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Address for reprints: Toshiki Kuno, MD, PhD, Department of Cardiology, Montefiore Medical Center, Albert Einstein Medical College, 111 East 210th St, Bronx, NY 10467–2401.
The optimal anticoagulation strategy for patients with bioprosthetic valves and atrial fibrillation remains uncertain. We conducted a meta-analysis using updated evidence comparing direct anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with bioprosthetic valves and atrial fibrillation.
Methods
Medline and Embase were searched through March 2021 to identify randomized controlled trials (RCTs) and observational studies investigating the outcomes of DOAC therapy and VKA therapy in patients with bioprosthetic valves and atrial fibrillation. The outcomes of interest were all-cause death, major bleeding, and stroke or systemic embolism.
Results
Our analysis included 4 RCTs and 6 observational studies enrolling a total of 6405 patients with bioprosthetic valves and atrial fibrillation assigned to a DOAC group (n = 2142) or a VKA group (n = 4263). Pooled analysis demonstrated the similar rates of all-cause death (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.77-1.05; P = .18; I2 = 0%) in the DOAC and VKA groups. However, the rate of major bleeding was significantly lower in the DOAC group (HR, 0.66; 95% CI, 0.48-0.89; P = .006; I2 = 0%), whereas the rate of stroke or systemic embolism was similar in the 2 groups (HR, 0.72; 95% CI, 0.44-1.17; P = .18; I2 = 39%).
Conclusions
DOAC might decrease the risk of major bleeding without increasing the risk of stroke or systemic embolism or all-cause death compared with VKA in patients with bioprosthetic valves and atrial fibrillation.
Direct oral anticoagulant therapy was associated with lower risk of bleeding without increasing the risk of ischemic events compared with vitamin K antagonists in patients with bioprosthetic valves and atrial fibrillation.
Our analysis of 4 randomized controlled trials and 5 observational studies showed an association between direct oral anticoagulant therapy and lower rates of major bleeding without increasing the risk of stroke or systemic embolism or all-cause death compared to vitamin K antagonists in patients with bioprosthetic valves and atrial fibrillation.
See Commentaries on pages 2060 and 2061.
Patients with bioprosthetic valve and atrial fibrillation require anticoagulation to prevent thromboembolic events, although the most effective therapeutic strategy is still uncertain. Direct oral anticoagulants (DOACs) are safe and efficacious alternatives to vitamin K antagonists (VKAs) for anticoagulation in patients with atrial fibrillation.
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.
A recent randomized controlled trial (RCT) showed noninferiority of rivaroxaban compared with VKAs at 12 months in patients with bioprosthetic mitral valves and atrial fibrillation.
Similarly, a recent meta-analysis of 4 RCTs showed similar rates of ischemic events, bleeding, and all-cause deaths with DOAC therapy and VKA therapy in patients with bioprosthetic valve and atrial fibrillation
; however, among the 4 RCTs, 2 trials were post hoc studies, and 1 trial was terminated prematurely because of low enrollment, and thus the update study is still warranted. We conducted a meta-analysis using updated evidence comparing DOAC therapy and VKA therapy in patients with bioprosthetic valves and atrial fibrillation.
Methods
This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards (Online Data Supplement).
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
Given the nature of our study, Institutional Review Board approval and informed written consent for publication were not required. A review protocol does not exist for this analysis.
Eligibility Criteria
Included studies met the following criteria: the study design was an RCT or an observational study, the study population comprised patients with atrial fibrillation and bioprosthetic valves, enrolled patients were assigned to a DOAC group and a VKA group, and outcomes included either all-cause mortality, major bleeding, or systemic embolism or stroke.
Information Sources and Search
All RCTs and observational studies that investigated the outcomes of DOAC therapy and VKA therapy in patients with bioprosthetic valves and atrial fibrillation were identified using a 2-level strategy. First, the Medline and Embase databases were searched through March 31, 2021, using Web-based search engines (PubMed and OVID). Search terms included “bioprosthesis or bioprosthetic or transcatheter aortic valve,” “DOAC or NOAC or oral anticoagulants or edoxaban or apixaban or rivaroxaban or dabigatran,” and “atrial fibrillation.” We did not apply any language limitations.
