As the European Medicines Agency (EMA) determines the fate of the cyclooxygenase 2 (COX-2) class abroad and the US Food and Drug Administration (FDA) readies for a rare advisory meeting in mid-February, new reports in the journal Circulation provide further evidence that COX-2s increase cardiovascular risk, as well as a better understanding of the mechanisms in these agents that may accelerate the atherogenic process.
A meta-analysis of two placebo-controlled trials, comprising 2000 patients, concluded that coronary artery bypass graft (CABG) patients taking valdecoxib (BextraR) and the experimental parecoxib (DynastatR), an intravenously administered prodrug of valdecoxib, were three times more likely to have a heart attack or stroke than someone taking placebo.1
"The jury is still out on whether this is a class effect and what to do about the drugs that remain on the market, but one is getting more evidence now that it is a class effect," Curt D. Furberg, MD, PhD, of Wake Forest University Baptist Medical Center in Winston-Salem, North Carolina, and co-author of the editorial in Circulation that presented the meta-analysis, told CIAOMed. In the editorial, Dr. Furberg called for a black box warning on both celecoxib (CelebrexR) and valdecoxib.
"The [meta-analysis] was the formal publication of news that we heard a month ago showing that there is a clear signal for valdecoxib," said Mark Fendrick, MD, professor of internal medicine and health management and policy at the University of Michigan Health System in Ann Arbor.
A second study by a team of researchers from the University of Pennsylvania in Philadelphia, found that the thromboxane or TxA2 produced by COX-1 accelerates atherosclerosis in mice prone to the disease. The study demonstrated that a drug blocking TxA2 slowed this process at its early stages, although it seemed ineffective once atherosclerosis was well established. Research shows that low-dose aspirin prevents heart attack and stroke by blocking TxA2 formation in platelets.
The study authors, led by Karine M. Egan, PhD, of the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania, pointed out that the addition of a COX-2 inhibitor induced changes that, if they occurred in humans, would have resulted in the formation of unstable plaque, leading to a greater likelihood of rupture and clot formation. They noted that these results have disturbing implications for patients at high cardiovascular risk treated with aspirin and a COX-2 inhibitor.
Researchers concluded that the new research is substantial enough to suggest that Pfizer should halt the planned study of celecoxib in patients with heart disease. "I don't understand the rationale and I don't know how to design [such a trial] in an ethical way," Dr. Furberg said. "If someone is at risk of heart attack, you have to give them aspirin, so how do you test Celebrex?
"It looks as if valdecoxib and rofecoxib [VioxxR] are more of a problem than celecoxib," he continued, "but what does that mean from a regulatory point of view in terms of restrictions?"
The initial review of celecoxib by the EMA included higher dose protocols as part of Pfizer's orphan drug application for the use of the drug in the treatment of adenomatous intestinal polyps in familial adenomatous polyposis. Following just completed discussions with the EMA Committee on Medicinal Products for Human Use, the company has agreed not to launch this drug in the European Union pending finalization of the assessment.3
Data on other COX-2 inhibitors, including etoricoxib (Arcoxiaâ„¢), lumiracoxib (PrexigeR), parecoxib (DynastatR), and valdecoxib are currently being assessed. The group will continue its discussions at its next meeting in mid-February 2005. The FDA meeting will take place February 16-18, 2005, and assess the overall benefit to risk considerations of COX-2s.
In addition, the International COX-2 Study Group is slated to meet in Arlington, VA, January 28-30 to deliberate whether this is a class effect.
The Message Remains the Same
According to Dr. Fendrick, who also is co-editor in chief of the American Journal of Managed Care, the much larger question is whether we should be using COX-2 blockers in patients at risk for cardiovascular events. "For me, the message is to remind people why these drugs were developed in the first place and that's for their improved gastrointestinal safety profile, not better efficacy," he said. "Patients with pre-existing cardiac risk who take an aspirin a day and a coxib get none of the GI safety advantage."
The bottom line is that "using a COX-2 alone in a trial of patients with cardiovascular risk is somewhat worrisome and using it with aspirin makes no sense at all," Dr. Fendrick pointed out.
References:
- Furberg CD, Psaty BM, FitzGerald GA. Parecoxib, valdecoxib, and cardiovascular risk. Circulation. 2005; 111:249.
- Egan KM, Wang M, Lucitt MB, et al. Cyclooxygenases, thromboxane, and atherosclerosis. Plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism. Circulation. 2005; 111:334-342.
- Update from the European Medicines Agency on COX-2 inhibitors [press release]. London: European Medicine Agency Review; Available at: http://www.emea.eu.int. Accessed January 24, 2005.