Even before making the connection between drugs such as Vioxx and heart attacks, many doctors were becoming concerned that the heavily advertised drugs known as COX-2 inhibitors were being over-used, often by patients unlikely to benefit from this costly but innovative pharmaceutical class.
In the January 25, 2005, issue of the Archives of Internal Medicine, researchers from the University of Chicago and Stanford University School of Medicine use data from the National Center for Health Statistics to show that most of the growth in COX-2 use between 1999 and 2002 occurred in patients at little risk for side effects from the drugs COX-2s were developed to replace.
"We found a rapid nationwide shift away from older, inexpensive drugs with better established safety and efficacy to newer, costly drugs with no real history," said study author G. Caleb Alexander, M.D., M.S., instructor of medicine and a member of the MacLean Center for Clinical Medical Ethics at the University of Chicago.
"We pursued our analysis because of concerns that this was an example of overuse of a newer, more expensive class of medications," said co-author Randall S. Stafford, M.D., Ph.D., associate professor and Director of the Program on Prevention Outcomes and Practice at Stanford University. "As with other examples in the treatment of high blood pressure, diabetes and some infections, there appears to be a tendency for new drugs to be used in a wider array of situations than supported by scientific studies."
The COX-2 inhibitors, introduced early in 1999, were widely promoted as "super aspirin." Ordinary aspirin blocks both COX-2, which triggers inflammation, as well as COX-1, which protects the stomach lining and helps to decrease the risk of GI bleeds and stomach ulcers. These newer and far more expensive drugs were designed to target only COX-2 and to be used to treat patients with chronic inflammatory disorders such as arthritis.
The COX-2 inhibitors are no more effective in relieving pain than aspirin, ibuprofen, or any of the traditional non-steroidal anti-inflammatory drugs (NSAIDs), but they cause fewer of the gastrointestinal side effects that often trouble long-term high-dose NSAID users. In exchange for reduced GI risk, however, they cost 10 to 15 times as much as the drugs they replaced.
Within a year of being introduced, these drugs were bringing in billions of dollars of annual revenue. These drugs were also heavily promoted to physicians and to the general public. In 2000 alone, Vioxx was the most aggressively promoted drug on the market, including $161 million of direct-to-consumer advertising.
The researchers wondered how many of these prescriptions were going to patients who were not likely to benefit from them -- those with minimal risk of the gastrointestinal problems that can be caused by standard anti-inflammatory drugs.
They used data from two large nationally representative surveys of patient visits to doctors' offices. Then they looked at the use of NSAIDs versus COX-2 prescriptions and compared them to treatment guidelines that stratify patients into different treatment groups based on the risks of gastrointestinal symptoms.
The guidelines recommend that patients with "very low risk" of GI problems (31% of patients in this study) or "low risk" (42%) receive traditional NSAIDs. Patients with "moderate risk" (25%) could receive COX-2s or NSAIDs depending on the expected length of treatment. Patients at "high risk" (2%) should take COX-2 inhibitors.
They authors found that the COX-2 inhibitors were frequently prescribed for all four groups and that they quickly gained market share, bounding from nowhere to 35 percent of anti-inflammatory prescriptions examined in 1999, the year they were introduced, to 61 percent by 2001.
They also found that most people who received prescriptions were at very low or low risk for GI bleeds and thus did not really need a COX-2 inhibitor. Despite the guidelines, 1.7 million, or 12 percent of patients at very low risk, received COX-2 prescriptions in 1999. That number increased to 7.6 million or 40 percent of very low risk patients by 2001 before declining slightly in 2002. At the same time, 6.8 million patients, or 40 percent of those at low risk, got COX-2 drugs in 1999, which increased to 17.6 million or 66 percent of low risk patients in 2002.
Over time, growth in COX-2 inhibitor use was most likely to come from those users least likely to benefit from these drugs.
By 2000, more patients were receiving COX-2 inhibitors than standard NSAIDs, including an estimated 16 million people suffering from congestive heart failure, or liver or kidney dysfunction, which are considered relative contra-indications to both COX-2s or NSAIDs.
"What we saw was widespread, rapid adoption of an interesting and promising but expensive and largely untested medication by millions of people with little or nothing to gain from long-term use," Alexander said. "The findings," the authors note, "demonstrate the challenge of limiting innovative therapies to the settings in which they are initially targeted and maximally cost-effective."
Carolanne Dai of the University of Chicago was the lead author of the paper. The research was supported by the MacLean Center for Clinical Medical Ethics at the University of Chicago, the National Institute of Aging, and the Agency for Healthcare Research and Quality.