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Direct thrombin inhibitors in cardiovascular disease

Abstract

Limitations of commonly used anticoagulants, unfractionated heparin, low-molecular-weight heparin, and oral vitamin K antagonists have prompted the development of alternative therapies. Direct thrombin inhibitors are a new class of anticoagulants that bind directly to thrombin and inhibit its interaction with substrates. In this Review, we critically examine the evidence from randomized controlled trials for the efficacy and safety of the parenteral direct thrombin inhibitors bivalirudin and argatroban, and the novel oral direct thrombin inhibitor dabigatran etexilate, in cardiovascular and thrombotic disease.

Key Points

  • Bivalirudin is an effective and safer alternative to heparin with or without the addition of a glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes or those undergoing percutaneous coronary intervention

  • Argatroban seems to be a viable treatment for patients with heparin-induced thrombocytopenia, but its role in treating other conditions remains uncertain

  • Dabigatran is an attractive alternative to low-molecular-weight heparin for the prevention of venous thromboembolism in patients undergoing major orthopedic surgery, and to warfarin for the long-term treatment of venous thromboembolism

  • The most-compelling indication for dabigatran is as an alternative to warfarin for stroke prevention in patients with atrial fibrillation, where it has been shown to reduce morbidity and mortality

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Figure 1: Trials of bivalirudin in patients undergoing PCI.
Figure 2: Trials of bivalirudin in patients with non-ST-segment elevation myocardial infarction ACS.
Figure 3: Trials of bivalirudin in patients with ST-segment elevation myocardial infarction acute coronary syndrome.
Figure 4: Trials of argatroban in patients with HIT.
Figure 5: Trials of dabigatran in the prevention of venous thromboembolism.
Figure 6: Trials of dabigatran in the prevention of stroke and thromboembolism in patients with atrial fibrillation.

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K. Arsenault and J. Eikelboom researched the data for the article. All the authors contributed substantially to discussion of its contents, writing the manuscript, and reviewing/editing it before submission.

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Correspondence to Kyle A. Arsenault.

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Competing interests

R. P. Whitlock declares that he is a member of the speakers' bureau of AstraZeneca and Boehringer Ingelheim. In addition, he has received grant or research support from Boehringer Ingelheim. J. W. Eikelboom declares the he is a member of the speakers' bureau and has received grant or research support from each of the following companies: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol–Myers Squibb, Eli Lilly, Johnson & Johnson, Pfizer, and Sanofi. K. A. Arsenault and J. Hirsh declare no competing interests.

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Arsenault, K., Hirsh, J., Whitlock, R. et al. Direct thrombin inhibitors in cardiovascular disease. Nat Rev Cardiol 9, 402–414 (2012). https://doi.org/10.1038/nrcardio.2012.61

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