October 13, 2004
Starkweather, B.S. and Asher Kimchi M.D.
Los Angeles, CA - In
a report to be published on October 21, 2004 in the New England
Journal of Medicine, author Garret A. Fitzgerald suggests that
Vioxx may not be the only drug of its type that raises the risk
of heart attack and stroke.
Vioxx belongs to
the class of drugs that selectively inhibits cyclooxygenase-2
(COX-2), an enzyme that produces prostaglandins E2 and I2,
mediators of inflammation. By not inhibiting cyclooxygenase-1
(COX-1), whose products provide cytoprotection in the gastric
epithelium, these coxibs were thought to decrease the incidence
of gastric side effects when compared to traditional NSAIDS that
inhibit both cyclooxygenases.
prostaglandin I2 has been shown to inhibit platelet aggregation,
cause vasodilation and prevent the proliferation of vascular
smooth muscle cells in vitro. It was previously thought that
prostaglandin I2 was primarily a product of COX-1 in the
endothelium, but more recent studies in mice and humans has
shown that COX-2 is actually the dominant source.
The major product
of COX-1 in platelets, thromboxane A2, has effects that directly
oppose prostaglandin I2, causing platelet aggregation,
vasoconstriction, and vascular smooth muscle proliferation.
selectively inhibiting COX-2, the vascular effects will be those
of thromboxane A2, since prostaglandin I2 production has been
inhibited. This could lead to increased risk of stroke or heart
attack due to an exaggerated thrombotic response to the rupture
of an atherosclerotic plaque. Other effects could include
elevated blood pressure and accelerated atherogenesis.
Vioxx has been
removed from the market by Merck. Dr. Fitzgerald suggests in
this report that until the FDA determines whether these effects
apply to this class of drugs as a whole, it would seem prudent
to avoid coxibs in patients who have cardiovascular disease or
who are at risk for it.