Advertisement
Canadian Journal of Cardiology

The Guideline-Policy Gap in Direct-Acting Oral Anticoagulants Usage in Atrial Fibrillation: Evidence, Practice, and Public Policy Considerations

      Abstract

      Atrial fibrillation has a high disease burden—both in prevalence and associated consequences. Despite anticoagulation being an effective treatment in atrial fibrillation, stroke prevention is slow to reflect evidence-based practice. Real-world data reveal a substantial portion of patients who would benefit from anticoagulation, yet do not receive it adequately or at all. A large part of this suboptimal treatment is due to the underutilization of direct oral anticoagulants (DOACs). In response to abundant evidence published over a short timeframe, international guidelines have adopted DOAC usage ahead of policy and fund holders. This paper reviews the evidence and values that influence published guidelines, patient-physician decision making, and policy framework on DOAC usage. An important factor is the access gap between patients who qualify for DOAC according to evidence-based guidelines and the subset of this cohort who are eligible for DOAC based on government funded policy. We analyse the Canadian health system in detail—including drug approval and funding process. Health care systems in other countries are explored, with emphasis on similar universal health care systems that may help overcome barriers common to Canada. We will discuss strategies to: (1) improve awareness of the risk and preventability of stroke; (2) enable physicians to provide evidence-based DOAC usage; (3) empower patients to improve adherence and persistence; (4) collect real-life data that encourages patient self-monitoring, physician outcomes auditing, and building evidence that is useful for policy makers; and (5) use postmarketing data in negotiating shared risk management between pharmaceuticals and government to improve access to DOACs.

      Résumé

      La fibrillation auriculaire (FA) impose un fardeau très lourd, sur le plan tant de sa prévalence que de ses conséquences. Malgré l’efficacité de l’anticoagulation contre la FA, la prévention des accidents vasculaires cérébraux (AVC) tarde à suivre la pratique fondée sur les données probantes. Les données obtenues en situation réelle montrent qu’une fraction appréciable de patients chez lesquels l’anticoagulation serait bénéfique ne reçoivent pas ce traitement, ou le reçoivent selon des modalités inappropriées. Ce traitement sous-optimal s’explique en grande partie par la sous-utilisation des anticoagulants oraux directs (AOD). En réponse à l’abondance des données probantes publiées en peu de temps, les lignes directrices internationales ont devancé les décideurs et les bailleurs de fonds en préconisant l’utilisation des AOD. Cet article présente une recension des données probantes et des valeurs qui influencent les lignes directrices publiées, la prise de décision patient-médecin et le cadre politique relativement à l’utilisation des AOD. L’écart en matière d’accès au traitement entre les patients admissibles aux AOD selon les lignes directrices fondées sur des données probantes et le sous-ensemble de cette cohorte qui y est admissible en fonction des politiques gouvernementales constitue un facteur important. Nous analysons en profondeur le système de santé canadien, y compris le processus d’homologation et de financement des médicaments. Nous explorons aussi les systèmes de santé d’autres pays, en nous arrêtant plus particulièrement aux systèmes de soins de santé universels semblables au nôtre qui pourraient aider à surmonter les obstacles rencontrés au Canada. Nous discutons des stratégies permettant d’atteindre les objectifs suivants : 1) améliorer la sensibilisation au risque et au caractère évitable de l'AVC 2) permettre aux médecins d’offrir l’utilisation des AOD selon les pratiques fondées sur des données probantes; 3) habiliter les patients à améliorer leur observance et leur persévérance; 4) recueillir des données en situation réelle afin d’encourage l’autosurveillance du patient et la vérification des résultats par le médecin et de constituer un corpus de données probantes susceptibles d’être utiles aux décideurs; 5) utiliser les données post-commercialisation dans la négociation de la gestion partagée des risques entre les sociétés pharmaceutiques et le gouvernement afin d’améliorer l’accès aux AOD.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Heart and Stroke Foundation Canada
        Atrial fibrillation and stroke; 2016.
        (Available at:) (Accessed March 13, 2018)
        • Krahn A.D.
