Studies provide new evidence on risks associated with Cox-2 inhibitors and NSAIDs

September 12, 2006

Two new review studies evaluating the safety of the pain-relieving medications selective cyclooxygenase 2 (COX-2) inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) find increased cardiovascular and kidney risks. The studies and an accompanying editorial were posted online today by JAMA because of the public health implications of the findings. The articles will appear in the October 4 print issue of JAMA.

"It is estimated that more than 30 million people worldwide take nonsteroidal anti-inflammatory drugs (NSAIDs) daily for treatment of pain and inflammation," according to background information provided in one of the articles. Adverse effects of some conventional NSAIDs include toxic gastrointestinal (GI) effects, as well as adverse renal (kidney) effects. "Overall, an estimated 2.5 million individuals in the United States annually experience adverse renal effects caused by use of NSAIDs," the authors write. "With decreased risk of adverse GI effects, a class of drugs that selectively inhibits COX-2 enzyme was introduced for analgesia (pain relief) and the treatment of arthritis." According to the authors, the adverse renal effects of selective COX-2 inhibition are unclear. Evidence is accumulating on the potential class effect of COX-2 inhibitors on cardiovascular risk. Two COX-2 inhibitors have already been withdrawn from the market: rofecoxib (marketed as Vioxx) and valdecoxib (marketed as Bextra).

Jingjing Zhang, M.D., Ph.D., from Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues evaluated the adverse risks of renal events and arrhythmia (disturbance of the normal heart rhythm) events in patients prescribed COX-2 inhibitors from a systematic review of the medical literature to determine if these negative side-effects involve every drug in this class.

"In this comprehensive meta-analysis of 114 randomized trials of COX-2 inhibitors comprised of 116,094 participants, rofecoxib uniquely increased risks of renal events (peripheral edema, renal dysfunction, hypertension) and arrhythmia events, with apparent adverse effects by the end of year 2000 and 2004, respectively," the researchers write. "However, the results did not show adverse effects of other COX-2 inhibitors on renal events and arrhythmia, indicating no overall evidence for a COX-2 inhibitor class effect."

In conclusion, the authors write: "Notably for policy and clinical decision making, our results also suggest that a time-cumulative meta-analytic approach for examining available trial safety data would have helped clarify apparently adverse effects several years earlier than the current report. The knowledge of all potential adverse effects is important and indeed time-sensitive, for physicians and patients both need complete information about risks and benefits to properly use COX-2 inhibitors and other clinical treatments." They continue, "future drug safety monitoring of emerging clinical treatments may benefit from continuous cumulative meta-analytic aggregation of safety data for all drug-approval applications and experimental agents." (JAMA. 2006; 296:doi:10.1001/jama.296.13.jrv60015. Available pre-embargo to the media at

Editor's Note: Corresponding author Mr. 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. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

In a related study, Patricia McGettigan, M.B.B.S., B.Pharm., F.R.A.C.P., Ph.D., and David Henry, M.B., Ch.B., F.R.C.P., from The University of Newcastle, New South Wales, Australia, conducted a meta-analysis of the observational studies in the medical literature to compare the risks of serious cardiovascular events (predominantly, myocardial infarction [heart attack]) with individual NSAIDs and cyclooxygenase 2 inhibitors (COX-2).

In background information, the authors write that interest in the cardiovascular effects of the relatively selective inhibitors of COX-2 has been intense. Although rofecoxib was withdrawn from world markets, celecoxib (marketed as Celebrex) "continues to be widely used, despite meta-analyses of randomized controlled trials showing an increased risk of myocardial infarction." The authors add, "attention has turned to the cardiovascular safety of the older non-selective non-steroidal anti-inflammatory drugs (NSAIDs). These agents are used extensively and some are available in many countries without prescription."

The authors based their analysis on 17 case-control analyses that included 86,193 cases with cardiovascular events and over 500,000 controls, and six cohort analyses that included 75,520 users of selective COX-2 inhibitors, 375,619 users of nonselective NSAIDs, and nearly 600,000 unexposed participants.

"A dose-related risk was evident with rofecoxib (relative risk 1.33 with 25 milligrams or less per day and 2.19 with more than 25 mg/day)," the authors report. "The risk was elevated during the first month of treatment. Celecoxib was not associated with an elevated risk of vascular occlusion. Among older non-selective drugs, diclofenac had the highest risk with a summary relative risk of 1.40. The other drugs had summary relative risks close to one: naproxen, 0.97; piroxicam, 1.06; and ibuprofen 1.07." The authors state that this review "contradicts claims of a 'protective' effect of naproxen and raises serious questions about the safety of diclofenac ..."

"In conclusion, controlled data from observational and randomized studies confirm a dose-related risk of cardiovascular events with selective COX-2 inhibitors. The observational data indicate that the risk increases early in treatment. An older NSAID, diclofenac, seems to share this risk and, unlike celecoxib, it appears to be harmful at commonly used doses. We believe there are grounds for reviewing its regulatory status." (JAMA. 2006; 296: doi:10.1001/JAMA.296.13.jrv60011. Available pre-embargo to the media at

Editor's Note: Funding for this review was provided through project grants from the National Health and Medical Research Council of Australia and the National Heart Foundation Australia. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: The Seduction of Common Sense In an accompanying editorial, David J. Graham, M.D., M.P.H., from Silver Spring, MD writes, "in this issue of JAMA, two systematic reviews [by Zhang et al and by McGettigan and Henry] provide clarity on a topic that has been dominated more by disinformation than reason." He also discusses the findings of these two new studies and places them in context of other reports on risks associated with COX-2 inhibitors and other NSAIDS.

Dr. Graham writes, "What does this all mean? First, rofecoxib increases the risk of acute MI at low and high doses. ... There is no initial 18-month period of immunity from risk. Celecoxib also increases risk at doses higher than 200 mg/d; at lower doses, the potential risk is less clear. Several other NSAIDs increase risk, including the COX-2 selective NSAIDs diclofenac and meloxicam, and the non-selective NSAID indomethacin and probably ibuprofen. Meta-analyses of randomized clinical trials and observational studies agree that naproxen is neutral for MI risk."

Dr. Graham also mentions that another COX-2 inhibitor NSAID, etoricoxib (which is not approved for use in the United States), recently was reported to have a risk of thrombotic cardiovascular events similar to diclofenac, with the implication that etoricoxib is safe from a cardiovascular perspective. However, he points out that "etoricoxib was compared with diclofenac, a drug shown to substantially increase the risk of acute MI" in another previous study and in the meta-analysis by McGettigan and Henry.

Dr. Graham concludes, "if the lessons of recent history have been learned, the FDA's concerns will now be squarely focused on patient safety rather than corporate profitability, and, ultimately, common sense will prevail." (JAMA. 2006; 296:doi.10.1001/JAMA.296.13.jed60058). Available to the media pre-embargo at

Editor's Note: Dr. Graham reported no financial conflicts of interest, but reported that he was subpoenaed as a federal government expert by plaintiffs, for the purpose of providing testimony (in May 2006) that may be used in a number of Vioxx-related lawsuits, and reported that he received no compensation for this activity, other than his federal salary.

Dr. Graham is an employee of the U.S. Food and Drug Administration. This editorial was written by Dr. Graham as an officially approved outside activity in his private capacity and not as a Food and Drug Administration employee. The views expressed in this Editorial are the author's own, and do not reflect the official policy or position of the Food and Drug Administration.

The JAMA Network Journals

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