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  • Review Article
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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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References

  1. Garcia, D. A., Baglin, T. P., Weitz, J. I. & Samama, M. M. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141 (2 Suppl.), e24S–e43S (2012).

    Article  CAS  Google Scholar 

  2. Lee, C. J. & Ansell, J. E. Direct thrombin inhibitors. Br. J. Clin. Pharmacol. 72, 581–592 (2011).

    Article  CAS  Google Scholar 

  3. Eriksson, B. I. et al. Prevention of thromboembolism with use of recombinant hirudin: results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having total hip replacement. J. Bone Joint Surg. Am. 79, 326–333 (1997).

    Article  CAS  Google Scholar 

  4. Eriksson, B. I. et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N. Engl. J. Med. 337, 1329–1335 (1997).

    Article  CAS  Google Scholar 

  5. Greinacher, A. & Warkentin, T. E. The direct thrombin inhibitor hirudin. Thromb. Haemost. 99, 819–829 (2008).

    Article  CAS  Google Scholar 

  6. Warkentin, T. E., Greinacher, A. & Koster, A. Bivalirudin. Thromb. Haemost. 99, 830–839 (2008).

    Article  CAS  Google Scholar 

  7. Witting, J. I., Bourdon, P., Brezniak, D. V., Maraganore, J. M. & Fenton, J. W. 2nd Thrombin-specific inhibition by and slow cleave of hirulog-1. Biochem. J. 283, 737–743 (1992).

    Article  CAS  Google Scholar 

  8. White, H. D. Pharmacological and clinical profile of bivalirudin in the treatment of patients with acute coronary syndrome. Expert Opin. Drug Metab. Toxicol. 5, 529–538 (2009).

    Article  CAS  Google Scholar 

  9. Koster, A. et al. An assessment of different filter systems for extracorporeal elimination of bivalirudin: an in vitro study. Anesth. Analg. 96, 1316–1319 (2003).

    Article  CAS  Google Scholar 

  10. Jeske, W. P., Fareed, J., Hoppensteadt, D. A., Lewis, B. & Walenga, J. M. Pharmacology of argatroban. Expert Rev. Hematol. 3, 527–539 (2010).

    Article  CAS  Google Scholar 

  11. Hursting, M. J. et al. Novastan (brand of argatroban): a small-molecule, direct thrombin inhibitor. Semin. Thromb. Hemost. 23, 503–516 (1997).

    Article  CAS  Google Scholar 

  12. Sciulli, T. M. & Mauro, V. F. Pharmacology and clinical use of bivalirudin. Ann. Pharmacother. 36, 1028–1041 (2002).

    Article  CAS  Google Scholar 

  13. Hirsh, J. Heparin. N. Engl. J. Med. 324, 1565–1574 (1993).

    Google Scholar 

  14. Hirsh, J., Anand, S. S., Halperin, J. L. & Fuster, V. Guide to anticoagulant therapy: heparin. A statement for healthcare professionals from the American Heart Association. Circulation 103, 2994–3018 (2001).

    Article  CAS  Google Scholar 

  15. Walenga, J. M. et al. Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia. Thromb. Res. 105, 401–405 (2002).

    Article  CAS  Google Scholar 

  16. Shantsila, E., Lip, G. Y. & Chong, B. H. Heparin-induced thrombocytopenia: a contemporary clinical approach to diagnosis and management. Chest 135, 1651–1664 (2009).

    Article  CAS  Google Scholar 

  17. Bittl, J. A. et al. Treatment with bivalirudin (hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N. Engl. J. Med. 333, 764–769 (1995).

    Article  CAS  Google Scholar 

  18. Bittl, J. A. et al. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am. Heart J. 142, 952–959 (2001).

    Article  CAS  Google Scholar 

  19. Lincoff, A. M. et al. Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET). Am. Heart J. 143, 847–853 (2002).

    Article  CAS  Google Scholar 

  20. Lincoff, A. M. et al. Comparison of bivalirudin versus heparin during percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to reduced Clinical Events [REPLACE]-1 trial). Am. J. Cardiol. 93, 1092–1096 (2004).

    Article  CAS  Google Scholar 

  21. Lincoff, A. M. et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 289, 853–863 (2003).

    Article  CAS  Google Scholar 

  22. Lincoff, A. M. et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 292, 696–703 (2004).

    Article  CAS  Google Scholar 

  23. Cohen, D. J. et al. Economic evaluation of bivalirudin with provisional glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial. J. Am. Coll. Cardiol. 44, 1792–1800 (2004).

    CAS  PubMed  Google Scholar 

  24. Kastrati, A. et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N. Engl. J. Med. 359, 688–696 (2008).

    Article  CAS  Google Scholar 

  25. Parodi, G. et al. Comparison of bivalirudin and unfractionated heparin plus protamine in patients with coronary heart disease undergoing percutaneous coronary intervention (from the Antithrombotic Regimens aNd Outcome [ARNO] trial). Am. J. Cardiol. 105, 1053–1059 (2010).

