Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation: A Population-Based Cohort Study

The title of this paper ".....in patients with valvular atrial fibrillation" is misleading. The ACC/AHA reports that "Valvular AF generally refers to AF in the setting of moderate-to-severe mitral stenosis (potentially requiring surgical intervention) or in the presence of an artificial (mechanical) heart valve." This paper explicitly excludes patients with mechanical heart valves, and the vast majority of those with mitral disease apparently have "other unspecified mitral valve disease." While the premise of the study seems to be that many patients with a variety of valvular disease were excluded from the original DOAC trials, the distinction between "valvular atrial fibrillation" and "patients with atrial fibrillation who also have valvular heart disease" seems to be glossed over. Casual readers may be left with the impression that this manuscript contradicts current ACC/AHA guidelines on the subject, which it does not (the mitral stenosis sensitivity analysis also includes aortic stenosis, making it difficult to draw a conclusion of efficacy of DOACs vs warfarin in that group). 

The article of Dawwas et al adds valuable information regarding use of Direct oral anticoagulants (DOACs).(1) However, the title, abstract, and introduction may be delivering a message different from the contents of their research. The American College of Cardiology Clinical Expert Consensus Document Task Force defined non-valvular atrial fibrillation (AF) as AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair.(2) The American College of Chest Physicians guidelines considered valvular heart disease and AF to include mitral stenosis and prosthetic heart valves.(3) Clinical trials have varied in their definitions of valvular AF. Most studies generally conformed to these definitions, excluding patients with moderate or severe mitral stenosis or/and prosthetic valves. Fewer studies defined valvular AF as valvular disease requiring surgery or hemodynamically relevant valve disease.(4) Dawwas et al definition of valvular AF differed from any of the above; their definition was “aortic, mitral, tricuspid, or pulmonary valve” using ICD-9 and ICD-10 codes, which encompassed all stenotic and regurgitant rheumatic, non-rheumatic, and congenital disorders. Some of their ICD-9 codes included unspecified pulmonary valve anomaly (746.00) and tricuspid atresia (746.1). They also excluded patients with prosthetic heart valves. Therefore, the definition of “valvular AF” in this article is very different from the common definition of “valvular AF” used in clinical trials, which were quoted by the authors in their article’s introduction. Whereas there is a concern for effectiveness and safety of DOAC in patients with mitral valve stenosis,(4) we are not aware of any concern for administration of DOAC in pulmonary or tricuspid regurgitation. Therefore, grouping all of these different diseases under one group namely “valvular AF” can be misleading.

We are concerned that the article title and abstract as they stand now may result in providers believing that it is now safe to give DOAC to patient with rheumatic mitral stenosis or mitral valve procedure since this is the common definition of valvular AF. Ishak A. Mansi, MD1,2,3; Department of Medicine, VA North Texas Health Care System, and Department of Internal Medicine and Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas. Sujata Bhushan, MD;1,2 Department of Medicine, VA North Texas Health Care System, and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. David E. Albracht, MD1,2 Department of Medicine, VA North Texas Health Care System, and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.

References:

1. Dawwas GK, Dietrich E, Cuker A, Barnes GD, Leonard CE, Lewis JD. Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation : A Population-Based Cohort Study. Ann Intern Med. 2021.

2. Doherty JU, Gluckman TJ, Hucker WJ, Januzzi JL, Jr., Ortel TL, Saxonhouse SJ, et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation: A Report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol. 2017;69(7):871-98.

3. Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):546S-92S.

4. Fauchier L, Philippart R, Clementy N, Bourguignon T, Angoulvant D, Ivanes F, et al. How to define valvular atrial fibrillation? Arch Cardiovasc Dis. 2015;108(10):530-9.

In this cohort study, Dawwas et al. included 56,336 propensity score-matched patients with valvular atrial fibrillation (AF) and demonstrated direct oral anticoagulants (DOACs) were associated with lower risks of ischemic stroke or systemic thromboembolism and major bleeding when compared to warfarin (1).  There are several issues with study design, execution, and interpretation of the results.  The term “valvular AF” is commonly confused as AF in patients with valvular heart disease (VHD), which is incorrect.  Valvular AF is defined as AF in patients with moderate to severe mitral stenosis (MS) or mechanical heart valve.  In contrast, nonvalvular AF is defined as AF in the absence of moderate-to-severe mitral stenosis or a mechanical heart valve (2).  In this study, patients with bioprosthetic or mechanical heart valves were excluded, while patients with AF and concomitant any VHD were incorrectly labeled as “valvular AF.”  Moreover, even amongst the included patients, it remains unclear how many patients had moderate to severe MS.

