But over the next four years, it turned out that Vioxx was adopted way beyond that market niche: millions of people who had little risk of gastrointestinal bleeding ended up getting prescriptions for Vioxx, Celebrex and other medicines in their class, known as COX-2 inhibitors.

The overuse of these drugs is documented in a study published in the Jan. 25 issue of the Archives of Internal Medicine by Randall Stafford, MD, PhD, associate professor of medicine at the Stanford University School of Medicine, and University of Chicago researchers G. Caleb Alexander, MD, and Carolanne Dai. Their findings reveal that 63 percent of the growth in COX-2 use from 1999 through 2002 occurred in patients with minimal risk of suffering gastrointestinal bleeding from NSAIDs.

Stafford said the problems associated with COX-2 inhibitors should serve as a cautionary tale about the growing trend of turning custom-fit medications into one-size-fits-all remedies. The researchers attribute the overuse of the drugs to several non-clinical factors-including heavy marketing and the tendency of patients and physicians to equate "newer" with "better" medicines-that have spurred sales of other drugs as well.

"This phenomenon is not limited to COX-2 inhibitors," Stafford said, noting that it also happened with drugs for hypertension, diabetes and some infections. "There are a number of instances where use has expanded beyond the narrow clinical situations in which the drugs are most effective and cost-effective."

The medical profession has a term for expanding the use of a drug beyond its intended target population: "therapeutic creep." In the case of COX-2s, not only does this expansion mean that millions of people paid more for a drug without reaping a substantial medical benefit, but it now appears they unnecessarily exposed themselves to the risk of heart problems, Stafford said.

COX-2 inhibitors have been at the center of a controversy since last September when Vioxx was pulled from the market after clinical trials showed that it posed significant risks of heart attacks. Similar findings were also recently reported for Celebrex, although it is still available.

What makes the widespread use of COX-2s so troubling is that they aren't any more effective at controlling pain than NSAIDs. While they were seen as a welcome alternative for those at greatest risk of gastrointestinal side effects from NSAIDs, they are more expensive. A daily dose of Vioxx at $2.64 costs about six times as much as a daily dose of ibuprofen at 42 cents, according to a 2002 compendium of drug prices.

For the study, Stafford and his colleagues looked at national databases that tracked patient visits to their physicians between 1999 and 2002 and the types of medications being either continued or prescribed. Additionally, they used a tool developed at Stanford in the 1990s to categorize patients according to their risk of gastrointestinal bleeding from NSAIDs.

According to the study, 73 percent of the patients had either a very low or low risk of GI bleeding from NSAIDs, meaning that there was no pressing medical reason for them to switch to COX-2 inhibitors. However, this was the group where the greatest growth in COX-2 use occurred. The study showed the number of physician visits associated with COX-2 use in these patients increased from approximately 9.5 million in 1999 to 20.9 million in 2002, accounting for 63 percent of the growth in the drugs' use during that time.

Patients most likely to benefit from COX-2s-those with either moderate or high risk of GI bleeding-accounted for the remaining 37 percent increase.

The researchers point to a couple of key factors behind the rapid growth of COX-2s. Prime among these is the heavy marketing of the medications. In 2000, for instance, Vioxx topped all direct-to-consumer drug advertising with expenditures of $161 million. The researchers also found that during the time period they studied, COX-2s eroded NSAID market share while increasing the total market demand for painkillers.

A second critical factor is the tendency among patients and physicians to believe that newer drugs are better than existing medications. "Drugs are approved on the basis of their superiority to placebo, not their superiority to existing drugs," Stafford said. "I think people misunderstand the nature of FDA approval and the criteria used to allow drugs to enter the market."

Stafford noted that nearly all drugs carry some risks, but physicians and patients are generally willing to use them if the likely benefits outweigh the harms. Many people, for instance, are allergic to antibiotics and yet physicians accept this inherent risk in patients who have significant bacterial illnesses because the benefits of treatment usually outweigh the risk of allergic reaction. For COX-2 inhibitors, however, the risks may outweigh the benefits, especially for patients at low risk for gastrointestinal bleeding, he said.

"It's too unsophisticated to brand any drug as being 'dangerous' or 'not dangerous'," Stafford said. "It depends on the setting in which the drug is used and the characteristics of the patient it's prescribed for."

Note: If no author is given, the source is cited instead.

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