Cyclooxygenase-2 (COX-2) agents inhibit prostacyclin (via inhibition of endothelial COX-2) but do not inhibit thromboxane (which is synthesized in platelets by COX-1). Prostacyclin is a vasodilator and also inhibits platelet aggregation, while thromboxane is a vasoconstrictor and promoter of platelet aggregation. There has been concern, therefore, that COX-2 inhibitors may lead to increased prothrombotic activity and, therefore, increased cardiovascular events. Mukherjee et al (JAMA 286:954-959, 2001) reviewed several recent published reports on COX-2 agents, as well as data submitted to the US Food and Drug Administration by pharmaceutical companies.
The study focused on two major randomized trials that investigated the gastrointestinal safety of rofecoxib (Vioxx) and celeoxib (Celebrex). These were the Vioxx Gastrointestinal Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term Arthritis Safety Study (CLASS; 8059 patients). In the VIGOR trial, the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attack) with rofecoxib treatment compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; p=.002). There was no significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory agents in CLASS. [It should be noted that patients in the CLASS trial were allowed to take concomitant aspirin, a thromboxane inhibitor, while those in the VIGOR trial were not.] The annualized myocardial infarction rates for COX-2 inhibitors in both VIGOR and CLASS were significantly higher than that in the placebo group of a recent meta-analysis of 23,407 patients in primary prevention trials (0.52%); 0.74% with rofeccoxib (p=.04 compared with the placebo group of the meta-analysis) and 0.80% with celecoxib (p=.02 compared with the placebo group of the meta-analysis).
The authors raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors and suggest that further prospective trials are indicated to determine the magnitude of the risk.
Editorial Comment: The potential cardiovascular effects of COX-2 agents remains to be fully elucidated. The CLASS and VIGOR trials were not designed to investigate cardiovascular events, and the analysis of these data was done on a post hoc basis. Furthermore, the validity of comparison of data from the two COX-2 trials with those from historical controls is questionable. Nonetheless, the data are concerning and it will be important to clarify the real risk of cardiovascular events in COX-2 treated patients in prospective long-term studies.
Meanwhile, the health care provider must weigh the potential risks and benefits of COX-2 inhibitors in each individual patient. The CLASS and VIGOR studies clearly show that COX-2 inhibitors are associated with a significantly reduced risk of serious GI events compared to conventional NSAIDs. However, in the CLASS trial, the concomitant use of low dose aspirin for cardiovascular prophylaxis negated this “protective” GI effect. Thus, the patient taking both aspirin and a COX-2 inhibitor may have a lower risk for cardiovascular events but a higher risk of serious GI events than a patient taking a COX-2 inhibitor alone.
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