Arachidonic Acid Metabolism in Human Platelets and Endothelium

Aspirin has been on the market for 115 years. Beginning with the marketing of indomethacin for the treatment of rheumatoid arthritis in 1963, at least 20 other nonsteroidal anti-inflammatory drugs (NSAIDs) with aspirin-like actions have been developed over the past 50 years, culminating with the introduction of a new class of selective inhibitors of cyclooxygenase (COX)-2, the coxibs, approximately 15 years ago. The NSAIDs represent the single most crowded family of drugs sharing the same therapeutic activities and mechanism of action, perhaps reflecting the unmet therapeutic need in the area of pain management and the large interindividual variability in response to these agents. NSAIDs provide symptomatic relief of pain and inflammation associated with a variety of human disorders, including the rheumatic diseases. Their shared therapeutic actions (ie, analgesic, anti-inflammatory, and antipyretic) are usually accompanied by mechanismbased adverse effects that can, at least in part, be attenuated as a function of individual pharmacokinetic or pharmacodynamic properties. Nuances in the tolerability of different NSAIDs had been described in the precoxib era on the basis of clinical trials of a few hundred patients treated for up to a few months with soft end points. More recently, however, important differences in safety have been demonstrated in head-to-head randomized comparisons of individual coxibs and 1 or more traditional NSAIDs that involved tens of thousands of patients treated for up to a few years with hard end points. Even more significantly, the interpretation of the effects of NSAIDs has been greatly enhanced by the availability, for the first time, of large, placebo-controlled trials that aimed to assess the potential for chemoprevention of colorectal cancer by rofecoxib or celecoxib. As a result of these developments, the whole field of NSAIDs has been illuminated during the past 15 years. Although epidemiological studies had previously associated regular use of NSAIDs with some aspects of vascular toxicity such as enhanced risk of congestive heart failure, a novel aspect of cardiotoxicity associated with COX-2 inhibition emerged from the coxib trials, that is, increased risk of atherothrombotic vascular events. This was largely unexpected and paradoxical, given that the prototypic COX-2 inhibitor, aspirin, had been clearly shown to be cardioprotective over a wide range of doses up to 1500 mg daily. The aim of this article is to review the evidence and to discuss the mechanisms underlying the cardiovascular effects of traditional NSAIDs and coxibs, trying to reconcile the pharmacology of COX isozyme inhibition with its clinical readouts. In doing so, we shall rely primarily on the results of the recently completed meta-analysis of individual participant data from randomized trials because it provides the most reliable information on the effects of the most widely prescribed NSAIDs on serious clinical outcomes.