Abstract
Background: Japanese patients undergoing transcatheter aortic valve replacement (TAVR) are often female and have a small body size, potentially impacting bleeding risk with antithrombotic therapy. Outcomes of direct oral anticoagulant use in these patients with atrial fibrillation (AF) need to be clarified.
Methods and Results: This prespecified analysis included Japanese patients from ENVISAGE-TAVI AF, a prospective, randomized, open-label, adjudicator-masked trial that compared treatment with edoxaban and vitamin K antagonists (VKAs) in patients with AF after TAVR. The primary efficacy and safety outcomes were net adverse clinical events (NACE; composite of all-cause death, myocardial infarction, ischemic stroke, systemic embolic event, valve thrombosis, and International Society on Thrombosis and Haemostasis [ISTH]-defined major bleeding) and ISTH-defined major bleeding, respectively. Intention-to-treat (ITT) and on-treatment analyses were performed. Overall, 159 Japanese patients were enrolled (edoxaban group: 82, VKA group: 77) and followed for on average 483 days. Mean patient age was 83.8 years; 52.2% were female. In the ITT analysis, NACE rates were 10.9%/year with edoxaban and 12.5%/year with VKA (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.38–1.90); major bleeding occurred in 8.9%/year and 7.3%/year, respectively (HR, 1.17; 95% CI, 0.45–3.05). In edoxaban- and VKA-treated patients, rates of ischemic stroke were 1.8%/year and 1.0%/year, respectively; fatal bleeding rates were 0.9%/year and 2.0 %/year. On-treatment results were similar to ITT.
Conclusions: In Japanese patients with AF after successful TAVR, edoxaban and VKA treatment have similar safety and efficacy profiles.
Transcatheter aortic valve replacement (TAVR) is an increasingly used therapeutic strategy to treat severe aortic stenosis worldwide.1 Atrial fibrillation (AF) is common in patients following TAVR; the recommended treatment to prevent thromboembolic events in these patients is oral anticoagulation.2–4 Direct oral anticoagulants (DOACs) have emerged as an alternative therapeutic strategy to vitamin K antagonists (VKA) for the treatment of patients with AF after TAVR.3 The use of DOACs vs. VKA for the treatment of non-valvular AF has increased after the results of large, global clinical trials; however, differences in outcomes by country are generally not reported in these trials.3,5–8 The majority of Japanese patients undergoing TAVR are female and have a small body size, which may impact bleeding risk with antithrombotic therapy.9 Data on clinical outcomes after treatment with DOACs in Japanese patients with AF after TAVR are needed to appropriately treat this patient population.
ENVISAGE-TAVI AF was a multinational, prospective, randomized trial that compared the efficacy and safety of edoxaban, a direct factor Xa inhibitor, with that of VKA in patients after successful TAVR.10,11 In the global analysis of ENVISAGE-TAVI AF, edoxaban was non-inferior to VKA with respect to the primary efficacy outcome, the composite of net adverse clinical events (NACE).11 However, edoxaban was associated with higher rates of major bleeding, due to more major gastrointestinal (GI) bleeding in the edoxaban group.11 ENVISAGE-TAVI AF enrolled patients from 173 centers in 14 countries; regional analyses are needed to determine if outcomes for specific populations are consistent with global findings.11
The objective of this subanalysis of the ENVISAGE-TAVI AF trial was to compare the efficacy and safety of edoxaban with VKA in the treatment of Japanese patients with AF after successful TAVR.
Methods
Study Design
The detailed design of the ENVISAGE-TAVI AF trial is published.10 Briefly, it was a global, multicenter, prospective, randomized, open-label, adjudicator-masked trial that compared the efficacy and safety of edoxaban to that of VKA in patients with prevalent or incident AF after successful TAVR.10,11 It was conducted in accordance with the ethical principles of the Declaration of Helsinki, International Conference on Harmonisation-Good Clinical Practice, and all applicable Japanese laws and regulations concerning clinical research. Medical Corporation Tokushukai Certified Institutional Review Board for Clinical Trials reviewed the study protocol and informed consent documents following the 2018 Clinical Research Act of Japan. The study was registered in the Japan Registry of Clinical Trials (No. jRCTs031180144). Patients provided written informed consent before enrollment.
