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Originally Published 4 April 2022
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Edoxaban Versus Dual Antiplatelet Therapy for Leaflet Thrombosis and Cerebral Thromboembolism After TAVR: The ADAPT-TAVR Randomized Clinical Trial

Duk-Woo Park, MD https://orcid.org/0000-0001-6643-0239 [email protected], Jung-Min Ahn, MD https://orcid.org/0000-0003-4031-391X, Do-Yoon Kang, MD, Kyung Won Kim, MD, Hyun Jung Koo, MD, Dong Hyun Yang, MD https://orcid.org/0000-0001-5477-558X, Seung Chai Jung, MD, … Show All … , Byungjun Kim, MD, Yiu Tung Anthony Wong, MD https://orcid.org/0000-0001-9321-5067, Cheung Chi Simon Lam, MD, Wei-Hsian Yin, MD, Jeng Wei, MD, Yung-Tsai Lee, MD, Hsien-Li Kao, MD https://orcid.org/0000-0002-5278-3540, Mao-Shin Lin, MD, Tsung-Yu Ko, MD, Won-Jang Kim, MD, Se Hun Kang, MD, Sung-Cheol Yun, PhD, Seung-Ah Lee, MD https://orcid.org/0000-0002-4093-7928, Euihong Ko, MD, Hanbit Park, MD, Dae-Hee Kim, MD https://orcid.org/0000-0002-8275-4871, Joon-Won Kang, MD, Jae-Hong Lee, MD https://orcid.org/0000-0001-7368-4560, and Seung-Jung Park, MD https://orcid.org/0000-0002-9187-5405 for the ADAPT-TAVR InvestigatorsAuthor Info & Affiliations
Circulation
Volume 146, Number 6
https://doi.org/10.1161/CIRCULATIONAHA.122.059512
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VIEW EDITORIAL:Missing Pieces of the Transcatheter Aortic Valve Replacement Subclinical Leaflet Thrombosis Puzzle

Abstract

Background:

It is unknown whether the direct oral anticoagulant edoxaban can reduce leaflet thrombosis and the accompanying cerebral thromboembolic risk after transcatheter aortic valve replacement. In addition, the causal relationship of subclinical leaflet thrombosis with cerebral thromboembolism and neurological or neurocognitive dysfunction remains unclear.

Methods:

We conducted a multicenter, open-label randomized trial comparing edoxaban with dual antiplatelet therapy (aspirin plus clopidogrel) in patients who had undergone successful transcatheter aortic valve replacement and did not have an indication for anticoagulation. The primary end point was an incidence of leaflet thrombosis on 4-dimensional computed tomography at 6 months. Key secondary end points were the number and volume of new cerebral lesions on brain magnetic resonance imaging and the serial changes of neurological and neurocognitive function between 6 months and immediately after transcatheter aortic valve replacement.

Results:

A total of 229 patients were included in the final intention-to-treat population. There was a trend toward a lower incidence of leaflet thrombosis in the edoxaban group compared with the dual antiplatelet therapy group (9.8% versus 18.4%; absolute difference, −8.5% [95% CI, −17.8% to 0.8%]; P=0.076). The percentage of patients with new cerebral lesions on brain magnetic resonance imaging (edoxaban versus dual antiplatelet therapy, 25.0% versus 20.2%; difference, 4.8%; 95% CI, −6.4% to 16.0%) and median total new lesion number and volume were not different between the 2 groups. In addition, the percentages of patients with worsening of neurological and neurocognitive function were not different between the groups. The incidence of any or major bleeding events was not different between the 2 groups. We found no significant association between the presence or extent of leaflet thrombosis with new cerebral lesions and a change of neurological or neurocognitive function.

Conclusions:

In patients without an indication for long-term anticoagulation after successful transcatheter aortic valve replacement, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant. The effects on new cerebral thromboembolism and neurological or neurocognitive function were also not different between the 2 groups. Because the study was underpowered, the results should be considered hypothesis generating, highlighting the need for further research.

Registration:

URL: https://www.clinicaltrials.gov. Unique identifier: NCT03284827.

Clinical Perspective

What Is New?

•
In the ADAPT-TAVR trial (Anticoagulation Versus Dual Antiplatelet Therapy for Prevention of Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement) comparing the potential effect of edoxaban with dual antiplatelet therapy in patients without an indication for long-term anticoagulation after transcatheter aortic valve replacement, the incidence of leaflet thrombosis was numerically lower with edoxaban than with dual antiplatelet therapy, but this was not statistically significant.
•
The treatment effect on reduction of leaflet thrombosis was not associated with a reduction of new cerebral thromboembolism and a new development of neurological or neurocognitive dysfunction. In addition, there was no significant relationship between subclinical leaflet thrombosis and an increased risk of cerebral thromboembolism and neurological dysfunction.
•
The incidence of any or major bleeding events was not significantly different between the 2 groups.

What Are the Clinical Implications?

