Direct Oral Anticoagulants Are Now Available for Patients With Atrial Fibrillation and Bioprosthetic Heart Valves

Atrial fibrillation (AF) is conventionally divided into “valvular” and “non-valvular”. In the 2012 focused update of the European Society of Cardiology (ESC) guidelines for the management of AF,¹ the term “valvular AF” was used to denote AF related to rheumatic valvular diseases (predominantly mitral stenosis) or prosthetic heart valves. However, in relation to artificial valves, it was not clearly mentioned whether bioprosthetic valves should be categorized as “valvular” or “non-valvular”.¹ The 2020 ESC guidelines recommended that this terminology should be abandoned.² Nevertheless, these definitions are clinically important for physicians to select an appropriate oral anticoagulant in patients with AF and bioprosthetic valves because direct oral anticoagulants (DOACs) are currently only approved for patients with non-valvular AF.

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Definition of Non-Valvular AF in Guidelines

In the Japanese Circulation Society (JCS) 2013 guidelines for the pharmacotherapy of AF,³ bioprosthetic valves were categorized as “valvular”. However, several studies using DOACs for patients with AF and bioprosthetic valves demonstrated that DOACs were non-inferior to warfarin in terms of effectiveness and safety.^4–6 Accordingly, bioprosthetic valves were considered categorized as “non-valvular” in a joint consensus document from the Heart Rhythm Associations of Europe, Asia, Africa, and Latin America in 2017.⁷ The 2019 American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) focused update of the 2014 AHA/ACC/HRS guideline also supported this standpoint.⁸ Furthermore, in the latest JCS/Japanese Heart Rhythm Society (JHRS) 2020 guideline on pharmacotherapy for cardiac arrhythmias,⁹ bioprosthetic valves were classified as “non-valvular”.

Effectiveness and Safety of DOACs in Patients With AF and Bioprosthetic Valves

Accordingly, DOACs can be prescribed to patients with AF and bioprosthetic valves, including after transcatheter aortic valve implantation (TAVI). However, real-world data regarding the effectiveness and safety of DOACs in these patients remain limited,^4–6,10,11 especially for patients with aortic bioprosthetic valves.¹² In contrast, the effectiveness and safety of DOACs in patients with “valvular AF”, including those with mechanical heart valves or moderate to severe mitral stenosis, has never been proven.^13,14

In the Dabigatran Versus Warfarin After Bioprosthesis Valve Replacement for the Management of Atrial Fibrillation Postoperatively (DAWA) pilot study,⁵ the effect of dabigatran was similar to that of warfarin in preventing the formation of intracardiac thrombi. Among the 191 patients with bioprosthetic valves in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial,⁴ rates of primary net clinical outcomes (stroke/systemic embolism, major bleeding, and death) were lower in patients receiving edoxaban than among those receiving warfarin, regardless of edoxaban dose. In addition, the rate of major bleeding in patients receiving a lower dose of edoxaban was significantly lower than that in patients receiving warfarin. In the 104 patients with bioprosthetic valves in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trail,¹⁰ no significant differences were observed between apixaban and warfarin for any outcome. Moreover, in the 1,005 patients with AF and mitral bioprosthetic valves in the Rivaroxaban for Valvular Heart Disease and Atrial Fibrillation (RIVER) trial,¹¹ rivaroxaban was non-inferior to warfarin regarding the mean time until the primary outcome of death, major cardiovascular events, or major bleeding. Most recently, among the 1,426 patients with mainly prevalent AF who underwent successful TAVI in the Edoxaban versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation–Atrial Fibrillation (ENVISAGE-TAVI AF) trial,¹² edoxaban was non-inferior to vitamin K antagonists regarding the composite primary outcome of adverse clinical events; however, the incidence of major bleeding was higher in patients receiving edoxaban than in those receiving vitamin K antagonists. These results raise another query in relation to the different effects of DOACs between patients after surgical aortic valve replacement (SAVR) and TAVI.

Effects of DOACs on Outcomes in Japanese Patients With AF and Aortic Bioprosthetic Valves

In this issue of the Journal, Miyake et al elucidated important concerns.¹⁵ In that study, the authors investigated the effects of DOACs vs. warfarin in 479 patients with AF and aortic bioprosthetic valves using data from the BioProsthetic Valves with Atrial Fibrillation (BPV-AF) Registry. The incidence of the primary outcome, defined as a composite of stroke, systemic embolism, major bleeding, heart failure requiring hospitalization, all-cause death, or bioprosthetic valve reoperation, was comparable in the DOAC and warfarin groups (adjusted hazard ratio [HR] 0.88; 95% confidence interval [CI] 0.51–1.50; Figure), regardless of the type of aortic valve procedure (SAVR or TAVI; P=0.577 for interaction).¹⁵ The secondary endpoints for effectiveness and safety were also comparable between the 2 groups, specifically stroke/systemic embolism (HR 0.45; 95% CI 0.10–2.01) and major bleeding (HR 0.99; 95% CI 0.28–3.51; Figure). Finally, Miyake et al concluded that DOACs can be used as alternatives to warfarin in patients with AF and aortic bioprosthetic valves.¹⁵ These results support those of previous studies.^4,5,10–12

Figure.

Effects of direct oral anticoagulants (DOACs) vs. warfarin on outcomes in patients with bioprosthetic valves. *Adjusted for heart failure, left ventricular ejection fraction, hypertension, age, diabetes, stroke/transient ischemic attack, vascular disease, sex, body weight, antiplatelet use, estimated glomerular filtration rate, type of atrial fibrillation, and type of aortic valve procedure. **Composite of stroke, systemic embolism, major bleeding, heart failure requiring hospitalization, all-cause death, or bioprosthetic valve reoperation. (Reproduced with permission from Miyake M, et al.¹⁵)

Concluding Remarks

DOACs are now available for patients with AF and bioprosthetic valves, regardless of the valve position (mitral or aortic) and the type of aortic valve procedure (SAVR or TAVI).

Disclosures

E.K. has received remuneration from Daiichi-Sankyo and Ono Pharmaceutical.

References

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