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Thromb Haemost 2016; 115(02): 257-270
DOI: 10.1160/th15-02-0181
Review Article
Schattauer GmbH

Incorporating edoxaban into the choice of anticoagulants for atrial fibrillation

Jeffrey I. Weitz
1   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
2   Biochemistry and Medical Sciences, McMaster University, Hamilton, Ontario, Canada
3   Thrombosis and Atherosclerosis Research Institute, McMaster University Hamilton, Ontario, Canada
,
John Eikelboom
1   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
3   Thrombosis and Atherosclerosis Research Institute, McMaster University Hamilton, Ontario, Canada
› Author Affiliations
Further Information

Publication History

Received: 27 February 2015

Accepted after major revision: 10 September 2015

Publication Date:
21 November 2017 (online)

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Summary

The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for stroke prevention in many patients with nonvalvular atrial fibrillation. Edoxaban, an oral factor Xa inhibitor, is the newest entrant in this class. Results of the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE AF) study demonstrate that edoxaban is noninferior to warfarin for prevention of stroke and systemic embolic events, and is associated with significantly less major bleeding, including intracranial bleeding, and reduced cardiovascular mortality. With a net clinical benefit over warfarin, edoxaban is well positioned as a choice among the NOACs, which include dabigatran, rivaroxaban, and apixaban. But how will clinicians choose amongst them? The purpose of this paper is to (a) place the ENGAGE AF trial results into context with results of the studies with the other NOACs, and (b) aid clinicians in selection of the right anticoagulant for the right atrial fibrillation patient.

Keywords

Anticoagulant - atrial fibrillation - edoxaban - non-vitamin K oral anticoagulants
 