•
Subclinical leaflet thrombosis has not been proven to affect the clinical outcomes for patients who underwent transcatheter aortic valve replacement; thus, this imaging phenomenon should not dictate the antithrombotic therapy.
•
The absence of evidence of temporally related adverse clinical sequelae of imaging-detected subclinical leaflet thrombosis does not support the routine imaging screening tests for the detection of this phenomenon and imaging-guided antithrombotic strategies in cases without hemodynamic or clinical significance.
Editorial, see p 494
Transcatheter aortic-valve replacement (TAVR) has become the established treatment for symptomatic severe aortic stenosis on the basis of clinical evidence from multiple large-scale randomized clinical trials.1–7 Most of these trials used dual antiplatelet therapy (DAPT; aspirin plus clopidogrel) as the default antithrombotic strategy after TAVR, which was empirically based on expert consensus. However, because possible subclinical leaflet thrombosis and reduced leaflet motion by 4-dimensional computed tomography (CT) were reported and the potential risk of consequent embolic stroke was of concern,8 several observational studies have suggested that these phenomena could be associated with an increased risk of ischemic cerebrovascular events and that oral anticoagulation (OAC) was more effective than antiplatelet therapy in the prevention or treatment of leaflet thrombosis.9–13
To resolve this unmet issue and to define the optimal antithrombotic strategy after TAVR, several randomized clinical trials have been conducted.14–19 Most of these trials support a less potent antithrombotic strategy with a reduction of primary net clinical benefit, driven mainly by a lower risk of bleeding events. On the basis of these data, updated clinical guidelines recommend that aspirin or single antiplatelet therapy should be used in most patients with no indication for long-term OAC after TAVR.20,21 However, it is still questioned whether a less potent antiplatelet therapy is sufficient to prevent leaflet thrombosis and to reduce the risk of cerebral thromboembolic events.22 In addition, further and more systematic study of this imaging phenomenon to clarify the underlying mechanism of a thromboembolic risk and to assess its clinical consequences is eagerly awaited.
Recently, the ENVISAGE-TAVI AF trial (Edoxaban Versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation–Atrial Fibrillation) showed that the non–vitamin K direct anticoagulant (NOAC) edoxaban was noninferior to vitamin K antagonists for the primary composite of adverse events but was associated with a higher risk of major bleeding in patients who had an indication for OAC for atrial fibrillation after TAVR.19 In ADAPT-TAVR (Anticoagulation Versus Dual Antiplatelet Therapy for Prevention of Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement), we investigated the effect of edoxaban compared with DAPT for the prevention of leaflet thrombosis and the accompanying potential risks of cerebral thromboembolization and neurological or neurocognitive dysfunction in patients who did not have an indication for OAC after successful TAVR.

Methods

The data, analytical methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.

Trial Design and Oversight

ADAPT-TAVR was a multinational, multicenter, prospective, randomized, open-label, adjudicator-masked trial.23 The trial was conducted in compliance with the International Council for Harmonization and the Declaration of Helsinki. The trial protocol was approved by the ethics committees and corresponding health authorities for all participating sites. All patients provided written informed consent to participate before trial enrollment.
This study was an investigator-initiated trial and was funded by the CardioVascular Research Foundation (Seoul, Korea) and Daiichi Sankyo Korea Co, Ltd. The funders assisted in the design of the protocol but had no role in the conduct of the trial or in the analysis, interpretation, or reporting of the results. The sponsor covered all costs associated with the trial, including the cost of the anticoagulants and all imaging, neurological, and laboratory tests for trial purposes that were not otherwise clinically indicated. Data analyses were conducted by the Clinical Research Center of Cardiology in Asan Medical Center (Seoul, Korea) and were executed under the academic leadership of the investigators. An independent data and safety monitoring board provided oversight by periodically reviewing all reported serious adverse events. The principal investigator (D.-W.P.) had unrestricted access to the data after the database was locked. All the authors reviewed and critiqued subsequent drafts and vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. Detailed information on participating centers (Table S1) and trial organization (roles and responsibilities; Table S2) is provided in the Supplemental Material.

Patient Selection and Randomization

Patients ≥18 years of age without an indication for long-term anticoagulation who had undergone successful TAVR for severe aortic stenosis were eligible for enrollment. Successful TAVR was defined as correct positioning of any approved transcatheter bioprosthetic aortic valve into the proper anatomic location with the intended valve performance and without unresolved periprocedural complications.24 Key exclusion criteria were any established indication for anticoagulation (eg, atrial fibrillation), any absolute indication for DAPT (eg, acute coronary syndromes or recent or concomitant percutaneous coronary intervention), and severe renal insufficiency prohibiting CT imaging (estimated glomerular filtration rate <30 mL per minute per 1.73 m2 of body surface area); the detailed inclusion and exclusion criteria are provided in Table S3. After written informed consent had been obtained, eligible patients were randomly assigned in a 1:1 ratio to receive edoxaban or DAPT through an interactive web-response system, stratified according to device type (balloon expandable or self-expandable) and participating center. Randomization occurred 24 hours to 7 days after TAVR and before hospital discharge.

Trial Treatment and Follow-Up

The edoxaban (experimental) group received 60 mg once daily or 30 mg once daily with dose-reduction criteria (a creatinine clearance [Cockcroft-Gault formula] of 30 to 50 mL/min, a low body weight of ≤60 kg, or concomitant use of certain P-glycoprotein inhibitors) for 6 months. The DAPT (control) group received aspirin at 100 mg once daily plus clopidogrel at 75 mg once daily for 6 months, which was the standard of care after TAVR for patients who did not have an indication for OAC at the time of trial enrollment.25,26 Edoxaban was supplied by the sponsor to the participating sites, and antiplatelet drugs (aspirin and clopidogrel) were supplied according to local practice. In cases with new-onset atrial fibrillation after TAVR, the assigned treatment remained as the protocol in the edoxaban group, and alternative use of NOACs or vitamin K antagonists was allowed in the DAPT group at the discretion of the treating physician.23
After enrollment, patients were followed up at 1, 3, and 6 months. Data collected during follow-up visits include clinical symptoms, health status, and any related clinical events, including rehospitalization or unintended hospital visits. For compliance check of study medications, the investigators have kept track of investigational drugs dispensed or administered to the subjects, which were used for compliance calculation. For all patients, a transthoracic echocardiogram was routinely performed immediately after TAVR and at 1 and 6 months, and hemodynamic structural valve deterioration was determined according to the standardized definitions.27

