Prothrombotic Effects of COX-2 Inhibitors: Is it a Class Effect?
Presented at: The annual meeting of the American College of Legal Medicine, March 4, 2005, San Diego, CA.
The inhibition of the cyclooxygenase (COX) 1 and 2 enzymes was discovered as the mechanism of action of aspirin by John Vane in the late 1960s or early 1970s. This discovery earned Dr. Vane both a Nobel Prize and a Knighthood. Other non-steroidal anti-inflammatory drugs (NSAIDs) like indomethacin, ibuprofen, and naproxen also act by inhibiting the COX enzymes to reduce pain, inflammation and temperature; however, their therapeutic benefit is accompanied by undesirable side effects such as gastritis and NSAID-related renal disease like interstitial nephritis, which are also related to COX inhibition leading to decreases in cytoprotective prostaglandins (PGs) (eg, PGE 2 ) and other prostaglandins which have local hormonal activity as vasodilators in certain tissues and organs such as the vasa recta of the kidney (eg, PGE 2 and PGI 2 ).
Discovery of two families of COX enzymes, COX-1 and COX-2, and the recognition that COX-2 enzymes are more involved with the formation of the mediators of pain and inflammation than COX-1 enzymes provided a more specific site of action for the new generation of selective inhibitors of the COX-2 enzyme, which were marketed with the claim that they were less likely to cause gastric irritation in patients who could not tolerate inhibitors of both classes of COX like aspirin, ibuprofen and naproxen.
However, the endogenous biosynthesis of prostaglandins is a complicated biological system which begins with the fatty acid arachidonic acid, which is converted to a common precursor of PGs, PGH 2 , which “cascades” down into the formation of other
biologically active autocoids. Divergent pathways lead to the formation of PGE 2 and PGI 2 which help maintain capillary dilatation, or the formation of thromboxane A 2 (TXA 2 ), a vasoconstrictor and potent promoter of platelet aggregation. The relative “balance” between opposing actions of these two families of PGs can affect an individual’s risk of experiencing a CVA or MI related to ischemic, thrombotic events.
Two randomized, placebo controlled trials in patients immediately following coronary-artery bypass grafting (CABG) showed that Bextra®, another COX-2 inhibitor, increased the risk of serious cardio-vascular outcomes 3 fold over placebo. An NIH trial was halted on Dec. 17, 2004 when Celebrex-treated pts experienced twice as many MIs as pts on placebo. Another NIH study comparing Celebrex® to Aleve® (naproxen) in pts with Alzheimer’s Disease unexpectedly found 50% more cardiovascular events in pts taking Aleve® than in the placebo group.
Vioxx has been withdrawn from the market and currently, things do not look promising for other members of this class. A relative inhibition of COX-2 over COX-1 appears to upset the balance in the biosynthetic cascade and produce a prothrombotic action leading to an intolerable increase in MIs and CVAs. Other agents producing the same imbalance
are likely to affect physiological processes in a similar way. Even non-selective COX inhibitors like naproxen may not be safe. Daily use of COX-2 inhibitors is discouraged.