Healthy Skepticism Library item: 989

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Publication type: news

Hensley S.
Pfizer to Test All-or-Nothing Bet Could Pave Way for Broader Use Of Popular Arthritis Drug
Wall Street Journal 2004 Oct 18

Full text:

In a surprising turn in the debate over the safety of popular arthritis drugs, pharmaceuticals company Pfizer Inc. announced today plans to fund a large-scale clinical trial of Celebrex’s ability to prevent heart attacks and strokes in patients with serious cardiovascular disease.

The study, expected to enroll its first patients in the next few months, will test Celebrex against a sugar pill in thousands of people with osteoarthritis and a history of serious heart disease, such as a previous heart attack or severe angina.

Such patients largely have been excluded from the prospective studies of the drugs called Cox-2 inhibitors, an omission that has confounded doctors’ efforts to understand the true risk from these medicines.

“The point will be to show that Celebrex is actually beneficial in people with known coronary disease,” says Jeffrey Borer, a professor of cardiovascular medicine at Weill Medical College, Cornell University, New York and a member of the study’s executive committee.

Pfizer’s move is remarkable as it comes less than three weeks after rival Merck & Co. pulled its rival Cox-2 drug, Vioxx, from the market after finding it was linked to an increase in heart-attack and stroke risk. And on Friday, Pfizer told doctors that Bextra, its second-generation Cox-2 pill, was associated with a higher risk of heart attacks and strokes in two studies of patients after bypass surgery. Pfizer shares fell on the news, falling 58 cents, or 2%, to $28.50 at 4 p.m. in New York Stock Exchange composite trading.

The new trial represents an all-or-nothing bet by New York-based Pfizer on Celebrex, the best-selling Cox-2 drug in the world. If, as Pfizer expects, the study supports a rising theory among heart specialists that taming inflammation in the body could protect patients from heart disease, the test could pave the way for even broader use of Celebrex. If the study finds an increase in heart trouble, the results could force swift backpedaling on a drug that is on track to achieve $3 billion in sales this year.

That one drug in a class could protect patients from heart disease while another could increase their risk reflects what some researchers believe is a difference in how the medicines affect the health of blood-vessel walls. While all the Cox-2 drugs combat inflammation and pain by blocking the same enzyme in the body, the medicines are chemically different, which could explain the varying severity of side effects. The mechanisms of Celebrex and Vioxx when it comes to cardiovascular risk aren’t well understood. Vioxx may have some beneficial effects that are outweighed by other aspects of the drug.

There are commonalities among drugs in a class. “But there are always differences among [molecules], which is why there are so many different drugs,” Dr. Borer says. “They do some things the same and some things differently….It’s perfectly reasonable to expect that one may have different actions than the other.”

Pfizer is confident that Celebrex will pass the test, based on preliminary evidence from small clinical tests, an absence of problems in many epidemiological studies that fingered Vioxx and animal experiments. In a recent study by a Food and Drug Administration scientist and the health-maintenance organization Kaiser Permanente that documented the increased cardiovascular risk from Vioxx, Celebrex use appeared to slightly diminish the risk.

Some research offers potential explanations for why Celebrex may be safer than Vioxx. Celebrex improves the function of blood vessels, while Vioxx doesn’t, according to research in animals and small numbers of patients conducted by Frank Ruschitzka, a cardiologist at University Hospital, Zurich. Dr. Ruschitzka is helping design the Celebrex trial. The University of Zurich also will coordinate the new study.

Nevertheless, questions are mounting about the safety of the rest of the class of Cox-2 inhibitors, including Celebrex, after the Vioxx withdrawal. Vioxx was found to double the risk of heart attacks and strokes in patients enrolled in a company test of the drug’s ability to prevent colon cancer.

Celebrex researchers plan to track the patients in their study for two years to see whether the drug affects the occurrence of serious cardiovascular events, such as sudden death, heart attack or stroke. To participate in the test, patients recently must have survived acute coronary syndrome, a condition stemming from narrowing of the arteries that supply oxygen to the heart.

Patients in the study will be allowed to take other medicines, such as cholesterol reducers, blood-pressure pills and aspirin. Even with aggressive treatment, patients with acute coronary syndrome could have a 6% or greater risk of a heart attack, stroke or other serious cardiovascular illness per year, Dr. Borer says. By studying patients who are at high risk of serious cardiovascular events, the researchers enhance the chances of seeing a difference in the group receiving Celebrex compared with those taking a placebo.

Throughout the Vioxx storm, Pfizer has steadfastly defended the cardiovascular safety of Celebrex, the top selling Cox-2 drug in the world. “We’ve never really seen the problem in Celebrex” that Vioxx had, says Mitch Gandelman, vice president of the world-wide medical oncology/pain and inflammation group at Pfizer. Some scientists claim there is a class effect based on the way Cox-2 fights inflammation and pain. “We just feel that’s oversimplified and incorrect,” Dr. Gandelman says.

A rising theory in cardiology holds that inflammation of the blood vessels may be as important a factor in causing heart disease as cholesterol. If so, the right anti-inflammatory drug, perhaps even a Cox-2, could help rather than harm patients.

Pfizer expects the study will cost tens of millions of dollars.