|
||||||
|
|
|
|
|||||||||||
|
|||||||||||||
| ||||||||||||||||||||||||||||||||||||
Drug company executives and millions of arthritis sufferers breathed a sighof relief on February 18, when a joint Food and Drug Administration (FDA)advisory committee recommended that the controversial COX-2 inhibitor drugsshould remain available on the market despite growing evidence that they areassociated with an increased risk of cardiovascular events.
If the FDA follows its usual procedure and takes the joint committee'sadvice, new limitations may be imposed on indications or contraindications forthe drugs, and packaging requirements may include revised labeling and alikely "black box" warning.
In light of new clinical information that continues to accumulate in themedical literature, clinicians are rethinking the selection of patients forCOX-2 inhibitors, particularly people with diabetes and others vulnerable tocardiovascular risk.
"If you have diabetes, the key is to take aspirin and stay away fromthese drugs," says Michael Farkouh, MD, director of the cardiac careunit at New York University Medical Center and chair of the TherapeuticArthritis Research and Gastrointestinal Event Trial (TARGET) study.
WARNING SIGNS
During three days of testimony and scientific presentations, a jointmeeting of the FDA's Arthritis Advisory Committee and the Drug Safety and RiskManagement Advisory Committee considered the future of COX-2 inhibitors, aclass of drug that includes billion-dollar sellers rofecoxib (Vioxx, Merck),celecoxib (Celebrex, Pfizer), and valdecoxib (Bextra, Pfizer).
When introduced in 1999, COX-2 inhibitors were hailed as effective drugsfor treating arthritis that avoided the harmful gastrointestinal effects ofnonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen.The drugs were aggressively marketed through direct-to-consumeradvertising.
On September 30, 2004, Merck voluntarily withdrew the blockbuster drugrofecoxib from the market. The Adenomatous Polyp Prevention on Vioxx (APPROVe)trial was terminated early when it was discovered that patients takingrofecoxib had twice the risk of heart attack and stroke compared to thosereceiving placebo.
Since then, a flurry of papers have appeared in medical journals findingexcess cardiovascular risk among patients taking COX-2 inhibitors. JAMA,New England Journal of Medicine, and Archives of InternalMedicine all have carried special reports on the subject.
In a New England Journal of Medicine editorial accompanying threestudies of COX-2 inhibitors, published on the eve of the joint advisorycommittee meeting, editor-in-chief Jeffrey M. Drazen, MD, suggested that,because safer alternatives are available for most patients, the toxic effectsof COX-2 inhibitors may not justify their continueduse.1
During the joint advisory committee meeting, the panel was asked whethercardiovascular risks are greater for rofecoxib than for other COX-2 inhibitorsand, if so, whether safety issues can be addressed by labeling or the drugsshould be taken off the market. In a close 17 to 15 vote, the committeerecommended that rofecoxib remain on the market.
Many observers expected a recommendation to halt the sale of COX-2 drugs.David J. Graham, MD, FDA's associate director for science and medicine, hasassumed the mantel of whistleblower in the effort to take COX-2 inhibitors andother drugs of questionable safety off the market. He argued before the jointadvisory committee that the risks of COX-2 inhibitors outweigh the benefit topeople with arthritis.
Graham said that the additional risks of COX-2 inhibitors are aspotentially harmful as cigarette smoking, hypertension, or diabetes.
Studies of COX-2 inhibitors done to date "raise more questions thanthey answer," he says. Until more research is completed and thecardiovascular risks of COX-2 inhibitors are fully understood, "we'reflying blind," says Graham.
PEOPLE WITH DIABETES
Experts say that COX-2 inhibitors are being taken by patients who don'tneed them, either because they don't suffer the gastrointestinal effects ofNSAIDs or they also take aspirin to reduce the risk of heart attack andthereby eliminate any protective effect on the gastrointestinal tract.
"The beneficial effect of these COX-2 [inhibitors] is negated byadding aspirin," says Farkouh. "Most diabetics over the age of 50take aspirin."
COX-2 inhibitors may pose particular risk to people with diabetes. In theJanuary 24, 2005, issue of Archives of Internal Medicine, JamesSowers, MD, and colleagues reported that blood pressure was significantlygreater among patients with hypertension, osteoarthritis, and diabetes whenthey took rofecoxib than when they receivedcelecoxib.2
For patients with diabetes, "doctors have to realize that [COX-2inhibitors] are an additional risk factor," says Graham. "It wouldbe prudent to choose a drug with lower risk."
Farkouh contends that NSAID drugs may not be much better than COX-2inhibitors in terms of cardiovascular risk. "If you have patients athigh risk of heart disease or who have a high Framingham score, if you havediabetes and one other risk factor, there is a highly significant excess riskof heart attacks if you're on ibuprofen," he says.
The FDA joint advisory committee is considering changes in the regulationof several arthritis drugs, including COX-2 inhibitors and NSAIDs. Indicationsfor the drugs may exclude patients with high cardiovascular risk, includingpatients with diabetes, and the agency may require a "black box"warning on the product labels. Some at the meeting suggested formulating COX-2inhibitors into lower dosages. FDA may also prohibit COX-2 inhibitors frombeing marketed directly to consumers.
Because Merck voluntarily withdrew rofecoxib, if the FDA agrees with thejoint advisory committee, the company can have its product back on storeshelves in short order.
Reverberations from the COX-2 inhibitor episode, however, continue to shakethe FDA and the industry. On February 15 the agency announced the creation ofan independent Drug Safety Oversight Board, which would be charged withmonitoring and evaluating health risks such as the COX-2 inhibitors.
The FDA is expected to announce its decision on COX-2 inhibitors withinmonths. 
What to Do About COX-2
Until the FDA makes its decision on COX-2 inhibitors and issues changes tothe labeling or indications of the drugs, there is little in the way ofconcrete recommendations for doctors and patients.
Here are some points for doctors and arthritis patients to consider:
References
2. Sowers JR, White WB, Pitt B, et al.: The effects ofcyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on24-hour blood pressure in patients with hypertension, osteoarthritis, and type2 diabetes. Arch Intern Med 165: 161–268, 2005.
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| ||||||||||||||||||||||||||||||||||||
|
||||||
|
| DOC News | Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |
