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Thromb Haemost 2014; 111(04): 575-582
DOI: 10.1160/TH13-09-0803
Theme Issue Article
Schattauer GmbH

New oral anticoagulant agents – general features and outcomes in subsets of patients

Sam Schulman
1   Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, Canada
2   Karolinska Institutet, Stockholm, Sweden
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Further Information

Publication History

Received: 29 September 2013

Accepted after minor revision: 19 January 2013

Publication Date:
29 November 2017 (online)

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Summary

During the past four years the phase III trials on stroke prophylaxis in atrial fibrillation and on treatment of venous thromboembolism have been completed for four new oral anticoagulants – dabigatran, apixaban, edoxaban and rivaroxaban. The studies have revealed advantages in terms of a reduced risk of bleeding, most importantly of intracranial bleeding. These anticoagulants also have favourable pharmacokinetics, eliminating the need for routine laboratory monitoring and dose adjustments. There are, however, some differences between the drugs in certain subsets of patients, according to patient characteristics or to indication for treatment. These features are reviewed here. The management of patients in association with invasive procedures or major bleeding is also discussed. Finally, a strategy of how to select patients for warfarin or the new anticoagulants and thereafter possibly also among the latter is outlined.

Keywords

Thrombin inhibitor - Xa inhibitor - atrial fibrillation - venous thromboembolism
 

  • References

  • 1 Gage BF, Waterman AD, Shannon W. et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.. J Am Med Assoc 2001; 285: 2864-2870.
    CrossrefPubMedGoogle Scholar
  • 2 Camm AJ, Kirchhof P, Lip GY. et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).. Europace 2010; 12: 1360-1420.
    CrossrefPubMedGoogle Scholar
  • 3 Olesen JB, Torp-Pedersen C, Hansen ML. et al. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study.. Thromb Haemost 2012; 107: 1172-1179.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Miyasaka Y, Barnes ME, Gersh BJ. et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence.. Circulation 2006; 114: 119-125.
    CrossrefPubMedGoogle Scholar
  • 5 Krijthe BP, Kunst A, Benjamin EJ. et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060.. Eur Heart J 2013; 34: 2746-2751.
    CrossrefPubMedGoogle Scholar
  • 6 Mikkelsen AP, Lindhardsen J, Lip GY. et al. Female sex as a risk factor for stroke in atrial fibrillation: a nationwide cohort study.. J Thromb Haemost 2012; 10: 1745-1751.
    CrossrefPubMedGoogle Scholar
  • 7 Tse HF, Wang YJ, Ahmed Ai-Abdullah M. et al. Stroke prevention in atrial fibrillation--an Asian stroke perspective.. Heart Rhythm 2013; 10: 1082-1088.
    CrossrefPubMedGoogle Scholar
  • 8 Lip GY, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe.. Chest 2012; 142: 1489-1498.
    CrossrefPubMedGoogle Scholar
  • 9 Deitelzweig SB, Johnson BH, Lin J. et al. Prevalence of clinical venous throm-boembolism in the USA: current trends and future projections.. Am J Hematol 2011; 86: 217-220.
    CrossrefPubMedGoogle Scholar
  • 10 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation.. N Engl J Med 2009; 361: 1139-1151.
    CrossrefPubMedGoogle Scholar
  • 11 Granger CB, Alexander JH, McMurray JJ. et al. Apixaban versus warfarin in patients with atrial fibrillation.. N Engl J Med 2011; 365: 981-992.
    CrossrefPubMedGoogle Scholar
  • 12 Patel MR, Mahaffey KW, Garg J. et al. Rivaroxaban versus warfarin in nonvalvu-lar atrial fibrillation.. N Engl J Med 2011; 365: 883-891.
    CrossrefPubMedGoogle Scholar
  • 13 Giugliano RP, Ruff CT, Braunwald E. et al. Edoxaban versus warfarin in patients with atrial fibrillation.. N Engl J Med 2013; 369: 2093-2104.
    CrossrefPubMedGoogle Scholar
  • 14 The Hokusai-VTE Investigators.. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism.. N Engl J Med 2013; 369: 1406-1415.
    CrossrefPubMedGoogle Scholar
  • 15 Agnelli G, Buller HR, Cohen A. et al. Oral apixaban for the treatment of acute venous thromboembolism.. N Engl J Med 2013; 369: 799-808.
    CrossrefPubMedGoogle Scholar
  • 16 Bauersachs R, Berkowitz SD, Brenner B. et al. Oral rivaroxaban for symptomatic venous thromboembolism.. N Engl J Med 2010; 363: 2499-2510.
    CrossrefPubMedGoogle Scholar
  • 17 Buller HR, Prins MH, Lensing AW. et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.. N Engl J Med 2012; 366: 1287-1297.
    CrossrefPubMedGoogle Scholar
  • 18 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism.. N Engl J Med 2009; 361: 2342-2352.
    CrossrefPubMedGoogle Scholar