        • Manfreda J.
        • Tate R.B.
        • Mathewson F.A.
        • Cuddy T.E.
        The natural history of atrial fibrillation: incidence, risk factors and prognosis in the Manitoba follow-up study.
        Am J Med. 1995; 98: 476-484
        • Chugh S.S.
        • Havmoeller R.
        • Narayanan K.
        • et al.
        Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 study.
        Circulation. 2014; 129: 837-847
        • Lin H.-J.
        • Wolf P.A.
        • Kelly-Hayes M.
        • et al.
        Stroke severity in atrial fibrillation. The Framingham study.
        Stroke. 2018; 24: 1-12
        • Benjamin E.J.
        • Blaha M.J.
        • Chiuve S.E.
        • et al.
        Heart disease and stroke statistics—2017 update: a report from the American Heart Association.
        Circulation. 2017; 135: e146-e603
      1. Heart and Stroke Foundation. Different Strokes: 2017 Stroke Report; 2017. Available at: http://www.heartandstroke.ca/-/media/pdf-files/canada/stroke-report/strokereport2017en.ashx. Accessed March 22, 2018.

        • Gladstone D.J.
        • Bui E.
        • Fang J.
        • et al.
        Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated.
        Stroke. 2009; 40: 235-240
        • Connolly S.J.
        • Ezekowitz M.D.
        • Yusuf S.
        • et al.
        Dabigatran versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2009; 361: 711-723
        • Patel M.R.
        • Mahaffey K.W.
        • Garg J.
        • et al.
        Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
        N Engl J Med. 2011; 365: 883-891
        • Granger C.B.
        • Alexander J.H.
        • McMurray J.J.
        • et al.
        Apixaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2011; 36511: 981-992
        • Giugliano R.P.
        • Ruff C.T.
        • Braunwald E.
        • et al.
        Edoxaban versus warfarin in patients with atrial fibrillation.
        N Engl J Med. 2013; 369: 2093-2104
        • Hess P.L.
        • Mirro M.J.
        • Diener H.-C.
        • et al.
        Addressing barriers to optimal oral anticoagulation use and persistence among patients with atrial fibrillation: proceedings, Washington, DC, December 3-4, 2012.
        Am Hear J. 2014; 168: 239-247
        • Partington S.L.
        • Abid S.
        • Teo K.
        • Oczkowski W.
        • O’Donnell M.J.
        Pre-admission warfarin use in patients with acute ischemic stroke and atrial fibrillation: the appropriate use and barriers to oral anticoagulant therapy.
        Thromb Res. 2007; 120: 663-669
        • Andrade J.G.
        • Macle L.
        • Nattel S.
        • Verma A.
        • Cairns J.
        Contemporary atrial fibrillation management: a comparison of the current AHA/ACC/HRS, CCS, and ESC guidelines.
        Can J Cardiol. 2017; 33: 965-976
        • Cairns J.A.
        • Connolly S.
        • Mcmurtry S.
        • Stephenson M.
        • Talajic M.
        Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter.
        Can J Cardiol. 2011; 27: 27-30
        • Dolan G.
        • Smith L.A.
        • Collins S.
        • Plumb J.M.
        Effect of setting, monitoring intensity and patient experience on anticoagulation control: a systematic review and meta-analysis of the literature.
        Curr Med Res Opin. 2008; 24: 1459-1472
        • Xian Y.
        • O’Brien E.C.
        • Liang L.
        • et al.
        Association of preceding antithrombotic treatment with acute ischemic stroke severity and in-hospital outcomes among patients with atrial fibrillation.
        J Am Med Assoc. 2017; 317: 1057
        • Chan E.W.
        • Lau W.C.Y.
        • Siu C.W.
        • et al.
        Effect of suboptimal anticoagulation treatment with antiplatelet therapy and warfarin on clinical outcomes in patients with nonvalvular atrial fibrillation: A population-wide cohort study.
        Heart Rhythm. 2016; 13: 1581-1588
        • Ruff C.T.
        • Giugliano R.P.
