Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities
Tilo Grosser, … , Susanne Fries, Garret A. FitzGerald
Tilo Grosser, … , Susanne Fries, Garret A. FitzGerald
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):4-15. https://doi.org/10.1172/JCI27291.
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Science in Medicine

Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities

Abstract

Inhibitors selective for prostaglandin G/H synthase-2 (PGHS-2) (known colloquially as COX-2) were designed to minimize gastrointestinal complications of traditional NSAIDs — adverse effects attributed to suppression of COX-1–derived PGE2 and prostacyclin (PGI2). Evidence from 2 randomized controlled-outcome trials (RCTs) of 2 structurally distinct selective inhibitors of COX-2 supports this hypothesis. However, 5 RCTs of 3 structurally distinct inhibitors also indicate that such compounds elevate the risk of myocardial infarction and stroke. The clinical information is biologically plausible, as it is compatible with evidence that inhibition of COX-2–derived PGI2 removes a protective constraint on thrombogenesis, hypertension, and atherogenesis in vivo. However, the concept of simply tipping a “balance” between COX-2–derived PGI2 and COX-1–derived platelet thromboxane is misplaced. Among the questions that remain to be addressed are the following: (a) whether this hazard extends to all or some of the traditional NSAIDs; (b) whether adjuvant therapies, such as low-dose aspirin, will mitigate the hazard and if so, at what cost; (c) whether COX-2 inhibitors result in cardiovascular risk transformation during chronic dosing; and (d) how we might identify individuals most likely to benefit or suffer from such drugs in the future.

Authors

Tilo Grosser, Susanne Fries, Garret A. FitzGerald

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Figure 5

The spectrum of selectivity for COX inhibition.

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The spectrum of selectivity for COX inhibition. (A) The relative affinit...
(A) The relative affinities of tNSAIDs and coxibs (open circles) for COX-1 and COX-2. The concentrations required to inhibit COX-1 and COX-2 by 50% (IC50) have been measured using whole-blood assays of COX-1 and COX-2 activity in vitro. The diagonal line indicates equivalent COX-1 and COX-2 inhibition. Drugs plotted below the line (orange) are more potent inhibitors of COX-2 than drugs plotted above the line (green). The distance to the line is a measure of selectivity. Note the log scale. For example, lumiracoxib is the compound with the highest degree of selectivity for COX-2 as its distance to the line is the largest. Celecoxib and diclofenac have similar degrees of selectivity for COX-2, as their distances to the line are similar; however, diclofenac is active at lower concentrations and thus located more to the left. Figure modified with permission from The New England Journal of Medicine (28). (B) Implication of the relative degrees of selectivity. Increasing degrees of selectivity for COX-2 are associated with augmented cardiovascular risk while increasing degrees of selectivity for COX-1 are associated with augmented GI risk. The relative size of the circles indicates approximately the variation in sample sizes among the trials.