Is it appropriate to use DOAC within first 3 months of surgical dual bioprosthetic valve replacement in patients with atrial fibrillation?

Comment by InpharmD Researcher

Current clinical practice guidelines do not suggest the use of DOACs with bioprosthetic valves unless there is a baseline indication for DOAC use. There may be benefits over vitamin K antagonists (VKAs) when looking at risk of mortality and bleeding, although evidence is conflicting. Some studies have suggested that DOACs result in improvement in mortality, bleeding, and stroke in patients with bioprosthetic valves, while others have found no difference between DOACs and VKAs. Other data, however, report excess thromboembolic and bleeding events associated with DOACs in patients with bioprosthetic valves. Although some data have been promising, further prospective trials are needed to establish conclusive evidence regarding use of DOACs in patients with bioprosthetic valves.

Background

The European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) 2021 guidelines do not recommend routine oral anticoagulation use unless transcatheter aortic valve replacements (TAVR) patients have other indications that require oral anticoagulation (Level of evidence: B), which was echoed in expert consensus from the 2019 Canadian Cardiovascular Society Position Statement, where direct oral anticoagulants (DOACs) may be used for other indications as per standard guidelines or in combination with aspirin in TAVR patients with atrial fibrillation. The American College of Cardiology/American Heart Association Joint Committee (AHA/ACC) also clearly stated in their 2020 guidelines that in the absence of other indications that require oral anticoagulation, use of rivaroxaban is contraindicated (Level of evidence: B). The American College of Chest Physicians 2012 guidelines recommended the use of aspirin plus clopidogrel in the first 3 months over vitamin K antagonists (VKAs) and over no platelet therapy, but do not mention the use of DOACs in patients with bioprosthetic valves. In the absence of a compelling indication for chronic oral anticoagulation, single antiplatelet therapy is preferred over a DOAC, although authors of a 2022 review proposed there is a need for future randomized trials to bridge the knowledge gap for whether DOACs should be preferred over VKAs. The authors also do not specify whether a particular DOAC is preferred following TAVR. [1], [2], [3], [4], [5]

A 2022 narrative review discussed the use of DOACs in mechanical and bioprosthetic heart valves. DOACs are considered an option for patients with bioprosthetic heart valve/ transcatheter aortic valve implantation (TAVI) with concurrent indication for anticoagulation. Regarding the choice of anticoagulant, safety data exists for apixaban in patients undergoing TAVI and with a baseline indication for anticoagulation. Rivaroxaban may be used in younger patients who are at least 3 months out from the surgically placed bioprosthetic value. Edoxaban has demonstrated a possible increased risk of bleeding (especially gastrointestinal) for patients undergoing TAVI. Dabigatran has shown to have similar results to warfarin in preventing short-term intracardiac thrombus in surgically placed bioprosthetic mitral and/or aortic valves in younger patients in one trial. However, this trial was terminated early and statistical power was not attained. DOAC as a group may reduce mortality and bleeding compared to VKAs, although limitations of registry studies should be noted. [6]

For patients with bioprosthetic heart valves/TAVI without a baseline indication for anticoagulation, the goal is to utilize single antiplatelet therapy lifelong, without any additional antithrombotics. Harm has been shown with rivaroxaban and apixaban in this group of patients undergoing TAVI with possible increase in the risk of death, thromboembolism, and bleeding as well as non-cardiovascular mortality. Additionally, inclusive evidence exists for edoxaban and dabigatran. It was suggested that in the face of insufficient high-quality clinical trial evidence, there is significant heterogeneity in the antithrombotic regimen after a bioprosthetic valve. Further large, randomized-controlled trials should assess the long-term safety and efficacy of each DOAC in comparison to VKAs in older patients, as reflective of the typical bioprosthetic valve-receiving patient. Until robust randomized clinical trials are available, providers must remain cautious about DOAC use in bioprosthetic valves and consider individual patient characteristics when selecting an antithrombotic strategy. [6]

