Healthy Skepticism Library item: 823

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Publication type: news

Winslow R, Won TESORIERO, Wilde MATHEWS.
Where Findings On Painkillers Leave Patients: FDA Panel's Recommendations Could Revive Merck's Vioxx; Balancing the Risks With Relief
THE WALL STREET JOURNAL 2005 Feb 22

Full text:

For Julie Stuhlmacher, the prospect that the painkiller Vioxx could return to the market is a godsend.

Since Merck & Co. withdrew the drug over worries about heart risk last September, the 24-year-old loan officer from Lexington, S.C., has tried various alternatives, including Celebrex and Bextra, to relieve her severe arthritis pain. Most left her unable to get through the day without breaking into tears.

To get the benefit she got from Vioxx, she says, “I’m willing to take the risk.”

Assessing those risks is the challenge that now faces patients and doctors in the wake of last week’s landmark recommendation by a Food and Drug Administration panel that opens the door for Vioxx to return to the market. The panel narrowly voted that Vioxx and Pfizer Inc.‘s Bextra should remain available. It more strongly endorsed keeping Pfizer’s Celebrex available. But it said that all three increased the risk of cardiovascular problems such as heart attacks and strokes in patients. The FDA is expected to act on the panel’s suggestions within the next few weeks.

Keeping one or all three of the painkillers (known collectively as Cox-2 inhibitors) on the market despite heightened cardiovascular risk will pose a tough new challenge for patients, doctors and drug makers to rein in use of the popular medicines and minimize chances that they will do more harm than good.

Making matters more complex is that, despite anecdotal evidence that some patients get more relief only with certain drugs, clinical trials haven’t shown Vioxx, Celebrex or Bextra to be more effective than older, less expensive painkillers.

In Friday’s decision, the FDA panel sent a clear signal: The drugs carry enough of a risk that doctors should prescribe them only to the small group of patients who would draw enough unique benefits to outweigh the risks.

For patients using Cox-2s, the message from last week’s hearings, doctors say, is to take them in the lowest possible dose for the shortest possible time. That suggests that people who take the pills for a sprained ankle or intermittent muscle pain would be at much lower risk of cardiovascular problems than people who take them daily for chronic arthritic pain.

• Narrowly endorsed having Bextra and Vioxx on the market and more strongly supported Celebrex

• Found all three drugs, called Cox-2 inhibitors, were linked to risk of heart problems

• Called for strong warnings on labels of all three drugs, as well as other restrictions.

• Voted for cautions on the labels of older painkillers.

While the absolute numbers of patients suffering adverse events was small in the studies — for instance, roughly an additional 15 heart attacks and strokes per 1,000 patients over three years in one a major Vioxx study — the FDA’s concerns are heightened because the drugs have been used by millions of patients. That means even rare side effects can end up affecting tens of thousands of patients.

The heart risk was most pronounced with Vioxx. In a study using a routine 25-milligram-a-day dose that led Merck to withdraw the drug last September, risk of heart attack and stroke doubled after 18 months compared to a placebo. For Celebrex, which seemed the safest of three drugs, heightened risk showed up in a study involving 400 milligrams and 800 milligrams a day, but not in the 200 milligram daily doses typically prescribed for pain. Bextra’s risk was found in heart-surgery patients.

Most members of the FDA advisory panel on Friday also urged the agency to require companies to describe the cardiovascular risk in “black-box warnings” on the drugs’ package inserts — boldface type bordered by heavy black lines, the most severe warning the FDA has in its regulatory tool box. And the majority of the committee recommended a ban or severe restrictions on direct-to-consumer advertising campaigns, marketing efforts that made Celebrex and Vioxx among the pharmaceutical industry’s most popular drugs.

The FDA isn’t required to follow the recommendations of its panels, though it usually does. John Jenkins, director of the FDA’s office of new drugs, said the agency is committed to try to reach conclusions based on last week’s hearings “within the next few weeks,” but some changes, such as new labels, can take longer to go into effect.

Translating the new developments into better practices among doctors and patients will be a tall order. “You’ve got a big consumer and physician education challenge, and I don’t think the machinery is there either at the FDA or in the companies to handle it,” says John M. Pinney, president of Pinney Associates, a Bethesda, Md., consultant on risk-management issues. He says companies will need to rethink how they communicate with doctors and patients to help insure that Cox-2s aren’t prescribed for people who can do well with alternatives.

Even the value of black-box warnings on drugs used for such commonplace conditions is controversial. Hayes Wilson, chief of rheumatology at Piedmont Hospital in Atlanta, worries that they may scare patients away from medicines they need. Others say patients might not get a chance to read them at all, noting that package inserts aren’t always provided when patients pick up a bottle of pills at the pharmacy counter.

“We have a clear history that black-box warnings aren’t always as powerful a shaper of prescribing as we would like them to be,” says Jerry Avorn, a professor at Harvard Medical School and author of “Powerful Medicines, the Benefits, Risks and Costs of Prescription Drugs.” “My biggest fear is that these drugs will become the Martha Stewart of pharmacology: a brief bout with notoriety and then they come back stronger than ever.”

Significantly, the advisory panel also voted unanimously for cautions on the labels of more than 20 other painkillers that aren’t Cox-2 inhibitors, a group that includes popular drugs such as ibuprofen. Though there are few useful studies about the cardiovascular safety of many of those drugs, committee members said they were concerned that they may carry risks similar to Celebrex and the other newer painkillers.

Jonathan Coblyn, director of the Center for Arthritis and Joint Diseases at Brigham and Women’s Hospital, Boston, believes many doctors are confused by the back-and-forth over Cox-2 inhibitors — or are hard-pressed to explain it to patients. “The doctor who is booking patients every 15 minutes can’t have the 20-minute conversation it takes” to fully discuss risks and treatment options, he says.

For patients such as Ms. Stuhlmacher, the South Carolina loan officer, who is young and free of heart problems, the risk of harm from a Cox-2 is very small, doctors say, and the choice is easy. But for many others, especially older patients who have arthritis and are also at risk for cardiovascular disease, weighing choices of medicines is complicated.

Doctors say such patient are candidates for combining a conventional painkillers such as aspirin or naproxen, marketed as Aleve by Bayer AG, with an over-the-counter stomach acid-reducer such as Pepcid or Prilosec. Though Cox-2s are intended to reduce risk of gastrointestinal bleeding associated with older pills, they aren’t, on average, better at pain relief.

Adding a pill such as Prilosec to a traditional, non-Cox-2 painkiller “would confer the same [gastrointestinal] safety as using a Cox-2 alone,” says Dr. Coblyn, who is also associate professor of medicine at Harvard Medical School. “Why not go with the drug that is probably safer,” from a cardiovascular perspective, he asks.

Patients who aren’t sure of their heart risk might consider getting their cholesterol, blood sugar and blood pressure tested, or even a stress test, before embarking on long-term use of a Cox-2, doctors say. And once on the drugs, regular blood pressure checks would be advisable, says Christopher Cannon, cardiologist at Brigham and Women’s Hospital, since Cox-2 drugs are known to increase blood pressure.

Since Vioxx’s withdrawal in September provoked worries that the panel addressed last week, doctors have generally shied away from the entire class of Cox-2s, according to data from market-research firm ImpactRx, Mount Laurel, N.J. To James Fries, a rheumatologist at Stanford University, that is a good thing. “Overall it will help health if something dampens down use of these a bit,” he says. “I don’t know what the appropriate use is, but the current use is too high.”