Antagonism of the antithrombotic and anti-atherosclerotic actions of aspirin by rofecoxib in the cholesterol-fed rabbit

BACKGROUND AND PURPOSE Most patients at elevated cardiovascular risk receive long-term aspirin (ASA) anti-platelet treatment. The present study specifically addresses the pharmacological interactions between selective COX-2 inhibitors and ASA and the possible consequences for the thrombotic risk during long-term treatment. EXPERIMENTAL APPROACH New Zealand white rabbits were fed a standard laboratory diet supplemented with 1% cholesterol (CON) for 12 weeks. Age-matched control rabbits were fed the same standard diet without addition of cholesterol (SD). Rabbits were randomly assigned to one of the following groups: rofecoxib (ROFE, 25 mg.kg(-1), bid), acetylsalicylic acid (ASA, 5 mg.kg(-1), bid) or a combination of both (ASA + ROFE). At the end of the feeding period, the severity of atherosclerotic plaque formation was assessed in the aorta. Thrombus formation was assessed in the left carotid artery using a modified Folts procedure. KEY RESULTS Treatment of cholesterol-fed rabbits with ASA significantly reduced plaque formation. This reduction in lesion size was not observed in animals treated with the combination of rofecoxib and ASA. In the modified Folts model, treatment with either rofecoxib or ASA increased the total blood flow above that of untreated animals. This increase was statistically significant in the case of ASA, while cotreatment with rofecoxib abolished this ASA effect completely and reduced the total flow rate to the levels seen in untreated hypercholesterolaemic controls. CONCLUSIONS COX-2 inhibition by rofecoxib attenuates the antithrombotic and anti-atherosclerotic effects of ASA during long-term treatment in cholesterol-fed rabbits.