Study Selection and Data Collection Process
Relevant studies were identified through a manual search of secondary sources, including references of initially identified articles, reviews, and commentaries. All references were downloaded for consolidation, elimination of duplicates, and further analyses. Two independent and blinded authors (Y.Y. and T.K.) conducted a literature search and reviewed the search results separately to select the studies based on our inclusion and exclusion criteria. Disagreements were resolved by consensus.
Data Items
We sought data according to the PICOS framework as follows: P (population), patients with atrial fibrillation and biprosthesis; I (intervention), DOAC; C (comparison), VKA; O (outcome), all-cause mortality, major bleeding, and systemic embolism or stroke; and S (study type), RCTs and observational studies.
Risk of Bias in Individual Studies
Study quality was assessed independently by 2 blinded authors (Y.Y. and T.K.) using the Cochrane Collaboration risk of bias 2.0 tool for RCTs
The primary outcome of interest was all-cause mortality, and the secondary efficacy outcome was systemic embolism or stroke. The primary safety outcome was major bleeding. We accepted the criterion of major bleeding from each study. Systemic embolism or stroke was defined as ischemic stroke, systemic embolism, and/or transient ischemic attack. Hazard ratios (HRs) of each outcome were extracted from each trial.
Synthesis of Results
RevMan version 5.3 (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used to combine HRs in a random-effects model. A P value of <.05 was considered statistically significant.
Risk of Bias Across Studies and Additional Analyses
ProMeta 3 (https://idostatistics.com/prometa3/) was used to perform sensitivity analyses and examine funnel plot asymmetry. Funnel plot asymmetry suggesting publication bias was assessed mathematically using Egger's linear regression test.
Significant heterogeneity was considered to be present when the I2 index was >50% or P for heterogeneity was <.05. Sensitivity analyses were performed by limiting patients with surgical bioprostheses.
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.
that enrolled a total of 6405 patients with bioprosthetic valves and atrial fibrillation assigned to the DOAC group (n = 2142) or the VKA group (n = 4263) (Figure 1).
Figure 1Workflow for selecting eligible articles according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria in search of original studies for this meta-analysis.
Study profiles and patient characteristics are summarized in Tables 1 and 2. In all the RCTs, the VKA dose was adjusted to maintain a target international normalized ratio (INR) of 2.0 to 3.0. In the RCTs, the DOAC regimens included 110 mg of dabigatran twice daily,
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.
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.
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.
The quality of RCTs and observational trials is summarized in Figure E1 and Table E1. The definitions of major bleeding and systemic embolism or stroke in the various studies are shown in Table E2.
Results of Individual Studies and Synthesis of Results
Pooled analysis demonstrated the similar rates of all-cause death (HR, 0.90; 95% CI, 0.77-1.05; P = .18; I2 = 0%) between the DOAC and VKA groups (Figure 2). However, the rates of major bleeding were significantly lower in the DOAC group (HR, 0.66; 95% CI, 0.48-0.89; P = .006; I2 = 0%) (Figure 3), whereas the rates of stroke or systemic embolism were similar in the 2 groups (HR, 0.72; 95% CI, 0.44-1.17; P = .18; I2 = 39%) (Figure 4). All the outcomes were consistent between the RCTs and the observational studies (P for interaction = .77, I2 = 0 for all-cause deaths; P for interaction = .78, I2 = 0 for major bleeding; and P for interaction = .36, I2 = 0 for stroke).
Figure 2Comparison of all-cause deaths for direct oral anticoagulant (DOAC) and vitamin K antagonist (VKA) therapy in patients with a bioprosthetic valve and atrial fibrillation using a random-effects model. (Left) Studies analyzed with their corresponding hazard ratios (HRs) and 95% confidence intervals (CIs). (Right) Forest plot of the data. The horizontal lines represent the values within the 95% CI of the underlying effects. The vertical line indicates an HR of 1. IV, Inverse variance.
Figure 3Comparison of major bleeding for direct oral anticoagulant (DOAC) and vitamin K antagonist (VKA) therapy in patients with a bioprosthetic valve and atrial fibrillation using a random-effects model. (Left) Studies analyzed with their corresponding hazard ratio (HRs) and 95% confidence intervals (CIs). (Right) Forest plot of the data. The horizontal lines represent the values within the 95% CI of the underlying effects. The vertical line indicates an HR of 1. IV, Inverse variance.