        • 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
        • Tawfik A.
        • Bielecki J.M.
        • Krahn M.
        • et al.
        Systematic review and network meta-analysis of stroke prevention treatments in patients with atrial fibrillation.
        Clin Pharmacol Adv Appl. 2016; 8: 93-107
        • Graham D.J.
        • Reichman M.E.
        • Wernecke M.
        • et al.
        Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation.
        Circulation. 2014; 131: 157-164
        • Lauffenburger J.C.
        • Farley J.F.
        • Gehi A.K.
        • Rhoney D.H.
        • Brookhart M.A.
        • Fang G.
        Effectiveness and safety of dabigatran and warfarin in real-world US patients with non-valvular atrial fibrillation: a retrospective cohort study.
        J Am Heart Assoc. 2015; 4: 1-12
        • Tamayo S.
        • Peacock W.F.
        • Patel M.
        • et al.
        Characterizing major bleeding in patients with nonvalvular atrial fibrillation: a pharmacovigilance study of 27 467 patients taking Rivaroxaban.
        Clin Cardiol. 2015; 38: 63-68
        • Laliberté F.
        • Cloutier M.
        • Nelson W.W.
        • et al.
        Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients.
        Curr Med Res Opin. 2014; 30: 1317-1325
        • Bai Y.
        • Deng H.
        • Shantsila A.
        • Lip G.Y.H.
        Rivaroxaban versus dabigatran or warfarin in real-world studies of stroke prevention in atrial fibrillation: systematic review and meta-analysis.
        Stroke. 2017; 48: 970-976
        • Yao X.
        • Abraham N.S.
        • Sangaralingham L.R.
        • et al.
        Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation.
        J Am Heart Assoc. 2016; 5: 1-19
        • Larsen T.B.
        • Skjøth F.
        • Nielsen P.B.
        • Kjældgaard J.N.
        • Lip G.Y.H.
        Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study.
        Br Med J. 2016; 353: i3189
        • Center for Drug Evaluation and Administration, Food and Drug Administration
        Drug safety and availability—FDA drug safety communication: FDA study of medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with pradaxa (dabigatran) compared to warfarin.
        Center for Drug Evaluation and Research, 2014 (Available at:) (Accessed March 13, 2018)
        • Halperin J.L.
        • Hankey G.J.
        • Wojdyla D.M.
        • et al.
        Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor xa inhibition compared with vitamin k antagonism for prevention of stroke and embolism.
        Circulation. 2014; 130: 138-146
        • Avgil-Tsadok M.
        • Jackevicius C.A.
        • Essebag V.
        • et al.
        Dabigatran use in elderly patients with atrial fibrillation.
        Thromb Haemost. 2015; 115: 152-160
        • Deitelzweig S.
        • Luo X.
        • Gupta K.
        • et al.
        Real world evaluation of major bleeding risk and costs for all causes and bleeding-related health services among elderly patients with nonvalvular atrial fibrillation treated with apixaban or warfarin.
        J Am Coll Cardiol. 2017; 69: 312
        • Okumura K.
        • Lip G.Y.H.
        • Akao M.
        • et al.
        Edoxaban for the management of elderly Japanese patients with atrial fibrillation ineligible for standard oral anticoagulant therapies: rationale and design of the ELDERCARE-AF study.
        Am Heart J. 2017; 194: 99-106
        • Akao M.
        • Yamashita T.
        • Okumura K.
        Study design of J-ELD AF: a multicenter prospective cohort study to investigate the efficacy and safety of apixaban in Japanese elderly patients.
        J Cardiol. 2016; 68: 554-558
        • Staerk L.
        • Gerds T.A.
        • Lip G.Y.H.
        • et al.
        Standard and reduced doses of dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation: a nationwide cohort study.
        J Intern Med. 2018; 283: 45-55
        • Skjøth F.
        • Larsen T.B.
        • Rasmussen L.H.
        • Lip G.Y.H.
        Efficacy and safety of edoxaban in comparison with dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation: an indirect comparison analysis.
