All drugs in the coxib class confer varying, dose-dependent risks of cardiovascular (CV) events, according to a new unpublished analysis presented by David Graham, MD, MPH, a medical officer at the Center for Drug Evaluation and Research in Rockville, Maryland. Dr. Graham presented his data Thursday at a 3-day US Food and Drug Administration (FDA) advisory panel meeting in Gaithersburg, Maryland. The panel is expected to make a recommendation Friday that could lead to stricter warnings on the labels of coxibs, restrictions on their use, or even withdrawal of the remaining drugs in the class.
Dr. Graham gathered data from the California Medicaid program, Medi-Cal, on more than 15,000 myocardial infarction (MI) patients. According to his preliminary analysis, celecoxib (Celebrex(R)) raises risk of MI at higher doses, but not at doses of 200 mg/day or less, while valdecoxib (Bextra(R)) is safe at doses of 20 mg/day or less. He suggested that there is no safe dose of rofecoxib (Vioxx(R)), which in his analysis increased MI risk even at doses of 25 mg or less. Moreover, this risk manifests early and is evident within 30 days of initiating therapy.
"I believe, based on the evidence, that there is a COX-2 effect and this COX-2 effect is dose dependent," Dr. Graham told the panel. "We see evidence of this with rofecoxib, celecoxib and valdecoxib, and the difference between rofecoxib and the other two is that a safe dose was not identified," he stated.
He indicated that for high-dose coxibs, the CV risk is more significant than smoking, hypertension, or diabetes, adding that "for low-dose, it's probably more than hypertension, less than diabetes, and a little less than smoking."
Dr. Graham noted that randomized controlled trials analyzing the CV risk associated with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) have not been conducted. "Let's look to see if there are [findings indicating risk] somewhere in observational studies that we believe are reasonably well-done and large," he proposed, adding, "[we should] look in a systematic way [to see] if we can identify some bad actors."
"If most of the compass arrows are pointing in the same direction for NSAIDs, I sort of place then on the suspect list," Dr. Graham noted, suggesting that the safety of the non-selective COX inhibitor indomethacin (Indocin(R)) should be examined.
"Let's weed the garden of bad actors and try to identify drugs, based on the evidence we have, that appear to be less risky," he said. "These are the drugs the public should use -- and then, do we want [the others] on the market or not?"
Caution urged in interpretation of findings
Arthritis Foundation President and CEO Jack Klippel, MD, urges caution in interpreting Dr. Graham's data, however. "We have to recognize that this data has not undergone peer review or critique," he emphasizes to CIAOMed.
Furthermore, Dr. Klippel suggests that the benefits of coxibs are being largely overlooked in Dr. Graham's analysis. The data are "not balanced around the benefit of these drugs, and one could make an argument about the side effects of any drug," he notes. "We are talking [in this hearing] about benefits and risks."
Reference:
US Food and Drug Administration. Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee; February 16-18, 2005; Gaithersburg, Md.