Journal of Thrombosis and Thrombolysis

, Volume 39, Issue 3, pp 264–272 | Cite as

Anticoagulation therapy in 2015: where we are and where we are going



Oral anticoagulants are a mainstay for the prevention and treatment of venous and arterial thrombosis. In 2015, the non-vitamin K oral anticoagulants (NOACs) are already replacing warfarin for many indications. Ongoing studies are focused on development of antidotes and specific reversal agents for the NOACs, and assessing their utility for prevention of cardiovascular events in patients with heart failure, coronary or peripheral artery disease, or embolic stroke of unknown source. This paper (a) lists the current indications for the NOACs; (b) reviews the current impact of the NOACs in each of these indications; (c) outlines future opportunities for the NOACs, and (e) provides perspective on new anticoagulant strategies that may be safer than the NOACs.


Anticoagulants Dabigatran Rivaroxaban Apixaban Antidotes Non-vitamin K oral anticoagulants 


  1. 1.
    Raskob GE, Angchaisuksiri P, Bianco AN, Buller H, Gallus A, Hunt BJ, Hylek EM, Kakkar A, Konstantinides SV, McCumber M, Ozaki Y, Wendelboe A, Weitz JI (2014) Thrombosis: a major contributor to the global disease burden. J Thromb Haemost 12:1580–1590CrossRefGoogle Scholar
  2. 2.
    Ruff C, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383:955–962CrossRefPubMedGoogle Scholar
  3. 3.
    Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE (2001) Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 285:2370–2375CrossRefPubMedGoogle Scholar
  4. 4.
    Kim S (2008) Changes in surgical loads and economic burden of hip and knee replacements in the US: 1997–2004. Arthritis Rheum 59:481–483CrossRefPubMedGoogle Scholar
  5. 5.
    Kurtz S, Ong K, Lau E, Mowat F, Halpern M (2007) Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am 89:780–785CrossRefPubMedGoogle Scholar
  6. 6.
    Colwell CW, Collis DK, Paulson R, McCutchen JW, Bigler GT, Lutz S, Hardwick ME (1999) Comparison of enoxaparin and warfarin for the prevention of venous thromboembolic disease after total hip arthroplasty. Evaluation during hospitalization and three months after discharge. J Bone Joint Surg Am 81:932–940CrossRefPubMedGoogle Scholar
  7. 7.
    Leclerc JR, Gent M, Hirsh J, Geerts WH, Ginsberg JS (1998) The incidence of symptomatic venous thromboembolism during and after prophylaxis with enoxaparin: a multi-institutional cohort study of patients who underwent hip or knee arthroplasty. Canadian Collaborative Group. Arch Intern Med 158:873–878CrossRefPubMedGoogle Scholar
  8. 8.
    Friedman RJ, Gallus AS, Cushner FD, Fitzgerald G, Anderson FA, Global Orthopedic Registry Investigators (2008) Physician compliance with guidelines for deep-vein thrombosis prevention in total hip and knee arthroplasty. Curr Med Res Opin 24:87–89CrossRefPubMedGoogle Scholar
  9. 9.
    Warwick D, Friedman RJ, Agnelli G, Gil-Garay E, Johnson K, FitzGerald G, Turibio FM (2007) Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events; findings from the Global Orthopedic Registry. J Bone Joint Surg Br 89:799–807CrossRefPubMedGoogle Scholar
  10. 10.
    Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S, Ortel TL, Pauker SG, Colwell CW, American College of Chest Physicians (2012) Prevention of VTE in orthopaedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th Ed.: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 141:e278S–e325SCrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Loke YK, Kwok CS (2011) Dabigatran and rivaroxaban for prevention of venous thromboembolism—systematic review and adjusted indirect comparison. J Clin Pharm Ther 36:111–124CrossRefPubMedGoogle Scholar
  12. 12.
    Raskob GE, Gallus AS, Pineo GF, Chen D, Ramirez LM, Wright RT, Lassen MR (2012) Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint Surg Br 94:257–264CrossRefPubMedGoogle Scholar
  13. 13.
    Lassen MR, Raskob GE, Gallus AS, Pineo G, Chen D, Portman RJ (2009) Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 361:594–604CrossRefPubMedGoogle Scholar
  14. 14.
    Duran A, Senggupta N, Diamantopoulos A, Forster F, Kwong L, Lees M (2012) Cost effectiveness of rivaroxaban versus enoxaparin for prevention of post-surgical venous thromboembolism from a U.S. payer’s perspective. Pharmacoeconomics 30:87–101CrossRefPubMedGoogle Scholar
  15. 15.
    Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR, American College of Chest Physicians (2012) Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention and thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 141:e419S–e945SCrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Kearon C (2003) Natural history of venous thromboembolism. Circulation 107:122–130CrossRefGoogle Scholar
