Goodman & Gilman, 11^th Ed. 2006, p. 684:  “Selective inhibition of COX-2 depress PGI­­-2 formation by endothelial cells without concomitant inhibition of platelet thromboxane.  Experiments in mice suggest that PGI-2 restrains the cardiovascular effects of TXA-2, affording a mechanism by which selective inhibitors might increase the risk of thrombosis (McAdam et al, 19999, Catella-Lawson et al., 1999).  This mechanism should pertain to individuals otherwise at risk of thrombosis, such as those with rheumatoid arthritis, as the relative risk of myocardial infraction is increased in these patients compared to patients with osteoarthritis or no arthritis.”  {Patients who would be taking long-term COX-2 inhibitors.  However, the study, which took theory into reality, was not of that group, but rather a test to see if it reduced the risk of Alzheimer’s disease.  At 16 months the study was stopped because of a 2.5 increase in myocardial infraction, and 3.4 at the higher dose.}

Goodman & Gilman, 11^th Ed. 2006, p. 690:  “Although aspirin is regarded as the standard against which other drugs should be compared for treatment of rheumatoid arthritis, many clinicians favor the use of other NSAIDs perceived to have better gastrointestinal tolerability, even though this perception remains unproven by convincing clinical trials.”  {As I pointed out, most test use a coated NSAID compared to an uncoated aspirin, and often at lower therapeutic dose.--jk}

The coxibs (COX-2-selective NSAIDs) do not inhibit production of platelet thromboxane (a potent platelet agonist and vasoconstrictor), but selectively suppress endothelial prostacyclin (an intrinsic vasodilator and platelet inhibitor).  It has been hypothesised that selective inhibition of prostacyclin production by coxibs without concomitant platelet inhibition leads to thrombosis in at-risk individuals

{DATED BECAUSE IT WAS WRITTEN BEFORE VIOXX WAS BANNED}

Medical Journal of Australia, MJA 2004; 181 (10): 524-525

Journal of the Australian Medial Association, Established 1914

What is the basis for the increased cardiovascular risk?

Traditional non-steroidal anti-inflammatory drugs (NSAIDs) suppress prostaglandin synthesis by inhibiting both constitutively expressed COX-1 (primarily responsible for “housekeeping” functions such as gastric protection and haemostasis) and the inducible COX-2 (which is upregulated in inflammatory conditions). The coxibs (COX-2-selective NSAIDs) do not inhibit production of platelet thromboxane (a potent platelet agonist and vasoconstrictor), but selectively suppress endothelial prostacyclin (an intrinsic vasodilator and platelet inhibitor).. It has been hypothesised that selective inhibition of prostacyclin production by coxibs without concomitant platelet inhibition leads to thrombosis in at-risk individuals 10,11 However, alternative hypotheses suggest that blockade of COX-2 in atheromatous plaques may reduce vascular inflammation and the progression of vascular disease, and perhaps even prevent events.9,12

Is the thrombotic risk a class effect?

The celecoxib studies have not demonstrated an increased risk of thrombosis,2,7,8 but there are no long-term safety studies. Several second-generation coxibs have recently been approved for use in the United States (Lumiracoxib, Valdecoxib) and Europe (Etoricoxib, a derivative of rofecoxib). While randomised trials involving these drugs have not shown a significant increase in thrombosis risk,13,14 they have not excluded it. Consequently, their potential risk for causing cardiovascular events has also been questioned.8,11 Given the clear demonstration of increased cardiovascular risk with rofecoxib, it is now incumbent on drug manufacturers and regulatory authorities to demonstrate cardiovascular safety for all existing and new coxibs.