Healthy Skepticism Library item: 933

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Publication type: news

Pollack A.
New Scrutiny of Drugs in Vioxx's Family
New York Times 2004 Oct 4

Full text:

Now that Merck has removed its arthritis painkiller Vioxx from the market after tests found that it increased the risk of heart attacks and strokes, its rival Pfizer is taking a surprising stance. Pfizer says it is looking into whether its somewhat similar drug, Celebrex, may actually help prevent heart attacks.

“We’re not running away from cardiology,’‘ Dr. Mitch Gandelman, a Pfizer vice president, said in an interview on Friday, adding that a couple of studies on a very small scale by university scientists suggested that Celebrex could be good for cardiovascular health. “We are actually looking into cardiology.’‘

Dr. Gandelman acknowledged that evidence for this is scant and inconclusive.
But it is part of Pfizer’s effort to distance itself from Merck’s problems and provide an answer to what has become a central question: Is it a class effect? Do all the drugs in the widely prescribed group known as COX-2 inhibitors carry the same risk as Vioxx?

Millions of patients and billions of dollars in sales could be affected by the answer. Spurred by heavy advertising, COX-2 inhibitors took off faster than any other group of drugs after Celebrex and Vioxx went on sale in 1999.
Sales of the two medications, plus those of the newer Bextra, exceeded $6 billion worldwide last year.

Patients discontinuing Vioxx can now decide whether to switch to one of the other COX-2 inhibitors on the market – Celebrex or Bextra, another Pfizer product.

And it is possible that safety concerns could delay approval of two other drugs that are in advanced stages of development – Merck’s Arcoxia and Prexige from Novartis – as well as several further behind.

Merck said last week that it would no longer sell Vioxx because a study showed a higher risk of heart attacks and strokes among patients who had taken it for longer than 18 months. The reason for the greater risk is not known.

Many experts say that Celebrex, the oldest and biggest seller in the category, is somewhat different chemically from Vioxx and has not shown signs of increasing cardiovascular risk in clinical trials or in studies examining medical records of people who have taken the drug.

Dr. Daniel Solomon, a rheumatologist and epidemiologist at Brigham and Women’s Hospital in Boston, said, “I feel comfortable as a clinician, as someone prescribing these drugs, that it has a clean bill of health.” By contrast, he and others said, several studies dating to 2000 pointed to a risk for Vioxx.

But Dr. Eric J. Topol, chairman of the cardiovascular medicine department at the Cleveland Clinic, said that the drugs had not been tested adequately in people with heart disease, even though such people use them. “The real answer is we don’t know,’‘ he said.

There have been at least a couple of studies on animals suggesting that Celebrex could be harmful to the cardiovascular system. And a Food and Drug Administration reviewer expressed concern over cases of elevated blood pressure and edema, or swelling, in a clinical trial of Bextra as a painkiller in patients undergoing coronary bypass surgery, according to agency files obtained in a lawsuit by the advocacy group Public Citizen.

Dr. Gandelman said that the results of animal studies using Celebrex varied and that, in any case, such studies did not always reflect what happens with people. As for the Bextra study, he said, “It’s a finding in a narrow type of surgery, and it’s a use we would not recommend.’‘

Pfizer issued a statement on Friday saying that three trials involving a total of 6,000 patients that have been under way for several years had not shown any significant safety issues. The tests are trying to determine whether Celebrex can help prevent colon cancer or prevent or slow Alzheimer’s disease.

For the moment, investors seem to think that Pfizer’s sales will rise as a result of the withdrawal of Vioxx. Pfizer’s shares, which had recently been battered, rose 42 cents on Thursday, the day Merck said it would withdraw its drug, and 37 cents more on Friday, closing at $30.97.

Still, fears of a class effect could slow sales of Pfizer’s drugs in the long run and could increase focus on the COX-2 inhibitors, which cost many times as much as drugs like aspirin but are not more effective in relieving pain. Their main benefit is that they are supposed to lower the rate of ulcers and gastrointestinal bleeding, though that has not been established to the F.D.A.‘s satisfaction with Celebrex and Bextra. And some doctors say the COX-2 drugs are being used by many people with no real risk of ulcers.

“This is an opportunity for people to re-evaluate the need for these more expensive options in general,’‘ Dr. Solomon of Brigham and Women’s Hospital said.

