As reported by Newsweek, November 12, 2004.

Doctors Don’t Agree on Bextra Risk

A new study reveals that the risks associated with Vioxx may extend to other popular painkillers in its class, but Pfizer—and some doctors—disagree

By Jennifer Barrett Ozols

Less than six weeks after Vioxx was pulled from pharmacy shelves because of evidence it increased a patient's risk of heart attack or stroke, some researchers are raising similar concerns about Bextra, another popular arthritis-pain reliever in the same class of drugs as Vioxx.

The drug’s manufacturer, Pfizer, insists that an increase of heart problems was observed only in studies involving patients at very high risk for heart disease who were undergoing cardiac surgery—a disclosure the drug company made last month. But new research released during a meeting of the American Heart Association on Wednesday found that patients who were given Bextra—one of just two Cox-2 inhibitors still sold in the United States—had more than double the number of heart attacks or strokes as those given placebos. The study was based on data on 5,930 patients that had taken part in 12 different trials.

“Our analysis shows the cloud over the Cox-2 inhibitors is getting darker,” says Dr. Curt Furberg, a professor at Wake Forest University School of Medicine who conducted the study with Dr. Garret FitzGerald, a cardiologist and pharmacologist at the University of Pennsylvania. Cox-2 is an enzyme produced by the body that plays a role in pain and inflammation.

On Sept. 30, Merck & Co. voluntarily stopped selling Vioxx, one of its most popular drugs, with $2.5 billion in sales last year, after a long-term study showed that patients taking the medication had twice the risk of a heart attack compared to those who'd been given a placebo. The company has since been accused of suppressing data that revealed the risk well before the drug was recalled. A congressional hearing is scheduled for next Thursday to examine whether Merck and the government ignored earlier safety concerns.

But Pfizer, which makes both Bextra and a second Cox-2 inhibitor, the popular Celebrex, has repeatedly stressed that its drugs have not shown the same risks as Vioxx. The company released a statement Thursday accusing Furberg and FitzGerald of drawing “unsubstantiated conclusions” about the cardiovascular safety of its drugs, by improperly combining data from heart surgery patients and lower-risk arthritis sufferers. “What they did was pick and choose which information to present and they pooled certain pieces of information that, perhaps, it was not appropriate to pool,” Dr. Gail Cawkwell, a Cox-2 medical director at Pfizer, told NEWSWEEK. “And that, unfortunately, presents a picture that is more frightening than it should be.”

On Thursday, after Furberg came forward with his analysis on Bextra, the Food and Drug Administration removed him from its drug-safety advisory panel charged with studying the safety of all Cox-2 inhibitors, citing potential conflicts. Furberg will be allowed to testify at public hearings but will not participate in the panel's scheduled February meeting. Furberg says he was surprised by the decision and maintains that his conclusions were not biased but based on "evidence collected in a scientific way." He adds that he and FitzGerald examined data on high-risk patients who had cardiac surgery separately from data on patients with a low risk of heart disease before pooling the results. They found, on average, patients who took Bextra had about double the risk of a stroke or heart problems than those taking a placebo. (The researchers did not examine patients on Celebrex).

“The result is [Bextra] looks like Vioxx, and we need to be careful,” says Furberg. “Pfizer is basically saying 'Our drug is safe until we have more information,' and my position is the opposite. I am saying we need to know it is safe before we use it on a large scale.”

Bextra and Celebrex are among several so-called nonsteroidal anti-inflammatory drugs (NSAIDs) taken regularly by an estimated 33 million Americans, according to MedicineNet, an online resource produced by a nationwide network of physicians. Cox-2 inhibitors, which are more expensive than over-the-counter pain relievers, are often prescribed for long-term conditions such as arthritis because they may be safer for the stomach than other NSAIDs like aspirin and ibuprofrin. From January through September of this year, nearly 41 million prescriptions were written for Cox-2 inhibitors, a 2 percent increase from the same period in 2003, according to IMS Health, a company that tracks drug industry trends. Data for the period following the Vioxx recall has not yet been released.

But in a nationwide survey released Thursday by Pri-Med Institute, nearly two thirds of primary-care physicians polled last month after the Vioxx recall said they believe that all Cox-2 inhibitors may prove to pose a greater risk of heart attack and stroke. Still, most said their effectiveness in relieving chronic pain in arthritis patients warrants their continued use, as long as the patients don’t show evidence of heart disease.

“These findings underscore the need to educate physicians further on the safety of Cox-2 inhibitors as a class in order to overcome the insecurities which have arisen since the recent Vioxx withdrawal,” says Anne Goodrich, research director at Pri-Med Institute, which plans to do a follow-up survey to gauge how the new findings on Bextra might be interpreted by physicians.

Not all doctors agree that the dangers posed by Vioxx necessarily extend to other Cox-2 inhibitors. Dr. William White, a professor of medicine at the University of Connecticut Health Center, calls the new analysis "way off base” because it combines data from arthritis patients with data from patients who underwent heart surgery and took high doses of medicine. “You’re reporting information that has not undergone scientific or medical or peer review. It was not scrutinized,” adds White, who was the principal investigator of a study published earlier this year in the American Journal of Therapeutics that examined trial data on nearly 8,000 arthritis patients.

His study found that the incidence rate of cardiovascular problems among arthritis patients taking Bextra over periods ranging from six to 52 weeks (considered short- and intermediate-term treatment) was comparable to those taking a placebo or another NSAID.

White maintains that while Vioxx, Bextra and Celebrex all belong to the same class of drugs, they can behave differently. A two-year study led by R. Preston Mason, a faculty member at Harvard Medical School, published last week in the cardiovascular journal Atherosclerosis, found that Vioxx made some components of the blood more susceptible to chemical changes that contribute to heart disease while Celebrex did not.

A separate report released in September by Dr. David Graham, associate director for science in the FDA's Office of Drug Safety, analyzed 1.4 million patients who were treated from 1999 through 2001 and found patients taking higher doses of Vioxx (more than 25 milligrams daily) had more than triple the risk of heart attacks and sudden cardiac death than those taking Celebrex. Pfizer says Celebrex has been studied now in about 40,000 patients. “We have not seen increased cardiovascular-type risks,” says Pfizer’s Cawkwell.

In fact, Pfizer has just begun enrolling patients for a study to look at the potential benefits Celebrex might have for the heart. Cawkwell says further studies of Bextra are also in the works, though it may be a year or more until the company begins enrolling patients for the trials.

In the meantime, patients concerned about the potential risks of Cox-2 inhibitors should speak with their doctors, who in turn may have to rely on their own judgment about the medications—until more research becomes available.