April 15, 2005

Bextra’s removal points to need to improve safety

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James May, M.D., left, and Anup Sabharwal, M.D., evaluate wave pulse forms by applanation tonography in a subject with hypercholesterolemia.
photo by Dana Johnson

Bextra’s removal points to need to improve safety

Researchers at Vanderbilt University Medical Center say that while they support last week's withdrawal of the painkiller Bextra from the market, more needs to be done to improve drug safety.

Bextra is the second in a class of blockbuster COX-2 inhibitors to be pulled from the market because of concerns that long-term use of high doses of the drugs may increase the risk of heart attacks and strokes. Vioxx was removed in September.

A third COX-2 inhibitor, Celebrex, will stay on the market, but with a stringent “black box” warning also required by the U.S. Food and Drug Administration for prescription non-steroidal anti-inflammatory drugs (NSAIDs) including Feldene, Naprosyn and Voltaren.

“The FDA's actions should go a long way in helping people make appropriate decisions about using NSAIDs every day for years,” said Marie R. Griffin, M.D., MPH, professor of Preventive Medicine and Medicine. “In the meantime, we need large clinical trials to better define risks and benefits of long-term use, and whether some NSAIDs offer distinct advantages over others.”

Studies of Celebrex also should continue, 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. “I think use (of Celebrex) should be limited, especially in older people, many of whom are at moderate to high risk of heart attacks and strokes,” she said.

The FDA's actions went further than the recommendations of a blue-ribbon advisory panel chaired by Vanderbilt's Alastair J.J. Wood, M.D., in February. A narrow majority of panelists voted to keep Bextra and Celebrex on the market — and to bring Vioxx back — as long as the drug labels included black box warnings.

Wood, professor of Pharmacology and Medicine who voted against marketing Vioxx and Bextra, applauded the FDA for “asserting itself and taking a strong stand.”

“When a bare minority votes to keep a drug on the market, that's not a safety endorsement — it's a devastating indictment,” he told the Washington Post last week.

While the FDA said it would “carefully review any proposal” to resume the marketing of Vioxx, "it seems inconceivable to me that Merck (the manufacturer) would try to bring it back,” he told the Los Angeles Times.

Traditional NSAIDs block both the inflammatory COX-2 enzyme and the COX-1 enzyme, which is thought to protect the stomach lining. As a result, NSAIDs can increase the risk of gastrointestinal bleeding.

Drugs that selectively inhibit COX-2 enzyme were designed to avoid gastrointestinal problems. However, they may have an unintended consequence — accelerating atherosclerosis. Some non-selective NSAIDs also may increase cardiovascular risk, although the evidence is not as strong as it is with the COX-2 inhibitors.

Wood worried that widespread use of the black box warnings on prescription NSAIDs to warn of the increased risk of cardiovascular problems and gastrointestinal bleeding might “trivialize” the Celebrex label.

Patients who need pain therapy should start with naproxen, the medicine found in Naprosyn and Aleve, accompanied by an over-the-counter heartburn medication like Prilosec.

“Only a very tiny group of patients at particular risk of complicated ulcers but at low risk of heart attacks and strokes should consider taking Celebrex,” he said.

Wood also warned that the agency's actions do not solve an underlying problem — how to improve the safety of the nation's drug supply. “The increased risk of a common problem like a heart attack will not be picked up from our current reporting system,” he told the Los Angeles Times.

Griffin agreed, and called for independent funding to conduct the large clinical trials necessary to answer important questions that remain. “Funding for large trials done to determine safety or to compare two or more drugs should come from the government, not industry,” she said.

In the area of cancer prevention, Wood agreed with Raymond N. DuBois, M.D., Ph.D., director of the Vanderbilt-Ingram Cancer Center: the benefits of prescribing Celebrex may sufficiently outweigh the risks in patients at high risk of developing colorectal cancer.

“Hopefully we will find safer ways to interrupt the COX-2 pathway,” added DuBois, who is internationally known for his pioneering studies linking COX-2 to the development of colorectal cancer.

Last fall, for example, he and his colleagues reported that blocking a “downstream” cellular receptor called PPAR-delta inhibited development of pre-cancerous colon polyps in mice.