Factor Xa Inhibitors for Patients after Mechanical Heart Valve Replacement?

Stephen Gerfer; Maria Grandoch; Thorsten C.W. Wahlers; Elmar W. Kuhn

doi:10.1055/s-0041-1736242

The Thoracic and Cardiovascular Surgeon, Table of Contents

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?

Authors

Stephen Gerfer

¹Department of Cardiothoracic Surgery, Heart Center, University Hospital of Cologne, University of Cologne, Cologne, Germany
Maria Grandoch

²Institute of Pharmacology and Clinical Pharmacology, Medical Faculty and University Hospital of Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
Thorsten C.W. Wahlers

¹Department of Cardiothoracic Surgery, Heart Center, University Hospital of Cologne, University of Cologne, Cologne, Germany
Elmar W. Kuhn

¹Department of Cardiothoracic Surgery, Heart Center, University Hospital of Cologne, University of Cologne, Cologne, Germany

Abstract

All articles of this category

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

Full Text

References

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
2 Wiegner R, Chakraborty S, Huber-Lang M. Complement-coagulation crosstalk on cellular and artificial surfaces. Immunobiology 2016; 221 (10) 1073-1079
3 Altman R, Hemker HC. Contact activation in the extrinsic blood clotting system. Thromb Diath Haemorrh 1967; 18 (3-4): 525-531
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
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
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
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
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
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
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
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
12 Seiler C. Management and follow up of prosthetic heart valves. Heart 2004; 90 (07) 818-824
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
14 Roudaut R, Serri K, Lafitte S. Thrombosis of prosthetic heart valves: diagnosis and therapeutic considerations. Heart 2007; 93 (01) 137-142
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
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
17 Cannegieter SC, Rosendaal FR, Briët E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994; 89 (02) 635-641
18 Orensky IA, Holdford DA. Predictors of noncompliance with warfarin therapy in an outpatient anticoagulation clinic. Pharmacotherapy 2005; 25 (12) 1801-1808
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
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
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
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
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
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
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
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
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
28 Franco Moreno AI, Martín Díaz RM, García Navarro MJ. Direct oral anticoagulants: an update. Med Clin (Barc) 2018; 151 (05) 198-206
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
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
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
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
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
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
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
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
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
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
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
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
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
42 Sharma S, Singh S. Dabigatran in patients with mechanical heart valves. N Engl J Med 2014; 370 (04) 381-382
43 Hylek EM. Dabigatran and mechanical heart valves—not as easy as we hoped. N Engl J Med 2013; 369 (13) 1264-1266
44 Mann KG, Brummel K, Butenas S. What is all that thrombin for?. J Thromb Haemost 2003; 1 (07) 1504-1514
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
46 Forsberg P, DeSancho MT. Role of novel anticoagulants for patients with mechanical heart valves. Curr Atheroscler Rep 2014; 16 (11) 448
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
48 Mueck W, Stampfuss J, Kubitza D, Becka M. Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 2014; 53 (01) 1-16
49 Byon W, Garonzik S, Boyd RA, Frost CE. Apixaban: A Clinical Pharmacokinetic and Pharmacodynamic Review. Clin Pharmacokinet 2019; 58 (10) 1265-1279