    Article  CAS  Google Scholar 

  26. Tavano, D. et al. Comparison of bivalirudin monotherapy versus unfractionated heparin plus tirofiban in patients with diabetes mellitus undergoing elective percutaneous coronary intervention. Am. J. Cardiol. 104, 1222–1228 (2009).

    Article  CAS  Google Scholar 

  27. Kastrati, A. et al. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N. Engl. J. Med. 365, 1980–1989 (2011).

    Article  Google Scholar 

  28. Ebrahimi, R. et al. Bivalirudin vs heparin in percutaneous coronary intervention: a pooled analysis. J. Cardiovasc. Pharmacol. Therapeut. 10, 209–216 (2005).

    Article  CAS  Google Scholar 

  29. Chew, D. P. et al. Bivalirudin provides increasing benefit with decreasing renal function: a meta-analysis of randomized trials. Am. J. Cardiol. 92, 919–923 (2003).

    Article  CAS  Google Scholar 

  30. Stone, G. W. et al. Bivalirudin for patients with acute coronary syndromes. N. Engl. J. Med. 355, 2203–2216 (2006).

    Article  CAS  Google Scholar 

  31. Stone, G. W. et al. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial. JAMA 298, 2497–2506 (2007).

    Article  CAS  Google Scholar 

  32. Pinto, D. S. et al. Economic evaluation of bivalirudin with or without glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for early invasive management of acute coronary syndromes. J. Am. Coll. Cardiol. 52, 1758–1768 (2008).

    Article  CAS  Google Scholar 

  33. Stone, G. W. et al. Bivalirudin during primary PCI in acute myocardial infarction. N. Engl. J. Med. 358, 2218–2230 (2008).

    Article  CAS  Google Scholar 

  34. Mehran, R. et al. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet 374, 1149–1159 (2009).

    Article  Google Scholar 

  35. Stone, G. W. et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomised controlled trial. Lancet 377, 2193–2204 (2011).

    Article  CAS  Google Scholar 

  36. Witzenbichler, B. et al. Impact of diabetes mellitus on the safety and effectiveness of bivalirudin in patients with acute myocardial infarction undergoing primary angioplasty: analysis from the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial. JACC Cardiovasc. Interv. 4, 760–768 (2011).

    Article  Google Scholar 

  37. Cortese, B. et al. Comparison of prolonged bivalirudin infusion versus intraprocedural in preventing myocardial damage after percutaneous coronary intervention in patients with angina pectoris. Am. J. Cardiol. 104, 1063–1068 (2009).

    Article  CAS  Google Scholar 

  38. Cortese, B. et al. Effect of prolonged bivalirudin infection on ST-segment resolution following percutaneous coronary intervention (from the PROBI VIRI 2 study). Am. J. Cardiol. 108, 1220–1224 (2011).

    Article  CAS  Google Scholar 

  39. Dangas, G. D. et al. Effect of switching antithrombin agents for primary angioplasty in acute myocardial infarction: the HORIZONS-SWITCH analysis. J. Am. Coll. Cardiol. 57, 2309–2316 (2011).

    Article  CAS  Google Scholar 

  40. Koutouzis, M. et al. Unfractionated heparin administration in patients treated with bivalirudin during primary percutaneous coronary intervention is associated lower mortality and target lesion thrombosis: a report from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Heart 97, 1484–1488 (2011).

    Article  CAS  Google Scholar 

  41. Kessler, D. P., Kroch, E. & Hlatky, M. A. The effect of bivalirudin on costs and outcomes of treatment of ST-segment elevation myocardial infarction. Am. Heart J. 162, 494–500.e2 (2011).

    Article  CAS  Google Scholar 

  42. Lee, M. S. et al. Comparison of bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitors in patients undergoing an invasive strategy: a meta-analysis of randomized clinical trials. Int. J. Cardiol. 152, 369–374 (2011).

    Article  Google Scholar 

  43. De Luca, G., Cassetti, E., Verdoia, M. & Marino, P. Bivalirudin as compared to unfractionated heparin among patients undergoing coronary angioplasty: a meta-analysis of randomized trials. Thromb. Haemost. 102, 428–436 (2009).

    Article  CAS  Google Scholar 

  44. Lewis, B. E. et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 103, 1838–1843 (2001).

    Article  CAS  Google Scholar 

  45. Lewis, B. E. et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch. Intern. Med. 163, 1849–1856 (2003).

    Article  CAS  Google Scholar 

  46. Lewis, B. E. et al. Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Catheter. Cardiovasc. Interv. 57, 177–184 (2002).

    Article  Google Scholar 

  47. Hirahara, T. et al. Prospective randomized study of argatroban versus heparin anticoagulation therapy after percutaneous coronary intervention for acute myocardial infarction [Japanese]. J. Cardiol. 44, 47–52 (2004).

