In two articles, published in Circulation, researchers from the University of Pennsylvania School of Medicine provide further evidence for the role of cyclooxygenases (COX) in heart-disease risk.
In one, a statistical meta-analysis of two placebo-controlled trials, the COX-2 inhibitor Bextra elevated the combined incidence of heart attack and stroke three-fold in coronary artery bypass graft (CABG) surgery patients. In the second, the investigators found that a fat produced by COX-1 speeds hardening of the arteries in a mouse model of atherosclerosis, which may have implications for low-dose aspirin therapy in heart patients.
Six years ago Garret FitzGerald, MD, Director of the Institute for Translational Medicine and Therapeutics at Penn, raised the possibility that selective COX-2 inhibitors might predispose patients otherwise at risk for an increased incidence of heart attack and stroke. This proposal was based initially on his studies of how celecoxib (Celebrex) and rofeocoxib (Vioxx) worked in human volunteers.
The first unequivocal evidence of this risk emerged with the Merck-sponsored APPROVe study of Vioxx, leading to withdrawal of the drug in September 2004. Evidence implicating a second member of the class, valdecoxib (Bextra) was presented by FitzGerald in a lecture at the American Heart Association (AHA) in November 2004. This work – a collaboration led by Curt Furberg of Wake Forrest University, along with Bruce Psaty of the University of Washington and FitzGerald – appears online January 17 in Circulation and in the January 25th print edition of the journal.
In this first study, the researchers used a conventional statistical approach called meta-analysis to combine the findings of two trials to obtain a stronger estimate of the risk of heart attack plus stroke than is possible from looking at either trial alone. Their analysis suggests that the COX-2 inhibitor Bextra elevated the combined incidence of heart attack and stroke three-fold in the study population of CABG patients.
Two placebo-controlled trials of Bextra and parecoxib (Dynastat) were performed in patients undergoing coronary artery bypass graft surgery. These studies were sponsored by Pfizer, Inc. In both cases, intravenous Dynastat, which is converted to Bextra within minutes in the body, was given before oral dosing with Bextra. The first involved roughly 400 patients and dosing lasted 14 days. Concern was prompted by an apparent cardiovascular signal and the FDA did not grant approval to Dynastat, despite clear evidence of pain relief from the Dynastat/Bextra combination compared to placebo. A second, larger study was performed in which the dose of Bextra was reduced, as was the dosing period to 10 days. The figures from this study are now incorporated in a revised drug label for Bextra available at the FDA website (www.fda.gov).
This result is consistent with the original mechanism proposed by FitzGerald in 1999 that COX-2 inhibitors may be problematic for those at risk for heart disease. COX-2 is the main source of a fat – prostacyclin or PGI2 – which protects the heart from factors that activate the clotting system, harden the arteries, and raise blood pressure. "Although a clinical trial is a crude detection system for uncommon side effects, such as the cardiovascular risk from coxibs, we predicted that a signal would be detected faster and in smaller studies in patients with activated clotting systems," says FitzGerald. "It is well known that this is true of coronary artery bypass graft surgery patients." Studies of sufficient size and duration to detect the expected rates of cardiovascular events in arthritis patients have not been performed with Bextra.
While FitzGerald stresses that the emergence of a cardiovascular signal with a second COX-2 inhibitor rendered the argument for a class effect of the risk "compelling," the early cessation of a placebo-controlled trial of celecoxib (Celebrex) in December 2004 by the National Cancer Institute (because of an excess incidence of heart attack and stroke) appeared to put the matter beyond dispute.