  • References

  • 1 Wolf PA. et al. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991; 22: 983-988.
    CrossrefPubMedGoogle Scholar
  • 2 McGrath ER. et al. Association of atrial fibrillation with mortality and disability after ischaemic stroke. Neurology 2013; 81: 825-832.
    CrossrefPubMedGoogle Scholar
  • 3 Rahman F. et al. Global epidemiology of atrial fibrillation. Nat Rev Cardiol 2014; 11: 639-654.
    CrossrefPubMedGoogle Scholar
  • 4 Go AS. et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 2014; 129: e28-e292.
    CrossrefPubMedGoogle Scholar
  • 5 January CT. et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014; 64: e1-e76.
    CrossrefPubMedGoogle Scholar
  • 6 Camm AJ. et al. 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 2012; 33: 2719-2747.
    CrossrefPubMedGoogle Scholar
  • 7 You JJ. et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e531S-575S.
    CrossrefPubMedGoogle Scholar
  • 8 Ogilvie IM. et al. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med 2010; 123: 638-645 e634.
    CrossrefPubMedGoogle Scholar
  • 9 Ansell J. et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 160S-198S.
    CrossrefPubMedGoogle Scholar
  • 10 Baker WL. et al. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm 2009; 15: 244-252.
    PubMedGoogle Scholar
  • 11 Cotte FE. et al. Vitamin K antagonist treatment in patients with atrial fibrillation and time in therapeutic range in four European countries. Clin Ther 2014; 36: 1160-1168.
    CrossrefPubMedGoogle Scholar
  • 12 Biskupiak J. et al. Cost implications of formulary decisions on oral anticoagulants in nonvalvular atrial fibrillation. J Manag Care Pharm 2013; 19: 789-798.
    PubMedGoogle Scholar
  • 13 Schulman S. et al. Direct and indirect costs of management of long-term warfarin therapy in Canada. J Thromb Haemost 2010; 08: 2192-2200.
    CrossrefPubMedGoogle Scholar
  • 14 Ruff CT. 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.
    CrossrefPubMedGoogle Scholar
  • 15 Stangier J. et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64: 292-303.
    CrossrefPubMedGoogle Scholar
  • 16 Frost C. et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol 2013; 76: 776-786.
    CrossrefPubMedGoogle Scholar
  • 17 Kubitza D. et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther 2005; 78: 412-421.
    CrossrefPubMedGoogle Scholar
  • 18 Ogata K. et al. Clinical safety, tolerability, pharmacokinetics, and pharmacody-namics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 2010; 50: 743-753.
    CrossrefPubMedGoogle Scholar
  • 19 Mendell J. et al. The Effect of Rifampin on the Pharmacokinetics (PK) and Pharmacodynamics (PD) of Edoxaban in Healthy Subjects. J Thromb Haemost. 2014 12. Abstract COA26.
    PubMedGoogle Scholar
  • 20 Mendell J. et al. Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. Am J Cardiovasc Drugs 2013; 13: 331-342.
    CrossrefPubMedGoogle Scholar
  • 21 Blech S. et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36: 386-399.
    CrossrefPubMedGoogle Scholar
  • 22 Raghavan N. et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009; 37: 74-81.
    CrossrefPubMedGoogle Scholar
  • 23 Weinz C. et al. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos 2009; 37: 1056-1064.
    CrossrefPubMedGoogle Scholar
  • 24 Bathala MS. et al. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos 2012; 40: 2250-2255.
    CrossrefPubMedGoogle Scholar
  • 25 Matsushima N. et al. Bioavailability and safety of the factor Xa inhibitor edox-aban and the effects of quinidine in healthy subjects. Clin Pharm Drug Dev 2013; 02: 358-366.
    PubMedGoogle Scholar
  • 26 ELIQUIS® (apixaban) tablets for oral use. Full Prescribing Information. Bristol-Myers Squibb Company; Princeton, NJ, USA and Pfizer Inc, NY, NY, USA: 2014
    Google Scholar
  • 27 PRADAXA® (dabigatran etexilate mesylate). Full Prescribing Information. Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT, USA: 2015
    Google Scholar
  • 28 XARELTO® (rivaroxaban) tablets. Full prescribing information. Janssen Pharmaceuticals; Titusville, NJ, USA: 2015
    Google Scholar
  • 29 Mikkaichi T. et al. Edoxaban transport via P-glycoprotein is a key factor for the drug’s disposition. Drug Metab Dispos 2014; 42: 520-528.
    CrossrefPubMedGoogle Scholar
  • 30 Connolly SJ. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
    CrossrefPubMedGoogle Scholar
  • 31 Patel MR. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
    CrossrefPubMedGoogle Scholar
  • 32 Granger CB. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
    CrossrefPubMedGoogle Scholar
  • 33 Giugliano RP. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369: 2093-2104.
    CrossrefPubMedGoogle Scholar
  • 34 Weitz JI. et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 2010; 104: 633-641.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 Salazar DE. et al. Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation. Thromb Haemost 2012; 107: 925-936.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Feinberg WM. et al. Prevalence, age distribution, and gender of patients with at-rial fibrillation. Analysis and implications. Arch Intern Med 1995; 155: 469-473.
    CrossrefPubMedGoogle Scholar
  • 37 Lopes RD. et al. Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J 2010; 159: 331-339.
    CrossrefPubMedGoogle Scholar
  • 38 Hylek EM. et al. Disparate stroke rates on warfarin among contemporaneous cohorts with atrial fibrillation: potential insights into risk from a comparative analysis of SPORTIF III versus SPORTIF V. Stroke 2008; 39: 3009-3014.
    CrossrefPubMedGoogle Scholar
  • 39 Giugliano RP. et al. Reduction in bleeding with edoxaban vs warfarin linked to lower all-cause mortality in 21,105 pateints randomized in the ENGAGE AF-TIMI 48 trial. Eur Heart J 2015; 35: 851-1187 Abstract 4874.
    PubMedGoogle Scholar
  • 40 Cohen E. et al. A longitudinal assessment of the natural rate of decline in renal function with age. J Nephrol 2014; 27: 635-641.
    CrossrefPubMedGoogle Scholar
  • 41 Go AS. et al. Impact of proteinuria and glomerular filtration rate on risk of thromboembolism in atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Circulation 2009; 119: 1363-1369.
    CrossrefPubMedGoogle Scholar
  • 42 Hijazi Z. et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation 2014; 129: 961-970.
    CrossrefPubMedGoogle Scholar
  • 43 Fox KA. et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011; 32: 2387-2394.
    CrossrefPubMedGoogle Scholar
  • 44 European Medicines Agency: Xarelto (rivaroxaban) Summary of product characteristics. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000944/human_med_001155.jsp&mid=WC0b01ac058001d124 Accessed December 10, 2014.
    PubMedGoogle Scholar
  • 45 Xarelto [monograph]. Toronto, Ontario. Bayer Inc. 2015. Available at: http://www.bayer.ca/en/products/healthcare-product-search Accessed July 30, 2015.
    PubMedGoogle Scholar
  • 46 Hohnloser SH. et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J 2012; 33: 2821-2830.
    CrossrefPubMedGoogle Scholar
  • 47 SAVAYSA™ (edoxaban) tablets for oral use. Full Prescribing Information. Parsippany, NJ: Daiichi Sankyo Inc.; 2015
    Google Scholar
  • 48 Robert-Ebadi H. et al. Use of anticoagulants in elderly patients: practical recommendations. Clin Interv Aging 2009; 04: 165-177.
    PubMedGoogle Scholar
  • 49 Eikelboom JW. 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
  • 50 PRADAXA: Indications, dosing and contra indications. Available at: http://www.boehringer-ingelheim.com/products/prescription_medicines/pradaxa/home/indications-dosing.html Boehringer Ingelheim Gmbh. 2014. Accessed July 10, 2015.
    PubMedGoogle Scholar
  • 51 Wang L. et al. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug Metab Dispos 2010; 38: 448-458.
    CrossrefPubMedGoogle Scholar
  • 52 Center for Drug Evaluation and Research (2012). Guidance for industry - Drug Interaction Studies. US Food and Drug Administration. Rockville, MD: Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf
    PubMedGoogle Scholar
  • 53 Zalesak M. et al. Higher persistence in newly diagnosed nonvalvular atrial fibrillation patients treated with dabigatran versus warfarin. Circ Cardiovasc Qual Outcomes 2013; 06: 567-574.
    CrossrefPubMedGoogle Scholar
  • 54 Nelson WW. et al. Medication persistence and discontinuation of rivaroxaban versus warfarin among patients with non-valvular atrial fibrillation. Curr Med Res Opin 2014; 30: 2461-2469.
    CrossrefPubMedGoogle Scholar
  • 55 Lip GY. et al. Patient outcomes using the European label for dabigatran. A post-hoc analysis from the RE-LY database. Thromb Haemost 2014; 111: 933-942.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 56 Vrijens B, Urquhart J. From monitoring to vigilance about patient adherence to new oral anticoagulants. Europace 2014; 16: 149.
    PubMedGoogle Scholar
  • 57 Heidbuchel H. et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013; 15: 625-651.
    CrossrefPubMedGoogle Scholar
