Study May ID Source of Vioxx Problem

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A private research team claims to have identified a unique action of the painkiller Vioxx (search), which is independent of its anti-inflammatory action, that might explain why it’s linked to heart attack and stroke and why other similar drugs might not be.

The researchers say the findings should reassure patients about the cardiovascular safety of other Cox-2 drugs (search), but two cardiologists contacted by WebMD remain unconvinced.

Vioxx was withdrawn from the market by manufacturer Merck & Co. a month and a half ago after research showed that long-term use doubled the risk of heart attack and stroke.

While some clinical trials have shown that another widely prescribed Cox-2, Pfizer’s Celebrex (search), is more heart friendly than Vioxx, The Cleveland Clinic cardiologist Steven E. Nissen, MD, says the jury is still out. Pfizer is a WebMD sponsor.

“The clinical evidence to date has not implicated [Celebrex],” he tells WebMD. “But this drug has also has not been studied as carefully in patients with a high risk of cardiovascular disease.”

Molecular Evidence

The newly reported study was conducted by researchers with Elucida Research of Beverly, Mass., and published in the latest issue of the journal Atherosclerosis. Elucida founder R. Preston Mason, PhD, says the two-year study uncovered important differences in the action of the Cox-2 drugs. These important differences may be key to linking Vioxx to cardiovascular disease risk.

In addition to Vioxx and Celebrex the researchers examined two other Cox-2s, Pfizer’s Bextra and Merck’s Arcoxia, which has not yet been approved for use in the U.S.

They found that Vioxx and Arcoxia (search) changed LDL or “bad” cholesterol in a way that could facilitate atherosclerosis and contribute to an increased risk of heart disease. Specifically, the researchers say the drug alters low-density lipoprotein or “bad” cholesterol, in a way that makes these cholesterol molecules more susceptible to free radical damage. The effects were found to be independent of the drugs’ Cox-2 function, and were not seen with the Pfizer drugs Celebrex and Bextra.

“This is the first evidence that there might be important differences in the molecules of these drugs that could account for differences in their cardiovascular safety," says Mason, who is also on the faculty of Harvard Medical School in Boston.

Mason tells WebMD that the research team received no drug company funding for the study. But he acknowledges that his company has received extensive funding from Pfizer, but not from Merck.

A spokesperson for Merck declined to comment on the study, saying that the company is aware of a number of potential mechanisms that have been proposed to explain the cardiovascular findings with Vioxx.

“At Merck we are currently reviewing and further analyzing the existing data and working with outside consultants to determine the best path forward for obtaining additional information and data necessary to further clarify the mechanism of action involved in the cardiovascular events seen with Vioxx,” he said.

“Based on this information we will assess the possibility that a potential mechanism-based risk could extend to other Cox-2 inhibitors and nonselective NSAIDs.” Examples of nonselective NSAIDs are ibuprofen and naproxen.

Bextra Safety Questioned

The findings of this study argue against an effect from an entire class of drugs, i.e. Cox-2 drugs, but another widely publicized study appears to support a class effect. Preliminary research reported Wednesday at the annual meeting of the American Heart Association in New Orleans, concluded that Bextra (search) (another drug of the Cox-2 class of anti-inflammatory drugs) may pose an even greater cardiovascular risk than Vioxx. The findings were based on data involving more than 2,000 heart bypass patients and nearly 5,700 arthritis patients, but a spokesperson for Pfizer says the researchers’ choice of studies was suspect.

“What they did was pool studies [combine data from several studies] that were not appropriate to pool and leave out other studies that should have been included,” the spokesperson told WebMD.

Gail Cawkwell, MD, PhD, who serves as Cox-2 medical director for Pfizer added that the study was presented without appropriate scientific review.

“This study gives such a misleading picture for prescribers and patients that we are anxious to make sure that it is not interpreted inappropriately,” she says.

What’s a Patient to Do?

The Cleveland Clinic cardiologist Nissen says until the adverse risk of heart disease for Cox-2 drugs is clear, arthritis patients and others with chronic pain might be better off using other nonsteroidal anti-inflammatory pain relievers if they don’t experience gastrointestinal problems with these drugs.

“I would certainly want patients to take a drug like naproxen (Aleve) first,” he says. “For those that experience GI intolerance it looks like [Celebrex] is a reasonable alternative, but we would like to see more studies of cardiovascular risk with this drug.”

Former American Heart Association president Robert Bonow, MD, agrees that more study is needed to prove the cardiovascular safety of Celebrex.

“I think the safety of this entire class of drugs has been called into question,” he tells WebMD. “Until we have more prospective trials — and I would hope that the FDA will mandate this — it would be prudent to recommend that these drugs be prescribed very carefully and to use alternatives in patients with proven heart disease.”

By Salynn Boyles, reviewed by Brunilda Nazario, MD

SOURCES: Walters et al., Atherosclerosis 2004; vol 177: pp 235-243. R. Preston Mason, PhD, president Elucida Research, Beverly, Mass.; and faculty member, Harvard Medical School, Boston. Steven E. Nissen, MD, cardiologist, The Cleveland Clinic. Robert Bonow, MD, professor of medicine; and chief of cardiology, Northwestern University, Chicago; former president, American Heart Association. Chris Loder, spokesman, Merck and Co. Gail Cawkwell, MD, PhD, Cox-2 medical director, Pfizer. WebMD Medical News: “Bextra Ups Heart Attack, Stroke Risk.”