Although the prior landmark randomized controlled trials (RCTs) demonstrated non-inferiority of DOACs compared to warfarin in patients with AF, patients with mechanical heart valves and moderate to several MS were excluded (2).  Furthermore, the RE-ALIGN trial comparing Dabigatran versus warfarin in patients with mechanical heart valves was terminated prematurely due to unacceptable thromboembolic and bleeding events in the dabigatran group (3).  

On the contrary, the RIVER trial demonstrated non-inferiority of rivaroxaban for primary outcome composite of death, major cardiovascular events, and major bleeding at 12 months compared to warfarin in AF patients with bioprosthetic mitral valve (although excluded mechanical prosthetic valve patients) (4).  Given the lack of safety and efficacy data of the DOAC’s use in mechanical prosthetic valves, current guidelines recommend against their use in true “valvular AF” patients (class III) (2). 

The clinical relevance of this study in today’s clinical practice remains unclear, especially when the authors incorrectly addressed the AF patients with a history of any VHD as “valvular AF.”  In fact, about 20% of the patients in the prior landmark clinical trials (comparing DOACs versus warfarin for non-valvular AF) had VHD.  Therefore, the study's conclusion is entirely misleading, as the authors have evaluated the outcomes of DOACs in patients with VHD and not in patients with “valvular AF,” both of which are completely separate clinical entities.  One has to be careful about interpreting the results of this study to make a meaningful interpretation of the data presented.

References

1. Dawwas GK, Dietrich E, Cuker A, Barnes GD, Leonard CE, Lewis JD. Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation : A Population-Based Cohort Study. Ann Intern Med. 2021.
2. Writing Group M, January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. 2019;16(8):e66-e93.
3. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-14.
4. Guimaraes HP, Lopes RD, de Barros ESPGM, Liporace IL, Sampaio RO, Tarasoutchi F, et al. Rivaroxaban in Patients with Atrial Fibrillation and a Bioprosthetic Mitral Valve. N Engl J Med. 2020;383(22):2117-26.

Dawwas and colleagues performed an important retrospective population-based cohort study to assess risk of ischemic stroke and systemic embolism in addition to risk of major bleeding among valvular atrial fibrillation (AF) patients anticoagulated with DOACs versus warfarin.¹

However, the generalizability of the study is limited due to the misguided classification of the valvular AF study population as a homogenous group. The term valvular AF as a substitute for any valvular heart disease (VHD) in patients with AF has fallen out of favor since the clinical consequences vary significantly based on valvular flow patterns in the left atrium.² ACC/AHA/HRS guidelines restrict the definition of valvular AF to include only mechanical heart valves or moderate-to-severe mitral stenosis as these subtypes confer much greater thromboembolic risks.^3-4 Recognizing the valvular AF population’s higher thromboembolic risk, patients with non-native heart valves and moderate-to-severe mitral stenosis were intentionally excluded from landmark clinical trials (RE-LY, ARISTOTLE, ROCKET-AF) investigating anticoagulation strategies in patients with non-valvular AF (including AF patients with VHD other than mechanical valves and mitral stenosis).⁵ 

Banerjee, et al, published an excellent study about anticoagulation utilization in AF patients with VHD that utilized ICD-10 diagnostic and OPCS4 procedure codes to distinguish subtypes based on valve replacement (mechanical, bioprosthetic), valvuloplasty, and valve disease (aortic, tricuspid, pulmonary, or mitral regurgitation/stenosis). Dawwas, et al. allude to the need for VHD subgroup analysis strategies in their discussion, but did not publish this data as they had difficulty extracting data that clearly defined VHD subtypes and the results for subjects with adequate data were not statistically significant. The authors should consider adopting a subgroup analysis similar to those used by Banerjee, et al. to describe each type of valvular disease. Should the results from Dawwas, et al’s study hold true for even one subtype of valvular AF patients, this has potential to drastically change prescribing practices and offer more convenient therapies for a significant portion of our AF population that would almost certainly increase medication compliance rates and reduce adverse events.

