Key Differences in Cardiovascular Risk Among COX-2 Inhibitors Identified
Posted on: Friday, 5 November 2004, 12:00 CST
BOSTON, Nov. 5 /PRNewswire/ -- Researchers have discovered additional evidence -- now at the molecular level -- that point to important differences between Vioxx and other COX-2 inhibitors. In a new study, it was observed that Vioxx caused biochemical changes that contribute to the development of heart disease. Celebrex, another widely prescribed COX-2 inhibitor, did not. The findings published today in a leading cardiovascular journal, Atherosclerosis, present a biological explanation for reported differences in cardiovascular safety observed with COX-2s.
Over the course of a two-year investigation, researchers found important differences in the way each COX-2 inhibitor acts on a key process linked to cardiovascular disease. Vioxx made certain lipid components of the blood, particularly low-density lipoprotein (LDL, "bad" cholesterol), more susceptible to free radical damage -- chemical changes that contribute to heart disease.
"Vioxx interacts at the molecular level in a way that Celebrex and other NSAIDs do not," explained lead investigator R. Preston Mason, Ph.D. "Lipids are important molecular building blocks in cells of the artery. Abnormal changes in the structure or shape of lipids caused by Vioxx, especially in LDL, may explain why they are more susceptible to oxidative damage, and therefore, contribute to cardiovascular damage. Similar effects on susceptibility of lipids to oxidative damage have been observed with cigarette smoking, diabetes and in patients who have had a recent heart attack. Interestingly, these adverse effects were independent of Vioxx's function as an inhibitor of the COX-2 enzyme -- thus explaining why it could be different from other drugs in its class."
These findings are consistent with clinical evidence demonstrating a marked difference between Vioxx and Celebrex. A recent FDA-funded retrospective analysis of 1.4 million patients showed that patients taking higher doses of Vioxx (more than 25 mg daily) had triple the risk of heart problems, including heart attacks and sudden cardiac death. Patients taking Celebrex demonstrated no increased risk of acute cardiac events. (Graham et al, presented at International Society of Pharmacoepidemiology, August 2004, and presented at American College of Rheumatology, October 2004).
"This news should be reassuring to patients and doctors," said Mason. "The cardiovascular issues associated with Vioxx should not be extrapolated to other COX-2 inhibitors. Having for the past fifteen years studied these types of drug-lipid interactions, it was clear to us that the effects we observed with Vioxx were very unusual and needed to be reported to the medical community."
To further test their hypothesis, researchers validated the findings at an independent laboratory at Tufts University in Boston. The scientists at Tufts were blinded to the COX-2 medications used. The study involved an analysis of the effects of each of the COX-2 inhibitors on the biochemistry of human blood samples through techniques not available in clinical practice. Whole plasma, isolated LDL particles and cell lipid components that did not contain the COX-2 enzyme were analyzed with advanced biochemical techniques while the effects of the drugs on lipid structure were analyzed by small-angle X-ray diffraction.
The study was conducted by Elucida Research LLC, a private laboratory in Beverly, MA, dedicated to independent and innovative biomedical research. Mason, president and founder of Elucida Research LLC, is a faculty member at Harvard Medical School. The other lead investigators in this study were Mary F. Walter, Ph.D. and Robert F. Jacob, Ph.D. of Elucida Research.
The scientific staff of Elucida Research conducted the study independently. No funding or impetus was provided from the pharmaceutical industry to initiate or conduct this study.
The study can be accessed on-line at: http://www.sciencedirect.com/science/journal/00219150
Elucida Research LLC
CONTACT: R. Preston Mason, Ph.D. of Elucida Research LLC,+1-978-771-9252, rpmason@elucidaresearch.com
Web site: http://www.sciencedirect.com/science/journal/00219150
Source: PRNewswire
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