Semin Thromb Hemost 2021; 47(06): 724-734
DOI: 10.1055/s-0041-1722846
Review Article

Alternatives for Vitamin K Antagonists as Thromboprophylaxis for Mechanical Heart Valves and Mechanical Circulatory Support Devices: A Systematic Review

Omayra C.D. Liesdek
1   Department of Cardiothoracic Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
2   Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Rolf T. Urbanus
2   Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Linda M. de Heer
1   Department of Cardiothoracic Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Kathelijn Fischer
2   Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Willem J.L. Suyker
1   Department of Cardiothoracic Surgery, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
,
Roger E.G. Schutgens
2   Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
› Author Affiliations

Abstract

The holy grail of anticoagulation in patients with intracardiac devices, such as mechanical heart valves (MHVs) and left ventricular assist devices (LVADs), comprises safe prevention of thrombosis without interrupting normal hemostasis. Device-induced thrombosis and anticoagulant-related bleeding problems are dreaded complications that may cause a significantly reduced quality of life and increased morbidity and mortality. Vitamin K antagonists are the current standard for oral anticoagulation therapy in patients with MHVs and LVADs. Even within the therapeutic range, hemorrhage is the primary complication of these drugs, which emphasizes the need for safer anticoagulants for the prevention of device-induced thrombosis. Device-induced thrombosis is a complex multifactorial phenomenon that likely requires anticoagulant therapy targeting multiple pathways. Here, we review the preclinical and clinical data describing the efficacy of a variety of anticoagulants as thromboprophylaxis after implantation of intracardiac devices.



Publication History

Article published online:
31 May 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Cannegieter SC, Rosendaal FR, Briët E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation 1994; 89 (02) 635-641
  • 2 Labaf A, Grzymala-Lubanski B, Stagmo M. et al. Thromboembolism, major bleeding and mortality in patients with mechanical heart valves- a population-based cohort study. Thromb Res 2014; 134 (02) 354-359
  • 3 Baumann Kreuziger LM, Kim B, Wieselthaler GM. Antithrombotic therapy for left ventricular assist devices in adults: a systematic review. J Thromb Haemost 2015; 13 (06) 946-955
  • 4 Kirklin JK, Naftel DC, Pagani FD. et al. Pump thrombosis in the Thoratec HeartMate II device: an update analysis of the INTERMACS registry. J Heart Lung Transplant 2015; 34 (12) 1515-1526
  • 5 Slaughter MS, Rogers JG, Milano CA. et al; HeartMate II Investigators. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009; 361 (23) 2241-2251
  • 6 Mehra MR, Goldstein DJ, Uriel N. et al; MOMENTUM 3 Investigators. Two-year outcomes with a magnetically levitated cardiac pump in heart failure. N Engl J Med 2018; 378 (15) 1386-1395
  • 7 Slaughter MS, Pagani FD, Rogers JG. et al; HeartMate II Clinical Investigators. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010; 29 (4, Suppl): S1-S39
  • 8 Aaronson KD, Slaughter MS, Miller LW. et al; HeartWare Ventricular Assist Device (HVAD) Bridge to Transplant ADVANCE Trial Investigators. Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation 2012; 125 (25) 3191-3200
  • 9 Rogers JG, Pagani FD, Tatooles AJ. et al. Intrapericardial left ventricular assist device for advanced heart failure. N Engl J Med 2017; 376 (05) 451-460
  • 10 Lin SS, Tiong IY, Asher CR, Murphy MT, Thomas JD, Griffin BP. Prediction of thrombus-related mechanical prosthetic valve dysfunction using transesophageal echocardiography. Am J Cardiol 2000; 86 (10) 1097-1101
