Pooled Analysis of Rofecoxib Placebo-Controlled Clinical Trial Data

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Background In September 2004, rofecoxib was voluntarily withdrawn from the worldwide market. Our objective was to determine whether and when analysis of published and unpublished placebo-controlled trials could have revealed cardiovascular risk associated with rofecoxib before its withdrawal as an example to inform future post-market 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 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 dosage ranged from 12.5 mg to 50 mg. As of December 2000, 21 (70%) of these trials had been completed and the risk of CVT adverse event or death was greater among subjects assigned to rofecoxib, with the difference being borderline statistically significant (Rate Ratio [RR]=2.18, 95% Confidence Interval [CI], 0.93–5.81; p=0.07). Subsequently collected data strengthened the statistical association (as of June 2001: RR=1.35, 95% CI, 1.00–1.96; p=0.05; as of April 2002: RR=1.39, 95% CI, 1.07–1.80; p=0.02). Conclusion Cumulative pooled analysis of all randomized, placebo-controlled trials demonstrates a progressing trend toward increased cardiovascular risk associated with rofecoxib compared with placebo as early as December 2000, reaching a P value of 0.05 by June 2001, nearly 3 and a half years before the manufacturer’s voluntary market withdrawal.

Trends in Prescription Drug Use Among Adults in the United States From 1999-2012

“…COX-2 inhibitors decreased, likely a result of rofecoxib being taken off the market in 2004. 27 On the other hand, use of narcotic analgesics rose from 1999–2000 to 2011–2012: while their increasing use may raise concern about the potential misuse/abuse of these drugs, it should be noted that use leveled off after 2003–2004. This flattening trend may reflect increased awareness of prescription opioid drug misuse/abuse, 28 although under-reporting of these drugs may have increased with awareness regarding their potential for abuse.…”

Promoting Transparency in Pharmaceutical Industry–Sponsored Research

“…74–76 We found that pooling clinical trial data demonstrated progressively increased cardiovascular risk as early as December 2000 and reached a P value of 0.05 by June 2001, nearly 3 and a half years before the manufacturer’s voluntary market withdrawal. 73 This issue is similarly illustrated by the recent controversy surrounding oseltamavir (Tamiflu). In the process of updating Cochrane Collaborative systematic review, several important research data inconsistencies were found.…”

“…73 We were interested in whether the drug’s cardiovascular risk could have been identified before its withdrawal, despite there being three previously-conducted company-sponsored meta-analyses demonstrating no increased risk. 74–76 We found that pooling clinical trial data demonstrated progressively increased cardiovascular risk as early as December 2000 and reached a P value of 0.05 by June 2001, nearly 3 and a half years before the manufacturer’s voluntary market withdrawal.…”

FDA Policy and Cardiovascular Medicine

“…For example, the cardiovascular risk associated with rofecoxib (Vioxx) was not apparent for several years after drug approval and eventually led to its market withdrawal. 83 Similarly, nearly a decade had passed after the approval of rosiglitazone (Avandia) before the risk of acute myocardial infarction was identified. 84 More recently, dronedarone (Multaq), a drug used to restore sinus rhythm and reduce hospitalization or death in intermittent atrial fibrillation, 85 was found to increase risk of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation.…”