February 25, 2005

Signals mixed on COX-2 panel

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Troy Mickens attends cardiac rehabilitation three times a week at the Dayani Center since his heart transplant in December.
photo by Dana Johnson

Signals mixed on COX-2 panel

An FDA advisory panel's recommendation last Friday to keep the arthritis drugs Celebrex, Bextra and Vioxx on the market has been widely misinterpreted as a “ringing endorsement,” said Alastair J.J. Wood, M.D., who chaired the panel.

A narrow majority of panelists voted to keep the COX-2 inhibitors on the market as long as the drug labels include strongly worded, “black-box” warnings about the increased risk for heart attacks and strokes. Some of those who voted to keep the drugs on the market did so under the condition that patients be required to sign consent forms indicating they understood the risk before they could get a prescription.

“Safety is not a majority vote,” insisted Wood, professor of Pharmacology and Medicine at Vanderbilt University Medical Center and an internationally known expert on drug metabolism. “It's not like winning the Super Bowl with a touchdown in the final five seconds.”

The U.S. Food and Drug Administration is expected to decide within a few weeks which of the panel's recommendations to implement.

The problem is that doctors are poorly equipped to determine which of their patients shouldn't take the drugs, Garret A. FitzGerald, M.D., chairman of Pharmacology at the University of Pennsylvania, said Tuesday during a lecture at Vanderbilt.

Even in patients with no signs of heart disease, long-term use of high doses of the drugs, which selectively block the inflammatory cyclooxygenase-2 (COX-2) enzyme, could accelerate atherosclerosis, he said.

FitzGerald, a former director of the Division of Clinical Pharmacology at Vanderbilt, added that “there are many other opportunities for therapeutic options” along the complicated cascade of biochemical steps that make up the cyclooxygenase pathway.

However, “no compounds are currently under clinical investigation, so it will be years before a new drug based on this concept could be on the market,” said Lawrence J. Marnett, Ph.D., director of the Vanderbilt Institute of Chemical Biology.

Some of these steps are being investigated at Vanderbilt, not only for relief of arthritis pain and inflammation, but as potential ways to help treat and prevent cancer and Alzheimer's disease.

The benefits of cancer prevention in humans would have to be very high, however, to justify a doubling of the risk of serious cardiovascular events associated with long-term use of the drugs at high doses, cautioned Marie R. Griffin, M.D., MPH, professor of Preventive Medicine and Medicine.

“This is equivalent to the risk incurred by (increased) blood pressure … or by smoking or by having diabetes or high cholesterol,” said Griffin, who with Wayne A. Ray, Ph.D., and their colleagues at Vanderbilt helped document the increased risk of heart attacks and strokes associated with Vioxx use.

Animal studies suggest that low doses of COX-2 inhibitors may be sufficient to shrink pre-cancerous polyps in the colon, responded Raymond N. DuBois, M.D., Ph.D., director of the Vanderbilt-Ingram Cancer Center.

“Preclinical studies indicate that very low doses of COX-2 selective inhibitors are effective in causing polyp regression when used in combination with agents that inhibit the epidermal growth factor signaling pathway,” he said. “Importantly, these lower doses have less risk for cardiovascular side effects.”

Another unanswered question is the potential cardiovascular risk attributed to non-steroidal anti-inflammatory drugs (NSAIDs) that block both COX enzymes. “I believe this will stimulate a lot of research to get to the bottom of the cardiovascular effects of all these very important compounds,” Marnett predicted.

Meanwhile, Griffin and others at Vanderbilt worry that the increased warnings about the cardiovascular risks of COX-2 inhibitors may fall on deaf ears.

“The panel meeting delineated the dangers, but it may not have effectively grappled with the issue of how to manage (the drugs),” said Dan M. Roden, M.D., director of the John A. Oates Institute for Experimental Therapeutics.

“Will direct-to-consumer advertising be banned? Is there a plan to see whether prescriptions to patients at risk for heart disease are tracked? I would not be surprised to see a panel dealing with the issue again at some point in the future,” Roden predicted.