Cox-2 inhibitors and cardiovascular disease: considerable heat, but not much light

Abstract

This editorial refers to ‘Effects of Celecoxib On Restenosis after Coronary Intervention and Evolution of Atherosclerosis (Mini-COREA) trial: celecoxib, a double-edged sword for patients with angina’, by H.-J. Kang et al. , doi:10.1093/eurheartj/ehs001 We are now in the second decade of controversy regarding the cardiovascular effects of cycloxygenase-2 (COX-2) inhibitors. The introduction of this class of drugs occurred on 31 December 1998, when the US Food and Drug Administration (FDA) approved the sale of celecoxib, followed shortly by the approval of rofecoxib on 20 May 1999. The market acceptance of these two drugs was extraordinary, and both rapidly achieved more than a billion dollars in annual sales. The science leading to the discovery of COX-2 inhibitors is a fascinating story and illustrates the creativity of the pharmaceutical industry in medicinal chemistry. By targeting the COX-2 enzyme, these drugs offered the hope for agents that would preserved the clinical benefits of non-steroidal anti-inflammatory drugs (NSAIDs) without the gastrointestinal (GI) adverse effects attributable to inhibition of the COX-1 isoform. By any reasonable assessment, this targeted therapeutic approach was initially a tremendous success. Studies showed that both COX-2 inhibitors possessed anti-inflammatory and analgesic effects comparable with conventional NSAIDs, but produced fewer symptomatic GI adverse effects. Then, in November 2000, a pivotal study, the VIGOR trial, showed that rofecoxib, compared with naproxen, also produced fewer complicated upper GI adverse events including severe bleeding, ulceration, and perforation.1 However, artfully concealed within the VIGOR manuscript was a dark secret about rofecoxib—although this drug enhanced GI safety, there were significantly more adverse thrombotic cardiovascular events, particularly myocardial infarctions. This safety issue received little public attention until we published an independent analysis of the VIGOR trial in August 2001.2 The rest of the story is now a matter of history and has been fully described in both …