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Semin Thromb Hemost 2009; 35(5): 515-524
DOI: 10.1055/s-0029-1234147
© Thieme Medical Publishers

New Anticoagulants for Atrial Fibrillation

Magdalena Sobieraj-Teague1 , Martin O’Donnell1 , John Eikelboom1
  • 1McMaster University, Hamilton, Ontario, Canada
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Publication History

Publication Date:
08 September 2009 (online)

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ABSTRACT

Atrial fibrillation is already the most common clinically significant cardiac arrhythmia and a common cause of stroke. Vitamin K antagonists are very effective for the prevention of cardioembolic stroke but have numerous limitations that limit their uptake in eligible patients with AF and reduce their effectiveness in treated patients. Multiple new anticoagulants are under development as potential replacements for vitamin K antagonists. Most are small synthetic molecules that target factor IIa (e.g., dabigatran etexilate, AZD-0837) or factor Xa (e.g., rivaroxaban, apixaban, betrixaban, DU176b, idrabiotaparinux). These drugs have minimal protein binding and predictable pharmacokinetics that allow fixed dosing without laboratory monitoring and are being compared with vitamin K antagonists or aspirin in phase III clinical trials. A new vitamin K antagonist (ATI-5923) with improved pharmacological properties compared with warfarin is also being evaluated in a phase III trial. None of the new agents have as yet been approved for clinical use.

KEYWORDS

Atrial fibrillation - anticoagulants - stroke - factor Xa inhibitor - direct thrombin inhibitor