Imaging Studies and Neurological and Neurocognitive Assessment

Enrolled patients were routinely scheduled for a contrast-enhanced, electrocardiogram-gated cardiac CT scans with full cardiac-cycle coverage (4-dimensional CT) at the time of the 6-month follow-up visit after randomization. The cardiac CT images were analyzed for the presence of hypoattenuated leaflet thickening (possible leaflet thrombosis), leaflet motion based on opening limitation, stent eccentricity (percent), and calcification burden.23,28 The degree of hypoattenuated leaflet thickening and the severity of reduced leaflet motion were classified according to the standard definition.29,30 Hypoattenuated thickening was also assessed at supravalvular, subvalvular, and sinus of Valsalva levels (Figure S1). The results of the 4-dimensional CT scan were concealed from the treating physician and patient until the end of the trial. Concomitantly, to detect possible cerebral thromboembolism, all patients were routinely scheduled for brain magnetic resonance imaging (MRI) scans at baseline (1–7 days after TAVR and before discharge) and at the 6-month follow-up. All brain MRI scans were obtained, including diffusion-weighted imaging, fluid-attenuated inversion recovery, and T2* gradient echo sequences, which are the important sequences for the imaging end point.31 The brain MRIs were analyzed for the occurrence, number, and volume of new lesions on the 6-month diffusion-weighted imaging, fluid-attenuated inversion recovery, and gradient echo images compared with baseline MRI, respectively.23
The trial-specific standardized 4-dimensional cardiac CT acquisition protocol and brain MRI protocol are provided in Tables S4 and S5, respectively. All participating sites were qualified for their CT and MRI machines and capability to perform the standardized acquisition protocol by the imaging core laboratory. All CTs and MRIs acquired from each site were anonymized and electronically transferred to a central server (AiCRO system; Asan Image Metrics, Seoul, Korea) for image archiving and blinded independent image review.32 Imaging measurements were performed at a central imaging core laboratory (Asan Image Metrics) in a blinded manner by independent cardiac radiologists and neuroradiologists who were not aware of the patients’ identities and the random treatment assignments.23
All study subjects were simultaneously scheduled for detailed neurological and neurocognitive function assessments at baseline (1–7 days after TAVR and before discharge) and at the 6-month follow-up. Neurological assessments included standard clinical scales of the National Institutes of Health Stroke Scale and the modified Rankin Scale, and neurocognitive function was assessed with the Montreal Cognitive Assessment, which was a recommended screening measure of global cognition and cognitive impairment.33 Worsening of neurological or neurocognitive end points was defined as ≥1-point increase in National Institutes of Health Stroke Scale score, ≥1-point increase in modified Rankin Scale score, or ≥1-point decrease in Montreal Cognitive Assessment score compared with baseline.34‚35 All neurological and cognitive assessments were performed by trained and certified staff members in each participating center who were blinded to brain MRI findings and group assignment.

End Points

The primary end point was the incidence of valve leaflet thrombosis on cardiac CT scans at 6 months. Key secondary end points were the presence and number of new cerebral lesions and total new lesion volume on brain MRI and the results of serial neurological and neurocognitive assessments between immediately after TAVR and 6 months. Other secondary end points included serial echocardiographic parameters, as well as efficacy and safety clinical end points, which included death, myocardial infarction, stroke, systematic thromboembolic event, bleeding events, and rehospitalization. All of the above outcomes and their components were adjudicated in a blinded manner by an independent clinical events committee according to the Valve Academic Research Consortium-224 and -3 defintions36 and the Neurologic Academic Research Consortium definitions.33 A full list of trial end points and their definitions are provided in Tables S6 and S7, respectively.

Statistical Analysis

The sample size was estimated to simultaneously meet the primary end point of the incidence of leaflet thrombosis on cardiac CT and to meet the key secondary end point of the total new lesion number on brain MRI.23 From the results from the RESOLVE registry (Assessment of Transcatheter and Surgical Aortic Bioprosthetic Valve Thrombosis and Its Treatment with Anticoagulation) and SAVORY registry (Subclinical Aortic Valve Bioprosthesis Thrombosis Assessed With 4D CT),9 we assumed an incidence of subclinical leaflet thrombosis of 15% in the DAPT group and 3% in the NOAC (edoxaban) group. It was estimated that 192 patients (96 patients in each arm) would need to be enrolled to provide a statistical power of 80% to detect this difference with a 2-sided significance level of 0.05. Under an assumption that 10% of the patients would be lost to CT follow-up, a total sample of at least 220 patients was deemed to be sufficient to evaluate the primary end point. The final sample size was also met to demonstrate our hypothesis for the key secondary end point of brain MRI findings; the edoxaban group would provide a 30% reduction of the number of new lesions compared with the DAPT group according to previous studies34‚37 (more details on the sample size estimation are provided in the Supplemental Material).
The main analyses were performed according to the intention-to-treat principle. Secondary analyses of the primary and secondary end points were also performed in the per-protocol population; these populations are defined in Figure S2. The percentages of patients with the primary and secondary CT end points (leaflet thrombosis and reduced leaflet motion) between the treatment groups were compared with either the χ2 test or the Fisher exact test as appropriate. In a sensitivity analysis to test for the effect of the loss of values attributable to missing CT data, missing values of the primary outcome data after randomization were imputed over a wide range of possible scenarios. The key secondary end points, consisting of total new lesion number and volume differences on MRI and the results of serial neurological and neurocognitive assessments (overall and its subcomponents) between the 2 randomized arms, were compared with the Wilcoxon rank-sum test or Student t test as appropriate. Change scores were calculated by subtracting immediate post-TAVR scores from the 6-month scores. Differences between medians were estimated with the independent-samples Hodges-Lehmann estimator. Cumulative event-free survival was estimated by Kaplan-Meier analyses. Cox proportional hazards regression models were used to analyze the time from randomization to the first occurrence of the efficacy and safety clinical end points. For the primary and secondary end points, risk differences, risk ratios, and corresponding 95% CIs were reported. The proportional hazards assumption was confirmed by the Schoenfeld residuals test and graphical log-minus-log method; no relevant violations of the underlying assumption were found. Last, we evaluated whether there was a significant association of subclinical leaflet thrombosis or reduced leaflet motion with the risks of cerebral thromboembolism, a decline of neurological or neurocognitive function, and adverse events.
Because analyses were not corrected for multiple comparisons, the results of analyses other than those of the primary end point should be interpreted with caution, and therefore, inferences drawn from unadjusted CIs may not be reproducible. All statistical analyses were performed with SAS software, version 9.4 (SAS Institute).

