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Use of Direct Oral Anticoagulant Medications For Atrial Fibrillation: Current Recommendations in Valvular Heart Disease

by Brian Cryder, PharmD, BCACP, CACP Associate Professor and Clinical Pharmacist; Midwestern University Chicago College of Pharmacy and Advocate Medical Group; Austin Ballew, PharmD, BCPS Ambulatory Care Clinical Pharmacist; Advocate Medical Group (Sykes Center)

Alternatives to warfarin have been long sought as more practical and safer options for stroke prevention in patients with atrial fibrillation (AF).  As oral direct thrombin inhibitors and factor Xa inhibitors were introduced for use in the United States - starting with dabigatran’s approval in 2010 - it has been with the caveat of “non-valvular” atrial fibrillation.  However, which specific heart valve conditions contraindicate the use of direct oral anticoagulants (DOACs) has not been consistently delineated in medical practice.  Guidelines from the American Heart Association and American College of Cardiology1-2 provide recommendations regarding the choice of oral anticoagulant in many patient subgroups with concomitant AF and valvular heart disease (VHD), but the emergence of transcatheter aortic valve replacement (TAVR) has added a new wave of evidence to consider. (See Table 1). This article aims to outline considerations when using DOACs in the treatment of valvular AF.

Mechanical Prosthetic Heart Valves
Warfarin has long been the sole oral anticoagulant used in patients with mechanical prosthetic valve (MPV) replacements, but in the past decade DOACs have been studied as an alternative.  To date, no past DOAC studies have included patients with concomitant AF and MPV.  

The phase 2 RE-ALIGN study sought to compare dabigatran (dosed to meet plasma trough levels > 50 ng/ml) to warfarin.3  RE-ALIGN primarily aimed to study the pharmacokinetics of dabigatran in this population, but the trial required early discontinuation due to excess in both thromboembolic and hemorrhagic complications when compared to warfarin. Researchers now attribute this therapeutic failure to localized thrombin generation triggering thrombosis in MPV-associated clotting rather than tissue factor as seen in non-valvular atrial fibrillation (NVAF) and venous thrombosis.3-5  Jaffer and colleagues discovered that MPV required dabigatran concentrations > 200 ng/ml to suppress thrombin generation to the same extent that warfarin does when maintained at INR levels between 2.0-3.5 thus  RE-ALIGN’s target of 50 ng/ml was insufficient.4  

More recently, researchers have tested the theory that moving upstream in the clotting cascade to factor Xa inhibition may have greater success in mitigating MPV-associated thrombosis, such as the common practice of using low molecular weight heparins when a patient cannot take warfarin.6-11 Small studies (< 10 patients) and case series utilizing apixaban or rivaroxaban have shown mixed results, but enough positive outcomes for investigators to initiate plans for a larger phase 2 trial comparing rivaroxaban 15 mg twice daily to warfarin.6-11

In vitro laboratory testing performed with apixaban and rivaroxaban revealed that neither anticoagulant suppressed thrombin generation sufficiently at clinically relevant concentrations.12  However, when Xa and thrombin were inhibited simultaneously (rivaroxaban and dabigatran in this investigation) effectiveness was improved, possibly explaining why heparin derivatives remain effective in clinical practice.  This leads many investigators to be pessimistic that rivaroxaban or apixaban alone will consistently provide sufficient anticoagulant coverage.  
Bioprosthetic Heart Valves

DOACs may have a place in therapy for patients with AF and bioprosthetic valves (BPV). Bioprosthetic valves are considered to be less thrombogenic than MPV and guidelines recommend short term anticoagulation (3-6 months) with VKA plus long term aspirin to discourage valve thrombosis.1-2     