        Thromb Haemost. 2014; 111: 981-988
        • Mantha S.
        • Ansell J.
        An indirect comparison of dabigatran, rivaroxaban and apixaban for atrial fibrillation.
        Thromb Haemost. 2012; 108: 476-484
        • Peng S.
        • Deger K.A.
        • Ustyugova A.
        • et al.
        Cost-effectiveness analysis of dabigatran versus rivaroxaban for stroke prevention in patients with non-valvular atrial fibrillation using real-world evidence in elderly US Medicare beneficiaries.
        Curr Med Res Opin. 2018; 34: 55-63
        • Macle L.
        • Cairns J.A.
        • Andrade J.G.
        • et al.
        The 2014 atrial fibrillation guidelines companion: a practical approach to the use of the Canadian Cardiovascular Society Guidelines.
        Can J Cardiol. 2015; 31: 1207-1218
        • Verma A.
        • Cairns J.A.
        • Mitchell L.B.
        • et al.
        2014 focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation ; for the CCS Atrial Fibrillation Guidelines Committee.
        Can J Cardiol. 2014; 30: 1114-1130
        • Skanes A.C.
        • Healey J.S.
        • Cairns J.A.
        • et al.
        Focused 2012 update of the Canadian Cardiovascular Society Atrial Fibrillation Guidelines: recommendations for stroke prevention and rate/rhythm control.
        Can J Cardiol. 2012; 28: 125-136
        • Macle L.
        • Cairns J.
        • Leblanc K.
        • et al.
        2016 focused update of the Canadian Cardiovascular Society Guidelines for the management of atrial fibrillation for the CCS Atrial Fibrillation Guidelines Committee.
        Can J Cardiol. 2016; 32: 1170-1185
        • Kirchhof P.
        • Benussi S.
        • Kotecha D.
        • et al.
        2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.
        Eur Heart J. 2016; 37: 2893-2962
        • January C.T.
        • Wann L.S.
        • Alpert J.S.
        • 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
        • CADTH
        Common drug review final CDEC recommendation apixaban; 2013.
        (Available at:) (Accessed March 13, 2018)
        • CADTH
        Common drug review CDEC final recommendation dabigatran; 2011.
        (Available at:) (Accessed March 13, 2018)
        • CADTH
        Common drug review CDEC final recommendation rivaroxaban; 2012.
        (Available at:) (Accessed March 13, 2018)
        • CADTH
        Common drug review CDEC final recommendation edoxaban; 2017.
        (Available at:) (Accessed March 13, 2018)
        • Government of Manitoba
        Manitoba—Exception Drug Status (EDS) Program.
        (Available at:) (Accessed March 19, 2018)
        • Government of Saskatchewan
        Saskatchewan Exception Drug Status Program.
        (Available at:) (Accessed March 19, 2018)
        • Alberta Blue Cross
        Special Authorization NOAC—Alberta Blue Cross.
        (Available at:) (Accessed March 19, 2018)
        • Province of British Columbia
        Special Authority Drugs—Province of British Columbia.
        (Available at:) (Accessed March 19, 2018)
      2. Quebec. Liste de Médicaments publiée par la Régie de l’assurance maladie du Québec; 2016.
        (Available at:) (Accessed March 19, 2018)
        • Nova Scotia Health
        Criteria for coverage of exception status drugs.
        (Available at:) (Accessed April 19, 2018)
        • Newfoundland Health
        Special authorization drug form—NOAC.
        (Available at:) (Accessed March 19, 2018)
        • New Brunswick Government
        New Brunswick drug plans formulary.
        (Available at:) (Accessed March 19, 2018)
        • PEI Health
        Special authorization drug form—NOAC.
        (Available at:) (Accessed March 19, 2018)
        • Ontario Government
        Formulary search—limited use NOAC.
        (Available at:) (Accessed April 19, 2018)
        • Thrombosis Canada
        Clinical guide—edoxaban.
        (Available at:) (Accessed April 17, 2018)
        • Thrombosis Canada
        Clinical guide—rivaroxaban.
