Cardiovascular effects of valdecoxib: transducing human pharmacology results into clinical read-outs

Abstract

Valdecoxib is an NSAID that is selective for COX-2 (commonly named coxibs). It exhibits anti-inflammatory, analgesic and antipyretic properties in animal models and humans due to inhibition of prostanoid synthesis primarily by affecting COX-2. In this review, the clinical results of cardiovascular effects of valdecoxib and its prodrug parecoxib were analyzed and the information from animal models and clinical pharmacology was exploited, that is, pharmacodynamic and pharmacokinetic data, to give a mechanistic interpretation. Similarly to other coxibs and some traditional (t)NSAIDs less selective for COX-2, such as diclofenac, valdecoxib may increase the risk of thrombotic events through a prostacyclin-based mechanism. The rapid and elevated thrombotic risk detected in two coronary artery bypass graft surgery trials with parecoxib and valdecoxib is coherent with almost complete suppression of COX-2 by supratherapeutic doses (particularly parecoxib), which plausibly translates into a deep suppression of prostacyclin. Drug potency, that is, the degree of suppression of COX-2-dependent prostacyclin, is proposed to represent a strong determinant in the increased incidence of thrombotic events associated with the use of COX-2 inhibitors and some tNSAIDs.

Keywords::

• aspirin
• cardiovascular toxicity
• COX-2
• coxibs
• NSAIDS
• parecoxib
• prostacyclin
• thromboxane
• valdecoxib

Acknowledgements

ML Capone and S Tacconelli both contributed equally to this work. The authors wish to thank LA Garcia Rodriguez and MG Sciulli for valuable advice and suggestions, and G Santini for preparation of the manuscript. The authors are very grateful to all the students of the laboratory of pharmacodynamic at CeSI for their enthusiasm and competence in performing concentration–response curves for NSAIDs and eicosanoid analyses. Finally, the authors thank GA FitzGerald and C Patrono for having introduced them into the stimulating and important field of clinical pharmacology of cyclooxygenase inhibition.

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