A 2022 literature review examined available evidence on the use of antithrombotic treatments in patients with mechanical and bioprosthetic heart valves (bPHV). Despite their lower structural durability, bPHVs are often preferred over mechanical prosthetic heart valves due to not requiring lifelong anticoagulation therapy. However, determining the optimal antithrombotic treatment and duration remains a matter of debate. Guidelines for bPHV are also predominantly based on limited nonrandomized studies and expert consensus. The use of DOACs after bPHV replacement can be considered in both the early post-operative phase as a replacement for traditional antithrombotic agents, and in the chronic post-surgical phase, particularly for patients requiring long-term oral anticoagulation therapy for reasons other than the bPHV implantation. Notably, many bPHV patients have a long-term anticoagulation need often due to atrial fibrillation. The evidence supporting DOAC use in bPHV patients without a pre-existing indication for long-term oral anticoagulation therapy is limited. This lack of supporting evidence is partly influenced by the outcomes observed in the RE-ALIGN trial, which investigated the use of dabigatran in patients with mechanical prosthetic heart valves and showed unfavorable outcomes, including excess thromboembolic and bleeding events, which lead to its premature termination. Encouraging findings have emerged from recent trials such as the ENAVLE trial, where patients receiving edoxaban (30 mg or 60 mg once daily) for the initial three months post-surgery demonstrated non-inferior efficacy and safety compared to warfarin. Additionally, similar positive outcomes were observed in other studies involving patients with bPHV who had a long-term indication for oral anticoagulation therapy. Despite these promising results, the need for further research and the development of formal guidelines regarding the definitive role of DOACs in this context is emphasized. It was noted that the introduction of TAVR has revitalized research in this field. However, due to its unique structural and procedural aspects, evidence for bPHV may not directly apply to TAVR. Applicable literature on DOACs in TAVR reveals that for patients without a prior indication for long-term anticoagulation, aspirin alone appears to be as effective as dual antiplatelet therapy in preventing cardiovascular events, with a lower bleeding risk. However, the use of DOACs in TAVR patients requiring long-term anticoagulation remains debated, as trials like GALILEO, which evaluated the use of rivaroxaban 10 mg daily in TAVR patients without a prior indication for long-term anticoagulation, were prematurely terminated due to safety concerns. Evaluation of the clinical benefits of DOACs over traditional anticoagulants in this context also requires further investigation. [7], [8], [9], [10]

A recent systematic review and meta-analysis (N= 10 articles; 4,088 patients) looked at the use of DOACs versus the use of warfarin in patients who underwent bioprosthetic valve replacement to assess safety and efficacy. Between DOACs and warfarin, pooled analyses revealed no significant differences in incidence of bleeds (16% vs. 17%; odds ratio [OR] 0.94; 95% confidence interval [CI] 0.56 to 1.57; p= 0.81; I2= 81%), stroke (2.5% vs. 3.3%; OR 0.75; 95% CI 0.41 to 1.38; p= 0.36; I2= 35%), nor all-cause mortality (9.2% vs. 13.7%; OR 0.85; 95% CI 0.68 to 1.07; p= 0.16; I2= 56%). A subgroup analysis of randomized controlled trials and prospective studies, however, revealed a lower risk of bleeding (9.8% vs. 13.4%; OR 0.70; 95% CI 0.52 to 0.95; p= 0.02; I2= 0%) and stroke (1.97% vs. 4.43%; OR 0.44; 95% CI 0.25 to 0.79; p= 0.006; I2= 0%) with DOACs. Conversely, there were no statistically significant differences in all-cause mortality between groups. Additionally, looking at retrospective and registry studies also did not reveal significant differences in the risk of stroke between both groups. The investigators concluded that DOAC use seemed to be as safe and effective as VKAs when used in patients with bioprosthetic valves for anticoagulation. Notably, heterogeneity was moderate to high among the studies, and variability in reporting may impact how compelling these findings are. [11]