        (Available at:) (Accessed April 17, 2018)
        • Thrombosis Canada
        Clinical guide—dabigatran.
        (Available at:) (Accessed April 17, 2018)
        • Thrombosis Canada
        Clinical guide—apixaban.
        (Available at:) (Accessed April 17, 2018)
        • Kakkar A.K.
        • Mueller I.
        • Bassand J.P.
        • et al.
        Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the International, Observational, Prospective GARFIELD Registry.
        PLoS One. 2013; 8: e63479
        • Halperin J.L.
        • Huisman M.
        • Diener H.-C.
        • et al.
        Patterns of newly detected atrial fibrillation and antithrombotic treatment in North America (GLORIA-AF Phase II).
        J Am Coll Cardiol. 2015; 65: A1520
        • Hsu J.C.
        • Maddox T.M.
        • Kennedy K.F.
        • et al.
        Oral anticoagulant therapy prescription in patients with atrial fibrillation across the spectrum of stroke risk.
        JAMA Cardiol. 2016; 1: 55
        • Kirchhof P.
        • Ammentorp B.
        • Darius H.
        • et al.
        Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC Guidelines on atrial fibrillation: primary results of the PREvention of thromboemolic events-European Registry in Atrial Fibrillation (PREFER in AF).
        Europace. 2014; 16: 6-14
        • Lip G.Y.H.
        • Laroche C.
        • Dan G.A.
        • et al.
        A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry.
        Europace. 2014; 16: 308-319
        • Steinberg B.
        • Shrader P.
        • Thomas L.
        • et al.
        Factors associated with non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with new-onset atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II).
        Am Heart J. 2017; 189: 40-47
        • Huisman M.V.
        • Rothman K.J.
        • Paquette M.
        • et al.
        The changing landscape for stroke prevention in AF: findings from the GLORIA-AF registry phase 2.
        J Am Coll Cardiol. 2017; 69: 777-785
        • Weitz J.I.
        • Semchuk W.
        • Turpie A.G.
        • et al.
        Trends in prescribing oral anticoagulants in Canada, 2008-2014.
        Clin Ther. 2015; 37: 2506-2514.e4
        • Yu A.Y.X.
        • Malo S.
        • Svenson L.W.
        • Wilton S.B.
        • Hill M.D.
        Temporal trends in the use and comparative effectiveness of direct oral anticoagulant agents versus warfarin for nonvalvular atrial fibrillation: a Canadian population-based study.
        J Am Heart Assoc. 2017; 6e007129
        • Xu Y.
        • Holbrook A.
        • Simpson C.
        • Dowlatshahi D.
        • Johnson A.
        Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a population-based descriptive analysis.
        Can Med Assoc J Open. 2013; 1: E115-E119
        • Mekaj Y.H.
        • Mekaj A.Y.
        • Duci S.B.
        • Miftari E.I.
        New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events.
        Ther Clin Risk Manag. 2015; 11: 967-977
        • Andrade J.G.
        • Krahn A.D.
        • Skanes A.C.
        • et al.
        Values and preferences of physicians and patients with nonvalvular atrial fibrillation who receive oral anticoagulation therapy for stroke prevention.
        Can J Cardiol. 2016; 32: 747-753
        • Eek A.K.
        • Øie E.
        • Granas A.G.
        Prescribing of NOACs has outnumbered warfarin: exploring how physicians choose anticoagulant treatments.
        Eur J Clin Pharmacol. 2018; 74: 323-330
        • Camm A.J.
        • Accetta G.
        • Ambrosio G.
        • et al.
        Evolving antithrombotic treatment patterns for patients with newly diagnosed atrial fibrillation.
        Heart. 2017; 103: 307-314
        • Beyer-Westendorf J.
        • Ehlken B.
        • Evers T.
        Real-world persistence and adherence to oral anticoagulation for stroke risk reduction in patients with atrial fibrillation.
        Europace. 2016; 18: 1150-1157
        • Dhillon S.K.
        • Mcmurtry M.S.
        • Bungard T.J.
