Selective cyclooxygenase-2 (COX-2) inhibitors and potential risk of cardiovascular events

Abstract

Selective cyclooxygenase-2 (COX-2) inhibitors were developed as a response to the gastrointestinal toxicity of conventional nonsteroidal anti-inflammatory agents (NSAIDs). However, COX-2 inhibitors decrease vascular prostacyclin (PGI₂) production and may disrupt the homeostatic mechanisms that limit the effects of platelet activation. Basic and clinical data raise concerns about a potential prothrombotic effect of this class of drugs. The widespread popularity of these agents mandates their prospective evaluation in patients with cardiovascular diseases or who are at risk for cardiovascular events.

Introduction

NSAIDs have proven analgesic, anti-inflammatory, and antithrombotic properties, but also have significant gastrointestinal toxicity. The gastrointestinal toxicity appears to be related to COX-1 inhibition [1]. In 1990, Fu et al.[2] detected a novel COX protein in monocytes stimulated by interleukin, and a year later Kujubu et al.[3] identified a gene with considerable homology to COX-1. Identification of this COX-2 protein rekindled the efforts of the pharmaceutical industry to produce a safer analgesic, anti-inflammatory drug via selective inhibition of COX-2, and this class of drugs was introduced in 1999. The COX-2 inhibitors generated rapid growth in the US antiarthritic market in 2000, with total sales exceeding $6 billion, and the volume of prescriptions reaching 121.3 million [4].

The development of COX-2 inhibitors as anti-inflammatory agents without gastric toxicity is based on the fact that COX-1 predominates in the stomach, yielding protective prostaglandins, while COX-2 is induced in inflammation, giving rise to pain, swelling, and discomfort. However, selective COX-2 inhibitors also decrease vascular PGI₂ production and may affect the balance between prothrombotic and antithrombotic eicosanoids [5]. Unlike the platelet inhibition afforded by COX-1 inhibitors, COX-2 inhibitors do not share this beneficial antithrombotic property. In contrast, by decreasing vasodilatory and anti-aggregatory PGI₂ production, COX-2 inhibitors may tip the balance in favor of prothrombotic eicosanoids (thromboxane A₂) and may lead to increased cardiovascular thrombotic events [6]. However, atherosclerosis is a process with inflammatory features [7], and selective COX-2 inhibitors may potentially have anti-atherogenic effects by virtue of inhibiting inflammation.