Clinical investigations have demonstrated a relationship between the extended use of
rofecoxib and increased risk for atherothrombotic events. This has led to the removal of
rofecoxib from the market and explicit cardiovascular safety warnings for other COX-2 selective and non-selective agents that remain on the market. Early explanations for the
cardiotoxicity of
rofecoxib, such as the relative cardioprotective effect of comparator agents (
naproxen) or an "imbalance" between
thromboxane and
prostacyclin biosynthesis due to an absence of concomitant
aspirin use, have not been substantiated by the evidence. New experimental findings indicate that the
cardiotoxicity of
rofecoxib is not a general class effect but may be due to its intrinsic chemical structure and unique primary metabolism. Specifically,
rofecoxib has been shown to increase the susceptibility of human
LDL and
cell membrane lipids to oxidative modification, a hallmark feature of
atherosclerosis.
Rofecoxib was also found to promote the non-enzymatic formation of
isoprostanes from
biological lipids, which act as important
mediators of inflammation in the
atherosclerotic plaque. The explanation for such
cardiotoxicity is that
rofecoxib forms a reactive
maleic anhydride in the presence of
oxygen due to its chemical structure and primary metabolism (cytoplasmic
reductase). By contrast, adverse effects on rates of
LDL and
membrane lipid oxidation were not observed with other chemically distinct (
sulfonamide)
COX-2 inhibitors under identical conditions. These findings provide a compelling rationale for distinguishing the differences in cardiovascular risk among COX-selective inhibitors on the basis of their intrinsic physico-chemical properties.