        The disconnect between novel oral anticoagulant eligibility and provincial drug coverage: an Albertan anticoagulation clinic audit.
        Can J Cardiol. 2015; 31: 1047-1050
        • Devereaux P.J.
        • Anderson D.R.
        • Gardner M.J.
        • et al.
        Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study.
        BMJ. 2001; 323: 1218-1222
        • Wallentin L.
        • Yusuf S.
        • Ezekowitz M.D.
        • 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
        • Piccini J.P.
        • Hellkamp A.S.
        • Lokhnygina Y.
        • et al.
        Relationship between time in therapeutic range and comparative treatment effect of rivaroxaban and warfarin: results from the ROCKET AF trial.
        J Am Heart Assoc. 2014; 3e000521
        • Xu Y.
        • Schulman S.
        • Dowlatshahi D.
        • et al.
        Direct oral anticoagulant- or warfarin-related major bleeding: characteristics, reversal strategies, and outcomes from a multicenter observational study.
        Chest. 2017; 152: 81-91
        • Hylek E.M.
        • Evans-Molina C.
        • Shea C.
        • Henault L.E.
        • Regan S.
        Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation.
        Circulation. 2007; 115: 2689-2696
        • Moulson N.
        • McIntyre W.F.
        • Oqab Z.
        • et al.
        The anticoagulation choices of internal medicine residents for stroke prevention in non-valvular atrial fibrillation.
        Postgrad Med J. 2017; 93: 308-312
        • Pollack Jr., C.V.
        • Reilly P.A.
        • Eikelboom J.
        • et al.
        Idarucizumab for dabigatran reversal.
        N Engl J Med. 2015; 6373: 511-520
        • Connolly S.J.
        • Milling T.J.
        • Eikelboom J.W.
        • et al.
        Andexanet alfa for acute major bleeding associated with factor Xa inhibitors.
        N Engl J Med. 2016; 375: 1131-1141
        • Siegal D.M.
        • Curnutte J.T.
        • Connolly S.J.
        • et al.
        Andexanet alfa for the reversal of factor Xa inhibitor activity.
        N Engl J Med. 2015; 373: 2413-2424
        • Ghadimi K.
        • Dombrowski K.E.
        • Levy J.H.
        • Welsby I.J.
        Andexanet alfa for the reversal of factor Xa inhibitor related anticoagulation.
        Expert Rev Hematol. 2016; 9: 115-122
        • Flaker G.C.
        • Belew K.
        • Beckman K.
        • et al.
        Asymptomatic atrial fibrillation: demographic features and prognostic information from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study.
        Am Heart J. 2005; 149: 657-663
        • Barra S.
        • Fynn S.
        Untreated atrial fibrillation in the United Kingdom: understanding the barriers and treatment options.
        J Saudi Heart Assoc. 2015; 27: 31-43
        • Healey J.S.
        • Connolly S.J.
        • Gold M.R.
        • et al.
        Subclinical atrial fibrillation and the risk of stroke.
        N Engl J Med. 2013; 366: 120-129
        • Murray S.
        • Lazure P.
        • Pullen C.
        • Maltais P.
        • Dorian P.
        Atrial fibrillation care: challenges in clinical practice and educational needs assessment.
        Can J Cardiol. 2011; 27: 98-104
        • Clarkesmith D.E.
        • Lip G.Y.H.
        • Lane D.A.
        Patients’ experiences of atrial fibrillation and non-vitamin K antagonist oral anticoagulants (NOACs), and their educational needs: a qualitative study.
        Thromb Res. 2017; 153: 19-27
        • Ghannam M.
        • Chugh A.
        Indications and appropriate selection of novel oral anticoagulants in patients with atrial fibrillation.
        Heart. 2017; 103: 1129-1137
        • McIntyre W.F.
        • Oqab Z.
        • Yazdan-Ashoori P.
        • et al.
        Stroke prevention for patients with atrial fibrillation: values and preferences of Canadian emergency medicine trainees.
        Am J Emerg Med. 2016; 34: 1685-1687
        • Yazdan-Ashoori P.
