Healthy Skepticism Library item: 507

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Publication type: news

Mathews A.
Big HMO Reconsiders Vioxx After Study Points to Heart Risks
The Wall Street Journal 2004 Aug 26

Full text:

One of the nation’s biggest health-maintenance organizations is reconsidering its use of the blockbuster arthritis medicine Vioxx after a major study based on data from its patients found that the Merck & Co. drug may increase the risk of serious heart problems.

The study, led by a Food and Drug Administration researcher, adds to the mounting safety questions surrounding Vioxx and is expected to boost its biggest rival, Pfizer Inc.‘s Celebrex.

Physician committees from the HMO, Kaiser Permanente, which has more than eight million members, will decide in the next few weeks how it will deal with the latest findings on Vioxx, which costs about $3 a day.

Vioxx had U.S. sales last year of about $2 billion, compared with about $2.8 billion for Celebrex, according to data from health-care information company NDCHealth, Atlanta.

The report found that higher doses of Vioxx appeared to triple patients’
risk of a heart attack or sudden cardiac death, when compared with the results for people who hadn’t recently taken any similar drug. Even at lower doses, Vioxx appeared to have a stronger association with the heart problems than Celebrex.

The study was initiated by the FDA and funded by an agency contract with Kaiser Permanente. Kaiser contributed resources, including programming, technical and clinical support. The lead author of the study, David Graham, is a medical officer in the FDA’s Office of Drug Safety. But as is typical for research performed by FDA staffers, the study has a disclaimer indicating that it doesn’t reflect the official views of the agency.

The study’s results carry added weight because it’s based on a large group of patients and follows studies dating as far back as 2001 that have signaled a link between Vioxx and heart risks.

As physician committees from Kaiser Permanente weigh their response to the findings, options include halting prescriptions of high doses of Vioxx or stopping use of the drug altogether by members, said David Campen, the Oakland, Calif., HMO’s medical director of drug information, utilization and technology and a co-author of the study.

“From a cardiovascular perspective, Celebrex and all other nonsteroidals are safer than Vioxx,” said Dr. Campen, who is also a rheumatologist, or specialist in joint diseases. “We’re going to take a serious look at the status of this product and its use in our members in light of these findings.” Celebrex also costs about $3 a day.

Mary Elizabeth Blake, a Merck spokeswoman, said the company “disagrees with the conclusion” of the study. She added that randomized trials comparing Vioxx with a placebo, including two that treated thousands of elderly patients, showed no significant difference in the rate of serious cardiovascular events in patients taking Vioxx. She said such trials are more authoritative than the new study and similar analyses based on observations of a population after treatment with a variety of medicines, which have inherent limitations that contribute to inconsistent results.

The FDA’s Dr. Graham defends the study’s findings and significance. It “had the statistical power to see these differences” between drugs, he said, adding that the study was “extremely large” and “carefully done.”

Among doctors and patients, the new study is likely to underscore concerns about Vioxx, known generically as rofecoxib, and bolster use of other drugs such as Celebrex, or celecoxib.

“It certainly casts doubt on the safety of high doses of rofecoxib,” said John Klippel, chief executive of the nonprofit Arthritis Foundation. The growing research “certainly questions whether they should be used at all.”
He added that in general, if a patient was at risk for heart problems, the growing evidence of a difference between Celebrex and Vioxx “would lead one to prescribe celecoxib instead of rofecoxib.”

The findings, even though they come in a study by an FDA drug-safety staffer, may increase pressure on the agency and Merck to consider stronger warning language for Vioxx’s label. Currently, the label says under the “precautions” section that “caution should be exercised when Vioxx is used in patients” with a history of heart disease, and offers data about the issue.

Vioxx, which came out in 1999, has been one of Merck’s top products as the company has struggled recently to find new breakthrough treatments. Besides osteoarthritis and rheumatoid arthritis, it is approved to treat conditions including acute pain and migraines. It is a Cox-2 inhibitor, a type of medicine that is supposed to carry fewer gastrointestinal problems than older painkillers in the category of nonsteroidal anti-inflammatory drugs, or NSAIDS. Merck has promoted Vioxx as creating fewer gastrointestinal problems than older drugs.

Merck’s share of the $6 billion U.S. market for Cox-2 drugs slipped to 32% last month from 43% in 2001, when the concerns about cardiovascular risks for Vioxx surfaced, according to data from NDCHealth. Vioxx’s woes have been good for Pfizer, which makes competing Cox-2 medicines Celebrex and Bextra, or valdecoxib.

“We feel that for Celebrex this is excellent news,” said Gail Cawkwell, Pfizer’s world-wide medical director for Celebrex. She said the study “is a good reflection of reality” because it looks at the experience of large numbers of patients being treated in routine clinical practice.

Novartis AG also has a potential rival waiting in the wings, its unapproved arthritis drug Prexige. In a study recently published in the medical journal the Lancet, researchers compared Prexige to older pain medications, and found it reduced pain without an increase in the rate of serious cardiovascular problems. Novartis has said it hopes to file for U.S.
approval by 2006.

The new study is only the latest to point to a possible heart risk tied to Vioxx. In a paper published this May in Circulation, the journal of the American Heart Association, researchers from a Harvard-affiliated hospital examined records from 54,475 Medicare patients. The study found that Vioxx use was “associated with an elevated relative risk” of heart attacks compared to use of Celebrex or no similar painkiller. That finding followed a high-profile article published in 2001 in the Journal of the American Medical Association, which pointed to similar possible risks.

The new results add to “a series of compelling and extremely worrisome points of evidence about the rofecoxib danger,” says Eric Topol, chairman of cardiovascular medicine at the Cleveland Clinic, who was an author of the
2001 analysis. “At the very least, I believe the FDA should put out a major warning regarding rofecoxib at doses greater than 25 mg.”

The study was unveiled yesterday at a conference of the International Society for Pharmacoepidemiology in Bordeaux, France. It drew on data from about 1.4 million Kaiser patients who had taken one of the NSAIDs. That included 40,405 who had taken Celebrex and 26,748 who had taken Vioxx.

The study focused on the risk of heart attacks and sudden cardiac deaths, and it compared patients who had taken the drugs with patients who hadn’t taken any NSAID for at least 60 days. By that comparison, patients who had taken doses of Vioxx higher than 25 milligrams a day were 3.15 times as likely to have a heart problem. The result reached statistical significance, though it was based on just 10 cases of serious heart problems in patients who took high doses of Vioxx. The authors wrote that their findings and other research “cast serious doubt on the safety” of the higher doses of Vioxx.

For lower doses of Vioxx, the heart problems were 1.29 times as likely as for the people who hadn’t taken NSAIDS recently, but this result wasn’t strong enough to achieve statistical significance. But the ratio was higher than those for any of the other painkillers examined — though some of these also weren’t statistically significant — and for the category of all recent NSAID use lumped together. There were 58 cases of heart attacks or sudden cardiac death among patients taking the lower doses of Vioxx.

Patients who took Celebrex were 14% less likely than those who hadn’t recently taken the painkillers to have heart problems, though this benefit also didn’t achieve statistical significance. There were 126 heart attacks or sudden cardiac deaths among those taking Celebrex.

The difference between the risk levels for Vioxx and Celebrex was big enough so that it did reach statistical significance, and the study’s authors concluded that Celebrex “may be safer” than Vioxx from a cardiovascular perspective. Still, the finding is a “suggestion, and not a conclusion,”
says Curt Furberg, a professor at Wake Forest University School of Medicine who examined the findings.