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Thorac Cardiovasc Surg 2023; 71(03): 189-194
DOI: 10.1055/s-0041-1736242
Review Article

Factor Xa Inhibitors for Patients after Mechanical Heart Valve Replacement?

Stephen Gerfer 
1   Department of Cardiothoracic Surgery, Heart Center, University Hospital of Cologne, University of Cologne, Cologne, Germany
,
Maria Grandoch
2   Institute of Pharmacology and Clinical Pharmacology, Medical Faculty and University Hospital of Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
,
Thorsten C.W. Wahlers
1   Department of Cardiothoracic Surgery, Heart Center, University Hospital of Cologne, University of Cologne, Cologne, Germany
,
Elmar W. Kuhn
1   Department of Cardiothoracic Surgery, Heart Center, University Hospital of Cologne, University of Cologne, Cologne, Germany
› Author Affiliations Funding None.
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Abstract

Patients with a mechanical heart valve need a lifelong anticoagulation due to the increased risk of valve thrombosis and thrombo-embolism. Currently, vitamin K antagonists (VKA) are the only approved class of oral anticoagulants, but relevant interactions and side effects lead to a large number of patients not achieving the optimal therapeutic target international normalized ration (INR). Therefore, steady measurements of the INR are imperative to ensure potent anticoagulation within a distinctive range. Direct oral anticoagulants (DOACs) with newer agents could serve as a possible alternative to VKAs in this patient cohort. DOACs are approved for several indications, e.g., atrial fibrillation (AF). They only have a minor interaction potential, which is why monitoring is not needed. Thereby, DOACs improve the livability of patients in need of chronical anticoagulation compared with VKAs. In contrast to dual platelet inhibition using aspirin in combination with an ADP receptor antagonist and the direct thrombin inhibitor dabigatran, the oral factor Xa inhibitors apixaban and rivaroxaban show promising results according to current evidence. In small-scale studies, factor Xa inhibitors were able to prevent thrombosis and thrombo-embolic events in patients with mechanical heart valves. Finally, DOACs seem to represent a feasible treatment option in patients with mechanical heart valves, but further studies are needed to evaluate clinical safety. In addition to the ongoing PROACT Xa trial with apixaban in patients after aortic On-X valve implantation, studies in an all-comer collective with rivaroxaban could be promising.

Keywords

direct oral anticoagulation - dabigatran - rivaroxaban - Edoxaban - apixaban - mechanical heart valve - mechanical mitral valve - mechanical aortic valve