Additionally, a recent 2022 observational study identified atrial fibrillation patients with valve repairs or replacements to compare the safety and effectiveness of DOACs versus warfarin. Between 2015 and 2019, patients with mitral valve repair and patients with TAVRs were divided into subgroups that received either warfarin or a DOAC (apixaban, rivaroxaban, and dabigatran). Of 8,089 bioprosthetic patients, DOACs were associated with a similar risk of mortality (adjusted hazard ratio [HR] 0.93; 95% CI 0.86 to 1.01; p= 0.08), a lower risk of bleeds (adjusted HR 0.86; 95% CI 0.80 to 0.93; p<0.001), and a higher risk of ischemic stroke (adjusted HR 1.27; 95% CI 1.13 to 1.43; p<0.001) versus warfarin after a median follow-up of 413 days. Notably, DOACs were associated with a higher risk of ischemic stroke regardless of valve location. Despite the increased risk in stroke, DOAC use provided a large reduction in major bleeding with similar all-cause mortality, and given warfarin's narrow therapeutic range and need for frequent monitoring, may benefit this patient population. It should be noted that as with other observational studies, results may be confounded by misclassification, inaccuracies in Medicare claims, and missing database information. [12]

PROACT Xa (ClinicalTrials.gov no. NCT04142658) was a phase 3 study evaluating the safety and efficacy of apixaban versus warfarin in patients with an aortic valve replacement, specifically an On-X Aortic Heart Valve or On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft. Patients were randomized 1:1 to receive apixaban 5 mg or 2.5 mg by mouth twice daily, or warfarin with an INR goal of 2 to 3. The primary endpoint was the composite of valve thrombosis and valve-related thromboembolism with a safety outcome of major bleeding. The trial was terminated after 863 participants were enrolled due to a great number of thromboembolic events occurring in the apixaban arm. [13], [14]

References:

[1] Granger C, Guedeney P, Collet JP. Antithrombotic Therapy Following Transcatheter Aortic Valve Replacement. J Clin Med. 2022;11(8):2190. Published 2022 Apr 14. doi:10.3390/jcm11082190
[2] Vahanian A, Beyersdorf F, Praz F, et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease [published correction appears in Eur Heart J. 2022 Feb 18;:]. Eur Heart J. 2022;43(7):561-632. doi:10.1093/eurheartj/ehab395
[3] Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears in Circulation. 2021 Feb 2;143(5):e229] [published correction appears in Circulation. 2023 Aug 22;148(8):e8]. Circulation. 2021;143(5):e72-e227. doi:10.1161/CIR.0000000000000923
[4] Asgar AW, Ouzounian M, Adams C, et al. 2019 Canadian Cardiovascular Society Position Statement for Transcatheter Aortic Valve Implantation. Can J Cardiol. 2019;35(11):1437-1448. doi:10.1016/j.cjca.2019.08.011
[5] Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e576S-e600S. doi:10.1378/chest.11-2305
[6] Ryu R, Tran R. DOACs in Mechanical and Bioprosthetic Heart Valves: A Narrative Review of Emerging Data and Future Directions. Clin Appl Thromb Hemost. 2022;28:10760296221103578. doi:10.1177/10760296221103578
[7] Ricottini E, Nusca A, Ussia GP, Grigioni F. Antithrombotic treatment for valve prostheses: Which drug, which dose, and when?. Prog Cardiovasc Dis. 2022;72:4-14. doi:10.1016/j.pcad.2022.05.008
[8] Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-1214. doi:10.1056/NEJMoa1300615
[9] Shim CY, Seo J, Kim YJ, et al. Efficacy and safety of edoxaban in patients early after surgical bioprosthetic valve implantation or valve repair: A randomized clinical trial. J Thorac Cardiovasc Surg. 2023;165(1):58-67.e4. doi:10.1016/j.jtcvs.2021.01.127
[10] Dangas GD, Tijssen JGP, Wöhrle J, et al. A Controlled Trial of Rivaroxaban after Transcatheter Aortic-Valve Replacement. N Engl J Med. 2020;382(2):120-129. doi:10.1056/NEJMoa1911425
[11] Bakr L, Elsayed A, Saleh O, Abdalraouf M, Ng GA, Ibrahim M. Safety and efficacy of direct oral anticoagulants in bioprosthetic valves: A systematic review and meta-analysis. Front Cardiovasc Med. 2023;10:1099591. Published 2023 Feb 27. doi:10.3389/fcvm.2023.1099591
[12] Mentias A, Saad M, Michael M, et al. Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation and Valve Replacement or Repair. J Am Heart Assoc. 2022;11(17):e026666. doi:10.1161/JAHA.122.026666
[13] 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. doi:10.1016/j.ahj.2020.06.014
[14] ClinicalTrials.gov. PROACT Xa - A Trial to Determine if Participants With an On-X Aortic Valve Can be Maintained Safely on Apixaban. https://clinicaltrials.gov/study/NCT04142658. Updated December 12, 2022. Accessed March 18, 2025.