  • 58 Connolly SJ. et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-817.
    CrossrefPubMedGoogle Scholar
  • 59 Ezekowitz MD. et al. Dabigatran and warfarin in vitamin K antagonist-naive and -experienced cohorts with atrial fibrillation. Circulation 2010; 122: 2246-2253.
    CrossrefPubMedGoogle Scholar
  • 60 Mahaffey KW. et al. Clinical outcomes with rivaroxaban in patients transitioned from vitamin K antagonist therapy: a subgroup analysis of a randomized trial. Ann Intern Med 2013; 158: 861-868.
    CrossrefPubMedGoogle Scholar
  • 61 Garcia DA. et al. Apixaban versus warfarin in patients with atrial fibrillation according to prior warfarin use: results from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial. Am Heart J 2013; 166: 549-558.
    CrossrefPubMedGoogle Scholar
  • 62 O’Donoghue ML. et al. Edoxaban vs. warfarin in vitamin K antagonist experienced and naive patients with atrial fibrillation. Eur Heart J 2015; 36: 1470-1477.
    CrossrefPubMedGoogle Scholar
  • 63 Mega JL. et al. Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015; 385: 2280-2287.
    CrossrefPubMedGoogle Scholar
  • 64 Abraham NS. et al. Comparative risk of gastrointestinal bleeding with dabi-gatran, rivaroxaban, and warfarin: population based cohort study. Br Med J 2015; 350: h1857.
    CrossrefPubMedGoogle Scholar
  • 65 Desai J. et al. Gastrointestinal bleeding with the new oral anticoagulants--defining the issues and the management strategies. Thromb Haemost 2013; 110: 205-212.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 66 Boehringer Ingelheim’s Investigational Antidote for Pradaxa(R) (dabigatran etex-ilate mesylate) Receives FDA Breakthrough Therapy Designation [press release]. Ridgefield, CT: Boehringer Ingelheim; June 26, 2014. http://us.boehringer-ingel-heim.com/news_events/press_releases/press_release_archive/2014/06-26-14-boehringer-ingelheim-investigational-antidote-pradaxa-dabigatran-etexilate-me-sylate-fda-breakthrough-therapy-designation.html Accessed October 6, 2014.
    Google Scholar
  • 67 Pollack Jr. CV. et al. Idarucizumab for Dabigatran Reversal. N Engl J Med. 2015 Epub ahead of print.
    PubMedGoogle Scholar
  • 68 Crowther M. et al. ANNEXA(TM)-A: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial, Demonstrating Reversal of Apixaban-Induced Anti-coagulation in Older Subjects by Andexanet alpha (PRT064445), a Universal Antidote for Factor Xa (fXa) Inhibitors. AHA Scientific Session 2014; 2014. Chicago, IL: 2014.
    Google Scholar
  • 69 Lu G. et al. In Vitro Characterization of Andexanet Alpha (PRT064445), a Specific fXa Inhibitor Antidote versus Aripazine (PER977), a Non-specific Reversal Agent. Circulation 2014; 130: A12218.
    PubMedGoogle Scholar
  • 70 Ansell JE. et al. Use of PER977 to Reverse the Anticoagulant Effect of Edoxaban. N Engl J Med. 2014 Epub ahead of print.
    PubMedGoogle Scholar
  • 71 Eerenberg ES. et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124: 1573-1579.
    CrossrefPubMedGoogle Scholar
  • 72 Levi M. et al. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost 2014; 12: 1428-1436.
    CrossrefPubMedGoogle Scholar
  • 73 Marlu R. et al. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108: 217-224.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 74 Zahir H. et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2014 Epub ahead of print.
    PubMedGoogle Scholar
  • 75 European Medicines Agency: Eliquis (apixaban) Summary of product characteristics. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148/WC500107728.pdf Accessed December 10, 2014.
    PubMedGoogle Scholar
  • 76 European Medicines Agency. Pradaxa (dabigatran). European public assessment report (EPAR) Product Information. 2015 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf (updated March 19, 2014) Accessed July 30, 2015.
    PubMed
  • 77 ELIQUIS [monograph]. Montreal, Quebec: Bristol-Myers Squibb Canada.; 2015 Availlable at: http://www.pfizer.ca/en/our_products/products/monograph/313 Accessed May 15, 2015.
    PubMedGoogle Scholar
  • 78 PRADAXA [monograph]. Burlington, Ontario: Boehringer-Ingelheim Canada Ltd.; 2015 Available at: http://boehringer-ingelheim.ca/content/dam/internet/opu/ca_EN/documents/humanhealth/product_monograph/Prada-xaPMEN.pdf Accessed July 30, 2015.
    PubMedGoogle Scholar
  • 79 LIXIANA®(edoxaban). Package Leaflet. Daiichi Sankyo Europe GmbH. Munich, Germany: 2015 Available at: https://www.medicines.org.uk/emc/PIL.30504.latest.pdf Accessed July 30, 2015.
    PubMedGoogle Scholar