Public Release:  Vioxx trial data shows early cardiovascular risk

Provides lessons for post-market pharmaceutical safety

The Mount Sinai Hospital / Mount Sinai School of Medicine

Evidence of cardiovascular risks associated with taking Vioxx, the popular, nonsteroidal anti-inflammatory drug (rofecoxib), could have been identified nearly four years before its manufacturer, Merck & Co. Inc., voluntarily pulled the drug from the market.

Led by Joseph Ross, MD, MHS, Assistant Professor of Geriatrics and Palliative Medicine and of Medicine at Mount Sinai School of Medicine, a team of six investigators analyzed 30 randomized, placebo-controlled trials of Vioxx that were made available through litigation and published their findings in the November 23 issue of Archives of Internal Medicine. Under new FDA disclosure requirements, the analysis may also serve as a blueprint for other independent post-market pharmaceutical safety studies.

"Independent, objective investigators can play a more active role in pharmaceutical safety surveillance, ideally in concert with the FDA and industry," said Dr. Ross. "Our study is an analytic approach that can be used to inform public health efforts. Comprehensive, rigorous analysis of clinical trial data allows the earlier identification of drug risks, promoting more informed treatment decisions, protecting the public's health, and perhaps saving lives."

The research team identified 30 randomized, placebo-controlled trials that enrolled a combined 20,152 individuals, lasted from four weeks to four years and assigned a range of 17 to 2,586 participants to take doses of Vioxx ranging from 12.5 milligrams to 50 milligrams. The authors pooled the data from these studies and analyzed the results cumulatively, as information from each newly completed clinical trial became available.

Their analysis showed that safety concerns arose almost four years before the drug was withdrawn from the market. Dr. Ross and his colleagues found that as of December 2000 -- when 21 of the 30 studies had been completed -- there was a strong concern that patients taking Vioxx were at a greater risk for adverse events or death from cardiovascular conditions or blood clots. Thereafter, collected data through June 2001 showed Vioxx to be associated with a 35 percent increase in risk of a cardiovascular event or death. The association with cardiovascular risk strengthened as more data became available. As of April 2002, the pooled analysis showed a 39 percent increased risk, and as of September 2004, a 43 percent increased risk.

Merck introduced Vioxx to the market in May 1999 and the drug quickly became a commercial success, with sales reaching $2 billion annually.

Dr. Ross and his colleagues performed their analysis in an effort to provide a blueprint for use of clinical trial data. In their paper, the authors concluded, "Because the recently enacted FDA Amendments Act requires public disclosure of trial results within the ClinicalTrials.gov database within 12-24 months of study completion, including both efficacy and safety outcomes, clinical trial data should be available to conduct iterative meta-analyses independent of the FDA and manufacturers."

"Physicians and the public deserve to be in a position to make informed choices about risk and benefits [of pharmaceutical products]," they wrote. "And the early disclosure and dissemination of information about potential risk after its recognition must be required."

Substantial amounts of clinical trial data that have rarely been fully utilized to understand drug efficacy or safety should now be available and can be used by independent investigators to complement and corroborate surveillance done by the FDA and the companies.

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About the Authors

The authors of the study include Joseph S. Ross, M.D., M.H.S., of the Mount Sinai School of Medicine in New York, NY; David Madigan, Ph.D., of Columbia University in New York, NY; Kevin P. Hill, M.D., M.H.S., of the Harvard University School of Medicine in Boston, MA; David S. Egilman, M.D., M.P.H., of the Brown University School of Medicine in Providence, RI; and Yongfei Wang, M.S., and Harlan M. Krumholz, M.D., S.M., of the Yale University School of Medicine in New Haven, CT.

Financial Disclosure Note: All of the authors have been compensated for their work as consultants at the request of plaintiffs in litigation against Merck & Co. Inc. related to rofecoxib in the United States. Co-author Dr. Madigan is currently a consultant at the request of plaintiffs in litigation against Merck and Co., Inc. related to rofecoxib in Australia and has been a consultant to Pfizer, Wyeth, Sanofi-Aventis, and Takeda and currently serves on the clinical review team of iGuard.org. Co-author 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 one 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.

About The Mount Sinai Medical Center

The Mount Sinai Medical Center encompasses The Mount Sinai Hospital and Mount Sinai School of Medicine. The Mount Sinai Hospital is one of the nation's oldest, largest and most-respected voluntary hospitals. Founded in 1852, Mount Sinai today is a 1,171-bed tertiary-care teaching facility that is internationally acclaimed for excellence in clinical care. Last year, nearly 50,000 people were treated at Mount Sinai as inpatients, and there were nearly 450,000 outpatient visits to the Medical Center.

Mount Sinai School of Medicine is internationally recognized as a leader in groundbreaking clinical and basic science research, as well as having an innovative approach to medical education. With a faculty of more than 3,400 in 38 clinical and basic science departments and centers, Mount Sinai ranks among the top 20 medical schools in receipt of National Institute of Health (NIH) grants. For more information, please visit www.mountsinai.org.

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