Results

Trial Population

From March 2018 through April 2021, 769 patients undergoing TAVR were assessed for eligibility, and a total of 235 patients underwent randomization after successful TAVR in 5 centers in 3 countries (South Korea, Hong Kong, and Taiwan; Figure 1); 115 patients were randomly assigned to the edoxaban group and 120 to the DAPT group. After randomization, 6 patients were excluded from analysis because these patients withdrew informed consent during the index hospitalization without ingestion of trial medications. Therefore, 111 patients receiving edoxaban and 118 patients receiving DAPT were included in the final intention-to-treat population.
Figure 1. Screening, randomization, treatment, and follow-up. CT denotes computed tomography, and MRI, magnetic resonance imaging. *Because some patients had multiple exclusion criteria, the sum of number in each exclusion category may exceed the total number of patients with exclusion criteria.
The demographic and clinical characteristics of the patients at baseline were similar between the 2 trial groups (Table 1). The mean age of the patients was 80.1 years, and 41.9% of the patients were men. The mean Society of Thoracic Surgeons risk score was 3.3%. At trial entry, 61.3% of the randomized population of the edoxaban group met any of the criteria for adjustment of the edoxaban dose and received reduced doses (30 mg once daily). The procedural and echocardiographic characteristics at baseline, which were well balanced between the 2 randomized groups, are described in Table 2.
Table 1. Baseline Clinical Characteristics of the Patients in the Intention-to-Treat Population*
CharacteristicEdoxaban group
(n=111)		DAPT group
(n=118)		P value
Age, y80.2±5.280±5.30.78
Male sex, n (%)49 (44.1)47 (39.8)0.51
Body weight ≤60 kg, n (%)55 (49.6)63 (53.4)0.56
Body mass index, kg/m2†24.8±3.824.8±4.30.99
Body surface area, kg/m21.60±0.171.59±0.160.51
STS risk score‡
 Mean3.1±2.13.5±2.70.74
 Category, n (%)0.20
  Low (<4)86 (77.5)86 (72.9) 
  Intermediate (4–8)23 (21.6)26 (22.0) 
  High (>8)1 (0.9)6 (5.1) 
EuroSCORE II value§2.3±3.52.4±2.10.32
NYHA class III or IV, n (%)30 (27.0)31 (26.3)0.90
Diabetes mellitus, n (%)35 (31.5)36 (30.5)0.87
Hypertension, n (%)81 (73.0)84 (71.2)0.76
Hyperlipidemia, n (%)81 (73.0)92 (78.0)0.38
Current smoker, n (%)7 (6.3)7 (5.9)0.91
Congestive heart failure, n (%)17 (15.3)12 (10.2)0.24
Coronary artery disease, n (%)32 (28.8)34 (28.8)0.99
Previous myocardial infarction, n (%)1 (0.9)2 (1.7)>0.99
Previous PCI, n (%)18 (16.2)14 (11.9)0.34
Previous CABG, n (%)2 (1.8)3 (2.5)>0.99
Previous cerebrovascular disease, n (%)6 (5.4)11 (9.3)0.26
Carotid disease, n (%)6 (5.4)5 (4.2)0.68
Peripheral arterial disease, n (%)7 (6.3)11 (9.3)0.40
Chronic lung disease, n (%)25 (22.5)31 (26.3)0.51
Serum creatinine, mg/dL0.94±0.290.94±0.290.86
Creatinine clearance by Cockcroft-Gault formula, mL/min61.0±21.559.2±18.70.50
Creatinine clearance ≤50 mL/min, n (%)38 (34.2)47 (39.8)0.38
CABG indicates coronary artery bypass grafting; DAPT, dual antiplatelet therapy; EuroSCORE, European System for Cardiac Operative Risk Evaluation; NYHA New York Heart Association; PCI, percutaneous coronary intervention; STS, Society of Thoracic Surgeons; and TAVR, transcatheter aortic-valve replacement.
*
Plus-minus values are mean±SD. Percentages may not total 100 because of rounding.
†
Body mass index is the weight in kilograms divided by the square of the height in meters.
‡
The risk model of the STS uses an algorithm that is based on the presence of coexisting illnesses to predict 30-day operative mortality. The STS score equals the predicted mortality expressed as a percentage. A score of >8% indicates high risk; 4% to 8%, intermediate risk; and <4%, low risk.
§
Scores on the EuroSCORE II range from 0 to 100, with higher scores indicating a greater risk of death within 30 days after the procedure.
Table 2. Baseline Procedural and Echocardiographic Characteristics of the Patients in the Intention-to-Treat Population*
CharacteristicEdoxaban group (n=111)DAPT group
(n=118)		P value
Procedural characteristics
 Pre-TAVR balloon valvuloplasty, n (%)40 (36.0)41 (34.8)0.84
 Valve type, n (%)0.61
  Balloon-expandable101 (91.0)105 (89.0) 
  Self-expandable10 (9.0)13 (11.0) 
 Specific valve type0.68
  Sapien 3100 (90.1)104 (88.1) 
  Evolut R5 (4.5)7 (5.0) 
  CoreValve0 (0.0)1 (0.8) 
  Evolut PRO3 (2.7)5 (4) 
  Acurate Neo3 (2.7)1 (0.8) 
 Valve size, mm0.59
  204 (3.6)6 (5.1) 
  2342 (37.8)39 (33.1) 
  251 (0.9)0 (0.0) 
  2646 (41.4)57 (48.3) 
  2918 (16.2)14 (11.9) 
  310 (0.0)1 (0.8) 
  340 (0.0)1 (0.8) 
 Valve-in-valve, n (%)0 (0.0)4 (3.4)0.12
 Transfemoral approach, n (%)110 (99.1)117 (99.2)>0.99
 Type of anesthesia, n (%)0.68
  General27 (24.3)26 (22.0) 
  Monitored care84 (75.7)92 (78.0) 
 Post-TAVR permanent pacemaker, n (%)13 (11.7)13 (11.0)0.87
Post-TAVR echocardiographic characteristics
 Aortic valve area, cm21.7±0.41.6±0.40.13
 Mean aortic valve gradient, mm Hg13.4±5.114.3±5.40.17
 Left ventricular ejection fraction, %64.4±10.064.2±9.50.86
 Paravalvular aortic regurgitation, n (%)>0.99
  None or mild105/ 108 (97.2)112/ 115 (97.3) 
  Moderate or severe3/ 108 (2.8)3/ 115 (2.7) 
DAPT indicates dual antiplatelet therapy; and TAVR, transcatheter aortic-valve replacement.
*
Plus-minus values are mean±SD. Percentages may not total 100 because of rounding.
During the trial period, overall drug compliance and detailed information on stopping of study medications are summarized in Table S8; Figure S2 provides the same information for the per-protocol population. At 6 months, ≈95% of eligible patients had cardiac CT and brain MRI scans, as well as neurological and neurocognitive function tests (Figure 1). Completeness of CT scans, serial MRI scans, serial neurological or neurocognitive function tests, and clinical assessments between the immediate post-TAVR period and 6 months is summarized in Table S9.

