Consider conservative stance on Cox-2 inhibitors

Article questions risk of CV events

Arthritis drugs rofecoxib (Vioxx) and celecoxib (Celebrex) may increase the risk of cardiovascular (CV) thrombotic events, according to a recent article published in the Aug. 22/29 issue of the Journal of the American Medical Association. But the article has become a lightening rod of controversy, with critics charging faulty analysis on the part of the article’s authors.

Rofecoxib and celecoxib are popular COX-2 inhibitors used to treat patients with osteoarthritis and adult rheumatoid arthritis. They were developed to fight the inflammation of arthritis without the stomach problems that can be attributed to aspirin and other anti-inflammatory drugs.

To define the cardiovascular effects of COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients without coronary artery disease, authors Debabrata Mukherjee, MD; Steven E. Nissen, MD; and Eric J. Topol, MD, of the Cleveland Clinic Foundation in Ohio studied the results of four clinical trials. These are the Vioxx Gastrointestinal Outcomes Research Study (VIGOR) and the Celecoxib Long-term Arthritis Safety Study (CLASS) — each with more than 8,000 patients — as well as two smaller trials with about 1,000 patients each.

In their analysis of the VIGOR trial, the Cleveland Clinic researchers found that the risk of serious cardiovascular events in the rofecoxib group (111 patients) was 2.2 times higher than in the naproxen group (50 patients). The CLASS trial with celecoxib demonstrated no significant difference in cardiovascular events compared with nonsteroidal anti-inflammatory drugs (NSAIDs). (The event rates are stratified by patients receiving aspirin and those not receiving aspirin.)

The researchers also compared the annualized myocardial infarction (MI) rates for the COX-2 inhibitors in both VIGOR and CLASS with the placebo group of a recent meta-analysis of more than 23,000 patients in aspirin primary prevention trials. In addition, they searched the adverse event reporting system of the U.S. Food and Drug Administration (FDA), which revealed 144 unduplicated thrombotic or embolic cases for celecoxib and 159 cases for rofecoxib.

The authors admit that their analysis has several significant limitations. For example, the increase in cardiovascular events in these trials was unexpected, and evaluation of these endpoints was not prespecified. However, they still say that the available data raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors. "Given the remarkable exposure and popularity of this new class of medications, we believe that it is mandatory to conduct a trial specifically assessing cardiovascular risk and benefit of these agents. Until then, we urge caution in prescribing these agents to patients at risk for cardiovascular morbidity."

The manufacturers respond

The drug companies strongly rebutted the JAMA article, calling its analysis flawed and unsound. They said it contained no new clinical information, and was based on an inappropriate re-analysis of several older clinical studies containing data that were not suitable for combination and comparison. For example, patients in these studies had different underlying diseases and different cardiovascular risk profiles.

Both Merck, based in Whitehouse Station, NJ, and Pharmacia, based in Peapack, NJ, said patient experience and other data showed their drugs, Vioxx and Celebrex, respectively, were safe. The manufacturers also previously had requested that the FDA review study results that the companies said indicated that warnings on the drug labels should be removed.

On Feb. 7 and 8, the FDA Arthritis Advisory Committee met to review the study results and to decide if either Celebrex or Vioxx should have the label warnings reduced or if the companies should change the prescribing information. The committee did not recommend any label changes for Celebrex. The committee also advised that a broad warning about ulcers should stay on Vioxx’s label, and a warning should exist that says Vioxx users had twice the risk of heart attacks and cardiovascular side effects as naproxen users. The FDA usually follows the recommendations of the committee, but is not required to do so. An FDA spokesperson says a decision should be made sometime this month.

A change of practice?

The drug manufacturers aren’t the only ones questioning the analysis of the Cleveland Clinic researchers; some cardiologists also are joining the chorus.

There is a tendency to discount the article on a couple of premises, says David Roffman, PharmD, BCPS, associate professor at the University of Maryland in Baltimore. Some physicians tend not to believe anything that they have not encountered in their own experience. Other researchers won’t pay attention to the issue without first seeing data from direct- controlled clinical trials that say they should change their current practice. "Both ends of the spectra are clearly there, and I have heard both ends from given individuals."

The article, however, has raised the antennae among the cardiology community, Roffman says. "The article in JAMA basically retrospectively identified an issue that was of potential concern to people who are at risk for coronary artery disease or strokes," he says. "But because the data were retrospective and the studies in and of themselves were not structured to look at this endpoint, the only thing this kind of data can do is let people be aware that this is a potential problem."

He believes that the researchers wanted to raise awareness. "Unless it is pointed out, the potential for something negative will never be investigated," Roffman says. "That is clearly the intention of the release of this kind of data. I think that is a valid approach to something that involves as many people as this potentially does."

A middle approach to this issue sounds reasonable to Roffman at this point. "If you want to manage patients conservatively, you might look at some alternatives rather than just arbitrarily putting patients on COX-2s because [the drugs] have in some cases less gastrointestinal toxicity associated with them."

Instead, he suggests re-evaluating which of the NSAIDs are perhaps a little less risky for people with high risk for coronary disease or patients who already have known coronary disease. "If you have a patient at high risk for coronary disease or patients who already have known coronary disease, and if you feel that GI toxicity is preventable given that a lot of these people are also on proton pump inhibitors for reflux disease, you might just use one of the older agents instead of one of the COX-2 inhibitors. In addition, they are always less costly."