        • Oqab Z.
        • McIntyre W.F.
        • et al.
        How do family medicine residents choose an anticoagulation regimen for patients with nonvalvular atrial fibrillation?.
        Prim Heal Care Res Dev. 2017; 18: 472-481
        • Connolly S.
        • Pogue J.
        • Hart R.
        • et al.
        Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel trial with Irbesartan for prevention of vascular events.
        Lancet. 2006; 367: 1903-1912
        • Bell A.D.
        • Gross P.
        • Heffernan M.
        • et al.
        Appropriate use of antithrombotic medication in Canadian patients with nonvalvular atrial fibrillation.
        Am J Cardiol. 2016; 117: 1107-1111
        • Thomas G.R.
        • Angaran P.A.
        • Mariano Z.
        • Mangat I.S.
        • Dorian P.
        Evaluation of atrial fibrillation stroke prevention therapies in the era of NOACs and evolving anticoagulation guidelines in Canada.
        Can J Cardiol. 2015; 31: S248-S249
        • Spyropoulos J.
        • Padbury C.
        Improving stroke prevention in atrial fibrillation: effectiveness of medical education.
        J Am Coll Cardiol. 2018; 71: A2651
        • McIntyre W.F.
        • Conen D.
        • Olshansky B.
        • et al.
        Stroke prevention strategies in North American patients with atrial fibrillation: the GLORIA-AF registry program.
        Clin Cardiol. 2018; 41: 744-751
        • Huang C.
        • Siu M.
        • Vu L.
        • Wong S.
        • Shin J.
        Factors influencing doctors’ selection of dabigatran in non-valvular atrial fibrillation.
        J Eval Clin Pract. 2013; 19: 938-943
        • Sholzberg M.
        • Gomes T.
        • Juurlink D.N.
        • et al.
        The influence of socioeconomic status on selection of anticoagulation for atrial fibrillation.
        PLoS One. 2016; 11: 1-12
        • CADTH
        Common drug review procedure for the CADTH; 2014.
        (Available at:) (Accessed March 13, 2018)
        • Government of Ontario—Ministry of Health and Long-Term Care
        How drugs are approved.
        (Available at:) (Accessed March 13, 2018)
        • Stone J.A.
        • Earl K.M.
        • O B.J.
        • et al.
        Aligning health care policy with evidence-based medicine: the case for funding direct oral anticoagulants in atrial fibrillation.
        Can J Cardiol. 2014; 30: 1245-1248
      3. NHS UK. Prescribing Outlook Report for 2016-2018; 2015. Available at http://www.ukmi.nhs.uk/filestore/ukmianp/2015PrescribingOutlook-NewMedicines-FINAL.pdf. Accessed March 22, 2018.

        • Vestergaard A.S.
        • Ehlers L.H.
        A health economic evaluation of stroke prevention in atrial fibrillation: guideline adherence versus the observed treatment strategy prior to 2012 in Denmark.
        Pharmacoeconomics. 2015; 33: 967-979
        • Verhoef T.I.
        • Redekop W.K.
        • Hasrat F.
        • de Boer A.
        • Maitland-van der Zee A.H.
        Cost effectiveness of new oral anticoagulants for stroke prevention in patients with atrial fibrillation in two different European healthcare settings.
        Am J Cardiovasc Drugs. 2014; 14: 451-462
        • Krejczy M.
        • Harenberg J.
        • Marx S.
        • et al.
        Comparison of cost-effectiveness of anticoagulation with dabigatran, rivaroxaban and apixaban in patients with non-valvular atrial fibrillation across countries.
        J Thromb Thrombolysis. 2014; 37: 507-523
        • López-López J.A.
        • Sterne J.A.C.
        • Thom H.H.Z.
        • et al.
        Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis.
        Br Med J. 2017; 359: j5058
        • Coyle D.
        • Coyle K.
        • Cameron C.
        • et al.
        Cost-effectiveness of new oral anticoagulants compared with warfarin in preventing stroke and other cardiovascular events in patients with atrial fibrillation.