Primary and Key Secondary End Points

In the intention-to-treat analysis, 10 of the 102 patients (9.8%) with CT scans that could be evaluated in the edoxaban group had at least 1 leaflet thrombosis compared with 20 of 109 (18.4%) in the DAPT group (difference, −8.5 percentage points [95% CI, −17.8 to 0.8]; P=0.076; Table 3 and Figure 2). Leaflet thrombosis with reduced motion of grade 3 or higher was observed in 3 of 102 patients (2.9%) in the edoxaban group and 8 of 109 (7.3%) in the DAPT group (difference, −4.4 percentage points [95% CI, −10.3 to 1.5]). Similar findings were noted in the analysis at the leaflet level. Results of sensitivity analyses of the primary end point in the intention-to-treat population and with a wide range of possible scenarios for missing CT data were also similar to those of the primary analysis (Figure S3). Consistent results were obtained in the per-protocol analysis, and detailed information on all available CT data analyses is reported in Table S10. The incidences of hypoattenuated thickening (possible thrombus) within the sinus of Valsalva (12.8% versus 22.0%, respectively) and at aortic valve complex dimension (37.3% versus 48.6%, respectively) were also lower in the edoxaban group than in the DAPT group.
Table 3. CT and MRI Imaging End Points and Neurological End Points in the Intention-to-Treat Population*
OutcomesEdoxaban
group, n/N (%)		DAPT
group, n/N (%)		Risk difference (95% CI), percentage pointsRisk ratio
(95% CI)		P value
4-Dimensional CT end points
 Hypoattenuated leaflet thickening†
  Patient level
   At least 1 thickened leaflet10/102 (9.8)20/109 (18.4)−8.54 (−17.82 to 0.73)0.53 (0.26 to 1.09)0.08
   At least 2 thickened leaflets4/102 (3.9)6/109 (5.5)−1.58 (−7.29 to 4.12)0.71 (0.21 to 2.45)0.75
   At least 3 thickened leaflets0/102 (0.0)2/109 (1.8)−1.83 (−4.49 to 0.82)NA0.50
  Leaflet level
   Leaflets with any degree of leaflet thickening14/306 (4.6)28/327 (8.6)−3.99 (−8.77 to −0.8)0.53 (0.25 to 1.15)0.11
   Leaflets with leaflet thickening >50% involvement6/306 (2.0)8/327 (2.5)−0.49 (−3.06 to 2.09)0.80 (0.24 to 2.70)0.72
 Reduced leaflet motion‡
  Patient level
   At least 1 thickened leaflet with grade ≥1 reduced motion10/102 (9.8)20/109 (18.4)−8.54 (−17.82 to 0.73)0.53 (0.26 to 1.09)0.08
   At least 1 thickened leaflet with grade ≥2 reduced motion6/102 (5.9)14/109 (12.8)−6.96 (−14.73 to 0.80)0.46 (0.18 to 1.15)0.08
   At least 1 thickened leaflet with grade ≥3 reduced motion3/102 (2.9)8/109 (7.3)−4.40 (−10.29 to 1.49)0.40 (0.11 to 1.47)0.15
  Leaflet level
   Leaflets with grade ≥1 reduced motion14/306 (4.6)28/327 (8.6)−3.99 (−8.77 to 0.8)0.53 (0.25 to 1.15)0.11
   Leaflets with grade ≥2 reduced motion9/306 (2.9)16/327 (4.9)−1.95 (−5.44 to 1.54)0.60 (0.23 to 1.58)0.30
   Leaflets with grade ≥3 reduced motion5/306 (1.6)8/327 (2.5)−0.81 (−3.31 to 1.69)0.67 (0.18 to 2.55)0.55
Brain MRI end points§
 Presence of new lesions, n/N (%)26/104 (25.0)22/109 (20.2)4.82 (−6.41 to 16.04)1.24 (0.75 to 2.04)0.40
  Presence of a single new lesion, n/N (%)19/104 (18.3)15/109 (13.8)4.51 (−5.34 to 14.36)1.33 (0.71 to 2.47)0.37
  Presence of multiple new lesions, n/N (%)7/104 (6.7)7/109 (6.4)0.31 (−6.35 to 6.97)1.05 (0.38 to 2.89)0.93
 Total new lesions, median (IQR), n1 (1 to 2)1 (1 to 3)0 (0 to 0)NA0.85
 Total new lesion volume, median (IQR), mm336.6 (13.7 to 145.0)43.9 (23.5 to 83.5)1.9 (−42.6 to 21.9)NA0.88
Neurological and neurocognitive function∥
 Neurologic assessment
  Paired NIHSS assessment, n/N (%)100/111 (90.0)108/118 (91.5)−1.44 (−8.93 to 6.06)0.98 (0.91 to 1.07)0.71
   Worsening, any, n/N (%)5/100 (5.0)4/108 (3.7)1.30 (−4.27 to 6.86)1.35 (0.37 to 0.49)0.74
   Worsening with new cerebral lesions, n/N (%)2/100 (2.0)1/108 (0.9)1.07 (−2.21 to 4.36)2.16 (0.20 to 23.46)0.61
  Paired modified Rankin Scale, n/N (%)100/111 (90.0)108/118 (91.5)−1.44 (−8.93 to 6.06)0.98 (0.91 to 1.07)0.71
   Worsening, any, n/N (%)2/100 (2.0)1/108 (0.93)1.07 (−4.14 to 19.70)2.16 (0.20 to 23.46)0.69
   Worsening with new cerebral lesions, n/N (%)1/100 (1.0)0/108 (0.0)−1.0 (−1.12 to 3.12)NA0.48
 Cognitive assessment     
  Paired Montreal Cognitive Assessment, n/N (%)100/111 (90.0)108/118 (91.5)−1.44 (−8.93 to 6.06)0.98 (0.91 to 1.07)0.71
   Worsening, any, n/N (%)30/100 (30.0)24/108 (22.2)7.78 (−4.15 to 19.70)1.35 (0.85 to 2.14)0.20
   Worsening with new cerebral lesions, n/N (%)7/100 (7.0)4/108 (3.7)3.30 (−2.84 to 9.44)1.89 (0.57 to 6.26)0.29
BARC indicates Bleeding Academic Research Consortium; CT, computed tomography; DAPT, dual antiplatelet therapy; IQR, interquartile range; MRI, magnetic resonance imaging; NA, not applicable; NIHSS, National Institute of Health Stroke Scale; and VARC, Valve Academic Research Consortium.
*
Analyses were not corrected for multiple comparisons. Relative risk was described by the risk ratio (for edoxaban compared with DAPT) and corresponding 95% CIs, which were calculated by the logistic regression analysis.
†
