Millions of people paid more for COX-2 drugs without reaping a substantial medical benefit, and many unnecessarily exposed themselves to the risk of heart problems.

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 the COX-2 inhibitors class.

Therapeutic Creep

The overuse of these drugs is documented in a study conducted by Randall Stafford, MD, PhD, associate professor of medicine at the Stanford University School of Medicine, and G. Caleb Alexander, MD, and Carolanne Dai, researchers at the University of Chicago.

Their findings, which are published in the January 25 issue of the Archives of Internal Medicine, 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.

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, says Stafford. Overuse of the drug was due 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, according to the research team.

"This phenomenon is not limited to COX-2 inhibitors," Stafford points out, 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, this expansion means not only that millions of people paid more for a drug without reaping a substantial medical benefit, but also that many unnecessarily exposed themselves to the risk of heart problems, Stafford says.

No More Effective at Pain Control

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 recently were reported for Celebrex as well, 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 either being 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.

Vioxx: No.1 in Direct-to-Consumer Advertising

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 says. "I think people misunderstand the nature of FDA approval and the criteria used to allow drugs to enter the market."

Nearly all drugs carry some risks, Stafford notes, but physicians and patients generally are 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 says.

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