Beyond heparin and warfarin: the new generation of anticoagulants

Abstract

Heparin and warfarin are widely used for the prevention and treatment of venous and arterial thromboembolism. Although effective, both agents have important limitations; for example, both drugs must be monitored, which is inconvenient for patients and for physicians. Heparin requires parenteral administration and can cause heparin-induced thrombocytopenia, an immune-mediated process that can lead to life-threatening thrombosis. Warfarin also has its limitations. Due to its slow onset of action, warfarin must be overlapped with heparin (or another rapidly acting anticoagulant) when treating patients with established thrombosis or who are at high risk for thrombosis. Warfarin dosing is variable because its activity is influenced by dietary intake of vitamin K, genetic polymorphisms in enzymes that are involved in its metabolism and numerous drug–drug interactions that promote or reduce its activity. New anticoagulants have been developed to overcome these problems. Building on a better understanding of coagulation pathways, advances in structure-based drug design and information derived from natural anticoagulants isolated from hematophagous organisms, most of the new anticoagulants target specific coagulation enzymes. Focussing on drugs that have at least completed Phase II evaluation, this article briefly reviews the coagulation pathways and its natural regulators; outlines the limitations of existing anticoagulants and identifies the opportunities for new ones; highlights the properties of selected new anticoagulants; describes the clinical trial results with these agents; and provides a perspective on their potential strengths and weaknesses.

Keywords::

• anticoagulants
• arterial thromboembolism
• direct thrombin inhibitors
• Factor Xa inhibitors
• pentasaccharides
• venous thromboembolism

Acknowledgements

This work was supported in part by Canadian Institutes of Health Research grants MOP 3992 and CTP 79846, Heart and Stroke Foundation of Ontario grants T4729 and T4730, and funds from the Ontario Research and Development Challenge Fund. J Weitz is the recipient of a Career Investigator Award from the Heart and Stroke Foundation of Ontario, the recipient of a Heart and Stroke Foundation of Ontario/J Fraser Mustard Chair in Cardiovascular Research and Canada Research Chair (tier 1) in Thrombosis at McMaster University.

Disclosure

J Weitz is a consultant for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, The Medicines Company, Bayer, Schering-Plough and Merck.

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