Initial data for DOAC use in patients with BPV and AF was limited since it came from the small subgroup analyses of the ARISTOTLE13 and ENGAGE-AF-TIMI 4814 trials, but a later meta-analysis15 pooled a more substantial cohort for analysis.  Compared to VKA, DOACs demonstrated reduction of stroke and systemic embolization (0.59 HR [0.13-2.69 95%CI]), lower risk of major bleeding (0.67 HR [0.27-1.63 CI]) and decreased all cause mortality (0.82 HR [0.24-2.81 CI]).  In a combined safety analysis with BPV and VHD, intracranial hemorrhage (0.46 HR [0.24-0.86 CI]), myocardial infarction (0.70 HR [0.50-0.99 CI], and major adverse cardiovascular events (0.91 HR [0.81-1.01 CI]) were reduced in the DOAC groups. The overall findings of the analysis in BPV mirror the larger population of patients with VHD. While all DOACs were similar in reducing stroke or systemic embolism (SSE), edoxaban 30 mg was associated with less bleeding and rivaroxaban was associated with increased risk of major bleeding including intracerebral hemorrhage (ICH).

These findings are congruent with the recently updated guidelines. Based on evidence provided, anticoagulation with apixaban or edoxaban in patients with AF after bioprosthetic valve replacement is reasonable as supported by the AHA 2019 focused update on Atrial Fibrillation guideline.2
Transcatheter Aortic Valve Replacement

Use of Transcatheter Aortic Valve replacement (TAVR) has increased rapidly from 2.6% of all patients admitted with aortic valve disease in 2012 up to 12.5% of admissions in 2016.16  Approximately 40% of patients requiring TAVR frequently have pre-existing AF or develop new-onset AF post-operatively; both groups carrying increased mortality risk after TAVR.17 Current guidelines recommend a combination of antiplatelet and oral anticoagulation to reduce valve leaflet thrombosis after TAVR.1 These recommendations are supported by limited data, so elucidating preferred antithrombotic options from emerging clinical studies should be prioritized. One limiting factor in applying existing data is that many studies - such as GALILEO18 and ADAPT-TAVR19 - exclude patients with pre-existing indications for anticoagulation, such as AF. Two ongoing studies that included AF patients are the ATLANTIS20 and ENVISAGE-TAVI AF.21

The GALILEO study did not show favorable outcomes for DOACs as it was terminated early due to increased risk of bleeding (1.50, 95% CI 0.95-2.37) and mortality (1.69, 95% CI 1.13-2.53) with rivaroxaban in patients without a pre-existing indication for anticoagulation.  A study by Seeger and colleagues revealed that at thirty days post-operatively, patients with AF taking aspirin and apixaban were less likely to develop life threatening bleeding (3.5% vs 5.3% p<0.01) and had fewer early safety endpoints (13.5% vs. 30.5% p< 0.01) compared to VKA.22   Another smaller study including patients undergoing TAVR with preexisting indications for anticoagulation (not exclusively AF) showed no significant difference in combined endpoint of death, stroke, embolism and bleeding between the DOAC and VKA groups (11% vs. 0.8%, p = 0.45).23 The data trends favored DOAC use over VKA, but was underpowered to produce statistically significant differences.

While there are suggestions of improved bleeding risk with DOAC compared to current practices, further studies are needed to explore duration of therapy and longer observation times while on DOAC therapy. Careful consideration should be taken regarding patient’s thrombotic and bleeding risk. The next year will bring results from a few large randomized controlled trials and may help shed light on this topic.