Publication History

Received: 02 May 2021

Accepted: 20 August 2021

Article published online:
11 December 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Dangas GD, Weitz JI, Giustino G, Makkar R, Mehran R. Prosthetic heart valve thrombosis. J Am Coll Cardiol 2016; 68 (24) 2670-2689
    CrossrefPubMedGoogle Scholar
  • 2 Wiegner R, Chakraborty S, Huber-Lang M. Complement-coagulation crosstalk on cellular and artificial surfaces. Immunobiology 2016; 221 (10) 1073-1079
    CrossrefPubMedGoogle Scholar
  • 3 Altman R, Hemker HC. Contact activation in the extrinsic blood clotting system. Thromb Diath Haemorrh 1967; 18 (3-4): 525-531
    PubMedGoogle Scholar
  • 4 Stavrou E, Schmaier AH. Factor XII: what does it contribute to our understanding of the physiology and pathophysiology of hemostasis & thrombosis. Thromb Res 2010; 125 (03) 210-215
    CrossrefPubMedGoogle Scholar
  • 5 Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation in hemostasis and thrombosis. Arterioscler Thromb Vasc Biol 2007; 27 (08) 1687-1693
    CrossrefPubMedGoogle Scholar
  • 6 Jaffer IH, Stafford AR, Fredenburgh JC, Whitlock RP, Chan NC, Weitz JI. Dabigatran is less effective than warfarin at attenuating mechanical heart valve-induced thrombin generation. J Am Heart Assoc 2015; 4 (08) e002322
    CrossrefPubMedGoogle Scholar
  • 7 Sparkenbaugh EM, Chantrathammachart P, Wang S. et al. Excess of heme induces tissue factor-dependent activation of coagulation in mice. Haematologica 2015; 100 (03) 308-314
    CrossrefPubMedGoogle Scholar
  • 8 Aimo A, Giugliano RP, De Caterina R, Non-Vitamin K. Non-vitamin K antagonist oral anticoagulants for mechanical heart valves: is the door still open?. Circulation 2018; 138 (13) 1356-1365
    CrossrefPubMedGoogle Scholar
  • 9 Noble S, Asgar A, Cartier R, Virmani R, Bonan R. Anatomo-pathological analysis after CoreValve revalving system implantation. EuroIntervention 2009; 5 (01) 78-85
    CrossrefPubMedGoogle Scholar
  • 10 Wolberg AS, Aleman MM, Leiderman K, Machlus KR. Procoagulant activity in hemostasis and thrombosis: Virchow's triad revisited. Anesth Analg 2012; 114 (02) 275-285
    CrossrefPubMedGoogle Scholar
  • 11 Chambers J, Cross J, Deverall P, Sowton E. Echocardiographic description of the CarboMedics bileaflet prosthetic heart valve. J Am Coll Cardiol 1993; 21 (02) 398-405
    CrossrefPubMedGoogle Scholar
  • 12 Seiler C. Management and follow up of prosthetic heart valves. Heart 2004; 90 (07) 818-824
    CrossrefPubMedGoogle Scholar
  • 13 Freudenberger RS, Hellkamp AS, Halperin JL. et al; SCD-HeFT Investigators. Risk of thromboembolism in heart failure: an analysis from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Circulation 2007; 115 (20) 2637-2641
    CrossrefPubMedGoogle Scholar
  • 14 Roudaut R, Serri K, Lafitte S. Thrombosis of prosthetic heart valves: diagnosis and therapeutic considerations. Heart 2007; 93 (01) 137-142
    CrossrefPubMedGoogle Scholar
  • 15 Nishimura RA, Otto CM, Bonow RO. et al. 2017 AHA/ACC focused update of the 2014 AHA/ACC Guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017; 135 (25) e1159-e1195
    CrossrefPubMedGoogle Scholar
  • 16 Baumgartner H, Falk V, Bax JJ. et al; ESC Scientific Document Group. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J 2017; 38 (36) 2739-2791
    CrossrefPubMedGoogle Scholar
  • 17 Cannegieter SC, Rosendaal FR, Briët E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994; 89 (02) 635-641
    CrossrefPubMedGoogle Scholar
  • 18 Orensky IA, Holdford DA. Predictors of noncompliance with warfarin therapy in an outpatient anticoagulation clinic. Pharmacotherapy 2005; 25 (12) 1801-1808
    CrossrefPubMedGoogle Scholar
  • 19 Kimmel SE, Chen Z, Price M. et al. The influence of patient adherence on anticoagulation control with warfarin: results from the International Normalized Ratio Adherence and Genetics (IN-RANGE) Study. Arch Intern Med 2007; 167 (03) 229-235
    CrossrefPubMedGoogle Scholar
  • 20 Butchart EG, Payne N, Li HH, Buchan K, Mandana K, Grunkemeier GL. Better anticoagulation control improves survival after valve replacement. J Thorac Cardiovasc Surg 2002; 123 (04) 715-723
    CrossrefPubMedGoogle Scholar
  • 21 Almeida GdeQ, Noblat LdeA, Passos LC, do Nascimento HF. Quality of life analysis of patients in chronic use of oral anticoagulant: an observational study. Health Qual Life Outcomes 2011; 9: 91
    CrossrefPubMedGoogle Scholar
  • 22 Eikelboom JW, Connolly SJ, Brueckmann M. et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013; 369 (13) 1206-1214
    CrossrefPubMedGoogle Scholar
  • 23 Iribarne A, Leavitt BJ, Robich MP. et al; Northern New England Cardiovascular Disease Study Group. Tissue versus mechanical aortic valve replacement in younger patients: a multicenter analysis. J Thorac Cardiovasc Surg 2019; 158 (06) 1529-1538.e2
    CrossrefPubMedGoogle Scholar
  • 24 Wilke T, Bauer S, Mueller S, Kohlmann T, Bauersachs R. Patient preferences for oral anticoagulation therapy in atrial fibrillation: a systematic literature review. Patient 2017; 10 (01) 17-37