  • 11 Dangas GD, Weitz JI, Giustino G, Makkar R, Mehran R. Prosthetic heart valve thrombosis. J Am Coll Cardiol 2016; 68 (24) 2670-2689
  • 12 Kaufmann F, Krabatsch T. Using medical imaging for the detection of adverse events (“incidents”) during the utilization of left ventricular assist devices in adult patients with advanced heart failure. Expert Rev Med Devices 2016; 13 (05) 463-474
  • 13 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. J Am Coll Cardiol 2017; 70 (02) 252-289
  • 14 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
  • 15 Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e44S-e88S
  • 16 Hammermeister K, Sethi GK, Henderson WG, Grover FL, Oprian C, Rahimtoola SH. Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial. J Am Coll Cardiol 2000; 36 (04) 1152-1158
  • 17 Kormos RL, Cowger J, Pagani FD. et al. The Society of Thoracic Surgeons Intermacs Database Annual Report: evolving indications, outcomes, and scientific partnerships. Ann Thorac Surg 2019; 107 (02) 341-353
  • 18 Litzler PY, Smail H, Barbay V. et al. Is anti-platelet therapy needed in continuous flow left ventricular assist device patients? A single-centre experience. Eur J Cardiothorac Surg 2014; 45 (01) 55-59
  • 19 Lalonde SD, Alba AC, Rigobon A. et al. Clinical differences between continuous flow ventricular assist devices: a comparison between HeartMate II and HeartWare HVAD. J Card Surg 2013; 28 (05) 604-610
  • 20 Bashir J, Legare JF, Freed DH, Cheung A, Rao V, Toma M. Multicentre Canadian experience with the HeartWare ventricular assist device: concerns about adverse neurological outcomes. Can J Cardiol 2014; 30 (12) 1662-1667
  • 21 Morgan JA, Brewer RJ, Nemeh HW. et al. Stroke while on long-term left ventricular assist device support: incidence, outcome, and predictors. ASAIO J 2014; 60 (03) 284-289
  • 22 Harvey L, Holley C, Roy SS. et al. Stroke after left ventricular assist device implantation: outcomes in the continuous-flow era. Ann Thorac Surg 2015; 100 (02) 535-541
  • 23 Whitson BA, Eckman P, Kamdar F. et al. Hemolysis, pump thrombus, and neurologic events in continuous-flow left ventricular assist device recipients. Ann Thorac Surg 2014; 97 (06) 2097-2103
  • 24 Teuteberg JJ, Slaughter MS, Rogers JG. et al; ADVANCE Trial Investigators. The HVAD left ventricular assist device: risk factors for neurological events and risk mitigation strategies. JACC Heart Fail 2015; 3 (10) 818-828
  • 25 Frontera JA, Starling R, Cho SM. et al. Risk factors, mortality, and timing of ischemic and hemorrhagic stroke with left ventricular assist devices. J Heart Lung Transplant 2017; 36 (06) 673-683
  • 26 Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348 (9028): 633-638
  • 27 Onishi A, St Ange K, Dordick JS, Linhardt RJ. Heparin and anticoagulation. Front Biosci 2016; 21: 1372-1392
  • 28 Tan CW, Wall M, Rosengart TK, Ghanta RK. How to bridge? Management of anticoagulation in patients with mechanical heart valves undergoing noncardiac surgical procedures. J Thorac Cardiovasc Surg 2019; 158 (01) 200-203
  • 29 Bauer KA, Hawkins DW, Peters PC. et al. Fondaparinux, a synthetic pentasaccharide: the first in a new class of antithrombotic agents - the selective factor Xa inhibitors. Cardiovasc Drug Rev 2002; 20 (01) 37-52
  • 30 Schlitt A, Buerke M, Hauroeder B. et al. Fondaparinux and enoxaparin in comparison to unfractionated heparin in preventing thrombus formation on mechanical heart valves in an ex vivo rabbit model. Thromb Haemost 2003; 90 (02) 245-251
  • 31 Sombolos KI, Fragia TK, Gionanlis LC. et al. Use of fondaparinux as an anticoagulant during hemodialysis: a preliminary study. Int J Clin Pharmacol Ther 2008; 46 (04) 198-203
  • 32 Kalicki RM, Aregger F, Alberio L, Lämmle B, Frey FJ, Uehlinger DE. Use of the pentasaccharide fondaparinux as an anticoagulant during haemodialysis. Thromb Haemost 2007; 98 (06) 1200-1207
