U.S. Halts Use of Celebrex in Cancer Trial

Will review heart safety of all cox-2 inhibitors

FRIDAY, Dec. 17, 2004 (HealthDayNews) -- The U.S. government announced Friday it has halted the use of Celebrex in a cancer trial because of heart risks, and it is reviewing the safety of all its clinical trials using similar painkillers.

The announcement may jeopardize the status of more than 40 National Institutes of Health (NIH) trials involving Celebrex and Bextra, the only two members of this family of drugs, called cox-2 inhibitors, still on the U.S. market. Nearly all of these trials involve cancer treatment.

Celebrex was the first of the cox-2 inhibitors, which quickly became popular because they ease pain without causing gastrointestinal problems such as aspirin or other nonsteroidal anti-inflammatory inhibitors. But their safety came under scrutiny in September, when the maker of a similar drug, Vioxx, withdrew it after studies found an increased cardiovascular risk.

"I have ordered a full review of all NIH-supported studies involving this class of drugs," NIH director Dr. Elias A. Zerhouni said Friday. "We are asking all the principal investigators to communicate directly with study participants and explain the risks and benefits of each trial."

The move doesn't mean that either U.S. regulators or Celebrex's maker, Pfizer Inc., is pulling the drug from the market. However, acting U.S. Food and Drug Administration commissioner Dr. Lester Crawford said that possibility remains because of the "great concern" over the safety record.

"We're leaving open all regulatory options as we move forward, but we do not have a decision yet on the fate of the product," Crawford said. "We are keeping all regulatory options open, including a black-box warning and a variety of regulatory approaches that are at our disposal."

The watchdog group Public Citizen called Friday for the removal of both Celebrex and Bextra, another Pfizer product. In light of the calls, the FDA once again defended itself against criticism about overseeing drugs already on the market. "I don't see this is a failure of the system," said Dr. John Jenkins, director of the FDA's Office of New Drugs.

The government's move came hours after Pfizer announced the results of two trials on Celebrex, one of which had less disappointing results. The company announcement, made Friday morning, said a second, separate cancer trial found no increased risk of heart problems tied to the drug. But Pfizer urged that all patients "being treated with Celebrex should discuss appropriate treatment options with their health-care professionals."

Celebrex is a cousin to Vioxx, whose maker, Merck & Co., pulled it from the market this fall because of increased cardiovascular risks found in patients who were taking it for pain for more than 18 months.

The latest blow to the cox-2 family of pain relievers brought immediate reaction from medical professionals.

"We knew this was coming," said Dr. Mark Fendrick, a professor of medicine at the University of Michigan School of Medicine. "Even if these drugs do remain on the market, given the availability of other therapies that provide equivalent pain relief and, if needed, equal levels of stomach protection, it would be extremely prudent to avoid these drugs until we know for sure -- and I emphasize for sure -- about their cardiovascular safety."

But in its statement, Pfizer said it was reviewing the data and warned against jumping to conclusions about the use of Celebrex for all patients. For instance, those patients enrolled in the two cancer trials were taking twice the dose recommended for people struggling with pain due to osteoarthritis, the company noted.

The trials, conducted by the National Cancer Institute, uncovered the cardiovascular problems in patients enrolled in the so-called Adenoma Prevention with Celecoxib -- the generic name for Celebrex -- (APC) trial. No problems were found in patients taking part in the Prevention of Spontaneous Adenomatopus Polyps (PreSAP) trial.

"It is important to understand that the APC trial results differ from both the PreSAP cardiovascular results as well as the large body of data that we and others have accumulated over time, in which an increased risk of serious cardiovascular events in arthritis patients, even at higher-than-recommended doses, had not been seen," said Dr. Joseph Feczko, president of worldwide development for Pfizer.

Celebrex is approved in the United States for the treatment of arthritis and pain at recommended doses of 100 milligrams to 400 milligrams per day. It is also approved for a rare genetic condition known as familial adenomatous polyposis at doses up to 800 milligrams per day. The two cancer trials both used doses above the levels recommended for arthritis and pain: 400 milligrams to 800 milligrams in the APC trial, and 400 milligrams per day in the PreSAP trial.

In the halted trial, those taking 200 milligrams of Celebrex twice a day had a 2.5 times increased risk of cardiovascular events vs. those taking a placebo, while those taking 400 milligrams twice a day had a 3.4-fold elevated risk. The endpoints were a composite of death, heart attack and stroke. Researchers couldn't determine if Celebrex had any benefit in preventing recurring polyps, said Dr. Ernie Hawk of the National Cancer Institute.

The two studies together have enrolled about 3,600 participants, some of whom have been involved in the research for more than four years. Pfizer estimated that about 2,400 participants evaluated in the cardiovascular analysis had completed two years of treatment.

The Data Safety and Monitoring Boards of both trials had conducted a preliminary review of data in September and October and decided to continue with the trials. The safety review boards then convened a panel of cardiovascular experts to conduct additional analysis. Pfizer received preliminary information from those reviews Thursday night. The full analyses have not yet been presented to the company.

Since Vioxx was pulled from the market, health experts have been wondering whether the heart problems were unique to that drug or all cox-2 inhibitors. The new details about Celebrex make it look more like the latter, said Dr. Richard Hayes, a cardiologist and an assistant professor of medicine at New York University School of Medicine.

"It sounds like a class-wide effect," he said.

Pfizer's Bextra had the strongest possible warning -- a black box -- added to its label in November, highlighting the possibility of serious skin reactions and saying the drug should not be used in people who have had bypass surgery.

On Friday, in response to the Celebrex announcement, the New England Journal of Medicine pushed up the release of a letter from faculty at Vanderbilt University School of Medicine recommending that clinicians stop prescribing Bextra "except in extraordinary circumstances." Two clinical trials had apparently shown a threefold higher risk of serious cardiovascular outcomes among people taking the drug.

Fendrick had this advice.

"In the media firestorm, people are forgetting why the drugs were developed in the first place, not to be better but to have a better GI [gastrointestinal] safety profile. And to me, it's ironic that a class of drugs developed for improved GI safety may meet its ultimate demise due to cardiovascular safety concerns," he said. "In light of this discouraging news, individuals who are taking Celebrex or Bextra should immediately contact their physician."

More information

The Arthritis Foundation has more on cox-2 inhibitors and other nonsteroidal anti-inflammatory drugs.

SOURCES: Dec. 17, 2004, news conference with Elias A. Zerhouni, M.D., director, National Institutes of Health; Lester Crawford, acting U.S. Food and Drug Administration Commisssioner; and John Jenkins, director, FDA Office of New Drugs; Pfizer Inc. statements; Richard Hayes, M.D., clinical assistant professor, medicine, New York University School of Medicine, New York City; Mark Fendrick, M.D., professor, medicine, University of Michigan School of Medicine, Ann Arbor; Associated Press
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