UC Davis scientists find link between arthritis pain reliever and cardiovascular events

A research team from the University of California, Davis and Peking University, China, has discovered a novel mechanism as to why the long-term, high-dosage use of the well-known arthritis pain medication, Vioxx, led to heart attacks and strokes. Their groundbreaking research may pave the way for a safer drug for millions of arthritis patients who suffer acute and chronic pain.

Using metabolomic profiling to analyze murine (rodent) plasma, the scientists discovered that Vioxx causes a dramatic increase in a regulatory lipid that could be a major contributor to the heart attacks and strokes associated with high levels of the drug and other selective COX-2 inhibitors, known as "coxibs."

"This is a major breakthrough that can lead to a better medication for people suffering from acute pain," said entomologist-chemist Bruce Hammock, a distinguished professor of entomology with a joint appointment at the UC Davis Cancer Center. The research took place in the laboratories of Hammock, cell biologist Nipavan Chiamvimonvat, UC Davis Division of Cardiovascular Medicine; and physiologist Yi Zhu, Peking University.

The research is to be published the week of Sept. 13 in the Proceedings of the National Academy of Sciences.

"Our metabolomics study discovered that 20-hydroxyeicosatetrasanoic acid, also known as 20-HETE, contributes to the Vioxx-mediated cardiovascular events," said UC Davis bioanalytical chemist Jun-Yan Liu, the senior author of the paper and a five-year member of the Bruce Hammock laboratory.

Millions of arthritis patients took Vioxx before its withdrawal from the global market in 2004. Vioxx, a nonsteroidal anti-inflammatory drug (NSAID) and coxib for acute and chronic pain, particularly for arthritis and osteoarthritis, was on the market for five years. Merck & Co. voluntarily withdrew it in September 2004 due to concerns about the increased risk of heart attacks and strokes.

The chronic administration of high levels of selective COX-2 inhibitors, particularly rofecoxib, and valdecoxib, increases the risk for cardiovascular disease, Liu said.

Cardiology expert Garrett J. Gross, professor in the Department of Pharmacology and Toxicology at the Medical College of Wisconsin, Milwaukee, who is not associated with the research, described the UC Davis-based research as "a highly significant finding."

"The recent discovery of Hammock and co-workers at UC Davis that murine plasma concentrations of 20-HETE may be a significant biomarker which may predict the susceptibility of patients to having an unfavorable cardiovascular event while taking selective COX-2 inhibitors such as rofecoxib is an important and novel finding," Gross said. "This discovery may help to unravel the unexpected occurrence and potential mechanism responsible for sudden cardiac death in a number of patients taking COX-2 inhibitors for inflammatory disorders such as arthritis. This a highly significant finding which may lead to a safer use of these drugs in selective patients with disabling inflammatory disorders and may lead to the development of more selective drugs for use in these types of patients."