REFERENCES

  • 1 Go A S, Hylek E M, Phillips K A et al.. 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. 2001;  285(18) 2370-2375
    CrossrefPubMedGoogle Scholar
  • 2 Miyasaka Y, Barnes M E, Gersh B J 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(2) 119-125
    CrossrefPubMedGoogle Scholar
  • 3 Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.  Arch Intern Med. 1994;  154(13) 1449-1457
    CrossrefPubMedGoogle Scholar
  • 4 Wolf P A, Abbott R D, Kannel W B. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.  Stroke. 1991;  22(8) 983-988
    CrossrefPubMedGoogle Scholar
  • 5 Dulli D A, Stanko H, Levine R L. Atrial fibrillation is associated with severe acute ischemic stroke.  Neuroepidemiology. 2003;  22(2) 118-123
    CrossrefPubMedGoogle Scholar
  • 6 Lin H J, Wolf P A, Kelly-Hayes M et al.. Stroke severity in atrial fibrillation. The Framingham Study.  Stroke. 1996;  27(10) 1760-1764
    CrossrefPubMedGoogle Scholar
  • 7 Wolf P A, Mitchell J B, Baker C S, Kannel W B, D’Agostino R B. Impact of atrial fibrillation on mortality, stroke, and medical costs.  Arch Intern Med. 1998;  158(3) 229-234
    CrossrefPubMedGoogle Scholar
  • 8 Hart R G, Pearce L A, Aguilar M I. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation.  Ann Intern Med. 2007;  146(12) 857-867
    CrossrefPubMedGoogle Scholar
  • 9 Lip G Y, Edwards S J. Stroke prevention with aspirin, warfarin and ximelagatran in patients with non-valvular atrial fibrillation: a systematic review and meta-analysis.  Thromb Res. 2006;  118(3) 321-333
    CrossrefPubMedGoogle Scholar
  • 10 Glazer N L, Dublin S, Smith N L et al.. Newly detected atrial fibrillation and compliance with antithrombotic guidelines.  Arch Intern Med. 2007;  167(3) 246-252
    CrossrefPubMedGoogle Scholar
  • 11 Hart R G, Benavente O, McBride R, Pearce L A. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.  Ann Intern Med. 1999;  131(7) 492-501
    PubMedGoogle Scholar
  • 12 Albers G W, Dalen J E, Laupacis A, Manning W J, Petersen P, Singer D E. Antithrombotic therapy in atrial fibrillation.  Chest. 2001;  119(1, suppl) 194S-206S
    CrossrefPubMedGoogle Scholar
  • 13 Go A S, Hylek E M, Borowsky L H, Phillips K A, Selby J V, Singer D E. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study.  Ann Intern Med. 1999;  131(12) 927-934
    PubMedGoogle Scholar
  • 14 Go A S, Hylek E M, Chang Y et al.. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice?.  JAMA. 2003;  290(20) 2685-2692
    CrossrefPubMedGoogle Scholar
  • 15 McCormick D, Gurwitz J H, Goldberg R J et al.. Prevalence and quality of warfarin use for patients with atrial fibrillation in the long-term care setting.  Arch Intern Med. 2001;  161(20) 2458-2463
    CrossrefPubMedGoogle Scholar
  • 16 Bradley B C, Perdue K S, Tisdel K A, Gilligan D M. Frequency of anticoagulation for atrial fibrillation and reasons for its non-use at a Veterans Affairs medical center.  Am J Cardiol. 2000;  85(5) 568-572
    CrossrefPubMedGoogle Scholar
  • 17 Bungard T J, Ghali W A, Teo K K, McAlister F A, Tsuyuki R T. Why do patients with atrial fibrillation not receive warfarin?.  Arch Intern Med. 2000;  160(1) 41-46
    CrossrefPubMedGoogle Scholar
  • 18 Jones M, McEwan P, Morgan C L, Peters J R, Goodfellow J, Currie C J. Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population.  Heart. 2005;  91(4) 472-477
    CrossrefPubMedGoogle Scholar
  • 19 Rose A J, Ozonoff A, Henault L E, Hylek E M. Warfarin for atrial fibrillation in community-based practise.  J Thromb Haemost. 2008;  6(10) 1647-1654
    CrossrefPubMedGoogle Scholar
  • 20 Shalev V, Rogowski O, Shimron O et al.. The interval between prothrombin time tests and the quality of oral anticoagulants treatment in patients with chronic atrial fibrillation.  Thromb Res. 2007;  120(2) 201-206
    CrossrefPubMedGoogle Scholar
  • 21 Hylek E M, Go A S, Chang Y et al.. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.  N Engl J Med. 2003;  349(11) 1019-1026
    CrossrefPubMedGoogle Scholar
  • 22 White H D, Gruber M, Feyzi J et al.. Comparison of outcomes among patients randomized to warfarin therapy according to anticoagulant control: results from SPORTIF III and V.  Arch Intern Med. 2007;  167(3) 239-245
    CrossrefPubMedGoogle Scholar
  • 23 Wienen W, Stassen J M, Priepke H, Ries U J, Hauel N. In-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate.  Thromb Haemost. 2007;  98(1) 155-162
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 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. 2007;  64(3) 292-303
    CrossrefPubMedGoogle Scholar
  • 25 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate.  Clin Pharmacokinet. 2008;  47(5) 285-295
    CrossrefPubMedGoogle Scholar
  • 26 Sanford M, Plosker G L. Dabigatran etexilate.  Drugs. 2008;  68(12) 1699-1709
    CrossrefPubMedGoogle Scholar
  • 27 Eriksson B I, Dahl O E, Rosencher N RE-MODEL Study Group 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. 2007;  5(11) 2178-2185
    CrossrefPubMedGoogle Scholar