Relevant Prescribing Information

Eliquis® (apixaban):
The safety and efficacy of ELIQUIS has not been studied in patients with prosthetic heart valves. Therefore, use of ELIQUIS is not recommended in these patients [15]

Xarelto® (rivaroxaban):
On the basis of the GALILEO study, use of XARELTO is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of XARELTO have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO is not recommended in patients with prosthetic heart valves. [16]

Pradaxa® (dabigatran):
The use of PRADAXA for the prophylaxis of thromboembolic events in patients with atrial fibrillation in the setting of other forms of valvular heart disease, including the presence of bioprosthetic heart valve, has not been studied and is not recommended. [17]

References:

[15] Eliquis (apixaban). Prescribing information. Bristol-Myers Squibb Company; 2021.
[16] Xarelto (rivaroxaban). Prescribing information. Janssen Pharmaceuticals Inc; 2024.
[17] Pradaxa (dabigatran). Prescribing information. Boehringer Ingelheim Pharmaceuticals Inc; 2023.

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is it appropriate to use DOAC within first 3 months of surgical dual bioprosthetic valve replacement in patients with atrial fibrillation?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-2 for your response.


 

Comparison Of The Efficacy And Safety Of Direct Oral Anticoagulants And Warfarin After Bioprosthetic Valve Replacements

Design

Retrospective cohort study

N= 197

Objective

To evaluate the efficacy and safety of direct oral anticoagulants (DOACs) in patients after a recent bioprosthetic valve replacement 

Study Groups

DOAC (n= 127)

Warfarin (n= 70)

Inclusion Criteria

Age ≥18 years; received bioprosthetic valve replacement; received either warfarin or a DOAC following bioprosthetic aortic valve replacement (AVR) or mitral valve replacement (MVR) surgery 

Exclusion Criteria

Mechanical valve replacement; discontinued anticoagulation before the 6-month period ended; switched anticoagulation during the 6-month follow-up period

Methods

Investigators retrospectively identified patients who had received a bioprosthetic valve replacement from January 2014 to June 2018 at an institution and reviewed each electronic medical record (EMR) for the 6-months post-valve placements to identify incidences of thromboembolic events or major bleeding. Outcomes were evaluated based on readmission. 

The decision to initiate anticoagulation after a bioprosthetic valve replacement was made on a case-by-case basis, considering other risk factors. If anticoagulation was initiated, the agent was chosen by the cardiothoracic surgeon with input from a consulting cardiologist.

Duration

6-months after procedure

Outcome Measures

Primary efficacy outcome: Thromboembolic complications within 6 months following surgery, defined as new diagnosis of ischemic stroke, myocardial infarction, or peripheral arterial emboli 

Primary safety outcome: Incidence of major bleeding within 6 months following surgery, as defined by the Journal of the American College of Cardiology (JACC)

Baseline Characteristics

 

DOAC (n= 127)

Warfarin (n= 70)

p-value

Age, years

71.9

74.5

0.99

Male

56.7%

55.7%

0.90

Chronic kidney disease

10.2%

24.3%

0.01

Anticoagulation prior to surgery

48.8%

67.1%

0.01

Concomitant antiplatelet

99.2%

98.6%

0.67

Results

Endpoint

DOAC (n= 127)

Warfarin (n= 70)

p-value

Thromboembolic complications

3 (2.4%)

0

0.20

Major bleeding

9 (7.1%)

2 (2.9%)

0.22

Adverse Events

Common Adverse Events: Not disclosed

Serious Adverse Events: Major bleeding – DOAC (7.1%) versus warfarin (2.9%); p=0.22

Study Author Conclusions

This small, exploratory study found similar rates of thromboembolic complications and major bleeding events in patients receiving a DOAC or warfarin within 6 months of receiving a bioprosthetic MVR or AVR. Larger, prospective trials are needed to evaluate the efficacy and safety of DOACs in this population.