    CrossrefPubMedGoogle Scholar
  • 25 Connolly SJ, Ezekowitz MD, Yusuf S. et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12) 1139-1151
    Google Scholar
  • 26 Patel MR, Mahaffey KW, Garg J. et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
    Google Scholar
  • 27 Proietti M, Romanazzi I, Romiti GF, Farcomeni A, Lip GYH. Real-world use of apixaban for stroke prevention in atrial fibrillation: a systematic review and meta-analysis. Stroke 2018; 49 (01) 98-106
    CrossrefPubMedGoogle Scholar
  • 28 Franco Moreno AI, Martín Díaz RM, García Navarro MJ. Direct oral anticoagulants: an update. Med Clin (Barc) 2018; 151 (05) 198-206
    CrossrefPubMedGoogle Scholar
  • 29 Maegdefessel L, Linde T, Krapiec F. et al. In vitro comparison of dabigatran, unfractionated heparin, and low-molecular-weight heparin in preventing thrombus formation on mechanical heart valves. Thromb Res 2010; 126 (03) e196-e200
    CrossrefPubMedGoogle Scholar
  • 30 McKellar SH, Abel S, Camp CL, Suri RM, Ereth MH, Schaff HV. Effectiveness of dabigatran etexilate for thromboprophylaxis of mechanical heart valves. J Thorac Cardiovasc Surg 2011; 141 (06) 1410-1416
    CrossrefPubMedGoogle Scholar
  • 31 Van de Werf F, Brueckmann M, Connolly SJ. et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: THE Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN). Am Heart J 2012; 163 (06) 931-937.e1
    CrossrefPubMedGoogle Scholar
  • 32 Jaffer IH, Fredenburgh JC, Stafford A, Whitlock RP, Weitz JI. Rivaroxaban and dabigatran for suppression of mechanical heart valve-induced thrombin generation. Ann Thorac Surg 2020; 110 (02) 582-590
    CrossrefPubMedGoogle Scholar
  • 33 Kaeberich A, Reindl I, Raaz U. et al. Comparison of unfractionated heparin, low-molecular-weight heparin, low-dose and high-dose rivaroxaban in preventing thrombus formation on mechanical heart valves: results of an in vitro study. J Thromb Thrombolysis 2011; 32 (04) 417-425
    CrossrefPubMedGoogle Scholar
  • 34 Greiten LE, McKellar SH, Rysavy J, Schaff HV. Effectiveness of rivaroxaban for thromboprophylaxis of prosthetic heart valves in a porcine heterotopic valve model. Eur J Cardiothorac Surg 2014; 45 (05) 914-919
    CrossrefPubMedGoogle Scholar
  • 35 Durães AR, Bitar YSL, Lima MLG. et al. Usefulness and safety of rivaroxaban in patients following isolated mitral valve replacement with a mechanical prosthesis. Am J Cardiol 2018; 122 (06) 1047-1050
    CrossrefPubMedGoogle Scholar
  • 36 Durães AR, de Souza Lima Bitar Y, Filho JAL. et al. Rivaroxaban versus warfarin in patients with mechanical heart valve: rationale and design of the RIWA study. Drugs R D 2018; 18 (04) 303-308
    CrossrefPubMedGoogle Scholar
  • 37 Duraes AR, de Souza Lima Bitar Y, Schonhofen IS. et al. Rivaroxaban versus warfarin in patients with mechanical heart valves: open-label, proof-of-concept trial-The RIWA study. Am J Cardiovasc Drugs 2021; 21 (03) 363-371
    CrossrefPubMedGoogle Scholar
  • 38 Roost E, Weber A, Alberio L. et al. Rivaroxaban in patients with mechanical heart valves: a pilot study. Thromb Res 2020; 186: 1-6
    CrossrefPubMedGoogle Scholar
  • 39 Lester PA, Coleman DM, Diaz JA. et al. Apixaban versus warfarin for mechanical heart valve thromboprophylaxis in a swine aortic heterotopic valve model. Arterioscler Thromb Vasc Biol 2017; 37 (05) 942-948
    CrossrefPubMedGoogle Scholar
  • 40 Jawitz OK, Wang TY, Lopes RD. et al. Rationale and design of PROACT Xa: a randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with a mechanical On-X Aortic Heart Valve. Am Heart J 2020; 227: 91-99
    CrossrefPubMedGoogle Scholar
  • 41 Puskas JD, Gerdisch M, Nichols D. et al; PROACT Investigators. Anticoagulation and antiplatelet strategies after on-X mechanical aortic valve replacement. J Am Coll Cardiol 2018; 71 (24) 2717-2726
    CrossrefPubMedGoogle Scholar
  • 42 Sharma S, Singh S. Dabigatran in patients with mechanical heart valves. N Engl J Med 2014; 370 (04) 381-382
    CrossrefPubMedGoogle Scholar
  • 43 Hylek EM. Dabigatran and mechanical heart valves—not as easy as we hoped. N Engl J Med 2013; 369 (13) 1264-1266
    CrossrefPubMedGoogle Scholar
  • 44 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Haemost 2003; 1 (07) 1504-1514
    CrossrefPubMedGoogle Scholar
  • 45 Chan NC, Weitz JI, Eikelboom JW. Anticoagulation for mechanical heart valves: will oral factor Xa inhibitors be effective?. Arterioscler Thromb Vasc Biol 2017; 37 (05) 743-745
    CrossrefPubMedGoogle Scholar
  • 46 Forsberg P, DeSancho MT. Role of novel anticoagulants for patients with mechanical heart valves. Curr Atheroscler Rep 2014; 16 (11) 448
    CrossrefPubMedGoogle Scholar
  • 47 Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 2009; ;15 Suppl 1: 9S-16S
    CrossrefPubMedGoogle Scholar
  • 48 Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 2014; 53 (01) 1-16
    CrossrefPubMedGoogle Scholar
  • 49 Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review. Clin Pharmacokinet 2019; 58 (10) 1265-1279
    CrossrefPubMedGoogle Scholar