  17. 17.
    Spyropoulos AC, Lin J (2007) Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations. J Manag Care Pharm 13:475–486PubMedGoogle Scholar
  18. 18.
    Lefebvre P, Coleman CI, Bookhart BK, Wang ST, Mody SH, Tran KN, Zhuo DY, Huynh L, Nutescu EA (2014) Cost-effectiveness of rivaroxaban compared with enoxaparin plus a vitamin K antagonist for the treatment of venous thromboembolism. J Med Econ 17(1):52–64CrossRefPubMedGoogle Scholar
  19. 19.
    Bamber L, Wang MY, Prins MH, Ciniglio C, Bauersachs R, Lensing AW, Cano SJ (2013) Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of acute symptomatic deep-vein thrombosis. Thromb Haemost 110(4):732–741CrossRefPubMedGoogle Scholar
  20. 20.
    Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ, RE-COVER Study Group (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361:2342–2362CrossRefPubMedGoogle Scholar
  21. 21.
    Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C, RE-COVER II Trial Investigators (2014) Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 129:764–772CrossRefPubMedGoogle Scholar
  22. 22.
    Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363:2499–2510CrossRefPubMedGoogle Scholar
  23. 23.
    Buller HR, Prins MH, Lensing AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux B, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A (2012) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 366:1287–1297CrossRefPubMedGoogle Scholar
  24. 24.
    Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI, AMPLIFY Investigators (2013) Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369:799–808CrossRefPubMedGoogle Scholar
  25. 25.
    Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369:1406–1415CrossRefPubMedGoogle Scholar
  26. 26.
    van der Hulle T, Kooiman J, den Exeter PL, Dekkers OM, Klok FA, Huisman MV (2014) 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 12:320–328CrossRefPubMedGoogle Scholar
  27. 27.
    Agnelli G, Buller HR, Cohe A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI, AMPLIFY-EXT Investigators (2013) Apixaban for extended treatment of venous thromboembolism. N Engl J Med 368:699–708CrossRefPubMedGoogle Scholar
  28. 28.
    Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ, RE-MEDY Trial Investigators (2013) Extended use of dabigatran, warfarin or placebo in venous thromboembolism. N Engl J Med 368:709–718CrossRefPubMedGoogle Scholar
  29. 29.
    Douxfils J, Buckinx F, Mullier F, Minet V, Rabenda V, Reginster JY, Hainaut P, Bruyere O, Dogne JM (2014) Dabigatran etexilate and risk of myocardial infarction, other cardiovascular events, major bleeding, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 3:e000515. doi:10.1161/JAHA.113.000515 CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, Sheu TC, Mott K, Goulding MR, Houstoun M, MaCurdy TE, Worrall C, Kelman JA (2014) Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for non-valvular atrial fibrillation. Circulation 74(11):1788–1795Google Scholar
  31. 31.
    Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB, Tsang TS (2006) Secular trends in incidence of atrial fibrillation in Olmstead County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 114:119–125CrossRefPubMedGoogle Scholar
  32. 32.
    Hart RG, Pearce LA, Aguilar MI (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 146:857–867CrossRefPubMedGoogle Scholar
  33. 33.
    Ogilvie IM, Newton N, Weiner SA, Cowell W, Lip GY (2010) Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med 123:638–645CrossRefPubMedGoogle Scholar
  34. 34.
    Camm AJ, Lip GY, DeCaterina R, Savelieva I, Atar D, Hohnioser SH, Hindricks G, Krichhof P, ESC Committee for Practice Guidelines (2012) 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 33:2719–2747CrossRefPubMedGoogle Scholar
  35. 35.
    You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, Hylek EM, Schulman S, Go AS, Hughes M, Spencer FA, Manning WJ, Halperin JL, Lip GY, American College of Chest Physicians (2012) Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 141:e531S–e575SCrossRefPubMedCentralPubMedGoogle Scholar
  36. 36.
    Skanes AC, Healey JS, Cairns JA, Dorian P, Gillis AM, McMurtry MS, Mitchell LB, Verma A, Nattel S, Canadian Cardiovascular Society Atrial Fibrillation Guidelines Committee (2012) Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol 28:125–136CrossRefPubMedGoogle Scholar
