Following discussions at a recent meeting of the EMEA's Committee for Medicinal Products for Human Use (CHMP), the agency concluded that available data show an increased risk of cardiovascular (CV) events for COX-2 inhibitors. The data also suggest a correlation between both dose and duration of use and the probability of suffering a CV event. As a result, the EMEA will now require that a contraindication be introduced for all COX-2 inhibitors in patients with a history of ischemic heart disease or stroke. As a further measure, etoricoxib (ArcoxiaR), which is not yet approved in the US, will be contraindicated in patients with uncontrolled hypertension.
The European agency also urged doctors to exercise caution when prescribing COX-2 inhibitors for patients with risk factors for heart disease such as hypertension, hyperlipidemia, diabetes, and smoking, as well as for patients with peripheral arterial disease. Given the association between CV risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment. The agency also indicated that these are interim measures pending the EMEA's finalization of the class review, expected in April 2005. The EMEA also concluded that more research is needed to evaluate the safety of COX-2 inhibitors and that ongoing trials examining CV risk should continue as planned.
All eyes on US FDA panel
During the second day of a 3-day advisory meeting, FDA panel members also discussed the safety of COX-2 inhibitors, and several physicians on the advisory committee seemed to support the conclusion that CV risk is indeed a class effect.2 Steven Nissen, MD, vice-chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic Foundation in Ohio, pointed out that there is at least one randomized controlled trial that shows an increased risk for each coxib. "This makes the grade in terms of a class effect," Dr. Nissen said.
Panel member Thomas Fleming, PhD, professor and chairman of the department of biostatistics at the University of Washington in Seattle, added that "there is a great deal of data giving us a general sense, [and] certainly individual doses, duration of therapy, [and the] nature of ancillary care are all factors that can influence the answer. There is conclusive evidence in the aggregate that there is a CV risk."
Calling CV risk the most significant issue facing the advisory panel, member Steven B. Abramson, MD, chairman of rheumatology at the Hospital for Joint Disease in New York City, said that, "there is a signal for all of these drugs."
References:
1. European Medicines Agency announces regulatory action on COX-2 inhibitors [press release]. London, UK: European Medicines Agency; February 17, 2005.
2. 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.