Thromb Haemost 2017; 117(07): 1283-1288
DOI: 10.1160/TH16-10-0807
60th Anniversary
Schattauer GmbH

New developments in anticoagulants: Past, present and future

Jeffrey I. Weitz
1   Departments of Medicine and Biochemistry and Biomedical Sciences, McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
,
Job Harenberg
2   Medical Faculty Mannheim, Ruprecht-Karls University Heidelberg, Mannheim, Germany
› Author Affiliations
Further Information

Publication History

Received: 24 October 2016

Accepted after major revision: 09 January 2017

Publication Date:
11 November 2017 (online)

Summary

Thrombosis is a leading cause of death and disability worldwide, and anticoagulants are the mainstay of its prevention and treatment. Starting with unfractionated heparin (UFH) and vitamin K antagonists (VKAs) such as warfarin, the choices of anticoagulants have exploded in the past 20 years. With over 90% subcutaneous bioavailability, no need for coagulation monitoring and dose adjustment, and a lower risk of heparin-induced thrombocytopenia, low-molecular-weight heparin and fondaparinux have replaced UFH for prevention and initial treatment of venous thromboembolism and for secondary prevention in cancer patients. In patients undergoing percutaneous interventions, bivalirudin is often used instead of UFH. Oral anticoagulation therapy has advanced with the introduction of the non-vitamin K antagonist oral anticoagulants (NOACs), which include dabigatran, rivaroxaban, apixaban and edoxaban. With efficacy at least equal to that of VKAs but with greater safety and convenience, the NOACs are now replacing VKAs for many indications. This paper a) highlights these advances, b) outlines how specific reversal agents for the NOACs will enhance their safety, c) reviews some of the ongoing trials with the NOACs, and d) describes the inhibitors of factor XII and XI that are under investigation as anticoagulants.

