Advertisement
Canadian Journal of Cardiology

Non-Vitamin K Antagonist Oral Anticoagulants in Adult Congenital Heart Disease

      Abstract

      Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have several advantages over VKAs that render them an attractive option for adults with congenital heart disease (CHD). Efficacy and safety data specific to the adult CHD population are emerging. Herein, we synthesize the growing literature regarding NOACs in adults with CHD and attempt to identify subgroups for which it appears reasonable to extrapolate data from populations without CHD. Small observational studies suggest that NOACs are safe and effective in selected adults with CHD. NOACs are contraindicated in patients with a mechanical valve, in those with mitral or tricuspid valve stenosis with enlarged and diseased atria, with or without a mitral or tricuspid bioprosthesis, and after recent cardiac surgery (< 3 months). There is currently insufficient evidence to recommend NOACs in patients with a Fontan circulation or cyanotic CHD. Growing literature supports the use of NOACs in patients without CHD who have various forms of valvular heart disease. Therefore, when an indication for oral anticoagulation is established, it appears reasonable to consider a NOAC instead of a VKA in adults with CHD lesions analogous to isolated mitral regurgitation, tricuspid regurgitation, or aortic regurgitation or stenosis. The NOAC agent selected and the prescribed dose should be tailored according to bleeding risk, body weight, renal function, and comedications, especially antiepileptic drugs. The decision to initiate a NOAC should be shared between the patient and care provider. Large-scale research studies are required to further assess safety and efficacy in selected patient subgroups.

      Résumé

      Les nouveaux anticoagulants administrés par voie orale (NACO) qui ne sont pas des antagonistes de la vitamine K (AVK) présentent plusieurs avantages comparativement aux AVK qui les rendent attrayants pour le traitement des adultes présentant une cardiopathie congénitale. Des données sur l’efficacité et l’innocuité portant précisément sur les adultes atteints de cardiopathie congénitale voient le jour. Nous résumons ici la littérature de plus en plus abondante sur l’administration de NACO chez des adultes atteints de cardiopathie congénitale et tentons d’identifier des sous-groupes pour lesquels il apparaît raisonnable d’extrapoler des données provenant de populations ne présentant pas de cardiopathie congénitale. Des études observationnelles de petite taille laissent supposer que les NACO sont sûrs et efficaces chez certains adultes choisis présentant une cardiopathie congénitale. Les NACO sont contre-indiqués chez les patients porteurs d’une prothèse valvulaire mécanique, ceux qui présentent une sténose mitrale ou tricuspide accompagnée d’une hypertrophie auriculaire, avec ou sans bioprothèse mitrale ou tricuspide, et ceux qui ont récemment subi une chirurgie cardiaque (< 3 mois). L’insuffisance des données probantes actuelles ne permet pas de recommander les NACO chez les patients atteints d’une cardiopathie congénitale cyanogène ou associée a une circulation de type Fontan. Des données de plus en plus abondantes corroborent l’usage des NACO chez les patients qui ne sont pas atteints de cardiopathie congénitale mais qui présentent diverses formes de valvulopathies. Par conséquent, lorsque l’anticoagulation par voie orale est indiquée, il semble raisonnable d’envisager un NACO plutôt qu’un AVK chez les adultes présentant des lésions congénitales analogues à une régurgitation mitrale isolée, à une régurgitation tricuspide ou à une régurgitation ou une sténose aortique. Le choix du NACO et de la dose doit se faire en fonction du risque de saignement, du poids corporel, de la fonction rénale et des médicaments administrés en concomitance, particulièrement s’il s’agit d’antiépileptiques. La décision d’amorcer un traitement par un NACO devrait être prise de concert par le professionnel de la santé et le patient. Des études de grande envergure sont nécessaires pour évaluer plus en profondeur l’innocuité et l’efficacité des NACO dans des sous-groupes de patients choisis.
      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

        • Khairy P.
        Thrombosis in congenital heart disease.
        Expert Rev Cardiovasc Ther. 2013; 11: 1579-1582
        • Khairy P.
        • Van Hare G.F.
        • Balaji S.
        • et al.
        PACES/HRS expert consensus statement on the recognition and management of arrhythmias in adult congenital heart disease: developed in partnership between the Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS). Endorsed by the governing bodies of PACES, HRS, the American College of Cardiology (ACC), the American Heart Association (AHA), the European Heart Rhythm Association (EHRA), the Canadian Heart Rhythm Society (CHRS), and the International Society for Adult Congenital Heart Disease (ISACHD).
