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Interim results from the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial demonstrated that rofecoxib was associated with an increased risk of cardiovascular events,1 leading to Merck's withdrawal of rofecoxib from the worldwide market in September 2004. In October 2008, long-term follow-up findings were published2; during a 1-year period of postdrug observation, increased cardiovascular risk associated with rofecoxib use persisted after stopping treatment.
These findings raise concerns about long-term risks incurred by individuals who had taken the drug. Data from only 1 other rofecoxib clinical trial, study 078,3 provides information about long-term off-drug cardiovascular risk after clinical trial drug discontinuation. Accordingly, our objective was to examine whether increased cardiovascular risk of rofecoxib persisted after stopping treatment in study 078.
We used data from study 078 made available through Vioxx litigation by Merck. Details of the randomized, double-blind trial that examined whether rofecoxib delayed progression of Alzheimer disease among adults with mild cognitive impairment have been published elsewhere.3 We only included subjects who took at least 1 dose of the study drug (rofecoxib, 25 mg/d, or placebo). Our prespecified outcome measure was incidence of any investigator-reported death or cardiovascular thromboembolic adverse event, identified from the adverse event reporting terms, as in prior research.4
Data were retrospectively analyzed in an intention-to-treat fashion, including all randomized individuals and adverse events as of the study termination date. Time at risk for events after stopping treatment began 14 days after the last dose, consistent with Merck's protocol defining off-drug events; subjects who were alive and had not previously had a cardiovascular event were deemed at risk. In all survival analyses, time of last contact or study termination, whichever was earlier, was used to censor time at risk. Kaplan-Meier estimates of cumulative event rates over time were used to construct event curves, which were compared with log-rank tests. Risk ratios (RRs) and 95% confidence intervals (CIs]) were calculated with Cox proportional hazards models. All statistical tests were 2-tailed and analyses were performed using the R statistical software environment, version 2.8.0 (http://www.r-project.org).
Among 1451 subjects, 723 were assigned to rofecoxib and 728 to placebo. Mean age was 75.0 years and 33% were female. Median duration of on-drug treatment was 623 days among rofecoxib-treated subjects and 724 days among those given placebo. Forty-three percent of subjects (n = 617) were at risk for a first event and had off-drug follow-up data available; median duration was 189 days among rofecoxib-treated subjects and 125 days among those given placebo.
During off-drug follow-up, 22 investigator-reported cardiovascular thromboembolic adverse events occurred among rofecoxib-treated subjects, 6 among subjects given placebo (RR, 2.97; 95% CI, 1.20-7.32; P = .02). Similarly, 23 deaths occurred among rofecoxib-treated subjects and 9 among subjects given placebo (RR, 2.10; 95% CI, 0.97-4.34; P = .06). Overall, an investigator-reported cardiovascular thromboembolic adverse event or death occurred during off-drug follow-up for 45 subjects, 32 in 287 patient-years among rofecoxib users and 13 in 234 patient-years among placebo users (RR, 2.01; 95% CI, 1.05-3.82; P = .03) (Figure).
Kaplan-Meier curves for investigator-reported cardiovascular thrombotic events and all-cause deaths observed during off-drug follow-up within study 078.
There was 100% increased cardiovascular risk associated with rofecoxib use during off-drug follow-up among study 078 subjects, confirming the 79% increased cardiovascular risk associated with rofecoxib use observed in APPROVe.2 Furthermore, estimates of off-drug cardiovascular risk from study 078 are likely conservative for 2 reasons. First, cardiovascular safety was not a primary or secondary outcome of the study and may not have been systematically collected or reported, raising issues of ascertainment bias. This issue is even more challenging because all patients had cognitive impairment. Second, study discontinuation rates were high and there was not a planned, rigorously conducted period of off-drug follow-up. In addition, our analysis updates the published findings from study 078, since a subsequent investigation suggested that these were incomplete.5
Implications for individuals who used rofecoxib are unclear, since it was withdrawn from the market nearly 5 years ago. To our knowledge, no studies have been conducted to determine for how long the increased cardiovascular risk associated with rofecoxib use persists, to elucidate the mechanism, or to examine whether there are long-term risks after discontinuation of other nonsteroidal anti-inflammatory drugs, selective or nonselective. To improve drug safety evaluation within clinical trials, periods of off-drug surveillance should be used when appropriate to ensure observation of long-term effects.
Correspondence: Dr Ross, Section of General Internal Medicine, Department of Medicine, Yale University School of Medicine, PO Box 208093, New Haven, CT 06520-8093 (email@example.com).
Author Contributions: Drs Ross, Madigan, and Krumholz had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the analysis. Study concept and design: Ross, Egilman, and Krumholz. Acquisition of data: Krumholz. Analysis and interpretation of data: Ross, Madigan, Konstam, and Krumholz. Drafting of the manuscript: Ross. Critical revision of the manuscript for important intellectual content: Ross, Madigan, Konstam, Egilman, and Krumholz. Statistical analysis: Madigan. Study supervision: Krumholz.
Financial Disclosure: With the exception of Dr Konstam, all authors were previously consultants at the request of plaintiffs in litigation against Merck and Co Inc related to rofecoxib in the United States. Dr Madigan was previously a consultant at the request of plaintiffs in litigation against Merck related to rofecoxib in Australia and against Pfizer Inc related to celecoxib in the United States. Dr Egilman is currently a consultant at the request of plaintiffs in litigation against Pfizer Inc related to gabapentin in the United States. Over the past 5 years, Dr Madigan has been a consultant to Pfizer, Wyeth, Sanofi-Aventis, and Takeda and currently serves on the clinical review team of iGuard.org. Dr Konstam has been a consultant to Merck, including work related to rofecoxib, as well as to AstraZeneca, Novartis, Sanofi, Biogen, Otsuka, Cardiokine, J&J, Pfizer, and Trevena. Dr Krumholz has had research contracts with the American College of Cardiology and the Colorado Foundation for Medical Care, has previously served on the advisory boards of Alere and Amgen, and currently serves on an advisory board with UnitedHealthcare, is a scientific advisor for Centegen, has been a subject expert for VHA Inc, has received speakers' compensation from the American College of Cardiology, and is editor-in-chief of Circulation: Cardiovascular Quality and Outcomes and Journal Watch Cardiology of the Massachusetts Medical Society.
Funding/Support: This project was not directly supported by any external grants or funds. Dr Ross is currently supported by the National Institute on Aging (grant K08AG032886) and the American Federation of Aging Research through the Paul B. Beeson Career Development Award Program.
This article was corrected for errors on January 5, 2011.
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