Hypoattenuated leaflet thickening was defined as visually identifiable increased leaflet thickness on contrast-enhanced multiplanar reformats, carefully aligned with the long and short axes of the valve prosthesis.29 The extent of leaflet thickening can be graded on a subjective 4-tier grading scale along the curvilinear orientation of the leaflet: no thickening, <25% involvement of leaflet; 25% to 50%, involvement of leaflet; 51% to 75%, involvement of leaflet; and >75%, involvement of leaflet.29,30 For leaflet-level analyses, logistic regression with generalized estimating equations was used to account for the natural correlation with measurements and the clustering effect on the same patient.
‡
Leaflet motion was assigned a grade from 0 to 4: grade 0 denotes unrestricted; grade 1, minimally restricted (with restriction limited to the base); grade 2, mildly restricted (involving more than the base but <50% of the leaflet); grade 3, moderately restricted (involving >50% but <75% of the leaflet); and grade 4, largely immobile.29,30 For leaflet-level analyses, logistic regression with generalized estimating equations was used to account for the natural correlation with measurements and the clustering effect on the same patient.
§
The presence and amount of new cerebral thromboembolic lesions were determined on the basis of fluid-attenuated inversion recovery images on brain MRI.
∥
Neurological and neurocognitive function data are reported as number (percent) of patients with a worsening of NIHSS, modified Rankin Scale, and Montreal Cognitive Assessment scores at the 6-month follow-up compared with baseline. Worsening is defined as ≥1-point increase in NIHSS, ≥1-point increase in modified Rankin Scale, or ≥1 point decrease in Montreal Cognitive Assessment scores compared with baseline.34‚35
Differences calculated as independent-samples Hodges-Lehmann median difference estimates.
Figure 2. CT imaging end points, MRI imaging end points, and neurological or neurocognitive function end points in the intention-to-treat population. A, Percentages of patients who had leaflet thrombosis and at least 1 prosthetic valve leaflet with reduced motion of grade 3 or higher in the edoxaban and dual antiplatelet groups. Degree of hypoattenuated leaflet thickening and severity of reduced leaflet motion were classified according to the standard definition.29,30 B, Percentages of patients who had new cerebral lesions, the median new lesion number, and the median total new lesion volume on serial magnetic resonance imaging (MRI) scans in the edoxaban and dual antiplatelet groups. Presence and amount of new cerebral thromboembolic lesions were determined from fluid-attenuated inversion recovery (FLAIR) images on the brain MRI. C, Percentages of patients with worsening of serial neurological testing (National Institute of Health Stroke Scale [NIHSS] and modified Rankin Scale) and those with worsening of neurocognitive function (Montreal Cognitive Assessment). Worsening is defined as ≥1-point increase on the NIHSS, ≥1-point increase on the modified Rankin Scale, or ≥1-point decrease in Montreal Cognitive Assessment scores compared with baseline.34‚35 DAPT indicates dual antiplatelet therapy.
In the intention-to-treat analysis, new cerebral lesions on serial MRI scans were found in 26 of 104 patients (25.0%) who were randomly assigned to the edoxaban group compared with 22 of 109 patients (20.2%) who were randomly assigned to the DAPT group (difference, 4.8 percentage points [95% CI, −6.4 to 16.0]; Table 3 and Figure 2). The median new lesion number was not different between the edoxaban group and the DAPT group (1 [interquartile range, 1–2] versus 1 [interquartile range, 1–3], respectively). The median total new lesion volume was also not significantly different between the edoxaban and DAPT groups (36.6 mm3 [interquartile range, 13.7–145.0 mm3] versus 43.9 mm3 [interquartile range, 23.5 to 83.5 mm3], respectively). Consistent results were obtained in the per-protocol analysis, and all available MRI data analyses are reported in Table S11.
In the intention-to-treat population, the percentages of patients with worsening of serial neurological testing were similar between the edoxaban group and the DAPT group (National Institutes of Health Stroke Scale, 5.0% [5 of 100] versus 3.7% [4 of 108], respectively; difference, 1.3 percentage points [95% CI, −4.3 to 6.9]; modified Rankin Scale, 2.0% [2 of 100] versus 0.9% [1 of 108], respectively; difference, 1.1 percentage points [95% CI, −4.1 to 19.7]; Table 3 and Figure 2). The proportion of patients with worsening of neurocognitive function was also similar (Montreal Cognitive Assessment, 30.0% [30 of 100] versus 22.2% [24 of 108], respectively; difference, 7.8 percentage points [95% CI, −4.2 to 19.7]). Uniform findings were observed in the per-protocol analysis, and all available information on neurological and neurocognitive function analyses is reported in Table S12.