        Heart Rhythm. 2014; 11: e102-e165
        • Stout K.K.
        • Daniels C.J.
        • Aboulhosn J.A.
        • et al.
        2018 AHA/ACC guideline for the management of adults with congenital heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        J Am Coll Cardiol. 2019; 73: 1494-1563
        • Hoffmann A.
        • Chockalingam P.
        • Balint O.H.
        • et al.
        Cerebrovascular accidents in adult patients with congenital heart disease.
        Heart. 2010; 96: 1223-1226
      1. Huynh K. Milestone 10: era of the NOACs [e-pub ahead of print]. Nat Rev Cardiol https://doi.org/10.1038/nrcardio.2017.180, accessed February 12, 2018.

        • 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
        • Bromley A.
        • Plitt A.
        A review of the role of non-vitamin K oral anticoagulants in the acute and long-term treatment of venous thromboembolism.
        Cardiol Ther. 2018; 7: 1-13
        • Eikelboom J.W.
        • Connolly S.J.
        • Brueckmann M.
        • et al.
        Dabigatran vs warfarin in patients with mechanical heart valves.
        N Engl J Med. 2013; 369: 1206-1214
        • Cheng K.
        • Harrogate S.
        • Orchard E.
        The use of novel oral anticoagulants in adult congenital heart disease: a single center experience.
        Am J Cardiol. 2016; 117: 312-313
        • Georgekutty J.
        • Kazerouninia A.
        • Wang Y.
        • et al.
        Novel oral anticoagulant use in adult Fontan patients: a single center experience.
        Congenit Heart Dis. 2018; 13: 541-547
        • Pinto C.
        • Samuel B.P.
        • Ratnasamy C.
        • Vettukattil J.J.
        Thrombosis in Fontan patient on apixaban.
        Int J Cardiol. 2015; 182: 66-67
        • Pujol C.
        • Niesert A.C.
        • Engelhardt A.
        • et al.
        Usefulness of direct oral anticoagulants in adult congenital heart disease.
        Am J Cardiol. 2016; 117: 450-455
        • Yang H.
        • Bouma B.J.
        • Mulder B.J.M.
        Is initiating NOACs for atrial arrhythmias safe in adults with congenital heart disease?.
        Cardiovasc Drugs Ther. 2017; 31: 413-417
        • Lip G.Y.H.
        • Collet J.P.
        • Caterina R.
        • et al.
        Antithrombotic therapy in atrial fibrillation associated with valvular heart disease: a joint consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology Working Group on Thrombosis, endorsed by the ESC Working Group on Valvular Heart Disease, Cardiac Arrhythmia Society of Southern Africa (CASSA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), South African Heart (SA Heart) Association and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLEACE).
        Europace. 2017; 19: 1757-1758
        • Wan D.
        • Tsui C.
        • Kiess M.
        • et al.
        Anticoagulation for thromboembolic risk reduction in adults with congenital heart disease.
        Can J Cardiol. 2017; 33: 1597-1603
        • Masuda K.
        • Ishizu T.
        • Niwa K.
        • et al.
        Increased risk of thromboembolic events in adult congenital heart disease patients with atrial tachyarrhythmias.
        Int J Cardiol. 2017; 234: 69-75
        • Bouchardy J.
        • Therrien J.
        • Pilote L.
        • et al.
        Atrial arrhythmias in adults with congenital heart disease.
        Circulation. 2009; 120: 1679-1686
        • Waldmann V.
        • Laredo M.
        • Abadir S.
        • Mondesert B.
        • Khairy P.
        Atrial fibrillation in adults with congenital heart disease.
        Int J Cardiol. 2019; 287: 148-154
        • Heidendael J.F.
        • Bokma J.P.
        • de Groot J.R.
        • et al.
        Weighing the risks: thrombotic and bleeding events in adults with atrial arrhythmias and congenital heart disease.
        Int J Cardiol. 2015; 186: 315-320
        • Khairy P.
        • Aboulhosn J.
        • Broberg C.S.
        • et al.
        Thromboprophylaxis for atrial arrhythmias in congenital heart disease: a multicenter study.
        Int J Cardiol. 2016; 223: 729-735
        • Khairy P.
        • Fernandes S.M.
        • Mayer Jr., J.E.
        • et al.
        Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery.
        Circulation. 2008; 117: 85-92
        • Diller G.P.
        • Giardini A.
        • Dimopoulos K.
        • et al.
        Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients.