Again, we commend the authors for this excellent contribution and hope it will urge research centers to establish more robust trials to more directly delineate the role of DOACs in patients with moderate-to-severe mitral stenosis, rheumatic mitral stenosis, and non-native valves.

References:

1. Dawwas GK, Dietrich E, et al. Effectiveness and safety of direct oral anticoagulants versus warfarin in patients with valvular atrial fibrillation. Ann Intern Med Epub ahead of print: 30 March 2021. doi:10.7326/M20-6194.
2. Banerjee A, Allan V, et al. Subtypes of atrial fibrillation with concomitant valvular heart disease derived from electronic health records: phenotypes, population prevalence, trends, and prognosis. Europace. 2019 Dec; 21(12):1776-84.
3. January CT, Wann LS, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in collaboration with the Society of Thoracic Surgeons. Circ. 2019 Jan; 140:e125-51.
4. Fauchier L, Philippart R, et al. How to define valvular atrial fibrillation? Arch Cardiovasc Dis. 2015 Jul; 108:530-9.
5. Owens RE, Kabra R, et al. Direct oral anticoagulant use in nonvalvular atrial fibrillation with valvular heart disease: a systematic review. Clin Cardiol. 2017 Jun; 40(6):407-12.

We thank Drs. Rodwin, Mansi and colleagues, and Shah and colleagues for their interest in our work,¹ and we appreciate their comments. Although the issue of defining valvular atrial fibrillation (AF) is relevant, the definition has evolved and differs slightly across practice guidelines. For example, in 2001, the American College of Cardiology/ American Heart Association/European Society of Cardiology (ESC) guidelines defined non-valvular AF as AF that occurs in the absence of rheumatic mitral valve disease or a prosthetic heart valve.² The 2012-focused update of the ESC guidelines for the management of AF defined valvular AF as AF associated with mitral valve disease or a prosthetic valve.³ In the same updates, the ESC indicated that no universal definition exists to differentiate between valvular and non-valvular AF.³ Despite these differences, the results from the subgroup analyses showed consistent findings in patients who have various forms of mitral valve disease as well as those specifically with mitral stenosis.

We agree with the authors that patients with mechanical heart valves are of interest and warrant further investigation. However, this patient subgroup accounted for only 4% of the total valvular AF population identified in our study. Finally, as noted in our limitations section, we were not able to assess the severity of valvular heart disease (VHD). We defined VHD based on international classification codes that precluded an assessment of disease severity, especially as it pertains to the subtype of VHD.

References

1. Dawwas GK, Dietrich E, Cuker A, Barnes GD, Leonard CE, Lewis JD. Effectiveness and safety of direct oral anticoagulants versus warfarin in patients with valvular atrial fibrillation : A population-based cohort study. Annals of internal medicine. 2021. doi: 10.7326/M20-6194.
2. Fuster V, Rydén LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: Executive summary. A report of the american college of cardiology/ american heart association task force on practice guidelines and the european society of cardiology committee for practice guidelines and policy conferences (committee to develop guidelines for the management of patients with atrial fibrillation): Developed in collaboration with the north american society of pacing and electrophysiology. J Am Coll Cardiol. 2001;38(4):1231-1266.  doi: 10.1016/s0735-1097(01)01587-x.
3. Camm AJ, Lip GYH, De Caterina R, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation: An update of the 2010 ESC guidelines for the management of atrial fibrillation. developed with the special contribution of the european heart rhythm association. Eur Heart J.2012;33(21):2719-2747. doi: 10.1093/eurheartj/ehs253.

Disclosures:

GDB has serves as a consultant for Pfizer/Bristol-Myers Squibb, Janssen, Portola, and Acelis Connected Health. AC has served as a consultant for Synergy and his institution has received research support on his behalf from Alexion, Bayer, Novartis, Novo Nordisk, Pfizer, Sanofi, and Spark. JDL has served as a consultant for Janssen Pharmaceuticals, Samsung Bioepis, Bristol-Myers Squibb, Merck, Celgen, Entasis Therapeutics and Bridge Biotherapeutics. JDL has served as a paid member of a data monitoring committee for Pfizer, UCB, Gilead, Arena Pharmaceuticals and Protagonist Therapeutics. JDL has received research funding from Janssen Pharmaceuticals and Takeda Pharmaceuticals. JDL has received educational grant funding from Takeda Pharmaceuticals.