Image: Celebrex
Mandel Ngan  /  AFP - Getty Images file
The FDA allowed Pfizer, maker of Celebrex, to keep that drug on the market after studies came to conflicting conclusions about its cardiovascular risk.
By Robert Bazell Chief science and health correspondent
NBC News
updated 4/10/2007 10:52:14 AM ET 2007-04-10T14:52:14
Commentary

The painkillers that can cause heart attacks are staging a comeback. Will the drive for profits once again trump sound science and proper medical practice?

Vioxx and Celebrex are the best-known drugs in a class called Cox-2 inhibitors. In one of the most sordid chapters in pharmaceutical-company history, the manufacturers got tens of millions of Americans to take the drugs for pain relief, even though they cost hundreds of times more than other drugs that work just as well. Plus, these pricey pills turned out to have scary side effects.

In 2004 Merck abruptly withdrew Vioxx from the market after a study linked the pills to a higher risk of heart attacks, touching off thousands of lawsuits.

The Food and Drug Administration allowed Pfizer, maker of Celebrex, to keep that drug on the market after studies came to conflicting conclusions about its cardiovascular risk. However, in 2005 the agency required a “black-box warning" label — the strongest kind — listing the dangers. The FDA persuaded Pfizer to stop selling a lesser-known Cox-2 inhibitor called Bextra.

Now Merck is back with another Cox-2 inhibitor. A panel of expert advisors to the FDA will consider Thursday whether to approve Arcoxia, even though some experts think it, too, could pose a danger for the heart.

At the same time, Pfizer is resuming its advertising of Celebrex. FDA officials say one purpose of black-box warnings is to put limits on advertising.But Pfizer is skirting the restriction with a two-and-a-half minute commercial, which can be seen at the Celebrex Web site. While the ad does carry the warning that Celebrex “may increase the chance of heart attack or stroke which may lead to death,” it states that it is “not clear” that the drug carries more risk than many older pain relievers and that the FDA requires the same warning on many of them.

It is true the FDA requires the warnings, but almost all experts in the field, including the American Heart Association, say the FDA is wrong — that Celebrex and other Cox-2 inhibitors are clearly more dangerous. Consumer advocacy group Public Citizen's Health Research Group petitioned the FDA to ban the ad.

That sounds like a lot of risk to treat a sore knee or knuckle, but that is the precisely what Pfizer (and Merck, if it wins approval for Arcoxia) is proposing.

No better than aspirin
About 20 million people in the United States suffer from osteoarthritis, pain at the joints that often comes with age. Another 4 million have rheumatoid arthritis, an autoimmune disease. For years, the major treatment for the pain and inflammation of arthritis was aspirin, which works quite well for many people. In some, however, continued use of large amounts of aspirin causes bleeding ulcers that can require hospitalization and can even be fatal.

In the 1970s drug companies developed a series of aspirinlike drugs called nonsteroidal anti-inflamatories or NSAIDs, including ibuprofen (sold as Motrin and Advil) and naproxen (sold as Aleve). Even with these drugs, an estimated one half of 1 percent of the people who take them end up hospitalized with bleeding ulcers and about one in five of those die from them, mostly people who are elderly and infirm.

The hope of the Cox-2 inhibitors, developed in the 1980s, was that they would relieve the pain and inflammation of arthritis without causing the stomach problems. Although drug-company public-relations representatives, eager reporters and some doctors hailed the Cox-2 inhibitors as “super aspirin,” it is critical to note that no one — not the companies, not the FDA — ever said they did a better job of controlling pain or inflammation than aspirin or any other NSAID. They were just supposed to be gentler on the stomach.

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With Celebrex, the FDA concluded that the major studies designed to show a benefit for the stomach were never good enough to allow the company to make that claim on the label. 

For Vioxx, the evidence of less harm to the stomach was clear, but so was the increased danger of heart attacks. Evidence presented at the Vioxx trials, including company memos, allege that Merck knew about the risk and tried to hide it for years.

Marketing blockbusters
When the FDA approved Celebrex in 1998 (at that time it was made by Searle, which later was acquired by Pfizer) and Vioxx in 1999, both companies knew that the relatively small number of arthritis sufferers at risk for bleeding ulcers would never give them the blockbuster drugs they wanted. They began two of the most expensive marketing campaigns in pharmaceutical history. Their goal was to get everyone with arthritis to take the Cox-2 inhibitors.

They succeeded wildly.

Remember Olympic gold medalistDorothy Hamill skating for Vioxx? And the ad proclaiming “Celebrate” (what exactly was never clear) for Celebrex? Eventually 60 percent of Americans with arthritis were taking Cox-2 inhibitors at a cost of $2 or $3 a day — instead of aspirin, ibuprofen or naproxen, which all cost pennies.

At meetings in 1997 and in publications in 1999, Dr. Garret Fitzgerald and his team at the University of Pennsylvania had shown how the mechanism designed to make Cox-2 inhibitors easy on the stomach could lead to heart problems. Over the next several years studies in humans showed that the fear was justified. 

The millions of people with chronic arthritis want and need a large selection of drugs to treat their pain and inflammation. Some drugs provide relief for some people, but not for others. The same holds for intolerable side effects. For a fraction of those people, Cox-2 inhibitors may be the best alternative.

There are many possible solutions, but they need not be the newest, most expensive and heavily advertised.

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