Is Concern About Cardiovascular Events With the New Coxib Class of Drugs Justified?

Thomas J. Schnitzer, MD, PhD



Medscape Editorial Note, February 9, 2005

Since the writing of this content, certain published data analyses and public announcements have called into question the cardiovascular safety of some of the COX-2 inhibitors and standard NSAIDs. Results of such publications may have affected certain information contained in this article, causing it to be outdated or possibly inaccurate. In order to keep our members current on this important therapeutic area, Medscape is providing regularly updated information related to NSAIDs in the Medscape NSAID Alert Center. This center includes commentary, abstracts, and statements from the US Food and Drug Administration, National Institutes of Health, and other policy makers, as well as other articles that are intended to provide supplementary information for assessing the accuracy of this content.

Rofecoxib (Vioxx) and celecoxib (Celebrex) are new drugs (coxibs) that have been widely used around the world because of their proven efficacy and enhanced GI safety compared with older nonsteroidal anti-inflammatory drugs (NSAIDs). Because it is estimated that 16,000 Americans die each year of NSAID-related GI bleeding,[1] having a drug that is safer for the GI tract is an important advance.

A recent report by Mukherjee and colleagues[2] published this week in JAMA suggests that these new drugs may pose a risk for increased cardiovascular events such as heart attacks and strokes. This analysis, which the authors admit "has several significant limitations," fails to provide data of sufficient quality to alter current recommendations regarding how these drugs should be used. It is important to understand that the recent report is not based on any new data; rather, it is an analysis of selective existing data that focuses almost entirely on 2 large studies of these drugs without including the equally large amount of data from other available studies.

Important to note, particularly for patients, is that the studies examined were not reflective of the usual clinical situation in several ways. First, the dose of drug used in both large studies was 2 times the maximum long-term dose approved by the FDA. This was purposely done to test the GI safety of these drugs (the primary outcome of these trials) and to provide a margin of safety for this conclusion. Second, one of these trials (VIGOR, involving rofecoxib), was conducted in a group of patients who all had the same disorder, rheumatoid arthritis. It is well known that an increased rate of cardiovascular events is associated with this disease. Furthermore, in this study, the control group of patients was receiving naproxen 500 mg twice daily, a dosage of drug that has been shown to have significant sustained effects on platelets similar to those of aspirin and would be expected to be cardioprotective.

Additionally, a recent large meta-analysis of the experience to date with rofecoxib from prospective randomized trials demonstrated no difference in cardiovascular risk for patients treated with rofecoxib compared with patients treated with either placebo or the NSAIDs diclofenac, ibuprofen, or nabumetone. The CLASS study, comparing celecoxib with diclofenac and ibuprofen, provided further supporting data demonstrating no difference in cardiovascular events between patients being treated with the standard NSAIDs and those receiving celecoxib.

What should be the consequences of this report? It is important to reemphasize the demonstrated GI safety of these drugs and the real benefit they provide to patients at high risk for serious gastrointestinal bleeding and ulcers. Patients who are at risk for cardiovascular events such as heart attacks and strokes should be on cardiovascular prophylaxis, which usually means daily low-dose aspirin therapy. In patients on aspirin prophylaxis, there is no evidence that coxibs are associated with any increase in untoward cardiovascular events, and coxibs are still considered to provide added GI safety compared with traditional NSAIDs. Thus, for the vast majority of patients, coxibs remain a safe and effective alternative to NSAIDs. Until further prospective data are available, these drugs should continue to be used as indicated in their labeling.


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