The coxibs and traditional nonsteroidal anti-inflammatory drugs: a current perspective on cardiovascular risks

Abstract

There is strong evidence from randomized clinical trials that the highly selective cox-2 inhibitors (coxibs), compared with placebo, cause an excess of serious cardiovascular events that are not mitigated by low-dose acetylsalicylic acid. Both Health Canada and the Food and Drug Administration have concluded that the excess cardiovascular events may be a 'class effect' of all the nonsteroidal anti-inflammatory drugs (NSAIDs), including traditional NSAIDs (tNSAIDs) and coxibs, and now require appropriate black box labelling of all these agents. Celecoxib and lumiracoxib are the only coxibs remaining on the market in Canada. The prostanoid pathways, the roles of cox-1 and cox-2, as well as the inhibitory effects of acetylsalicylic acid, traditional tNSAIDs and the coxibs, are briefly reviewed. Current recommendations for the ongoing use of coxibs and the tNSAIDs are summarized.

Figure 1)

Prostanoid pathways and the effects of acetylsalicylic acid (ASA), traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) and coxibs. Arachidonic acid is liberated from membrane phospholipids, is enzymatically transformed by cox-1 or cox-2 to prostaglandin (PG) G₂ and then to PGH₂, which is then converted by tissue-specific isomerases to a range of prostanoids that activate receptors to cause physiological effects. Low-dose ASA irreversibly inhibits cox-1, but inhibits cox-1 in the nucleated cells of the gastric mucosa and kidney in a dose-and time-dependent manner. High-dose ASA and tNSAIDs inhibit both cox-1 and cox-2. Coxibs inhibit only cox-2 (see text for details). Na Sodium; TxA₂ Thromboxane A₂

Figure 2)

The Adenomatous Polyp PRevention On Vioxx (APPROVe) trial (6). Kaplan-Meier estimates of the cumulative incidence of confirmed serious thrombotic events. Vertical lines indicate 95% CI. Reproduced from reference 6 with permission

Figure 3)

The Adenoma Prevention with Celecoxib (APC) trial (7). Kaplan-Meier estimates of the composite end point of death from cardiovascular causes, myocardial infarction, stroke and heart failure among patients who received celecoxib (200 mg twice daily or 400 mg twice daily) or placebo. The log-rank statistic of 8.73, which has two degrees of freedom, was used to determine the P value. Reproduced from reference 7 with permission