    PubMed  Google Scholar 

  48. Rössig, L. et al. Argatroban for elective percutaneous coronary intervention: the ARG-E04 multi-center study. Int. J. Cardiol. 148, 214–219 (2011).

    Article  Google Scholar 

  49. LaMonte, M. P. et al. Argatroban anticoagulation in patients with acute ischemic stroke (ARGIS-1): a randomized, placebo-controlled safety study. Stroke 35, 1677–1682 (2004).

    Article  CAS  Google Scholar 

  50. Hankey, G. J. & Eikelboom, J. W. Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 123, 1436–1450 (2011).

    Article  Google Scholar 

  51. Testa, L. et al. The direct thrombin inhibitor ximelagatran/melagatran: A systematic review on clinical applications and an evidence based assessment of risk benefit profile. Expert Opin. Drug Saf. 6, 397–406 (2007).

    Article  CAS  Google Scholar 

  52. Eriksson, B. I., Quinlan, D. J. & Eikelboom, J. W. Novel oral factor Xa and thrombin inhibitors in the management of thromboembolism. Annu. Rev. Med. 62, 41–57 (2011).

    Article  CAS  Google Scholar 

  53. Stangier, J., Rathgen, K., Stähle, H., Gansser, D. & Roth, W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br. J. Clin. Pharmacol. 64, 292–303 (2007).

    Article  CAS  Google Scholar 

  54. van Ryn, J. et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb. Haemost. 103, 1116–1127 (2010).

    Article  CAS  Google Scholar 

  55. The European Agency for the Evaluation of Medicinal Products: Committee for Proprietary Medicinal Products. Points to consider on clinical investigation of medicinal products for prophylaxis of intra and post-operative venous thromboembolic risk. Guideline CPMP/EWP/707/98 [online], (2000).

  56. Eriksson, B. I. et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 370, 949–956 (2007).

    Article  CAS  Google Scholar 

  57. Eriksson, B. I. et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II): a randomised, double-blind, non-inferiority trial. Thromb. Haemost. 105, 721–729 (2011).

    Article  CAS  Google Scholar 

  58. Eriksson, B. I. et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J. Thromb. Haemost. 5, 2178–2185 (2007).

    Article  CAS  Google Scholar 

  59. RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J. Arthroplasty 24, 1–9 (2009).

  60. Friedman, R. J. et al. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb. Res. 126, 175–182 (2010).

    Article  CAS  Google Scholar 

  61. Schulman, S. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N. Engl. J. Med. 361, 2342–2352 (2009).

    Article  CAS  Google Scholar 

  62. Schulman, S. et al. A randomized trial of dabigatran versus warfarin in the treatment of acute venous thromboembolism (RE-COVER II) [abstract 205]. Presented at the 53rd American Society of Hematology Annual Meeting and Exposition (2011).

  63. Schulman, S. et al. Dabigatran or warfarin for extended maintenance therapy of venous thromboembolism [abstract O-TH-033]. Presented at the 23rd Congress of the International Society on Thrombosis and Haemostasis (2011).

  64. Schulman, S. et al. Dabigatran versus placebo for extended maintenance therapy of venous thromboembolism [abstract O-MO-037]. Presented at the 23rd Congress of the International Society on Thrombosis and Haemostasis (2011).

  65. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N. Engl. J. Med. 363, 2499–2510 (2010).

  66. Connolly, S. J. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, 1139–1151 (2009).

    Article  CAS  Google Scholar 

  67. Connolly, S. J. et al. Newly identified events in the RE-LY trial. N. Engl. J. Med. 363, 1875–1876 (2010).

    Article  CAS  Google Scholar 

  68. Hurlen, M., Abdelnoor, M., Smith, P., Erikssen, J. & Arnesen, H. Warfarin, aspirin or both after myocardial infarction. N. Engl. J. Med. 347, 969–974 (2002).

    Article  CAS  Google Scholar 

  69. Lip, G. Y. & Lane, D. A. Does warfarin for stroke thromboprophylaxis protect against MI in atrial fibrillation patients? Am. J. Med. 123, 785–789 (2010).

    Article  CAS  Google Scholar 

  70. Granger, C. B. et al. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365, 981–992 (2011).

    Article  CAS  Google Scholar 

  71. Patel, M. R. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 365, 883–891 (2011).

    Article  CAS  Google Scholar 

  72. Eikelboom, J. W. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. Circulation 123, 2363–2372 (2011).

    Article  CAS  Google Scholar 

  73. Shah, S. V. & Gage, B. F. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation 123, 2562–2570 (2011).

    Article  Google Scholar 

  74. Oldgren, J. et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur. Heart J. 32, 2781–2789 (2011).

    Article  CAS  Google Scholar 

  75. Uchino, K. & Hernandez, A. V. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch. Intern. Med. 172, 397–402 (2012).

    Article  CAS  Google Scholar 

  76. Hohnloser, S. H. et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation 125, 669–676 (2012).

    Article  CAS  Google Scholar 

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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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