Commentary

Platelet cyclooxygenase (COX)-1 is a main source of the potent vasoconstrictor and platelet aggregator TxA₂. Macrovascular endothelial COX-2 is a main source of the potent vasodilator and platelet inhibitor PGI₂.¹ Thus, one might well have predicted that the highly COX-2-selective inhibitor, rofecoxib, would increase the risk for thrombosis. In an ex vivo assay in human whole blood, celecoxib was less COX-2-selective than rofecoxib, etodolac, or meloxicam, and only slightly more selective than nimesulide.²

The clinical research to date confirms the available basic research. Compared with non-selective NSAIDs, rofecoxib slightly decreases the risk for gastrointestinal (GI) haemorrhage but increases the risk for thrombosis. The most important celecoxib study (CLASS)¹ is now mired in controversy because of the publication of the more favourable 6 month data instead of the less favourable 12 month outcomes. Celexicob's failure to decrease GI events and failure to increase vascular events relative to ibuprofen and diclofenac could be explained by either the co-administration of aspirin allowed in CLASS or by its relatively modest COX-2 selectivity.

The concomitant use of aspirin, even at low doses, may largely negate the GI safety advantage of COX-2-selective NSAIDs. Additionally, some NSAIDs (eg, ibuprofen) seem to inhibit the protective effects of aspirin, whereas others (eg, diclofenac and rofecoxib) do not.⁴ The current well supported and widespread use of aspirin may increase depending on the results of the Aspirin in Asymptomatic Atherosclerosis Trial and other studies currently being done.

Physicians should continue to prescribe aspirin for secondary prevention of vascular events, with the understanding that patients who need aspirin will probably derive no safety advantage from COX-2-selective NSAIDs. Until additional pharmacodynamic studies and large clinical trials determine the clinical importance of its prothrombotic effects, rofecoxib should be avoided.