Patient Selection
Adult patients with AF after successful TAVR were eligible for enrollment in the ENVISAGE-TAVI AF trial. Key exclusion criteria included coexisting conditions associated with high bleeding risk, serious unresolved periprocedural complications, and contraindications to edoxaban and VKA per local label. The analysis currently presented included patients from Japan enrolled in the ENVISAGE trial from April 2017 through January 2020.
Randomization and Trial Treatment
Eligible patients were randomly assigned to receive edoxaban or VKA as the study drug using an interactive Web-response system, such that there was a 1 : 1 ratio of patients in the 2 study arms. Randomization occurred 12 hours to 7 days after TAVR. Patients randomized to the edoxaban group received 60 mg once daily unless one or more of the criteria were met for dose adjustment. Criteria for adjustment of the edoxaban dose to 30 mg once daily included creatinine clearance (Cockcroft-Gault formula) 15–≤50 mL/min, body weight ≤60 kg, and use of P-glycoprotein inhibitors.11 The target international normalized ratio (INR) for the VKA regimen was 2.0–3.0 (adjusted to 1.6–2.6 for patients aged ≥70 years).12 Patients were allowed to receive prespecified oral antiplatelet therapy at the discretion of the treating physician or at any time during the trial if medically indicated.
Patient follow-up occurred at 3 and 6 months after randomization and every 6 months thereafter. Patients included in the analysis were required to have a minimum of 6 months follow-up; the longest possible follow-up time was 36 months.
Outcomes
The primary efficacy outcome was the incidence of NACE, defined as the composite of all-cause death, myocardial infarction (MI), ischemic stroke, systemic embolic event (SEE), valve thrombosis, and major bleeding (International Society on Thrombosis and Haemostasis [ISTH] definition).13 The primary safety outcome was the incidence of ISTH-defined major bleeding. Secondary efficacy and safety outcomes in this analysis were the components of NACE; any stroke (ischemic, hemorrhagic, or undetermined); cardiovascular (CV) death (sudden, unexplained, and unwitnessed); major adverse cardiac and cerebrovascular events (defined as the composite of CV death, MI, stroke, or repeat coronary revascularization of the target lesion); major adverse cardiac events (defined as the composite of CV death, MI, or repeat coronary revascularization of the target lesion); intracranial hemorrhage (ICH); ISTH-defined fatal bleeding; life-threatening bleeding; the composite of ISTH-defined major and clinically relevant non-major (CRNM) bleeding; and ISTH-defined major GI bleeding.
Statistical Analysis
Clinical outcomes were compared between edoxaban and VKA arms in the intention-to-treat (ITT) population and the on-treatment population. The ITT population contains all patients randomized to the study drug regardless of whether they received a single dose of treatment. The time period for the ITT analysis is the overall study period (time from randomization to the patient’s last visit, an end-of-treatment visit at 36 months, an end-of-trial visit, or death, whichever occurred first). The on-treatment population consists of all randomized patients who received ≥1 dose of the assigned study drug. The time period for the on-treatment analysis is the period the patient was on the study treatment and up to 3 days after interruption or discontinuation of the study drug.
Results are presented as hazard ratios (HRs) with 2-sided 95% confidence intervals (CIs) based on a Cox proportional hazards regression model. HRs were only calculated for outcomes with >5 events in both treatment groups. Cumulative event-free survival was estimated with Kaplan-Meier analyses. All outcomes were summarized with the use of descriptive statistics (SAS software, version 9.2 or newer; SAS Institute).
Results
Patient Population
A total of 159 Japanese patients with AF after successful TAVR were enrolled in ENVISAGE-TAVI AF; 82 and 77 patients were randomized to the edoxaban and VKA arms, respectively (Figure 1). The ITT and on-treatment populations differed by only 1 patient, who was randomized to the edoxaban arm but never treated (Figure 1). Due to the similarities between the ITT and on-treatment patient populations, demographics and baseline clinical characteristics of patients are presented for the ITT population only. Baseline characteristics of patients were comparable between the edoxaban and VKA arms (Table 1). The mean patient age was 83.8 years and 52.2% of patients were female. Patients in the edoxaban arm were slightly older than those in the VKA arm; 52.4% of edoxaban patients were aged ≥85 years compared with 33.8% of VKA patients. Mean (standard deviation [SD]) creatinine clearance was 43.9 (16.4) in the edoxaban arm and 42.7 (15.0) in the VKA arm. The majority of patients in both treatment groups reported a history of hypertension and congestive heart failure. Oral antiplatelet agents were prescribed in 47.8% of patients in the ITT population at the time of randomization; 34.6% of patients were prescribed single antiplatelet therapy and 13.2% were prescribed dual antiplatelet therapy. In the edoxaban and VKA arms, 33 (40.2%) and 31 (40.3%) patients were prescribed antiplatelet therapy at randomization, respectively. At the time of randomization, 70 (85.4%) edoxaban patients and 66 (85.7%) VKA patients met ≥1 of the criteria for edoxaban dose adjustment to 30 mg.
