Further impugning the safety reputation of rofecoxib (Vioxx), new research shows that this coxib, but not others, increases the risk of acute myocardial infarction (MI) among elderly persons with no previous history of MI and that higher doses are associated with greater risks. The new findings appear in the February 1 online edition of Annals of Internal Medicine.

Moreover, in the new study, concomitant aspirin use mitigated the cardiovascular (CV) risk associated with low-dose rofecoxib, but not that associated with higher doses.

The population-based, retrospective cohort studies included 113,927 older residents of Quebec, Canada, aged 66 and older, who were treated with nonsteroidal anti-inflammatory drugs (NSAIDs) between January 1999 and June 2002. The incidence of MI increased 21% among those who took low doses of rofecoxib (defined as 25 mg/day or less) and by 73% in those who took high doses (more than 25 mg/day), the study found.

The new findings are consistent with results of both the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial and the Adenomatous Polyp Prevention on Vioxx (APPROVe) study. Results of the latter led to the drug's abrupt withdrawal.

Further, researchers point out that there was no evidence of increased risk of MI among other selective and nonselective NSAIDs, namely celecoxib (Celebrex), naproxen, and meloxicam.

"We provide evidence against a broad class effect for COX-2 mediated cardiotoxicity when used at usual doses," conclude researchers led by Linda E. Lévesque, BScPhm, MSc, pharmacist and McGill University PhD candidate in the Department of Epidemiology and Biostatistics at McGill University Health Centre in Montreal, Quebec. "Nevertheless given the widespread use of these agents and the increased risk seen in a recent cancer trial of high-dose celecoxib, further research should be undertaken."

In mid-December, the National Cancer Institute-sponsored Adenoma Prevention with Celecoxib (APC) trial found that patients receiving 400 mg to 800 mg of celecoxib daily, a 2- to 4-fold higher dose than that recommended for the management of arthritis, had a 2.5-fold increased risk of fatal and nonfatal CV events compared with placebo.

Unless and until new evidence to the contrary is uncovered, the authors write, "New agents with COX-2 inhibitory potency similar or greater than that of rofecoxib should be used only with extreme caution, even in populations at low risk for cardiovascular events."

The new study also demonstrates that the increased risk of MI is only present while taking the drug.

"This is an important point because there has been a lot of discussion about whether COX-2 is prothrombotic and might have a delayed effect and this argues against it," Vibeke Strand, MD, biopharmaceutical consultant and adjunct clinical professor in the division of immunology at Stanford University School of Medicine in Portola Valley, California, tells CIAOMed.

The Aspirin Factor

"Among people on normal doses of rofecoxib, aspirin is protective, but at high doses, it is not," points out Lee S. Simon, MD, rheumatologist and associate clinical professor of medicine at Harvard Medical School in Boston, Massachusetts. "There has been an argument from some that if you inhibit COX-2 and don't have a long inhibitory effect of COX-1, then you will not be protected," he says. "This would suggest that the etiology of the problem, however rare, is more complicated than just the long-term inhibition of COX-1."

The new study "lends more support for the more complex explanation of [the effect] being related to more than just not-inhibiting COX-1," Dr. Simon says. "It's a complex issue. Nitric oxide, hypertension, edema and all those things may play a role, [as well as] perhaps even the physiochemical characteristics of the drugs."

There's something about Vioxx

"This adds another piece to the puzzle by again saying that rofecoxib is different then celecoxib," Dr. Strand says. "Clearly there is also something going on with rofecoxib."

That said, "the message is 'proceed with caution,' but we can use celecoxib because even with rofecoxib at 25 mg/day, aspirin appears to mitigate the risk and if [prescribing physicians and patients] are still concerned with the available [coxibs], they should be used with baby aspirin," Strand suggests.

Reference:

Levesque LE, Brophy JM, Zhang B. The risk of myocardial infarction with cyclooxygenase-2 inhibitors: A population study of older adults. Ann Intern Med. 2005;152:1-10.