  • 33 Mahieu E, Claes K, Jacquemin M. et al. Anticoagulation with fondaparinux for hemodiafiltration in patients with heparin-induced thrombocytopenia: dose-finding study and safety evaluation. Artif Organs 2013; 37 (05) 482-487
  • 34 Tummala R, Kavtaradze A, Gupta A, Ghosh RK. Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. Int J Cardiol 2016; 214: 292-298
  • 35 Ribeiro PA, Al Zaibag M, Idris M. et al. Antiplatelet drugs and the incidence of thromboembolic complications of the St. Jude Medical aortic prosthesis in patients with rheumatic heart disease. J Thorac Cardiovasc Surg 1986; 91 (01) 92-98
  • 36 Hartz RS, LoCicero III J, Kucich V. et al. Comparative study of warfarin versus antiplatelet therapy in patients with a St. Jude Medical valve in the aortic position. J Thorac Cardiovasc Surg 1986; 92 (04) 684-690
  • 37 Schlitt A, Hauroeder B, Buerke M. et al. Effects of combined therapy of clopidogrel and aspirin in preventing thrombus formation on mechanical heart valves in an ex vivo rabbit model. Thromb Res 2002; 107 (1–2): 39-43
  • 38 Schlitt A, von Bardeleben RS, Ehrlich A. et al. Clopidogrel and aspirin in the prevention of thromboembolic complications after mechanical aortic valve replacement (CAPTA). Thromb Res 2003; 109 (2–3): 131-135
  • 39 McKellar SH, Thompson JL, Schaff HV. A model of heterotopic aortic valve replacement for studying thromboembolism prophylaxis in mechanical valve prostheses. J Surg Res 2007; 141 (01) 1-6
  • 40 McKellar SH, Thompson III JL, Garcia-Rinaldi RF, Macdonald RJ, Sundt III TM, Schaff HV. Short- and long-term efficacy of aspirin and clopidogrel for thromboprophylaxis for mechanical heart valves: an in vivo study in swine. J Thorac Cardiovasc Surg 2008; 136 (04) 908-914
  • 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 Eriksson BI, Dahl OE, Rosencher N. et al; RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5 (11) 2178-2185
  • 43 Eriksson BI, Dahl OE, Rosencher N. et al; RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370 (9591): 949-956
  • 44 Eriksson BI, Dahl OE, Huo MH. et al; RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105 (04) 721-729
  • 45 Kakkar AK, Brenner B, Dahl OE. et al; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372 (9632): 31-39
  • 46 Turpie AG, Lassen MR, Davidson BL. et al; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373 (9676): 1673-1680
  • 47 Lassen MR, Ageno W, Borris LC. et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358 (26) 2776-2786
  • 48 Eriksson BI, Borris LC, Friedman RJ. et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358 (26) 2765-2775
  • 49 Schulman S, Kearon C, Kakkar AK. et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
  • 50 Nunnelee JD. Review of an article: oral rivaroxaban for symptomatic venous thromboembolism. The EINSTEIN Investigators et al. N Engl J Med 2010; 363(26):2499-2510. J Vasc Nurs 2011; 29 (02) 89
  • 51 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
  • 52 Ahrens I, Bode C. Rivaroxaban for stroke prevention in atrial fibrillation and secondary prevention in patients with a recent acute coronary syndrome. Future Cardiol 2012; 8 (04) 533-541
  • 53 Masotti L, Campanini M. Pharmacology of new oral anticoagulants: mechanism of action, pharmacokinetics, pharmacodynamics. Ital J Med 2013; 7 (s8): 1-7
  • 54 de Souza Lima Bitar Y, Neto MG, Filho JAL. et al. Comparison of the new oral anticoagulants and warfarin in patients with atrial fibrillation and valvular heart disease: systematic review and meta-analysis. Drugs R D 2019; 19 (02) 117-126
  • 55 Ruff CT, Giugliano RP, 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 (9921): 955-962
  • 56 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