Table 1. Baseline Patient Demographics and Clinical Characteristics (ITT Population)
| |
Edoxaban
(n=82) |
VKA
(n=77) |
| Age (years), mean (SD) |
84.3 (4.7) |
83.4 (4.0) |
| ≥65 to <75, n (%) |
2 (2.4) |
2 (2.6) |
| ≥75 to <80, n (%) |
10 (12.2) |
8 (10.4) |
| ≥80 to <85, n (%) |
27 (32.9) |
41 (53.3) |
| ≥85 to <90, n (%) |
33 (40.2) |
21 (27.3) |
| ≥90, n (%) |
10 (12.2) |
5 (6.5) |
| Female, n (%) |
38 (46.3) |
45 (58.4) |
| Weight (kg), mean (SD) |
53.8 (10.1) |
53.1 (10.3) |
| BMI (kg/m2), mean (SD) |
22.1 (3.4) |
22.3 (3.2) |
| Creatinine clearance (CG formula mL/min), mean (SD) |
43.9 (16.4) |
42.7 (15.0) |
| Hypertension, n (%) |
67 (81.7) |
68 (88.3) |
| Diabetes mellitus, n (%) |
26 (31.7) |
29 (37.7) |
| Congestive heart failure, n (%) |
75 (91.5) |
76 (98.7) |
| History of stroke, n (%) |
14 (17.1) |
8 (10.4) |
| Prior PCI, n (%) |
19 (23.2) |
16 (20.8) |
| Prior MI, n (%) |
9 (11.0) |
5 (6.5) |
| CHA2DS2-VASc, mean (SD) |
4.6 (1.3) |
4.6 (1.1) |
| HAS-BLED, mean (SD) |
1.7 (0.7) |
1.5 (0.6) |
| STS risk score, mean (SD) |
6.5 (3.6) |
6.8 (4.5) |
| History of labile INR, n (%) |
3 (3.7) |
5 (6.5) |
| Indication for dose adjustment, n (%)* |
70 (85.4) |
66 (85.7) |
*Indications for adjustment of the edoxaban dose included a creatinine clearance of ≤50 mL/min, body weight of ≤60 kg, and concomitant therapy with a P-glycoprotein inhibitor. BMI, body mass index; CG, Cockcroft-Gault; CHA2DS2-VASc, congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 and sex category (female); HAS-BLED, hypertension, abnormal liver/renal function, stroke history, bleeding history or predisposition, labile INR, elderly, drug/alcohol usage; INR, international normalized ratio; ITT, intention-to-treat; MI, myocardial infarction; PCI, percutaneous coronary intervention; SD, standard deviation; STS, Society of Thoracic Surgeons; VKA, vitamin K antagonist.
Patients were followed for an average of 483 days. The mean and median percentage of time of INR within the therapeutic range in the VKA arm were 65.9% and 69.5%, respectively. During the study period, 26 (31.7%) patients in the edoxaban arm discontinued treatment, compared to 29 (37.7%) patients in the VKA arm (Supplementary Table 1).
Outcomes
The incidence of efficacy and safety outcomes and corresponding HRs in the ITT analysis are shown in Figure 2. The primary efficacy outcome of NACE occurred in 11 (10.9%/year) edoxaban patients and 12 (12.5%/year) VKA patients (HR, 0.85; 95% CI, 0.38–1.90; Table 2). The primary safety outcome of major bleeding occurred in 9 (8.9%/year) and 7 (7.3%/year) patients in the edoxaban and VKA arms, respectively (HR, 1.17; 95% CI, 0.45–3.05; Figure 3).