  37. 37.
    Harrington AR, Armstrong EP, Nolan PE Jr, Malone DC (2013) Cost-effectiveness of apixaban, dabigatran, rivaroxaban, and warfarin for stroke prevention in atrial fibrillation. Stroke 44:676–1681CrossRefGoogle Scholar
  38. 38.
    Hart RG, Diener HC, Yang S, Connolly SJ, Wallentin L, Reilly PA, Ezekowitz MD, Yusuf S (2012) Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with warfarin or dabigatran: the RE-LY Trial. Stroke 43:1511–1517CrossRefPubMedGoogle Scholar
  39. 39.
    Majeed A, Hwang HG, Connolly SJ, Eikelboom JW, Ezekowitz MD, Wallentin L, Brueckmann M, Fraessdorf M, Yusuf S, Schulman S (2013) Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation 128:2325–2332CrossRefPubMedGoogle Scholar
  40. 40.
    Hylek EM, Held C, Alexander JH, Lopes RD, DeCaterina R, Wojdyla DM, Huber K, Jansky P, Steg PG, Hanna M, Thomas L, Wallentin L, Granger CB (2014) Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: the ARISTOTLE Trial Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes. J Am Coll Cardiol 63:2141–2147CrossRefPubMedGoogle Scholar
  41. 41.
    Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, Sheu TC, Mott K, Goulding MR, Houstoun M, MaCurdy TE, Worrall C, Kelman JA (2015) Cardiovascular, bleeding and mortality risks in elderly medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 131(2):157–164CrossRefPubMedGoogle Scholar
  42. 42.
    Healey JS, Eikelboom J, Douketis J, Wallentin L, Oldgren J, Yang S, Themeles E, Heidbuchel H, Avezum A, Reilly P, Connolly SJ, Yusuf S, Ezekowitz M, RE-LY Investigators (2012) Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) randomized trial. Circulation 126:343–348CrossRefPubMedGoogle Scholar
  43. 43.
    Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, Nar H, Litzenburger T (2013) A specific antidote for dabigatran: functional and structural characterization. Blood 121:3554–3562CrossRefPubMedGoogle Scholar
  44. 44.
    Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, Luan P, Hutchaleelaha A, Inagaki M, Conley PB, Phillips DR, Sinha U (2013) A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 19:446–451CrossRefPubMedGoogle Scholar
  45. 45.
    Ansell J, Bakhru SH, Laulicht SS, Steiner SS, Grosso M, Brown K, Dishy V, Noveck RJ, Costin JC (2014) Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 371:2141–2142CrossRefPubMedGoogle Scholar
  46. 46.
    Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM, ATLAS ACS 2-TIMI 51 Investigators (2012) Varoxaban in patients with a recent acute coronary syndrome. N Engl J Med 366:9–19CrossRefPubMedGoogle Scholar
  47. 47.
    Weitz J (2014) Insights into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome. Thromb Haemost 112:924–931CrossRefPubMedGoogle Scholar
  48. 48.
    Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ, Sacco RL, Connolly SJ, Cryptogenic Stroke/ESUS International Working Group (2014) Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 3:429–438CrossRefGoogle Scholar
  49. 49.
    Yau JW, Liao P, Fredenburgh JC, Stafford AR, Revenko AS, Monia BP, Weitz JI (2014) Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. Blood 123:2102–2107CrossRefPubMedGoogle Scholar
  50. 50.
    Metafanov A, Leung PY, Gailani AE, Grach SL, Puy C, Cheng Q, Sun MF, McCarty OJ, Tucker EI, Kataoka H, Renne T, Morrissey JH, Gruber A, Gailani D (2014) Factor XII inhibition reduces thrombus formation in a primate thrombosis model. Blood 23:1739–1746CrossRefGoogle Scholar
  51. 51.
    Woodruff RS, Xu Y, Layzer J, Wu W, Ogletree ML, Sullenger BA (2013) Inhibiting the intrinsic pathway of coagulation with a factor XII-targeting RNA aptamer. J Thromb Haemost 11:1364–1373CrossRefPubMedGoogle Scholar
  52. 52.
    Buller HR, Bethune C, Bhanot S, Gailani D, Bonia BP, Raskob GE, Segers A, Verhamme P, Weitz JI, For the FXI-ASO TKA Investigators (2014) Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 372(3):232–240CrossRefPubMedGoogle Scholar
  53. 53.
    Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC (2013) National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardivasc Qual Outcomes 5:615–621CrossRefGoogle Scholar
  54. 54.
    Xu Y, Holbrook AM, Simpson CS, Dowlatshahi D, Johnson AP (2013) Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a population-based descriptive analysis. CMAJ Open 1:E115–E190CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Departments of Medicine and Biochemistry and Biomedical Sciences, The Thrombosis and Atherosclerosis Research InstituteMcMaster UniversityHamiltonCanada

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