Animal study on vascular effects of COX-2 inhibition

Download PDF Copy

Reviewed

Jan 17 2005

In an article by Egan et al, titled, "Cyclooxygenases, Thromboxane, and Atherosclerosis," published in the Jan 17 issue of Circulation: Journal of the American Heart Association researchers examined some of the molecular mechanisms of drugs affecting prostaglandin and thromboxane production.

In a genetic knock-out mouse model of atherosclerosis, the researchers found that the progression of atherosclerosis could be slowed by a drug (TP) blocking the thromboxane receptor (this would be expected to mimic the effects of low-dose aspirin), but not by inhibiting COX-1 and COX-2 simultaneously with indomethacin or by inhibiting COX-2 alone with MF tricyclic, an experimental COX-2 inhibitor. When this COX-2 inhibitor was given together with TP, the atherosclerotic plaques had fewer of the characteristics associated with "stable" plaques. Plaques are blockages in the blood vessels that can rupture and trigger a heart attack or stroke.

The authors believe that this study, if the results are similar to the processes in man, suggests that the combination of low-dose aspirin and a COX-2 inhibitor in patients might lead to plaque de- stabilization and an increased risk of cardiovascular events.

A related editorial, Furberg et al, titled, "Parecoxib, Valdecoxib and Cardiovascular Risk," presents a meta-analysis of two clinical studies, and examines the association between the administration of parecoxib, the intravenously administered prodrug of valdecoxib, followed by the use of valdecoxib (Bextra) itself, and coronary and cerebrovascular risk. In this combined analysis of a published and an unpublished study, there was a 3-fold higher risk of cardiovascular events with drug than with placebo. Dr. Garret A. FitzGerald is an author of both the editorial and the investigational study.

The authors of the editorial, who believe these findings when taken in context, represent a class effect, suggest that practitioners should be alerted to the potential for cardiovascular events with all COX-2 inhibitors, especially in patients at moderate to high risk of those events. They do suggest that there might be circumstances under which COX-2 inhibitors could be safely administered to patients at low risk of such events, but feel that these circumstances have not yet been defined.

The American Heart Association recommends that patients talk with their physician about their cardiovascular disease risk and treatment options for arthritis. "Each patient must be considered as an individual," said Alice K. Jacobs, M.D., American Heart Association president, "and we have many effective ways to reduce their risk of heart attack and stroke. An important part of our caring for patients is considering all the medications they take, and finding those that provide the greatest benefit and the least risk."