Table 2. Efficacy and Safety Outcomes (ITT Population)
| |
Edoxaban
(n=82) |
VKA
(n=77) |
HR‡
(95% CI) |
| NACE |
11 (10.9) |
12 (12.5) |
0.85 (0.38–1.90) |
| Major bleeding* |
9 (8.9) |
7 (7.3) |
1.17 (0.45–3.05) |
| Secondary outcomes |
| All-cause death |
3 (2.7) |
7 (7.0) |
NC |
| Cardiovascular death |
3 (2.7) |
5 (5.0) |
NC |
| Ischemic stroke |
2 (1.8) |
1 (1.0) |
NC |
| SEE |
0 |
0 |
NC |
| Valve thrombosis† |
0 |
0 |
NC |
| Myocardial infarction |
0 |
0 |
NC |
| Any stroke |
2 (1.8) |
2 (2.0) |
NC |
| MACCE |
5 (4.6) |
6 (6.0) |
NC |
| MACE |
4 (3.7) |
5 (5.0) |
NC |
| Fatal bleeding* |
1 (0.9) |
2 (2.0) |
NC |
| Life-threatening bleeding |
1 (0.9) |
2 (2.0) |
NC |
| Intracranial hemorrhage |
0 |
2 (2.0) |
NC |
| Major and/or CRNM bleeding* |
27 (32.5) |
20 (24.3) |
1.34 (0.76–2.37) |
| Major GI bleeding |
3 (2.8) |
4 (4.1) |
NC |
Data presented as n (%/year). *ISTH definition. †Valve thrombosis was defined as any thrombus attached to or near an implanted valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment. ‡HRs were only calculated for outcomes with >5 events in both treatment groups. %/year, per 100 person-years; CI, confidence interval; CRNM, clinically relevant non-major; GI, gastrointestinal; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; ITT, intention-to-treat; MACCE, major adverse cardiac and cerebrovascular events, defined as the composite of death from cardiovascular causes, MI, stroke, or repeat coronary revascularization of the target lesion; MACE, major adverse cardiac events, defined as the composite of death from cardiovascular causes, MI, or repeat coronary revascularization of the target lesion; MI, myocardial infarction; NACE, net adverse clinical events, defined as the composite of all-cause death, MI, ischemic stroke, SEE, valve thrombosis, and ISTH-defined major bleeding; NC, not calculated; SEE, systemic embolic event; VKA, vitamin K antagonist.
In the ITT analysis, ischemic stroke occurred in 2 (1.8%/year) edoxaban patients and 1 (1.0%/year) VKA patient (Table 2). The rate of ICH was 2.0%/year in the VKA group; there were no incidences in the edoxaban group. Major and/or CRNM bleeding occurred at rates of 32.5%/year in patients randomized to edoxaban and 24.3%/year in patients randomized to VKA (HR, 1.34; 95% CI, 0.76–2.37). In the edoxaban and VKA arms, the rates of major GI bleeding were 2.8%/year and 4.1%/year, respectively; the rates of fatal bleeding were 0.9%/year and 2.0%/year, respectively. SEE, valve thrombosis, and MI were similarly rare in both treatment groups. All-cause death occurred in 3 (2.7%/year) patients randomized to edoxaban and 7 (7.0%/year) patients randomized to VKA.
Outcomes in the on-treatment analysis were similar to those in the ITT analysis (Supplementary Figure). The primary efficacy outcome occurred in 11 (12.3%/year) edoxaban patients and 9 (10.2%/year) VKA patients (HR, 1.23; 95% CI, 0.52–2.91; Supplementary Table 2). The primary safety outcome of major bleeding occurred in 9 (10.1%/year) and 7 (8.0%/year) patients in the edoxaban and VKA arms, respectively (HR, 1.30; 95% CI, 0.49–3.43).
The secondary outcomes in the on-treatment analysis also occurred at rates comparable to those in the ITT analysis. Ischemic stroke occurred in 2 (2.1%/year) patients treated with edoxaban; no VKA-treated patients had an event (Supplementary Table 2). Major and/or CRNM bleeding occurred at rates of 34.3%/year and 23.4%/year in patients treated with edoxaban and VKA, respectively (HR, 1.28; 95% CI, 0.69–2.36). In edoxaban- and VKA-treated patients, the rates of major GI bleeding were 2.2%/year and 4.4%/year, respectively. All-cause death occurred in 2 (2.1%/year) patients receiving edoxaban and 2 (2.2%/year) patients receiving VKA.
Supplementary Table 3 shows the incidence of primary efficacy and safety outcomes relative to oral antiplatelet use during the study. A substantially higher percentage of patients receiving edoxaban who used oral antiplatelet agents at any point during the study experienced NACE (20.9%) and major bleeding (18.6%) events compared with those who did not use oral antiplatelet agents (5.1% and 2.6%, respectively). The proportion of patients in the VKA group who experienced these events was only slightly higher in patients with oral antiplatelet use (NACE, 17.1%; major bleeding, 9.8%) vs. those without oral antiplatelet use (NACE, 13.9%; major bleeding, 8.3%).
Discussion
This subanalysis of the ENVISAGE-TAVI AF trial compared the efficacy and safety of edoxaban with VKA in Japanese patients with AF after successful TAVR. Differences in clinical outcomes observed between edoxaban and VKA treatments were minimal. Edoxaban was associated with numerically lower rates of the primary efficacy outcome, NACE, and slightly higher rates of the primary safety outcome, major bleeding, compared with VKA. These results suggest edoxaban is a viable antithrombotic strategy for the treatment of Japanese patients with AF after TAVR.
Results were similar between patients in the ITT population and those in the on-treatment population (Supplementary Table 2 and Supplementary Figure). There was no change in the incidence of NACE for edoxaban when comparing ITT and on-treatment analyses; fewer NACE events occurred with VKA in the on-treatment analysis as compared with the ITT analysis. The number of patients with major bleeding events for both treatments remained the same in both analyses. Fewer NACE events in the on-treatment VKA analysis may be due to more conservatively estimated treatment effects in ITT analyses, which do not exclude patient non-compliance and discontinuation.14
Clinical trials have shown improved outcomes with DOACs as compared with VKA in patients with AF; however, many of these were global trials and not specific to patients undergoing TAVR.5–8 Japanese patients undergoing TAVR tend to have a smaller body size compared with those from Europe and other western countries, which may affect bleeding risk with antithrombotic therapies.9,15 In the global ENVISAGE-TAVI AF population, the mean (SD) body weight for the edoxaban and VKA patients was 74.6 (17.9) kg and 76.0 (17.3) kg, respectively.11 Body weight was substantially lower in the subgroup of Japanese patients presented in this analysis; the mean (SD) body weight for the edoxaban and VKA patients was 53.8 (10.1) kg and 53.1 (10.3) kg, respectively. Although the Japanese ENVISAGE-TAVI AF patients had a smaller body size than the global population, this did not translate into higher rates of major bleeding. The annualized rates of major bleeding in the global ENVISAGE-TAVI AF population were 9.7%/year with edoxaban and 7.0%/year with VKA (ITT analysis), compared to rates of 8.9%/year and 7.3%/year in the Japanese population, respectively.11 Similar bleeding rates between the global and Japanese populations despite markedly different body size is likely due to most Japanese patients meeting the criteria for edoxaban dose adjustment and subsequently receiving the reduced 30-mg edoxaban dose. In the global ENVISAGE-TAVI AF population, 46.3% of patients met any criteria for adjustment of the edoxaban dose compared with 85.5% in the Japanese population.11 These findings support the importance of adjusting the edoxaban dose in patients with a high-risk profile.
In the ITT analysis, the incidence of all-cause death was lower in patients in the edoxaban group compared with those in the VKA group. These findings agree with the Japanese multicenter prospective registry, OCEAN-SHD (Optimized CathEter vAlvular iNtervention Structural Heart Disease), which compared long-term clinical outcomes in patients with AF after successful TAVR receiving either DOACs or VKAs after they were discharged.16 OCEAN-SHD demonstrated a lower incidence of all-cause death with DOAC therapy compared with VKA.16 Notably, patients in OCEAN-SHD receiving VKA had a higher mean HAS-BLED score and mean Society of Thoracic Surgeons (STS) risk score than patients receiving DOACs, which may have contributed to higher mortality in the VKA group.16 In the current study, patients receiving VKA vs. edoxaban had mean STS risk scores of 6.8 vs 6.5, and mean HAS-BLED scores of 1.5 vs 1.7, respectively.
The rates of major bleeding in the Japanese subanalysis of ENVISAGE-TAVI AF are similar to those observed in the main trial;11 however, the higher rate of major bleeding in the global population was driven by a higher rate of major GI bleeding in the edoxaban arm. Annual major GI bleeding event rates in the global ENVISAGE trial were 5.4%/year in the edoxaban arm and 2.7%/year in the VKA arm.11 This trend is not observed in this subanalysis of Japanese patients, although notably, the Japanese patient cohort sample size is substantially smaller than the overall patient cohort. These results suggest the higher rate of major GI bleeding with edoxaban in the global ENVISAGE-TAVI AF results may be a regional rather than global trend. Additional subanalyses of ENVISAGE-TAVI AF focused on major bleeding will provide further insight into these trends.
Limitations of this subanalysis include the small sample size with notable variability in outcome data. Statistical comparisons between edoxaban and VKA are limited, as the ENVISAGE-TAVI AF trial was not powered to test for non-inferiority of edoxaban vs. VKA in the Japanese subanalysis. Larger studies adequately powered to statistically compare outcomes with edoxaban to VKA in Japanese patients are needed to confirm the results presented here. Other limitations of the ENVISAGE-TAVI AF trial also apply, such as an open-label design and follow-up visits affected by the coronavirus disease 2019 (COVID-19) pandemic since 2020.11
In this subanalysis of 159 Japanese patients with AF after successful TAVR, the incidences of the primary efficacy outcome (NACE) and the primary safety outcome (major bleeding) appeared to be similar for the edoxaban and VKA arms. Edoxaban was associated with numerically lower rates of NACE and numerically higher rates of major bleeding compared with VKA. Due to the relatively small sample size in this study, future studies in Japanese patients designed to detect treatment effects are needed to confirm these results.
Acknowledgments
The authors thank all the OCEAN-SHD investigators. Medical writing and editorial assistance were provided by Margaret Van Horn, PhD, CMPP, of AlphaBioCom, LLC (King of Prussia, PA, USA), and funded by Daiichi Sankyo, Inc.
Sources of Funding
The trial was supported by Daiichi Sankyo, Inc.
Disclosures
Y. Watanabe is a consultant for Edwards Japan, Medtronic Japan, and Abbott Japan; K. Hayashida is a clinical proctor for Edwards Lifesciences and Medtronic and a member of Circulation Journal’s Editorial Team; M. Yamamoto is a clinical proctor for Edwards Lifesciences and Medtronic; F. Yamanaka has no conflicts of interest to declare; K. Yamasaki is a clinical proctor for Edwards Lifesciences and Medtronic; T. Naganuma is a clinical proctor for Edwards Lifesciences and Medtronic; Y. Ohno is a clinical proctor for Medtronic; M. Yamawaki has no conflicts of interest to declare; N. Morioka has no conflicts of interest to declare; K. Mizutani is a clinical proctor for Edwards Lifesciences and Medtronic; N. Tada is a clinical proctor for Edwards Lifesciences and Medtronic; H. Ueno is a clinical proctor for Edwards Lifesciences and Medtronic; H. Nishina has no conflicts of interest to declare; M. Izumo is a consultant for Abbott Medical Japan and Edwards LifeSciences; Y. Nakajima received lecture fees from Boston Scientific and Abbott Medical; K. Ando reports lecture fees from Terumo, Japan Lifeline, Bristol Myers Squibb, Medtronic Japan, and Biotronik Japan; K. Takagi is a clinical proctor for Edwards Lifesciences; T. Kimura is an employee of Daiichi Sankyo Co., Ltd.; K. Sugio is an employee of Daiichi Sankyo Co., Ltd.; G. Dangas reports research grants to institution and support for attending meetings from Bayer and Daiichi Sankyo and consulting fees from Daiichi Sankyo; G. Dangas’ spouse reports research grants to institution and support for attending meetings from Bayer and Daiichi Sankyo and consulting fees from Daiichi Sankyo; N. M. Van Mieghem reports grants or contracts from Abbott, Abiomed, Boston Scientific, Daiichi Sankyo, Edwards Lifesciences, Medtronic, PulseCath BV, and Siemens; C. Hengstenberg is a clinical proctor for Edwards Lifesciences and Boston Scientific, and reports payment for speaker bureaus and support for attending meetings from Daiichi Sankyo and advisory board participation for Daiichi Sankyo; C. Chen is an employee of Daiichi Sankyo, Inc.; J. Jin is an employee of Daiichi Sankyo, Inc.; M. Unverdorben is an employee of Daiichi Sankyo, Inc.; S. Saito is a clinical proctor for Edwards Lifesciences and Medtronic.
IRB Information
This trial was approved by the Medical Corporation Tokushukai Certified Review Board (reference number, CRB3210004).
Data Availability
The de-identified participant data from this study will not be shared.
Supplementary Files
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-22-0093
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