Harvard School of Public Health
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Contact: Todd Datz
Author contact: Eric Ding, Sc.D. eding[at]post.harvard.edu
New, Comprehensive Analysis Shows That Rofecoxib (VIOXX), But Not Other COX-2 Inhibitor Drugs, Increases Risk of Adverse Kidney and Heart Rhythm Disorders
Review Study Recommends Stronger Drug Safety Surveillance System in U.S.
Embargoed for release: Tuesday, September 12, 2006, 4:00 PM EDT
Boston, MA -- Although COX-2 inhibitors were developed as a class of pain-relieving drugs without the adverse gastrointestinal effects of traditional NSAIDs, there has also been much debate and controversy about the safety of COX-2 inhibitors. One issue that remained unresolved was whether, as a class, all COX-2 inhibitor drugs had similar adverse effects, especially on risk of kidney and heart rhythm disorders.
In the first comprehensive review study of all available randomized trials on adverse renal and arrhythmia risks of COX-2 inhibitors, researchers from Harvard School of Public Health (HSPH), Brigham and Women's Hospital (BWH) and Harvard Medical School (HMS) have found clear evidence that the drugs do not all exhibit the same adverse effects. Notably, the study found that only VIOXX was associated with increased renal and arrhythmia risks; the other drugs in the class did not show increased risks. (Renal effects have to do with the kidney, blood pressure, and fluid retention; arrhythmia is an irregularity in the force or rhythm of the heartbeat.)
Because "of the public health implications of the findings," according to JAMA, the study, along with a related study and an accompanying editorial, will be published in an online early release on Tuesday, Sept. 12, 2006, at 4:00 p.m. EST (http://pubs.ama-assn.org/media/); additional supplemental information and results will be available online at that time at http://www.cox2drugreview.org/. The articles will appear in print in the Oct. 4 issue of JAMA (http://jama.ama-assn.org/).
Another key finding in this meta-analysis is that the adverse renal effects of rofecoxib (VIOXX) were apparent in the body of studies dating back to 2000, if careful safety monitoring of the data had been carried out. However, the adverse effects of rofecoxib were not known to physicians or the public because aggregation of cumulative safety data is not required and normally carried out, and the current passive monitoring system, such as FDA's MedWatch program, relies on voluntary spontaneous reporting of adverse drug events by general physicians and consumers. "The current passive system does not inform us about rates of adverse events to determine whether side effects are truly related to the drug," notes HSPH's Eric Ding, Sc.D., corresponding author of the study.
Selective COX-2 inhibitors were developed by pharmaceutical companies as drugs for relieving pain without the adverse gastrointestinal side effects of traditional non-steroidal anti-inflammatory drugs (NSAIDs), estimated to be used daily by more than 30 million people worldwide. Although rofecoxib (VIOXX) and valdecoxib (BEXTRA) were both voluntarily withdrawn from the market by their makers because of evidence of heart attack and stroke risks, celecoxib (CELEBREX) still remains in use by consumers, parecoxib (DYNASTAT) is still available in Europe, and other drugs in the class are still undergoing experimental development in humans. However, the adverse renal and arrhythmia risks have been relatively unknown for all COX-2 inhibitors.
The authors, Dr. Eric Ding, in the Departments of Epidemiology and Nutrition at HSPH, Dr. Jingjing Zhang, a research fellow in the Renal Division at BWH and HMS, and Dr. Yiqing Song, an instructor of medicine and associate epidemiologist in the Division of Preventive Medicine at BWH and HMS, set out to assess the safety of COX-2 inhibitors; whether the drugs possess a class effect (i.e. do they have similar effects); whether adverse risks were indicated in prior years; and the potential need for drug safety surveillance reform.
In one of the largest systematic reviews ever conducted in the medical literature, the investigators examined more than 500 trial reports and aggregated data from 114 double-blinded, randomized trials comprised of more than 116,000 participants, in order to examine the effects of the entire class of COX-2 inhibitors drugs: rofecoxib (VIOXX), celecoxib (CELEBREX), valdecoxib (BEXTRA), parecoxib (DYNASTAT), etoricoxib (ARCOXIA), and lumiracoxib (PRESTIGE). The large sample size allowed the researchers to investigate the effects of individual drugs within the general class of COX-2 inhibitors.
The findings indicated that rofecoxib was associated with an increased risk of both adverse renal events and arrhythmias, while the other drugs did not show increased risks. The study also showed that the COX-2 inhibitors did not exhibit a class effect.
"These results indicate that celecoxib is not as adverse as previously thought. As of now, it also does not appear unethical to currently continue development of the experimental drugs etoricoxib and lumiracoxib, given the available data. However, researchers must remain very cautious as results for etoricoxib and lumiracoxib are still inconclusive, awaiting further trials," said Dr. Song.
"We clearly still have a lot to learn about the pharmacological effects of COX-2 inhibitors. Meanwhile, both physicians and patients should exercise careful consideration before using NSAIDs and COX-2 inhibitors," added Dr. Zhang.
Finally, the authors strongly recommend that drug regulatory agencies adopt an active and cumulative drug safety surveillance system rather than relying on the current passive surveillance system. "Establishing an active and cumulative surveillance system that continuously aggregates all available trial results would help improve drug safety monitoring as it can immediately clarify whether a drug has particular adverse effects," said Ding. "The up-to-date knowledge of all potential side effects is important and indeed time-sensitive, as physicians and patients both need complete information about risks and benefits to properly prescribe and use COX-2 inhibitors and other clinical treatments."
Eric Ding was supported by a grant from the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) and by an institutional training grant from the National Cancer Institute, National Institutes of Health. Dr. Song was supported by grants from the NIDDK, National Institutes of Health.
(contact information updated 07/14/2007)
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Supplemental results to the large COX-2 inhibitor review in JAMA: "Adverse Effects of Cyclooxygenase-2 Inhibitors on Renal and Arrhythmia Events: Meta-Analysis of Randomized Trials"