Native Valve Pathologies

Despite the “non-valvular” inclusion criteria to the large-scale DOAC clinical trials, there were several VHD subtypes that were represented in the study populations.  From the combined cohorts of ARISTOTLE, ENGAGE-AF-TIMI 48, RE-LY, and ROCKET AF there were 10,633 patients with mitral regurgitation, 324 patients with mild mitral stenosis, 2,559 patients with aortic regurgitation, 1,238 patients with aortic stenosis, and 3,303 patients with tricuspid regurgitation.24  A meta-analysis of these four studies showed that in the cohort of VHD patients with AF, DOACs were not significantly different from warfarin in outcomes of overall mortality rate (HR 1.01, 95% CI 0.91-1.12) and major bleeding (HR 0.93, 95% CI 0.67-1.28).  DOACs collectively were better than warfarin in reduction of SSE (HR 0.70, 95% CI 0.60-0.82) similar to what was seen in the strictly non-valvular heart disease population.  Real-world studies have also demonstrated positive outcomes in both the Medicare population25 and a Midwest United States single- center outpatient cardiology practice.26  This data further reinforces the AHA/ACC recommendation “It is reasonable to use a DOAC as an alternative to a VKA in patients with AF and native aortic valve disease, tricuspid valve disease, or MR and a CHA2DS2-VASc score of 2 or greater.”1


Over the next decade, as the DOAC patents expire and become financially accessible to a larger pool of patients, it will be important to ensure efficacy and safety in the appropriate patient population.  Few experts anticipate major changes in current guidelines for DOAC use in MPV, BPV and most VHD, but post-TAVR anticoagulation will be shaped largely by the arrival of new research over the next several years. 