The cause of the Vioxx recall – the discovery of new risks five years after it went on the market – may also re-energize those who have criticized the way pharmaceutical companies market their treatments directly to consumers.
Such critics say industry ads do not sufficiently emphasize drugs’ potential risks. The industry argues that the ads help consumers recognize conditions they have and encourage them to seek help from doctors.

The effect of advertising on prescription drug sales can be unpredictable.
After a steep ascent, sales of Vioxx and Celebrex have barely grown recently, said Steve Scala, an analyst with SG Cowen. “In this class,’‘ he said, “drugs tend to get off to very quick starts followed by a quick leveling off’‘ as people try each new pain remedy that comes out. He predicted that sales of Bextra and Celebrex would get a short-term lift from the withdrawal of Vioxx from the market and then return to slower growth.

Both the COX-2 inhibitors and the older painkillers like aspirin, ibuprofen (sold under the brand names Motrin and Advil) and naproxen (Aleve) block an enzyme in the body called cyclooxygenase, or COX, that contributes to pain and inflammation. (Tylenol, a brand-name version of acetaminophen, works by a different mechanism to block pain, but not inflammation.)

There are two forms of COX, and one of them, COX-1, helps protect the stomach lining from acids. The older drugs block both forms, which is why they cause ulcers and gastrointestinal complications that have been estimated to result in 7,500 to 16,500 deaths a year in the United States.
The COX-2 inhibitors, as their name implies, block COX-2 much more than the stomach-protecting COX-1.

But the role of the COX enzymes in the body is not completely understood.
There is evidence that COX-1 helps promote blood clotting and COX-2 helps retard it. So blocking COX-2 but not COX-1 could tip the balance in favor of clotting, thereby increasing the risk of heart attacks.

But inflammation is also an important contributor to heart attacks and strokes. So controlling inflammation, as the newer drugs do, could conceivably have a helpful effect.

With the withdrawal of Vioxx, the F.D.A. is considering whether longer studies will be needed for COX-2 inhibitors – both those on the market and those still under development.

Dr. Sidney M. Wolfe, director of health research at Public Citizen, sharply criticized the agency for not requiring such studies after the initial evidence of a risk with Vioxx in 2000.

“It is very likely that there is some kind of class effect,’‘ Dr. Wolfe said. “You start demanding of all the companies that they do studies that are large enough and last long enough to prove if this is a problem.’‘

He also called for the F.D.A. to be extremely cautious about Merck’s Arcoxia and Novartis’s Prexige, saying, “No one can argue that these other two are needed rapidly because there’s nothing like them around.’‘

Dr. John Jenkins, who directs the agency’s Office of New Drugs, said, “The danger is if this is not a class effect, if this is unique to Vioxx, if you start asking for much longer data prior to approval, then you can blunt the product development pipeline.’‘ Drugs, he noted, can have benefits and not just risks.

The F.D.A.‘s thinking should become clear soon. It is scheduled to decide by the end of the month whether to approve Arcoxia, which is already on the market in many countries. Mr. Scala, the SG Cowen analyst, predicts that the F.D.A. will tell Merck that the drug is “approvable’‘ pending the outcome of an additional trial that should be completed in 2006.

Prexige is already approved for use in Britain and Novartis hopes for approval for use in the rest of Europe by the end of the year. The F.D.A.
rejected Novartis’s application last year, saying that more data would be needed on the drug’s effectiveness, according to Jörg Reinhardt, head of pharmaceutical development for the company. He said Novartis hoped to reapply in 2006.

The results of an 18,000-patient trial sponsored by Novartis, the largest ever for a COX-2 inhibitor, showed that the drug reduced the risk of gastrointestinal side effects without increasing the risk of heart attacks, when compared with ibuprofen and naproxen.

Still, in a commentary that accompanied publication of the results in the journal The Lancet in August, Dr. Topol of the Cleveland Clinic said they did “not clearly exonerate’‘ Prexige because the trial excluded many people with coronary artery disease. The trial also pointed out potential liver toxicity problems.

Dr. Reinhardt said that Dr. Topol’s view was not shared “by the totality of the medical community’‘ and that the results show Prexige does not have the risks of Vioxx.

“It cannot be the whole class that has the issue here,’‘ he said. “It seems to be this one compound.”

Nat Ives contributed reporting for this article.