Clinical Events and Echocardiographic Findings

At 6 months, the incidences of efficacy outcomes (death, myocardial infarction, stroke, or systematic thromboembolic event) were each <3% and were not different between the edoxaban group and the DAPT group (Table 4). Only 4 patients had a clinically overt ischemic stroke (2 patients in the edoxaban group and 2 patients in the DAPT group). The incidence of any or major bleeding events was also not different between the 2 groups.
Table 4. Clinical Outcomes in the Intention-to-Treat Population*
OutcomesEdoxaban
group, n/N (%)		DAPT
group, n/N (%)		Risk difference (95% CI), percentage pointsRisk ratio
(95% CI)		P Value
Clinical end points at 6 mo†
 Death3/111 (2.7)2/118 (1.7)1.01 (−2.80 to 4.82)1.48 (0.25 to 8.75)0.68
  Cardiovascular causes30   
  Noncardiovascular causes02   
  Valve-related mortality10   
 Myocardial infarction1/111 (0.9)3/118 (2.5)−1.64 (−4.98 to 1.70)0.45 (0.05 to 3.83)0.62
 Stroke2/111 (1.8)2/118 (1.7)0.11 (−3.29 to 3.51)1.05 (0.15 to 7.45)>0.99
  Ischemic22   
  Hemorrhagic00   
  Disabling10   
  Nondisabling12   
 Systemic thromboembolic event2/111 (1.8)0/118 (0.0)1.80 (−0.79 to 4.39)NA0.23
 Bleeding events     
  VARC-2 criteria13/111 (11.7)15/118 (12.7)−1.00 (−9.48 to 7.48)0.93 (0.44 to 1.96)0.82
   Minor bleeding711   
   Major bleeding63   
   Life-threatening or disabling bleeding/BARC type 501   
  VARC-3 criteria13/111 (11.7)15/118 (12.7)−1.00 (−9.48 to 7.48)0.93 (0.44 to 1.96)0.82
   Type 11013   
   Type 231   
   Type 300   
   Type 401   
  Rehospitalization according to VARC-3 criteria17/111 (15.3)14/118 (11.9)3.45 (−5.43 to 12.34)1.29 (0.67 to 2.49)0.45
   Procedure-related or valve-related hospitalization32   
   Other cardiovascular hospitalization43   
   Noncardiovascular hospitalization109   
BARC indicates Bleeding Academic Research Consortium; DAPT, dual antiplatelet therapy; NA, not applicable; and VARC, Valve Academic Research Consortium.
*
Analyses were not corrected for multiple comparisons.
†
Clinical end points were adjudicated according to the VARC-224 and VARC-336 definitions. Event rates (percent) were estimated with the use of a Kaplan-Meier survival analysis of data from the intention-to-treat population, and relative risk was described by the hazard ratio (for edoxaban compared with DAPT) and corresponding 95% CIs, which were calculated by the Cox proportional hazards models.
There were no significant differences in various echocardiographic parameters between the 2 randomized treatment groups at baseline, immediately after TAVR, and at the 6-month follow-up (Table S13). In addition, there was no significant between-group difference in the rate of hemodynamic structural valve deterioration according to the randomized treatment group and the presence or absence of leaflet thrombosis (Table S14).

Association of Leaflet Thrombosis With Cerebral Thromboembolism and Neurological and Neurocognitive Dysfunction

We assessed the association of subclinical leaflet thrombosis or reduced leaflet motion with the risks of cerebral thromboembolism, a decline of neurological or neurocognitive function, and relevant clinical outcomes (Table S15). There were no significant differences in the rates of new cerebral lesions on MRI, decline of neurological or neurocognitive function, and adverse clinical events between patients who had leaflet thrombosis or reduced leaflet motion of grade 3 or higher and those without these phenomena. In addition, there was no correlation between the number of leaflet thromboses and the number of new cerebral lesions (Figure 3) or serial changes of neurological or neurocognitive function (Figure 4). There were also no significant differences in the rates of new cerebral lesions and a decline of neurological and neurocognitive function, according to the presence or absence of any hypoattenuated thickening at the aortic valve complex, subvalvular, supravalvular, or sinus of Valsalva areas (Figure S4).
Figure 3. Correlation of severity of HALT with extent of new lesions on brain MRI. DWI indicates diffusion-weighted image; HALT, hypoattenuated leaflet thickening; FLAIR, fluid-attenuated inversion recovery; GRE, gradient echo; and MRI, magnetic resonance imaging.
Figure 4. Correlation of severity of HALT with decline of neurological and neurocognitive function. HALT indicates hypoattenuated leaflet thickening; MOCA, Montreal Cognitive Assessment; mRS, modified Rankin Scale; and NIHSS, National Institute of Health Stroke Scale.