Figure 4Comparisons of stroke or systemic embolism for direct oral anticoagulant (DOAC) and vitamin K antagonist (VKA) therapy in patients with a bioprosthetic valve and atrial fibrillation using a random-effects model. (Left) Studies analyzed with their corresponding hazard ratio (HRs) and 95% confidence intervals (CIs). (Right) Forest plot of the data. The horizontal lines represent the values within the 95% CI of the underlying effects. The vertical line indicates an HR of 1. IV, Inverse variance.
The sensitivity analysis after limiting patients with surgical bioprosthesis showed the similar rates of all-cause death (HR, 0.87; 95% CI, 0.74-1.05; P = .15; I2 = 0%) and stroke or systemic embolism (HR, 0.63; 95% CI, 0.36-1.12; P = .12; I2 = 39%) between the DOAC and VKA groups (Figures E2 and E3), whereas the rates of major bleeding were significantly lower in the DOAC group (HR, 0.53; 95% CI, 0.35-0.79; P = .002; I2 = 0%) (Figure E4).
Risk of Bias Across Studies
Publication bias was assessed using funnel plots (Figure E5), which showed no evidence of publication bias.
Discussion
Our analysis demonstrates the lower rates of major bleeding in the DOAC group compared with the VKA group in patients with bioprosthetic valves and atrial fibrillation (Figure 5). The rates of all-cause death and stroke or systemic embolism were similar in the 2 groups.
Figure 5A meta-analysis of 4 randomized control trials and 6 observational studies comparing direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) for patients with atrial fibrillation and a bioprosthetic valve showing lower major bleeding with DOACs compared to VKAs. IV, Inverse variance; CI, confidence interval.
Anticoagulation strategies for patients with bioprosthetic valves and atrial fibrillation are complicated, because bioprosthetic valves and atrial fibrillation cause thromboembolic complications via different mechanisms.
Antithrombic strategies for patients with bioprosthetic valves have been evolving. Data from the Danish National Patient Registry show higher rate of stroke, thromboembolic events, and cardiovascular deaths in the early postsurgical period after bioprosthetic aortic valve replacement in patients not treated with VKAs compared with those treated with VKAs
Association of warfarin therapy duration after bioprosthetic aortic valve replacement with risk of mortality, thromboembolic complications, and bleeding.
; however, given the very low risk of thromboembolism in bioprosthetic valve recipients without another indication for anticoagulation, guidelines recommend aspirin monotherapy or 3 to 6 months of VKA after bioprosthetic valve implantation.
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.
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.
although anticoagulation therapy is more frequently used in recipients of mitral valve replacement compared with recipients of aortic valve replacement.
Among patients without a bioprosthetic valve who have atrial fibrillation, the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial showed that rivaroxaban was noninferior to VKA for the prevention of stroke or systemic embolism.
Among patients with bioprosthetic valves and atrial fibrillation, the efficacy and safety of DOAC therapy were assessed in subgroup analyses of large-scale RCTs.
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.
The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial showed no significant differences between apixaban and warfarin for major bleeding or stroke/systemic embolism for patients with bioprosthetic valves and atrial fibrillation; however, only 156 of the 18,201 patients had bioprosthetic valves in the original trial.
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.
Similarly, the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) trial demonstrated that treatment with low-dose edoxaban had a similar rate of stroke/systemic embolism but a lower rate of major bleeding compared with VKA therapy in patients with bioprosthetic valves and atrial fibrillation, although only 133 of 21,105 patients had bioprosthetic valves in this trial.
The recent RIVER (Rivaroxaban for Valvular Heart Disease and Atrial Fibrillation) trial including 1005 patients with bioprosthetic mitral valves and atrial fibrillation demonstrated the noninferiority of rivaroxaban compared with VKA in terms of death, cardiovascular events, and major bleeding at 12 months.
; however, 2 of the RCTs were post hoc analyses and 1 RCT was terminated prematurely, which might have been underpowered. In the present meta-analysis, we included observational studies, and the results showed a significant decrease in major bleeding with DOAC therapy compared with VKA therapy without a significant interaction among the HRs from RCTs and observational studies in the outcomes of major bleeding (P for interaction = .78; I2 = 0).
