's possible role in the prevention or treatment of Alzheimer disease. All trials had been completed by April 2003.
  
  
  RESULTS
  In the 3 studies combined, the data indicated that rofecoxib more than tripled the risk of confirmed CVT death (risk ratio = 3.57 [1.48-9.72], P = .004). This finding reached the P < .05 level of significance by June 2001.
  
  
  CONCLUSIONS
  Intention-to-treat analysis of placebo-controlled studies of rofecoxib for Alzheimer disease demonstrated that the drug produced a significant increase in confirmed CVT deaths nearly 40 months before it was removed from the market. By contrast, published analyses of these trials were restricted to on-treatment analyses (ending 14 days after cessation of treatment) that did not reveal this risk. Intention-to-treat analyses of clinical trial data can reveal important information about potential drug risks and should be performed routinely and reported in a timely manner.
authors.affiliation: Department of Statistics, Columbia University, 1255 Amsterdam Avenue, New York, NY 10027, USA. david.madigan@columbia.edu
authors.forename: David
authors.initials: D
authors.lastname: Madigan
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Sigelman
authors.forename: James W
authors.initials: JW
authors.lastname: Mayer
authors.forename: Curt D
authors.initials: CD
authors.lastname: Furberg
authors.forename: Jerry
authors.initials: J
authors.lastname: Avorn
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D000544:Alzheimer Disease / Q000188:drug therapy*; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000401:mortality*; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D057194:Intention to Treat Analysis; D007783:Lactones / Q000009:adverse effects* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D013450:Sulfones / Q000009:adverse effects* / Q000627:therapeutic use; D013927:Thrombosis / Q000139:chemically induced / Q000401:mortality*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib