Comparison of Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation and Bioprosthetic Heart Valves

doi:10.1016/j.amjcard.2021.01.016

The American Journal of Cardiology

Volume 146, 1 May 2021, Pages 22-28

https://doi.org/10.1016/j.amjcard.2021.01.016 Get rights and content

There are limited data regarding direct oral anticoagulants (DOACs) for stroke prevention in patients with bioprosthetic heart valves (BHVs) and atrial fibrillation (AF). The objectives of this study were to evaluate the ambulatory utilization of DOACs and to compare the effectiveness and safety of DOACs versus warfarin in patients with AF and BHVs. We conducted a retrospective cohort study at a large integrated health care delivery system in California. Patients with BHVs and AF treated with warfarin, dabigatran, rivaroxaban, or apixaban between September 12, 2011 and June 18, 2020 were identified. Inverse probability of treatment-weighted comparative effectiveness and safety of DOACs compared with warfarin were determined. Use of DOACs gradually increased since 2011, with a significant upward in trend after a stay-at-home order related to COVID-19. Among 2,672 adults with BHVs and AF who met the inclusion criteria, 439 were exposed to a DOAC and 2233 were exposed to warfarin. For the primary effectiveness outcome of ischemic stroke, systemic embolism and transient ischemic attack, no significant association was observed between use of DOACs compared with warfarin (HR 1.19, 95% CI 0.96 to 1.48, p = 0.11). Use of DOACs was associated with lower risk of the primary safety outcome of intracranial hemorrhage, gastrointestinal bleeding, and other bleed (HR 0.69, 95% CI 0.56 to 0.85, p < 0.001). Results were consistent across multiple subgroups in the sensitivity analyses. These findings support the use of DOACs for AF in patients with BHVs.

Section snippets

Methods

This is a retrospective cohort study using data from the Kaiser Permanente Southern California (KPSC) Health System.¹¹ The study protocol was approved by the KPSC Institutional Review Board. A waiver of informed consent was obtained because of the observational nature of the study.

Adult patients (age ≥18 years) with AF and BHVs between September 12, 2011 and June 18, 2020 were initially identified using International Classification of Diseases (ICD) 9/10 codes (Supplementary Table 1). Presence

Results

The temporal utilization pattern of anticoagulation therapy is shown in Figure 1 and in the Supplementary Figure 1. At the start of the study period, the majority of patients were treated with warfarin. There was a gradual increase in the use of DOAC over time. The trend of the proportion of patients who treated with DOAC increased after March 19, 2020, when the State of California issued a stay-at-home order due to the COVID-19 pandemic.

To compare the effectiveness and safety of direct oral

Discussion

In this cohort of patients with BHVs and AF, we assessed the effectiveness and safety of DOACs compared with warfarin. The principal findings are as follows: first, DOACs were as effective as warfarin in preventing ischemic strokes, systemic embolism and transient ischemic attacks; second, patients treated with DOACs had fewer bleeding events, including fewer intracranial hemorrhage, when compared to warfarin; third, there was a gradual increase in DOAC use, with a marked increase after March

Authors’ Contributions

Lewei Duan: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Data Curation, Writing – Review & Editing, Visualization. Jason N Doctor: Supervision, Writing - Review & Editing, Methodology. John L Adams: Supervision. John A Romley: Supervision, Writing - Review & Editing, Methodology. Leigh-Anh Nguyen: Supervision, Data Curation. Jaejin An: Supervision, Writing - Review & Editing, Methodology. Ming-Sum Lee: Conceptualization, Methodology, Investigation,

Funding and Support

LD is supported in part by the Edwards Lifesciences Doctoral Fellowship.

Acknowledgments

The authors thank Ernest Shen, PhD, for critically reading the manuscript.

Disclosures

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper

References (30)

CT January 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
J Am Coll Cardiol
(2019)
B Bikdeli et al.
Global Covid-19 Thrombosis Collaborative Group EbtINE, the Iua SbtESCWGoPC, Right Ventricular F. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review
J Am Coll Cardiol
(2020)
ME Charlson et al.
A new method of classifying prognostic comorbidity in longitudinal studies: development and validation
J Chronic Dis
(1987)
GY Lip et al.
Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation
Chest
(2010)
R Pisters et al.
A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey
Chest
(2010)
JC Sun et al.
Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends
Lancet
(2009)
MC Fang et al.
Death and disability from warfarin-associated intracranial and extracranial hemorrhages
Am J Med
(2007)
CT Ruff et al.
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials
Lancet
(2014)
C van Walraven et al.
Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis
JAMA
(2002)
SJ Connolly et al.
Dabigatran versus warfarin in patients with atrial fibrillation
N Engl J Med
(2009)

CB Granger et al.

Investigators. Apixaban versus warfarin in patients with atrial fibrillation

N Engl J Med

(2011)

MR Patel et al.

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation

N Engl J Med

(2011)

JB Olesen et al.

Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naive atrial fibrillation patients: Danish nationwide descriptive data 2011-2013

Europace

(2015)

N Vinter et al.

Classification and characteristics of on-label and off-label apixaban use in Denmark and Sweden

Pharmacoepidemiol Drug Saf

(2019)

JW Eikelboom et al.

Dabigatran versus warfarin in patients with mechanical heart valves

N Engl J Med

(2013)

Cited by (22)

Non–Vitamin K Antagonist Versus Vitamin K Antagonist Oral Anticoagulant Agents After Transcatheter Aortic Valve Replacement
2024, JACC: Cardiovascular Interventions
Studies comparing long-term outcomes between non–vitamin K antagonist (VKA) oral anticoagulant agents (direct oral anticoagulant agents [DOACs]) and VKA anticoagulant agents after transcatheter aortic valve replacement (TAVR) are scarce, with conflicting results.
The aim of this study was to examine the periprocedural, short-term, and long-term safety and effectiveness of DOACs vs VKAs in patients undergoing TAVR via femoral access with concomitant indications for oral anticoagulation.
Consecutive patients undergoing transfemoral TAVR in the prospective national SwissTAVI Registry between February 2011 and June 2021 were analyzed. Net clinical benefit (a composite of all-cause mortality, myocardial infarction, stroke, and life-threatening or major bleeding) and the primary safety endpoint (a composite of life-threatening and major bleeding) were compared between the VKA and DOAC groups at 30 days, 1 year, and 5 years after TAVR.
After 1:1 propensity score matching, 1,454 patients were available for analysis in each group. There was no significant difference in the rate of the net clinical benefit and the safety endpoints between the groups as assessed at 30 days and 1 and 5 years post-TAVR between VKAs and DOACs. VKAs were associated with significantly higher rates of 1- year (HR: 1.28; 95% CI: 1.01-1.62) and 5-year (HR: 1.25; 95% CI: 1.11-1.40) all-cause mortality. Long-term risk for disabling stroke was significantly lower in the VKA group after excluding periprocedural events (HR: 0.64; 95% CI: 0.46-0.90).
At 5 years after TAVR, VKAs are associated with a higher risk for all-cause mortality, a lower risk for disabling stroke, and a similar rate of life-threatening or major bleeding compared with DOACs. (SwissTAVI Registry; NCT01368250)
An Evidence-Based Approach to Anticoagulation Therapy Comparing Direct Oral Anticoagulants and Vitamin K Antagonists in Patients With Atrial Fibrillation and Bioprosthetic Valves: A Systematic Review, Meta-Analysis, and Network Meta-Analysis
2023, American Journal of Cardiology
Direct oral anticoagulants (DOACs) are a newer class of anticoagulants that inhibit factor Xa or factor IIa and include drugs such as rivaroxaban, apixaban, edoxaban, betrixaban, and dabigatran. Although vitamin K antagonists (VKAs) have been traditionally used to prevent thromboembolic events, DOACs have gained popularity because of their faster onset and offset of action and reduced need for monitoring. This study aimed to provide more data for anticoagulants in patients with atrial fibrillation with bioprosthetic heart valves by incorporating all available trials to date. A search was performed across 5 electronic databases to identify relevant studies. We analyzed the data using a pooled risk ratio for categorical outcomes and used the I² test to determine heterogeneity. The quality of randomized controlled trials was assessed using the Cochrane risk of bias assessment tool, and the National Institutes of Health tool was used for observational studies. Our study included a frequentist network meta-analysis (MA) of the aggregate data to obtain the network estimates for the outcomes of interest. We retrieved 28 studies with a total of 74,660 patients with bioprosthetic heart valves. Our MA significantly showed that DOACs decrease the risk of all-cause bleeding (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.75 to 0.85, p >0.00001), stroke and systemic embolization (RR 0.89, 95% CI 0.80 to 0.99, p = 0.03), and intracranial bleeding outcomes (RR 0.62, 95% CI 0.45 to 0.86, p = 0.004) compared with VKA. In contrast, there was no significant difference between the compared groups in major bleeding (RR = 0.92, 95% CI 0.84 to 1.02, p = 0.10) and all-cause mortality outcomes (RR = 0.96, 95% CI 0.85 to 1.07, p = 0.43), respectively. In addition, the network MA results did not favor any of the studied interventions over each other (p <0.05) regarding all-cause bleeding, mortality, stroke and systemic embolization, and major bleeding outcomes. In conclusion, our study found that DOACs are more effective in reducing the risk of bleeding, stroke, systemic embolism, and intracranial bleeding than VKAs. However, no significant difference was observed in the incidence of gastrointestinal bleeding, major bleeding, thromboembolic events, and all-cause mortality. In addition, our network MA did not identify any specific DOAC treatment as more favorable than others.
DOAC versus VKA in patients with atrial fibrillation and bioprosthetic valves: a systematic review and meta-analysis
2023, Revista Espanola de Cardiologia
Los anticoagulantes orales directos (ACOD) se han mostrado eficaces y seguros en pacientes con fibrilación auricular; sin embargo, los pacientes con FA y bioprótesis están infrarrepresentados en los ensayos clínicos, por lo que la evidencia en este grupo es menor. Nuestro objetivo fue analizar la seguridad y eficacia de los ACODs en esta población revisando la información existente en la literatura.
Se realizó una búsqueda y revisión sistemática con los ensayos clínicos aleatorizados y estudios observacionales comparativos desde 2017 a enero de 2022, que comparasen ACODs y antagonistas de vitamina K (AVK) en pacientes con FA y bioprótesis. Se utilizó la hazard ratio al 95% del intervalo de confianza para comparar ambos grupos en términos de mortalidad total y cardiovascular, ictus/embolia sistémica y hemorragia mayor. Se realizó un metanálisis combinando los resultados de los estudios incluidos.
Se incluyeron 12 estudios (un total de 30.283 pacientes). Los ACODs se asociaron a una reducción significativa del 9% de la mortalidad total (HR = 0,91; IC95%, 0,85-0,97; p = 0,0068; I² = 8%), sin diferencias significativas en el riesgo de ictus/embolismo sistémico (HR = 0,87; IC95%, 0,67-1,14; p = 0,29; I² = 45%) o hemorragia mayor (HR = 0,82; IC95%, 0,67-1,00; p = 0,054; I² = 48.7%).
En pacientes con FA portadores de bioprótesis, los ACODs podrían asociarse a una reducción de la mortalidad total sin reducción de eficacia en la prevención de ictus/embolia sistémica o aumento del riesgo de hemorragia mayor.
Direct oral anticoagulant (DOAC) therapy has been shown to be safe and effective in patients with atrial fibrillation (AF). However, outcomes in AF patients with bioprosthetic valves are unclear, as this population has been underrepresented in clinical trials. The aim of this study was to assess the safety and efficacy of DOACs in this population based on the existing published literature.
A systematic search and review were conducted to identify randomized clinical trials and comparative observational studies published from 2017 to January 2022 that compared DOACs and vitamin K antagonists (VKAs) in AF patients with bioprosthetic valves. Hazard ratios (HR) were collected to compare the 2 treatments in terms of cardiovascular and all-cause mortality, stroke/systemic embolism, and major bleeding. A meta-analysis combining the results was performed.
We included 12 studies (30 283 patients). DOACs and VKAs were compared based on HRs at the 95% confidence interval. DOAC therapy was associated with a significant 9% reduction in all-cause mortality (HR, 0.91; 95%CI, 0.85-0.97; P = .0068; I² = 8%), with no significant differences in the risk of stroke/systemic embolism (HR, 0.87; 95%CI, 0.67-1.14; P = .29; I² = 45%) or major bleeding (HR, 0.82; 95%CI, 0.67-1.00; P = .054; I² = 48.7%).
DOAC therapy in AF patients with bioprosthetic valves may be associated with a significant reduction in all-cause mortality, with no reduction in the efficacy of stroke/systemic embolism prevention or increase in major bleeding risk.
Direct oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation and bioprosthetic valves: A meta-analysis
2023, Journal of Thoracic and Cardiovascular Surgery
Citation Excerpt :
In the RCTs, the DOAC regimens included 110 mg of dabigatran twice daily,9 60 mg of edoxaban daily,10 5 mg of apixaban twice daily,11 or 20 mg of rivaroxaban daily.3 Among the observational studies, apixaban was used in 1 study12; dabigatran, rivaroxaban, apixaban, and edoxaban were used in 2 studies13,17; and dabigatran, rivaroxaban, and apixaban were used in 2 studies.14,16 The DOAC regimen was not described in 1 observational study.15
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.
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.
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%).
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 anticoagulants for atrial fibrillation in early postoperative valve repair or bioprosthetic replacement
2023, Journal of Thoracic and Cardiovascular Surgery
Despite increased use of direct oral anticoagulants (DOACs), limited evidence guides their use in the early postoperative period after bioprosthetic valve implantation in patients with atrial fibrillation. Our objective was to describe the efficacy and safety of DOACs and warfarin in the first 3 months after surgical bioprosthetic valve replacement or repair in patients with atrial fibrillation.
This was a retrospective, registry-informed cohort study of surgical patients who underwent bioprosthetic valve replacement or repair, had concomitant atrial fibrillation and received oral anticoagulation at discharge. The primary efficacy outcome was a composite of death, ischemic stroke, transient ischemic attack, and systemic embolism; the primary safety outcome was a composite of major bleeding. Key secondary outcomes were comparative analyses of primary outcomes, temporal anticoagulation prescribing patterns, and 30-day readmission rates.
A total of 1743 patients were included. Of the 570 patients in the DOAC group, 17 (2%) met the composite efficacy outcome and 55 (10%) met the composite safety outcome. Of the 1173 patients receiving warfarin, 41 (3%) and 114 (10%) met the composite efficacy and safety outcomes, respectively. Comparative secondary analysis was not statistically significant for either the efficacy (adjusted odds ratio, 0.85; 95% confidence interval, 0.46-1.55, P = .59) or safety (adjusted odds ratio, 0.94; 95% confidence interval, 0.66-1.34, P = .76) outcomes. The 30-day readmission rates were similar between both groups.
Our results suggest DOACs may be safe and effective alternatives to warfarin in the early postoperative period after valve repair or surgical bioprosthetic replacement. Confirmation awaits adequately powered prospective studies.
2021 ESC/EACTS Guideline on the diagnosis and treatment of valvular heart disease: Developed by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) Working Groups on the diagnosis and treatment of valvular heart disease
2022, Revista Espanola de Cardiologia
The True Infection Rate (TIR) in the whole population of each country and the Infection Fatality Rate (IFR) for coronavirus disease 2019 (COVID-19) are unknown although they are important parameters. We devised a simple method to infer TIR and IFR based on the open data. The prevalence rate of the polymerase chain reaction (PCR) tests among the population (Examination Rate; ER) and the positive rate of PCR tests (Infection Rate; IR) for 66 countries were picked up at a website 5 times from April 10th to June 13th, 2020, and the trajectory of each country was drawn over the IR vs. ER plot. IR and ER showed a strong negative correlation for some countries, and TIR was estimated by extrapolating the regression line when the correlation coefficient was between -0.99 and -1. True/Identified Case Ratio (TICR) and IFR were also calculated using the estimated TIR. The estimated TIR well coincided with local antibody surveys. Estimated IFR took on a wide range of values up to 10%: generally high in the Western countries. The estimated IFR of Singapore was very low (0.018%), which may be related to the reported gene mutation causing the attenuation of the viral virulence.

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Comparison of Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation and Bioprosthetic Heart Valves

Section snippets

Methods

Results

Discussion

Authors’ Contributions

Funding and Support

Acknowledgments

Disclosures

J Am Coll Cardiol

J Am Coll Cardiol

J Chronic Dis

Chest

Chest

Lancet

Am J Med

Lancet

Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis

JAMA

Dabigatran versus warfarin in patients with atrial fibrillation

N Engl J Med

Investigators. Apixaban versus warfarin in patients with atrial fibrillation

N Engl J Med

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation

N Engl J Med

Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naive atrial fibrillation patients: Danish nationwide descriptive data 2011-2013

Europace

Classification and characteristics of on-label and off-label apixaban use in Denmark and Sweden

Pharmacoepidemiol Drug Saf

Dabigatran versus warfarin in patients with mechanical heart valves

N Engl J Med