        Eur Heart J. 2010; 31: 3073-3083
        • Pundi K.N.
        • Johnson J.N.
        • Dearani J.A.
        • et al.
        40-Year follow-up after the Fontan Operation: long-term outcomes of 1,052 patients.
        J Am Coll Cardiol. 2015; 66: 1700-1710
        • Giglia T.M.
        • Massicotte M.P.
        • Tweddell J.S.
        • et al.
        Prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the American Heart Association.
        Circulation. 2013; 128: 2622-2703
        • McCrindle B.W.
        • Manlhiot C.
        • Cochrane A.
        • et al.
        Factors associated with thrombotic complications after the Fontan procedure: a secondary analysis of a multicenter, randomized trial of primary thromboprophylaxis for 2 years after the Fontan procedure.
        J Am Coll Cardiol. 2013; 61: 346-353
        • Balling G.
        Fontan anticoagulation: a never-ending debate?.
        J Am Coll Cardiol. 2016; 68: 1320-1322
        • Jensen A.S.
        • Idorn L.
        • Thomsen C.
        • et al.
        Prevalence of cerebral and pulmonary thrombosis in patients with cyanotic congenital heart disease.
        Heart. 2015; 101: 1540-1546
        • Silversides C.K.
        • Granton J.T.
        • Konen E.
        • et al.
        Pulmonary thrombosis in adults with Eisenmenger syndrome.
        J Am Coll Cardiol. 2003; 42: 1982-1987
        • Niwa K.
        • Perloff J.K.
        • Kaplan S.
        • Child J.S.
        • Miner P.D.
        Eisenmenger syndrome in adults: ventricular septal defect, truncus arteriosus, univentricular heart.
        J Am Coll Cardiol. 1999; 34: 223-232
        • Broberg C.S.
        • Ujita M.
        • Prasad S.
        • et al.
        Pulmonary arterial thrombosis in Eisenmenger syndrome is associated with biventricular dysfunction and decreased pulmonary flow velocity.
        J Am Coll Cardiol. 2007; 50: 634-642
        • Perloff J.K.
        • Hart E.M.
        • Greaves S.M.
        • Miner P.D.
        • Child J.S.
        Proximal pulmonary arterial and intrapulmonary radiologic features of Eisenmenger syndrome and primary pulmonary hypertension.
        Am J Cardiol. 2003; 92: 182-187
        • Daliento L.
        • Somerville J.
        • Presbitero P.
        • et al.
        Eisenmenger syndrome. Factors relating to deterioration and death.
        Eur Heart J. 1998; 19: 1845-1855
        • Oechslin E.
        • Mebus S.
        • Schulze-Neick I.
        • et al.
        The adult patient with Eisenmenger syndrome: a medical update after Dana Point Part III: specific management and surgical aspects.
        Curr Cardiol Rev. 2010; 6: 363-372
        • Diller G.P.
        • Korten M.A.
        • Bauer U.M.
        • et al.
        Current therapy and outcome of Eisenmenger syndrome: data of the German National Register for congenital heart defects.
        Eur Heart J. 2016; 37: 1449-1455
        • Sandoval J.
        • Santos L.E.
        • Cordova J.
        • et al.
        Does anticoagulation in Eisenmenger syndrome impact long-term survival?.
        Congenit Heart Dis. 2012; 7: 268-276
        • Ammash N.
        • Warnes C.A.
        Cerebrovascular events in adult patients with cyanotic congenital heart disease.
        J Am Coll Cardiol. 1996; 28: 768-772
        • Jensen A.S.
        • Broberg C.S.
        • Rydman R.
        • et al.
        Impaired right, left, or biventricular function and resting oxygen saturation are associated with mortality in Eisenmenger syndrome: a clinical and cardiovascular magnetic resonance study.
        Circ Cardiovasc Imaging. 2015; 8e003596
        • Perloff J.K.
        Systemic complications of cyanosis in adults with congenital heart disease. Hematologic derangements, renal function, and urate metabolism.
        Cardiol Clin. 1993; 11: 689-699
        • Kuijpers T.
        • Spencer F.A.
        • Siemieniuk R.A.C.
        • et al.
        Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy alone for management of cryptogenic stroke? A clinical practice guideline.
        BMJ. 2018; 362: k2515
        • DeSimone C.V.
        • Friedman P.A.
        • Noheria A.
        • et al.
        Stroke or transient ischemic attack in patients with transvenous pacemaker or defibrillator and echocardiographically detected patent foramen ovale.
        Circulation. 2013; 128: 1433-1441
        • Khairy P.