 
  • References

  • 1 Wendelboe AM, Raskob GE. Global burden of thrombosis: Epidemiologic aspects. Circ Res 2016; 118: 1340-1347.
  • 2 Garcia DA, Baglin TP, Weitz JI. et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e24S-e43S.
  • 3 Ageno W, Gallus AS, Wittkowsky A. et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e44S-e88S.
  • 4 Weitz JI. Factor XI and factor XII as targets for new anticoagulants. Thromb Res 2016; 141 (Suppl. 02) S40-S45.
  • 5 Shah R, Rogers KC, Matin K. et al. An updated comprehensive meta-analysis of bivalirudin vs heparin use in primary percutaneous coronary intervention. Am Heart J 2016; 171: 14-24.
  • 6 Testa L, Bhindi R, Agostoni P. 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 2007; 6: 397-406.
  • 7 Chan NC, Eikelboom JW, Weitz JI. Evolving treatments for arterial and venous thrombosis: Role of the direct oral anticoagulants. Circ Res 2016; 118: 1409-1424.
  • 8 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383: 955-962.
  • 9 van der Hulle T, Kooiman J, den Exter PL. et al. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014; 12: 320-328.
  • 10 Li G, Holbrook A, Jin Y. et al. Comparison of treatment effect estimates of non-vitamin K antagonist oral anticoagulants versus warfarin between observational studies using propensity score methods and randomized controlled trials. Eur J Epidemiol 2016; 31: 541-561.
  • 11 Kirchhof P, Benussi S, Kotecha D. et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2016 Prepublished online
  • 12 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149: 315-352.
  • 13 Fay MR, Martins JL, Czekay B. Oral anticoagulant prescribing patterns for stroke prevention in atrial fibrillation among general practitioners and cardiologists in three European countries. ESC Congress 2016. ; Abstract P2597.
  • 14 Huisman MV, Rothman KJ, Paquette M. et al. Antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation: The GLORIA-AF registry, phase II. Am J Med 2015; 128: 1306-1313.
  • 15 Hsu JC, Maddox TM, Kennedy KF. et al. Oral anticoagulant therapy prescription in patients with atrial fibrillation across the spectrum of stroke risk: Insights from the NCDR PINNACLE registry. JAMA Cardiol 2016; 1: 55-62.
  • 16 Eikelboom JW, Quinlan DJ, van Ryn J. et al. Idarucizumab: The antidote for reversal of dabigatran. Circulation 2015; 132: 2412-2422.
  • 17 Glund S, Stangier J, Schmohl M. et al. Safety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trial. Lancet 2015; 386: 680-690.
  • 18 Pollack CV Jr, Reilly PA, Eikelboom J. et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373: 511-520.
  • 19 Lu G, DeGuzman FR, Hollenbach SJ. et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19: 446-551.
  • 20 Siegal DM, Curnutte JT, Connolly SJ. et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015; 373: 2413-2424.
  • 21 Connolly SJ, Milling TJ, Eikelboom JW. et al. Andexanet alfa for acute major bleeding associated with factor Xa Inhibitors. N Engl J Med 2016; 375: 1131-1141.
  • 22 Ansell JE, Bakhru SH, Laulicht BE. et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; 371: 2141-2142.
  • 23 Ansell JE, Laulicht BE, Bakhru SH. et al. Ciraparantag safely and completely reverses the anticoagulant effects of low molecular weight heparin. Thromb Res 2016; 146: 113-118.
  • 24 Hart RG, Diener HC, Coutts SB. et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13: 429-438.
  • 25 Mega JL, Braunwald E, Wiviott SD. et al ATLAS ACS 2-TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9-19.
  • 26 Cappato R Welsh R. Exploring unmet needs in venous and arterial thromboembolism with rivaroxaban. Thromb Haemost 2016; 116 (Suppl. 02) S2-S12.
  • 27 Simes J, Becattini C, Agnelli G. et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circ 2014; 130: 1062-1071.
  • 28 Weitz JI, Bauersachs R, Beyer-Westendorf J. et al. Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study. Thromb Haemost 2015; 114: 645-650.
  • 29 van Es N, Di Nisio M, Bleker SM. et al. Edoxaban for treatment of venous thromboembolism in patients with cancer. Rationale and design for the Hokusai VTE-cancer study. Thromb Haemost 2015; 114: 1268-1275.
  • 30 Gailani D, Bane CE, Gruber A. Factor XI and contact activation as targets for antithrombotic therapy. J Thromb Haemost 2015; 13: 1383-1395.
  • 31 Revenko AS, Gao D, Crosby JR. et al. Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. Blood 2011; 118: 5302-5311.
  • 32 Renné T, Gailani D. Role of Factor XII in hemostasis and thrombosis: clinical implications. Expert Rev Cardiovasc Ther 2007; 5: 733-741.
  • 33 Seligsohn U. Factor XI deficiency in humans. J Thromb Haemost 2009; 7 (Suppl. 01) 84-87.
  • 34 Yau JW, Liao P, Fredenburgh JC. et al. Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. Blood 2014; 123: 2102-2107.
  • 35 Zhang H, Lowenberg EC, Crosby JR. et al. Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. Blood 2010; 116: 4684-4692.
  • 36 Crosby JR, Marzec U, Revenko AS. et al. Antithrombotic effect of antisense factor XI oligonucleotide treatment in primates. Arterioscler Throm Vasc Biol 2013; 33: 1670-1678.
  • 37 Tucker EI, Marzec UM, White TC. et al. Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI. Blood 2009; 113: 936-944.
  • 38 Larsson M, Rayzman V, Nolte MW. et al. A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Sci Transl Med 2014; 6: 222ra217.
  • 39 David T, Kim YC, Ely LK. et al. Factor XIa-specific IgG and a reversal agent to probe factor XI function in thrombosis and hemostasis. Sci Transl Med 2016; 8: 353ra112.
  • 40 Woodruff RS, Xu Y, Layzer J. et al. Inhibiting the intrinsic pathway of coagulation with a factor XII-targeting RNA aptamer. J Thromb Haemost 2013; 11: 1364-1373.
  • 41 Deng H, Bannister TD, Jin L. et al. Synthesis, SAR exploration, and X-ray crystal structures of factor XIa inhibitors containing an alpha-ketothiazole arginine. Bioorg Med Chem Lett 2006; 16: 3049-3054.
  • 42 Wong PC, Crain EJ, Watson CA. et al. A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits. J Thromb Thrombolysis 2011; 32: 129-137.
  • 43 Quan ML, Wong PC, Wang C. et al. Tetrahydroquinoline derivatives as potent and selective factor XIa inhibitors. J Med Chem 2014; 57: 955-969.
  • 44 Al Horani RA, Ponnusamy P, Mehta AY. et al. Sulfated pentagalloylglucoside is a potent, allosteric, and selective inhibitor of factor XIa. J Med Chem 2013; 56: 867-878.
  • 45 Al Horani RA, Desai UR. Designing allosteric inhibitors of factor XIa. Lessons from the interactions of sulfated pentagalloylglucopyranosides. J Med Chem 2014; 57: 4805-4818.
  • 46 Buller HR, Bethune C, Bhanot S. et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372: 232-240.