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New evidence on risks associated with Cox-2 inhibitors and NSAIDs


Two review studies evaluating the safety of the selective cyclooxygenase 2 ( COX-2 ) inhibitors and non-steroidal anti-inflammatory drugs ( NSAIDs ) have found increased cardiovascular and kidney risks.

It is estimated that more than 30 million people worldwide take NSAIDs daily for treatment of pain and inflammation.


Adverse effects of some conventional NSAIDs include toxic gastrointestinal effects, as well as adverse renal 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 gastrointestinal effects, a class of drugs that selectively inhibits COX-2 enzyme was introduced for analgesia 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 Two COX-2 inhibitors have already been withdrawn from the market: Rofecoxib ( Vioxx ) and Valdecoxib ( Bextra ).

Jingjing Zhang, from Brigham and Women's Hospital and Harvard Medical School, Boston, and colleagues evaluated the adverse risks of renal events and arrhythmia 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."


In a related study, Patricia McGettigan, and David Henry, 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 ) with individual NSAIDs and cyclooxygenase 2 inhibitors ( COX-2 ).

Although Rofecoxib was withdrawn from world markets, Celecoxib ( 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 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 non-selective 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."


In an accompanying editorial, David J. Graham, from Silver Spring, 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.

Graham writes, " What does this all mean ? First, Rofecoxib increases the risk of acute myocardial infarction 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 myocardial infarction risk."

Graham also mentions that another COX-2 inhibitor NSAID, Etoricoxib ( Arcoxia, 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 myocardial infarction" in another previous study and in the meta-analysis by McGettigan and Henry.

Source: Journal of American Medical Association, 2006


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