  • 19 Schulman S, Kearon C, Kakkar AK. et al. Extended use of dabigatran, warfarin or placebo in venous thromboembolism.. N Engl J Med 2013; 368: 709-718.
    CrossrefPubMedGoogle Scholar
  • 20 O’Neil WM, Welner SA, Lip GY. Do open label blinded outcome studies of novel anticoagulants versus warfarin have equivalent validity to those carried out under double-blind conditions?. Thromb Haemost 2013; 109: 497-503.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Banerjee A, Lane DA, Torp-Pedersen C. et al. Net clinical benefit of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus no treatment in a ‘real world’ atrial fibrillation population: A modelling analysis based on a nationwide cohort study.. Thromb Haemost 2012; 107: 584-589.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Eikelboom JW, Wallentin L, Connolly SJ. 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 2011; 123: 2363-2372.
    CrossrefPubMedGoogle Scholar
  • 24 Hori M, Connolly SJ, Zhu J. et al. Dabigatran versus warfarin: effects on ischaemic and haemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation.. Stroke 2013; 44: 1891-1896.
    CrossrefPubMedGoogle Scholar
  • 25 Dans AL, Connolly SJ, Wallentin L. et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial.. Circulation 2013; 127: 634-640.
    CrossrefPubMedGoogle Scholar
  • 26 Agnelli G, Buller HR, Cohen A. et al. Apixaban for extended treatment of venous thromboembolism.. N Engl J Med 2013; 368: 699-708.
    CrossrefPubMedGoogle Scholar
  • 27 Eikelboom JW, Connolly SJ, Brueckmann M. et al. Dabigatran versus warfarin in patients with mechanical heart valves.. N Engl J Med 2013; 369: 1206-1214.
    CrossrefPubMedGoogle Scholar
  • 28 Healey JS, Eikelboom J, Douketis J. et al. Periprocedural bleeding and throm-boembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial.. Circulation 2012; 126: 343-348.
    CrossrefPubMedGoogle Scholar
  • 29 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate-- a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity.. Thromb Haemost 2010; 103: 1116-1127.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Khadzhynov D, Wagner F, Formella S. et al. Effective elimination of dabigatran by haemodialysis. A phase I single-centre study in patients with end-stage renal disease.. Thromb Haemost 2013; 109: 596-605.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Stangier J, Rathgen K, Stahle H. et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study.. Clin Pharmacokinet 2010; 49: 259-268.
    CrossrefPubMedGoogle Scholar
  • 32 Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in a life-threatening bleed occurring during cardiac ablation with factor eight inhibitor bypassing activity.. Crit Care Med 2013; 41: e42-e46.
    CrossrefPubMedGoogle Scholar
  • 33 Schulman S, Ritchie B, Goy JK. et al. Activated prothrombin complex concentrate for dabigatran-associated bleeding.. Br J Haematol 2014; 164: 308-310.
    CrossrefPubMedGoogle Scholar
  • 34 Schiele F, van Ryn J, Canada K. et al. A specific antidote for dabigatran: functional and structural characterisation.. Blood 2013; 121: 3554-3562.
    CrossrefPubMedGoogle Scholar
  • 35 Crowther M, Mathur V, Kitt M. et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced antico-agulation in healthy subjects by andexanet alfa (PRT064445), an antidote for FXa inhibitors.. Blood. 2013 122. Abstract 3636.
    PubMedGoogle Scholar
  • 36 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: 446-451.
    CrossrefPubMedGoogle Scholar
  • 37 Majeed A, Hwang H-G, Connolly S. et al. Management and outcomes of major bleeding on dabigatran or warfarin.. Circulation. 2013 epub ahead of print.
    PubMedGoogle Scholar
  • 38 Wallentin L, Yusuf S, Ezekowitz MD. et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.. Lancet 2010; 376: 975-983.
    CrossrefPubMedGoogle Scholar
  • 39 Blech S, Ebner T, Ludwig-Schwellinger E. et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans.. Drug Metab Dis- pos 2008; 36: 386-399.
    CrossrefPubMedGoogle Scholar
  • 40 Weinz C, Schwarz T, Kubitza D. et al. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans.. Drug Metab Dis-pos 2009; 37: 1056-1064.
    CrossrefPubMedGoogle Scholar
  • 41 Hohnloser SH, Oldgren J, Yang S. et al. Myocardial ischaemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial.. Circulation 2012; 125: 669-676.
    CrossrefPubMedGoogle Scholar
  • 42 Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of non-inferiority randomized controlled trials.. Arch Intern Med 2012; 172: 397-402.
    CrossrefPubMedGoogle Scholar
  • 43 Larsen TB, Rasmussen LH, Skjoth F. et al. Efficacy and safety of dabigatran etex-ilate and warfarin in ‘real world’ patients with atrial fibrillation: A prospective nationwide cohort study.. J Am Coll Cardiol 2013; 61: 2264-2273.
    CrossrefPubMedGoogle Scholar