        Value Heal. 2013; 16: 498-506
        • Pink J.
        • Lane S.
        • Pirmohamed M.
        • Hughes D.A.
        Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses.
        Br Med J. 2011; 343: 1-14
        • Sorensen S.V.
        • Kansal A.R.
        • Connolly S.
        • et al.
        Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation: a Canadian payer perspective.
        Thromb Haemost. 2011; 105: 908-919
        • Camm A.J.
        • Pinto F.J.
        • Hankey G.J.
        • et al.
        Non-vitamin K antagonist oral anticoagulants and atrial fibrillation guidelines in practice: barriers to and strategies for optimal implementation.
        Europace. 2015; 17: 1007-1017
        • Camm A.J.
        • Kirchhof P.
        • Lip G.Y.H.
        • et al.
        ESC 2010 Guidelines for the management of atrial fibrillation.
        Eur Heart J. 2010; 31: 2369-2429
        • Camm A.J.
        • Lip G.Y.H.
        • De Caterina R.
        • et al.
        2012 focused update of the ESC Guidelines for the management of atrial fibrillation.
        Eur Heart J. 2012; 33: 2719-2747
      4. National Institute for Health and Clinical Excellence (NICE). Dabigatran for Preventing Stroke and Systemic Embolism in People with Non-Valvular Atrial Fibrillation; 2008. Available at: https://www.nice.org.uk/guidance/ta249/resources/dabigatran-etexilate-for-the-prevention-of-stroke-and-systemic-embolism-in-atrial-fibrillation-pdf-82600439457733. Accessed March 22, 2018.

      5. National Institute for Health and Clinical Excellence (NICE). Apixaban for Preventing Stroke and Systemic Embolism in People with Non-Valvular Atrial Fibrillation; 2015. Available at: https://www.nice.org.uk/guidance/ta275/resources/apixaban-for-preventing-stroke-and-systemic-embolism-in-people-with-nonvalvular-atrial-fibrillation-pdf-82600614137797. Accessed March 22, 2018.

      6. National Institute for Health and Clinical Excellence (NICE). Rivaroxaban for Preventing Stroke and Systemic Embolism in People with Non-Valvular Atrial Fibrillation; 2012.

        • National Institute for Health and Clinical Excellence (NICE)
        Edoxaban for Preventing Stroke and Systemic Embolism in People with Non-Valvular Atrial Fibrillation; 2015.
        (Available at:) (Accessed March 22, 2018)
      7. National Institute for Health and Clinical Excellence (NICE). Consensun: Supporting Local Implementation of NICE Guidance on Use of the Novel (Non-Vitamin K Antagonist) Oral Anticoagulants in Non-Valvular Atrial Fibrillation; 2014. Available at: https://www.nice.org.uk/guidance/cg180/resources/nic-consensus-statement-on-the-use-of-noacs-243733501. Accessed on March 22, 2018.

        • Macaulay R.
        • Jamali E.
        NICE patient access schemes—a who, what, why, when and how.
        Value Heal. 2015; 18: A552
        • Tomek D.
        • Tomekova K.
        Pharmaceutical market access in emerging markets through innovative patient access schemes.
        Value Heal J. 2014; 17: A417
        • Lu C.Y.
        • Lupton C.
        • Rakowsky S.
        • et al.
        Patient access schemes in Asia-Pacific markets: current experience and future potential.
        J Pharm Policy Pract. 2015; 8: 1-12
        • Lu C.Y.
        • Macneill P.
        • Williams K.
        • Day R.
        Access to high cost medicines in Australia: ethical perspectives.
        Aust New Zealand Health Policy. 2008; 5: 1-7
        • Cox J.L.
        • de Pouvourville G.
        Achieving access: addressing the needs of payors and health technology assessment agencies: figure 1.
        Eur Hear J Suppl. 2015; 17: D15-D20
        • Apostolakis S.
        • Sullivan R.M.
        • Olshansky B.
        • Lip G.Y.H.
        Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin.
        Chest. 2013; 144: 1555-1563