The higher bleeding rates with VKA therapy might be related to the target INR in our analysis (2.0-3.0), given that a lower INR (2.0-2.5) might be associated with less bleeding compared with a higher INR (>2.5) in patients with nonvalvular atrial fibrillation,
and the same theory might apply to patients with bioprosthetic valves. Our results suggest that DOAC has a more favorable safety outcome compared with VKA while maintaining similar efficacy in preventing valve thrombosis and intracardiac thrombus in the setting of atrial fibrillation. Furthermore, because DOACs do not require monitoring of INR and are less influenced by food or concomitant medication than VKAs, DOAC therapy is an attractive alternative for many patients with a bioprosthetic valve and atrial fibrillation, suggesting guideline adjustments.
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.
Further large-scale RCTs comparing DOAC and VKA therapy are warranted in those patients, especially with an INR of 2 to 2.5, which could provide a balance between efficacy and safety.
This study has several limitations. First, we included 4 different regimens in the DOAC group and did not assess the efficacy and safety of each DOAC regimen. Second, we included patients with both aortic and mitral bioprosthetic valves, including those with transcatheter aortic valve replacement, although optimal strategies might differ for these patients. However, the sensitivity analysis limiting patients with surgical bioprostheses showed similar results. Third, our analysis included 5 observational studies and 2 trials that were subgroup analyses of RCTs, in which the compared subgroups were not randomized
and thus is subject to selection bias and confounders from these study designs. However, 5 of the 6 observational studies were determined to have a low risk of bias. Furthermore, patients with recent (≤3 months) valve replacement were excluded in the 2 RCTs
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.
the underlying thromboembolic risk in these studies might have differed from that in the other studies. Finally, the follow-up periods in the included studies were relatively short, and future trials with long-term follow-up are warranted.
Conclusions
Our findings indicate that DOAC therapy might decrease the risk of major bleeding without increasing the risk of stroke or systemic embolism or all-cause death compared with VKA in patients with bioprosthetic valves and atrial fibrillation.
Conflict of Interest Statement
The authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
Figure E2Comparison of all-cause deaths with direct oral anticoagulant (DOAC) and vitamin K antagonist (VKA) therapy in patients with a surgical bioprosthetic valve and atrial fibrillation using a random-effects model. (Left) Studies analyzed with their corresponding hazard ratios (HRs) and 95% confidence intervals (CIs). (Right) Forest plot of the data. The horizontal lines represent the values within the 95% CI of the underlying effects. The vertical line indicates an HR of 1. SE, Standard error; IV, inverse variance.
Figure E3Comparisons of stroke or systemic embolism with direct oral anticoagulant (DOAC) and vitamin K antagonist (VKA) therapy in patients with a surgical bioprosthetic valve and atrial fibrillation using a random-effects model. (Left) Studies analyzed with their corresponding hazard ratios (HRs) and 95% confidence intervals (CIs). (Right) Forest plot of the data. The horizontal lines represent the values within the 95% CI of the underlying effects. The vertical line indicates an HR of 1. SE, Standard error; IV, inverse variance.
Figure E4Comparisons of major bleeding with direct oral anticoagulant (DOAC) and vitamin K antagonist (VKA) therapy in patients with a surgical bioprosthetic valve and atrial fibrillation using a random-effects model. (Left) Studies analyzed with their corresponding hazard ratios (HRs) and 95% confidence intervals (CIs). (Right) Forest plot of the data. The horizontal lines represent the values within the 95% CI of the underlying effects. The vertical line indicates an HR of 1. SE, Standard error; IV, inverse variance.
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.
Fatal bleeding or symptomatic bleeding in a critical area or organ, or bleeding causing a decrease in hemoglobin level of 2 g/dL or leading to transfusion of ≥2 units of whole blood or red blood cells
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.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
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.
Association of warfarin therapy duration after bioprosthetic aortic valve replacement with risk of mortality, thromboembolic complications, and bleeding.
Vitamin K antagonists (VKAs) have been the mainstay of anticoagulation therapy after valve replacement, including bioprosthetic valves.1 Because the evidence for the need for VKA-based anticoagulation therapy in patients with bioprosthesis and sinus rhythm has been soft, guidelines have changed to recommending aspirin as routine treatment for this scenario.2,3
Over the last decade, direct oral anticoagulants (DOACs) have become increasingly common in clinical practice as an alternative to vitamin K antagonists (VKAs), such as warfarin. The lack of need for routine monitoring, serum levels largely independent of diet, and fewer medication interactions add to their preference over VKAs for many patients and prescribers. Despite a robust literature supporting their safety and efficacy overall, data relevant to patients with bioprosthetic valves remain limited.
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