Cyclooxygenase-2 Inhibitors and Cardivascular Risk

Park, Yong Beom

Abstract

Serious concerns about the cardiovascular safety of rofecoxib had been present since the VIOXX(R) Gastrointestinal Outcomes Research (VIGOR) study first suggested that the drug may increase the risk of myocardial infarction. Subsequent data from major observational studies further implicated the association of rofecoxib with arterial thromboembolic disease. In September 2004, rofecoxib was withdrawn from the worldwide market based on the safety findings of the Adenomatous Polyp Prevention on VIOXX (APPROVe) study, which indicated an increase risk of myocardial infarction and stroke among subjects randomized to rofecoxib. In December 2004, the results of the Adenoma Prevention with Celecoxib (APC) study demonstrated a dose-related increase in the risk of cardiovascular events among patients randomized to celecoxib when compared with placebo. Two other large prospective prevention studies of celecoxib, the Prevention of Spontaneous Adenomatous Polyps (Pre SAP) trial and the Alzheimer's Disease Antiinflammatory Prevention Trial (ADAPT) did not show any sign of increased cardiovascular risk. None of the reported randomized trials studying any COX-2 selective imhibitor, thus far, has been specifically designed to examine cardiovascular outcomes. Hence, no cardiovascular hypotheses have yet been formally tested. Long-term and adequately powered prospective randomized clinical trials in relevant patient populations with clinically appropriate pre-specified cardiovascular end-points, ideally comparing COX-2 selective inhibitors with traditional NSAIDs, are required. Until these trials are completed, careful risk:benefit analysis of any putative increase in cardiovascular risk versus known gastrointestinal benefit for individual agents needs to be undertaken.