  1. 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: e1159-e1195. DOI: 10.1161/CIR.0000000000000503
  2. January CT, Wann LS, 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.  Circulation 2019; 140: e125-e151. DOI: 10.1161/CIR.0000000000000665
  3. Eikelboom JW, Connolly SJ, Brueckmann M, et al.  Dabigatran versus warfarin in patients with mechanical heart valves.  N Engl J Med.  2013; 369: 1206-1214.  DOI: 10.1056/NEJMoa1300615
  4. Jaffer IH, Stafford AR, Fredenburgh JC, et al.  Dabigatran is less effective than warfarin at attenuating mechanical heart valve-induced thrombin generation.  J Am Heart Assoc. 2015; 4: e002322.  DOI: 10.1161/JAHA.115.002322
  5. Chan NC, Weitz JI, Eikelboom JW.  Anticoagulation for mechanical heart valves: Will oral factor Xa inhibitors be effective? Arterioscler Thromb Vasc Biol 2017; 37: 743-745.  DOI: 10.1161/ATVBAHA.117.309223
  6. 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: 942-948.  DOI: 10.1161/ATVBAHA.116.308649
  7. Roost E, Weber A, Alberio L, et al.  Rivaroxaban in patients with mechanical heart valves: A pilot study.  Thrombosis Research 2020; 186: 1-6. DOI: 10.1016/j.thromres.2019.12.005
  8. Duraes 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: 1047-1050. DOI: 10.1016/j.amjcard.2018.06.015
  9. Duraes AR, Bitar YSL, Filho JA, et al.  Rivaroxaban versus warfarin in patients with mechanical heart valve: rationale and design of the RIWA study.  Drugs in R&D 2018; 18: 303-308.  DOI: 10.1007/s40268-018-0249-5
  10. Carvalho Silva DM, Braga A, de Jesus I, Neves J.  Mechanical prosthetic heart valve thrombosis in a patient receiving rivaroxaban.  Cardiology 2019; 143: 116-120. DOI: 10.1159/000501361
  11. Kumar V, Kelly S, Raizada A, et al.  Mechanical valve thrombosis on rivaroxaban: Are novel anticoagulants really an option? Methodist Debakey Cardovasc J 2017; 13 (2): 73-75. DOI: 10.14797/mdcj-13-2-73
  12. 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; epub ahead of print.  DOI: 10.1016/j.athoracsur.2019.10.091
  13. Guimaraes PO, Pokorney SD, Lopes RD, et al.  Efficacy and safety of apixaban vs warfarin in patients with atrial fibrillation and prior bioprosthetic valve replacement or valve repair: Insights from the ARISTOTLE trial.  Clinical Cardiology 2019; 42: 568-571. DOI: 10.1002/clc.23178
  14. DeCaterina R, Renda G, Carnicelli AP, et al.  Valvular heart disease patients on edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial.  J Am Coll Cardiol 2017; 69 (11): 1372-1382.  DOI: 10.1016/j.jacc.2016.12.031
  15. Malik AH, Yandrapalli S, Aronow WS, Panza JA, Cooper HA.  Oral anticoagulants in atrial fibrillation with valvular heart disease and bioprosthetic heart valves.  Heart 2019; 105: 1432-1436.  DOI: 10.1136/heartjnl-2019-314767
  16. Goldsweig AM, Tak HJ, Chen LW, et al.  The evolving management of aortic valve disease: 5-year trends in SAVR, TAVR and medical therapy.  Am J Cardiol 2019; 124: 763-771. DOI: 10.1016/j.amjcard.2019.05.044
  17. Sherwood MW, Vora AN.  Challenges in aortic stenosis: Review of antiplatelet/anticoagulant therapy management with transcatheter aortic valve replacement (TAVR): TAVR with recent PCI, TAVR in the patient with atrial fibrillation, and TAVR thrombosis management.  Curr Cardiol Rep 2018; 20: 130.  DOI: 10.1007/s11886-018-1073-9  
  18. Dangas GD, Tijssen JGP, Wohrle J, et al.  A controlled trial of rivaroxaban after transcatheter aortic-valve replacement.  N Engl J Med 2020; 382: 120-9.  DOI: 10.1056/NEJMoa1911425
  19. Park DW.  Anticoagulation versus dual antiplatelet therapy for preventing leaflet thrombosis and cerebral embolization after transcatheter aortic valve thrombosis (ADAPT-TAVR).  Retrieved from:
  20. Collet JP, Berti S, Cequier A, et al.  Oral anti-Xa anticoagulation after trans-aortic valve implantation for aortic stenosis: The randomized ATLANTIS trial.  Am Heart J 2018; 200: 44-50.  DOI: 10.1016/j.ahj.2018.03.008
  21. Van Mieghem NM, Unverdorben M, Valgimigli M, et al.  Edoxaban versus standard of care and their effects on clinical outcomes in patients having undergone transcatheter aortic valve implantation in atrial fibrillation - Rationale and design of the ENVISAGE-TAVI AF trial.  Am Heart J 2018; 205: 63-9.  DOI: 10.1016/j.ahj.2018.07.006
  22. Seeger J, Gonska B, Rodewald C, Rottbauer W, Wohrle J.  Apixaban in patients with atrial fibrillation after transfemoral aortic valve replacement.  J Am Coll Cardiol Intv 2017; 10: 66-74. DOI: 10.1016/j.jcin.2016.10.023
  23. Geis NA, Kiriakou C, Chorianopoulos E, Uhlmann L, Katus HA, Bekeredjian R.  NOAC monotherapy in patients with concomitant indications for oral anticoagulation undergoing transcatheter aortic valve implantation.  Clin Res Cardiol 2018; 107: 799-806.  DOI: 10.1007/s00392-018-1247-x
  24. Pan KL, Singer DE, Ovbiagele B, et al.  Effects of non-vitamin K antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and valvular heart disease: A systematic review and meta-analysis. J Am Heart Assoc 2017; 6:e005835.  DOI: 10.1161/JAHA.117.005835
  25. Briasoulis A, Inampudi C, Akintoye E, Alvarez P, Panaich S, Vaughn-Sarrazin M.  Safety and efficacy of novel oral anticoagulants versus warfarin in medicare beneficiaries with atrial fibrillation and valvular heart disease.  J Am Heart Assoc 2018; 7: e008773. DOI: 10.1161/JAHA.118.008773
  26. Hampton ML, Tellor KB, Armbruster AL, Theodos G, Schwarze MW.  Evaluation of the safety and effectiveness of direct-acting oral anticoagulants in patients with atrial fibrillation and coexisting valvular heart disease.  Am J Cardiovasc Drugs 2020; Epub ahead of print.  DOI: 10.1007/s40256-020-00398-x  



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