InpharmD Researcher Critique

Data should be interpreted with caution due to the retrospective design and limited sample size. This trial was the only study identified analyzing DOAC use within 6 months of receiving a bioprosthetic valve. Although no significant difference was seen in thromboembolic complications and major bleeding between DOACs and warfarin, the incidence of each was so small that the safety and efficacy of DOACs following bioprosthetic valve placement cannot be truly evaluated.

 

References:

Pasciolla S, Zizza LF, Le T, Wright K. Comparison of the Efficacy and Safety of Direct Oral Anticoagulants and Warfarin After Bioprosthetic Valve Replacements. Clin Drug Investig. 2020;40(9):839-845. doi:10.1007/s40261-020-00939-x

 

Apixaban in Patients With Atrial Fibrillation After Transfemoral Aortic Valve Replacement

Design

Nonrandomized, prospective study

N= 617

Objective

To assess the impact of atrial fibrillation (AF) on outcome in transfemoral aortic valve replacement (TAVR) and to evaluate the safety and efficacy of apixaban compared with a vitamin K antagonist (VKA) in patients with AF after TAVR

Study Groups

Apixaban (n= 141)

Vitamin K antagonist (n= 131) 

Inclusion Criteria

Patients with aortic valve stenosis undergoing transcatheter aortic valve replacement

Exclusion Criteria

None specified

Methods

During the TAVR procedure, unfractionated heparin was administered (70 U/kg) after sheath insertion. Oral anticoagulation was restarted 48 h after TAVR when clinically safe in patients with previous or new-onset AF using either apixaban 2.5 mg BID or phenprocoumon (no dose or target INR was reported).

Duration

Follow-up: 30 days and 12 months 

Outcome Measures

Composite safety endpoint (all-cause mortality, all stroke, life-threatening bleeding, acute kidney injury, coronary obstruction, major vascular complications, or valve dysfunction requiring reintervention), major adverse cardiac events (MACE), rehospitalizations

Baseline Characteristics

 

Apixaban (n= 141)

Vitamin K antagonist (n= 131)

 

Age, years

82.1 ± 5.3 80.5 ± 6.3  

Women

71 (50.4%) 63 (48.1%)  
Coronary artery disease 

93 (66.0%)

77(58.8%)  

History of myocardial infarction 

25 (17.7%) 28 (21.4%)  

History of cardiac surgery 

18 (12.8%)  16 (12.2%)  

Peripheral or cerebral vascular disease 

117 (82.9%)  116 (88.5%)  

History of stroke or intracerebral bleeding 

16 (11.3%) 19 (14.5%)  

Permanent pacemaker 

23 (16.3%) 18 (13.7%)  

CHA2DS2-VAScore 

5.0 ± 1.2 4.9 ± 1.1  

Results

 

Apixaban (n= 141)

Vitamin K antagonist (n= 131)

p-value

Composite safety endpoint by 30 days

All-cause mortality

Stroke

Intracerebral bleeding

Life-threatening bleeding

19 (13.5%)

2 (1.4%)

3 (2.1%)

1 (0.7%)

5 (3.5%)

40 (30.5%)

5 (3.8%)

7 (5.3%)

0

7 (5.3%)

<0.01

0.22

0.17

0.34

<0.01

MACE at 12 months

22/81 (27.2%)

9/50 (18.0%)

0.34

All-cause mortality at 12 months

19/81 (23.4%) 6/50 (12.0%) 0.18

Rehospitalizations

14/81 (15.7%) 8/50 (16.0%) 0.87

Adverse Events

N/A

Study Author Conclusions

The early safety endpoint in patients with AF on apixaban was significantly better compared with VKA therapy.

InpharmD Researcher Critique

Limitations include the fact that this was not a randomized trial and it was an open-label study. Strengths include the sample size and wide inclusion criteria.

References:

Seeger J, Gonska B, Rodewald C, Rottbauer W, Wöhrle J. Apixaban in Patients With Atrial Fibrillation After Transfemoral Aortic Valve Replacement. JACC Cardiovasc Interv. 2017;10(1):66-74. doi:10.1016/j.jcin.2016.10.023