        • Landzberg M.J.
        • Gatzoulis M.A.
        • et al.
        Transvenous pacing leads and systemic thromboemboli in patients with intracardiac shunts: a multicenter study.
        Circulation. 2006; 113: 2391-2397
        • Hoffman M.
        • Monroe D.M.
        Impact of non-vitamin K antagonist oral anticoagulants from a basic science perspective.
        Arterioscler Thromb Vasc Biol. 2017; 37: 1812-1818
        • 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
        • Pollack Jr., C.V.
        • Reilly P.A.
        • Eikelboom J.
        • et al.
        Idarucizumab for dabigatran reversal.
        N Engl J Med. 2015; 373: 511-520
        • Jaffer I.H.
        • Stafford A.R.
        • Fredenburgh J.C.
        • et al.
        Dabigatran is less effective than warfarin at attenuating mechanical heart valve-induced thrombin generation.
        J Am Heart Assoc. 2015; 4e002322
        • Aimo A.
        • Giugliano R.P.
        • De Caterina R.
        Non-vitamin K antagonist oral anticoagulants for mechanical heart valves.
        Circulation. 2018; 138: 1356-1365
        • Connolly S.J.
        • Milling Jr., 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
        • Patel M.R.
        • Mahaffey K.W.
        • Garg J.
        • et al.
        Rivaroxaban vs warfarin in nonvalvular atrial fibrillation.
        N Engl J Med. 2011; 365: 883-891
        • Giugliano R.P.
        • Ruff C.T.
        • Braunwald E.
        • et al.
        Edoxaban vs warfarin in patients with atrial fibrillation.
        N Engl J Med. 2013; 369: 2093-2104
        • Connolly S.J.
        • Ezekowitz M.D.
        • Yusuf S.
        • et al.
        Dabigatran vs warfarin in patients with atrial fibrillation.
        N Engl J Med. 2009; 361: 1139-1151
        • Granger C.B.
        • Alexander J.H.
        • McMurray J.J.
        • et al.
        Apixaban vs warfarin in patients with atrial fibrillation.
        N Engl J Med. 2011; 365: 981-992
        • De Caterina R.
        • Renda G.
        • Carnicelli A.P.
        • et al.
        Valvular heart disease patients on edoxaban or warfarin in the ENGAGE AF-TIMI 48 Trial.
        J Am Coll Cardiol. 2017; 69: 1372-1382
        • Ezekowitz M.D.
        • Nagarakanti R.
        • Noack H.
        • et al.
        Comparison of dabigatran and warfarin in patients with atrial fibrillation and valvular heart disease: the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy).
        Circulation. 2016; 134: 589-598
        • Caldeira D.
        • David C.
        • Costa J.
        • Ferreira J.J.
        • Pinto F.J.
        Non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and valvular heart disease: systematic review and meta-analysis.
        Eur Heart J Cardiovasc Pharmacother. 2018; 4: 111-118
        • Vinereanu D.
        • Wang A.
        • Mulder H.
        • et al.
        Outcomes in anticoagulated patients with atrial fibrillation and with mitral or aortic valve disease.
        Heart. 2018; 104: 1292-1299
        • Pan K.L.
        • Singer D.E.
        • Ovbiagele B.
        • et al.
        Effects of non-vitamin K antagonist oral anticoagulants vs warfarin in patients with atrial fibrillation and valvular heart disease: a systematic review and meta-analysis.
        J Am Heart Assoc. 2017; 6e005835
        • Breithardt G.
        • Baumgartner H.
        • Berkowitz S.D.
        • et al.
        Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial.
        Eur Heart J. 2014; 35: 3377-3385
        • Carnicelli A.P.
        • De Caterina R.
        • Halperin J.L.
        • et al.
        Edoxaban for the prevention of thromboembolism in patients with atrial fibrillation and bioprosthetic valves.
        Circulation. 2017; 135: 1273-1275
        • Steffel J.
        • Verhamme P.
        • Potpara T.S.
        • et al.
        The 2018 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
        Eur Heart J. 2018; 39: 1330-1393
        • Windecker S.
        • Tijssen J.
        • Giustino G.
        • et al.
        Trial design: rivaroxaban for the prevention of major cardiovascular events after transcatheter aortic valve replacement: rationale and design of the GALILEO study.
        Am Heart J. 2017; 184: 81-87
        • Savarese G.
        • Giugliano R.P.
        • Rosano G.M.
        • et al.