  • 28 Eriksson B I, Dahl O E, Rosencher N RE-NOVATE Study Group et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.  Lancet. 2007;  370(9591) 949-956
    CrossrefPubMedGoogle Scholar
  • 29 Ginsberg J S, Davidson B L, Comp P C RE-MOBILIZE Writing Committee et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery.  J Arthroplasty. 2009;  24(1) 1-9
    CrossrefPubMedGoogle Scholar
  • 30 Ezekowitz M D, Reilly P A, Nehmiz G et al.. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study).  Am J Cardiol. 2007;  100(9) 1419-1426
    CrossrefPubMedGoogle Scholar
  • 31 Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects.  Eur J Clin Pharmacol. 2005;  61(12) 873-880
    CrossrefPubMedGoogle Scholar
  • 32 Weinz C, Schwartz T, Pleiss U. Metabolism and distribution of (14C) BAY 59-7939—an oral, direct factor Xa inhibitor—in rat, dog and human [abstract 196].  Drug Metab Rev. 2004;  36(suppl 1)
    PubMedGoogle Scholar
  • 33 Eriksson B I, Quinlan D J, Weitz J I. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development.  Clin Pharmacokinet. 2009;  48(1) 1-22
    CrossrefPubMedGoogle Scholar
  • 34 Kakkar A K, Brenner B, Dahl O E RECORD2 Investigators et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial.  Lancet. 2008;  372(9632) 31-39
    CrossrefPubMedGoogle Scholar
  • 35 Eriksson B I, Borris L C, Friedman R J RECORD1 Study Group et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.  N Engl J Med. 2008;  358(26) 2765-2775
    CrossrefPubMedGoogle Scholar
  • 36 Lassen M R, Ageno W, Borris L C RECORD3 Investigators et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.  N Engl J Med. 2008;  358(26) 2776-2786
    CrossrefPubMedGoogle Scholar
  • 37 Turpie A, Bauer K, Davidson B et al.. Comparison of ‘Xarelto’—an oral, direct factor Xa inhibitor and subcutaneous enoxaparin for thromboprophylaxis after total knee replacement (RECORD4: a phase 3 study). Paper presented at: European Federation of National Associations of Orthopaedics and Traumatology annual meeting May 29–June 1, 2008 Nice, France; Abstract F85
    PubMedGoogle Scholar
  • 38 Frost C, Yu Z, Nepal S. Apixaban, a direct factor Xa inhibitor: single-dose pharmacokinetics and pharmacodynamics of an intravenous formulation. Paper presented at: 37th American College of Chest Physicians annual meeting September 14–16, 2008 Philadelphia, PA;
    PubMedGoogle Scholar
  • 39 Raghavan N, Frost C E, Yu Z et al.. Apixaban metabolism and pharmacokinetics after oral administration to humans.  Drug Metab Dispos. 2009;  37(1) 74-81
    CrossrefPubMedGoogle Scholar
  • 40 Lassen M R, Davidson B L, Gallus A, Pineo G, Ansell J, Deitchman D. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement.  J Thromb Haemost. 2007;  5(12) 2368-2375
    CrossrefPubMedGoogle Scholar
  • 41 Buller H R. Late breaking clinical trial: a dose finding study of the oral direct factor xa inhibitor apixaban in the treatment of patients with acute symptomatic deep vein thrombosis – The Botticelli Investigators.  J Thromb Haemost. 2007;  5(suppl 2) , Abstract S-003
    PubMedGoogle Scholar
  • 42 Zafar M U, Vorchheimer D A, Gaztanaga J et al.. Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber.  Thromb Haemost. 2007;  98(4) 883-888
    PubMedGoogle Scholar
  • 43 Walenga J M, Jeske W P, Fareed J. Short- and long-acting synthetic pentasaccharides as antithrombotic agents.  Expert Opin Investig Drugs. 2005;  14(7) 847-858
    CrossrefPubMedGoogle Scholar
  • 44 Herbert J M, Hérault J P, Bernat A et al.. Biochemical and pharmacological properties of SANORG 34006, a potent and long-acting synthetic pentasaccharide.  Blood. 1998;  91(11) 4197-4205
    PubMedGoogle Scholar
  • 45 Trellu M, Perez Y, Ortiz J, Cheng S, Paty I. Bioequipotency of idraparinux and biotinylated idraparinux after single dose in healthy subjects.  , [Abstract P-T-678] J Thromb Haemost. 2007;  5(suppl 1) , Abstract P-T-678
    PubMedGoogle Scholar
  • 46 Buller H R, Destors J, Gallus A S, Prins M H, Raskob G E. Idrabiotaparinux, a biotinylated long-acting anticoagulant, in the treatment of deep venous thrombosis (EQUINOX study): safety, efficacy, and reversibility by avidin. Paper presented at: American Society of Hematology 2008 San Francisco, CA;
    PubMedGoogle Scholar
  • 47 Buller H R, Cohen A T, Davidson B van Gogh Investigators et al. Idraparinux versus standard therapy for venous thromboembolic disease.  N Engl J Med. 2007;  357(11) 1094-1104
    CrossrefPubMedGoogle Scholar
  • 48 Bousser M G, Bouthier J, Büller H R Amadeus Investigators et al. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial.  Lancet. 2008;  371(9609) 315-321
    CrossrefPubMedGoogle Scholar
  • 49 Ezekowitz M D, Milner P, Ellis D et al.. The utility of genotyping in the first evaluation of a novel vitamin K antagonist: ATI-5923.  Circulation. 2008;  118(Suppl 885) , Abstract 4415
    PubMedGoogle Scholar

Dr. Magdalena Sobieraj-Teague

Hamilton General Hospital

Level 7, Room 714, 237 Barton Street East, Hamilton, Ontario, L8L 2X2 Canada

Email: teaguem@mcmaster.ca

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