  • 57 Schomburg JL, Medina EM, Lahti MT, Bianco RW. Dabigatran versus warfarin after mechanical mitral valve replacement in the swine model. J Invest Surg 2012; 25 (03) 150-155
  • 58 Thompson JL, Hamner CE, Potter DD, Lewin M, Sundt TM, Schaff HV. Melagatran for thromboprophylaxis after mechanical valve implantation: results in a heterotopic porcine model. J Thorac Cardiovasc Surg 2007; 134 (02) 359-365
  • 59 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
  • 60 Terrovitis JV, Ntalianis A, Kapelios CJ. et al. Dabigatran etexilate as second-line therapy in patients with a left ventricular assist device. Hellenic J Cardiol 2015; 56 (01) 20-25
  • 61 Andreas M, Moayedifar R, Wieselthaler G. et al. Increased thromboembolic events with dabigatran compared with vitamin K antagonism in left ventricular assist device patients: a randomized controlled pilot trial. Circ Heart Fail 2017; 10 (05) e003709
  • 62 Reilly PA, Lehr T, Haertter S. et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
  • 63 D'Angelo A, Della Valle P, Crippa L, Fattorini A, Pattarini E, Viganò D'Angelo S. Relationship between international normalized ratio values, vitamin K-dependent clotting factor levels and in vivo prothrombin activation during the early and steady phases of oral anticoagulant treatment. Haematologica 2002; 87 (10) 1074-1080
  • 64 Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36 (02) 386-399
  • 65 Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007; 21 (03) 131-142
  • 66 Yau JW, Liao P, Fredenburgh JC, Roberts RS, Weitz JI. Only high levels of dabigatran attenuate catheter thrombosis in vitro and in rabbits. Thromb Haemost 2014; 112 (01) 79-86
  • 67 Zhu S, Diamond SL. Contact activation of blood coagulation on a defined kaolin/collagen surface in a microfluidic assay. Thromb Res 2014; 134 (06) 1335-1343
  • 68 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
  • 69 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
  • 70 Grehan JF, Hilbert SL, Ferrans VJ, Droel JS, Salerno CT, Bianco RW. Development and evaluation of a swine model to assess the preclinical safety of mechanical heart valves. J Heart Valve Dis 2000; 9 (05) 710-719
  • 71 Sharma H, Vetrugno V, Ludman P. Reversal of bioprosthetic aortic valve thrombosis using rivaroxaban-a case report. Front Cardiovasc Med 2020; 7: 87
  • 72 Duthoit G, Silvain J, Marijon E. et al. Reduced rivaroxaban dose versus dual antiplatelet therapy after left atrial appendage closure: ADRIFT a randomized pilot study. Circ Cardiovasc Interv 2020; 13 (07) e008481
  • 73 Maas C, Renné T. Coagulation factor XII in thrombosis and inflammation. Blood 2018; 131 (17) 1903-1909
  • 74 Yau JW, Liao P, Fredenburgh JC. et al. Selective depletion of factor XI or factor XII with antisense oligonucleotides attenuates catheter thrombosis in rabbits. Blood 2014; 123 (13) 2102-2107
  • 75 Larsson M, Rayzman V, Nolte MW. et al. A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Sci Transl Med 2014; 6 (222) 222ra17
  • 76 Wallisch M, Lorentz CU, Lakshmanan HHS. et al. Antibody inhibition of contact factor XII reduces platelet deposition in a model of extracorporeal membrane oxygenator perfusion in nonhuman primates. Res Pract Thromb Haemost 2020; 4 (02) 205-216
  • 77 Büller HR, Bethune C, Bhanot S. et al; FXI-ASO TKA Investigators. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372 (03) 232-240
  • 78 Weitz JI, Bauersachs R, Becker B. et al. Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty: the FOXTROT randomized clinical trial. JAMA 2020; 323 (02) 130-139
  • 79 Siller-Matula JM, Plasenzotti R, Spiel A, Quehenberger P, Jilma B. Interspecies differences in coagulation profile. Thromb Haemost 2008; 100 (03) 397-404
  • 80 Preis M, Hirsch J, Kotler A. et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood 2017; 129 (09) 1210-1215