        Efficacy and safety of novel oral anticoagulants in patients with atrial fibrillation and heart failure: a meta-analysis.
        JACC Heart Fail. 2016; 4: 870-880
        • Xiong Q.
        • Lau Y.C.
        • Senoo K.
        • et al.
        Non-vitamin K antagonist oral anticoagulants (NOACs) in patients with concomitant atrial fibrillation and heart failure: a systemic review and meta-analysis of randomized trials.
        Eur J Heart Fail. 2015; 17: 1192-1200
        • Park C.S.
        • Choi E.K.
        • Kim H.M.
        • et al.
        Increased risk of major bleeding in underweight patients with atrial fibrillation who were prescribed non-vitamin K antagonist oral anticoagulants.
        Heart Rhythm. 2017; 14: 501-507
        • Dimopoulos K.
        • Diller G.P.
        • Koltsida E.
        • et al.
        Prevalence, predictors, and prognostic value of renal dysfunction in adults with congenital heart disease.
        Circulation. 2008; 117: 2320-2328
        • Diener H.C.
        • Aisenberg J.
        • Ansell J.
        • et al.
        Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 2.
        Eur Heart J. 2017; 38: 860-868
        • Siontis K.C.
        • Zhang X.
        • Eckard A.
        • et al.
        Outcomes associated with apixaban use in patients with end-stage kidney disease and atrial fibrillation in the United States.
        Circulation. 2018; 138: 1519-1529
        • January C.T.
        • Wann L.S.
        • Calkins H.
        • et al.
        2019 AHA/ACC/HRS focused update of the 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 Clinical Practice Guidelines and the Heart Rhythm Society [erratum in: 2019;74:599].
        J Am Coll Cardiol. 2019; 74: 104-132
        • Lui G.K.
        • Saidi A.
        • Bhatt A.B.
        • et al.
        Diagnosis and management of noncardiac complications in adults with congenital heart disease: a scientific statement from the American Heart Association.
        Circulation. 2017; 136: e348-e392
        • Beyer-Westendorf J.
        • Michalski F.
        • Tittl L.
        • Hauswald-Dorschel S.
        • Marten S.
        Management and outcomes of vaginal bleeding and heavy menstrual bleeding in women of reproductive age on direct oral anti-factor Xa inhibitor therapy: a case series.
        Lancet Haematol. 2016; 3: e480-e488
        • De Crem N.
        • Peerlinck K.
        • Vanassche T.
        • et al.
        Abnormal uterine bleeding in VTE patients treated with rivaroxaban compared to vitamin K antagonists.
        Thromb Res. 2015; 136: 749-753
        • Chatterjee S.
        • Sardar P.
        • Biondi-Zoccai G.
        • Kumbhani D.J.
        New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation.
        JAMA Neurol. 2013; 70: 1486-1490
        • Raparelli V.
        • Proietti M.
        • Cangemi R.
        • et al.
        Adherence to oral anticoagulant therapy in patients with atrial fibrillation. Focus on non-vitamin K antagonist oral anticoagulants.
        Thromb Haemost. 2017; 117: 209-218
        • Chang S.H.
        • Chou I.J.
        • Yeh Y.H.
        • et al.
        Association between use of non-vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation.
        JAMA. 2017; 318: 1250-1259
        • Denas G.
        • Gennaro N.
        • Ferroni E.
        • et al.
        Effectiveness and safety of oral anticoagulation with non-vitamin K antagonists compared to well-managed vitamin K antagonists in naive patients with non-valvular atrial fibrillation: propensity score matched cohort study.
        Int J Cardiol. 2017; 249: 198-203
        • Mahaffey K.W.
        • Wojdyla D.
        • Hankey G.J.
        • 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
        • Diener H.C.
        • Aisenberg J.
        • Ansell J.
        • et al.
        Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 1.
        Eur Heart J. 2017; 38: 852-859
        • Renda G.
        • Ricci F.
        • Giugliano R.P.
        • De Caterina R.
        Non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and valvular heart disease.
        J Am Coll Cardiol. 2017; 69: 1363-1371
        • Avezum A.
        • Lopes R.D.
        • Schulte P.J.
        • et al.
        Apixaban in comparison with warfarin in patients with atrial fibrillation and valvular heart disease: findings from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.
        Circulation. 2015; 132: 624-632
        • Noseworthy P.A.
        • Yao X.
        • Shah N.D.
        • Gersh B.J.
        Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants vs warfarin in patients with atrial fibrillation and valvular heart disease.
        Int J Cardiol. 2016; 209: 181-183