Discussion

The ADAPT-TAVR trial compared the potential effect of edoxaban with DAPT for the prevention of leaflet thrombosis and the accompanying risks of cerebral thromboembolism and neurological or neurocognitive dysfunction by scientifically valid evaluations in patients without an indication for anticoagulation after TAVR. The main findings were as follows: (1) Although the use of edoxaban reduced the incidence of the primary end point of leaflet thrombosis at 6 months by 8.5 percentage points (risk ratio, 0.53), compared with DAPT, the difference was not statistically significant. (2) The effect on the reduction of leaflet thrombosis was not associated with a reduction of new cerebral lesions on MRI and a new development of neurological or neurocognitive dysfunction. (3) We did not find any association of subclinical leaflet thrombosis with an increased risk of cerebral thromboembolism and neurological end points.
Previous observational studies suggested that the incidence of subclinical leaflet thrombosis was not uncommon (range, 7%–38%), and this imaging phenomenon could be associated with an increased risk of stroke or transient ischemic attack.8–10,12,13 These studies also suggested that OAC use could reduce leaflet thrombosis, which was associated with numerically lower rates of cerebrovascular events compared with single antiplatelet therapy or DAPT. However, most of previous studies might be hampered by inherent limitations of observational studies, the different time points of CT evaluations, the lack of a causal relationship of leaflet thrombosis with cerebral thromboembolic events, and the heterogeneity of different antithrombotic agents, dosages, and combinations. In this clinical context, our ADAPT-TAVR trial adds new clinical evidence for the effect of a specific NOAC, edoxaban, in preventing leaflet thrombosis and the accompanying risks of cerebral thromboembolism and neurological/neurocognitive dysfunction, and it provides scientific verification of the causal relationship between subclinical leaflet thrombosis and consequent cerebral adverse ischemic events.
Until recently, several randomized clinical trials have tested that an NOAC-based strategy might be more effective than conventional antithrombotic strategies for the prevention of leaflet thrombosis and thromboembolic events in patients with or without OAC indication after TAVR.15,18,19,30 Although most of trials showed that the incidence of leaflet thrombosis and reduced leaflet motion was significantly lower with NOAC, this effect did not translate into an improvement in clinical efficacy outcomes, and it was significantly associated with an increased risk of major bleeding.15,18,19 Our ADAPT-TAVR trial also showed discordant or dissociative findings between a reduction of leaflet thrombosis and the risks of cerebral thromboembolism and neurological end points. Therefore, it should be recognized that subclinical leaflet thrombosis has not been proven to affect the clinical outcomes among patients undergoing TAVR and that this subclinical imaging phenomenon may not dictate the antithrombotic therapy (for prevention or treatment) after TAVR. Last, on the basis of such cumulative evidence of recent trials, including ADAPT-TAVR,14–16,18 decision making for optimal antithrombotic therapy after TAVR should consider patient-centered outcomes while preserving a favorable overall clinical benefit-risk balance; thus, single antiplatelet therapy should be the standard of care for patients without an indication of long-term OAC.20,21
Because possible subclinical leaflet thrombosis by 4-dimensional CT was reported in the Investigational Device Exemption study and registry studies,8 the US Food and Drug Administration has been closely monitoring this signal and its potential effect on the safety, effectiveness, and benefit-risk profile of bioprosthetic aortic valves.38 Until recently, it has not yet been determined whether this phenomenon is clinically meaningful with a possible association of cerebral thromboembolism and valve dysfunction or just represents a subclinical advanced-imaging phenomenon. To confirm this causal association, the ADAPT-TAVR trial conducted systematic serial evaluations of cardiac CT, brain MRI, and neurological or neurocognitive assessment, which provide insight into the temporal relationship and mechanisms underlying the potential detrimental effect of subclinical leaflet thrombosis on cerebral embolic events. Last, our study did not show any association between the presence or extent of subclinical leaflet thrombosis and a risk of cerebral thromboembolism and neurological or neurocognitive dysfunction. From the clinical viewpoint, the absence of evidence of temporally related adverse clinical sequelae of imaging-detected leaflet thrombosis and reduced leaflet motion may not support the routine imaging screening tests for the detection of subclinical leaflet thrombosis as well as imaging-guided antithrombotic strategy in cases without hemodynamic or clinical significance.
Other clinical trials using NOACs for preventing leaflet thrombosis and thromboembolic events have noted higher bleeding rates compared with antiplatelet therapy or conventional OAC.15,19 Recently, the ENVISAGE-TAVI AF trial showed that edoxaban was associated with a higher risk of major bleeding (attributable mainly to more major gastrointestinal bleeding) than vitamin K antagonists; 46.4% of the trial population met any of the criteria for adjustment of the edoxaban dose and received reduced doses.19 In contrast, given substantial interracial differences in demographic and clinical characteristics in patients undergoing TAVR,39 ≈61% of the randomized cohort in our trial received a reduced dose of edoxaban, and this may result in underestimation of bleeding risk if a similar strategy is applied in Western patients.
Several limitations of the trial should be considered. First, ADAPT-TAVR was an open-label trial, which was potentially subject to reporting and ascertainment bias. However, all CTs and MRIs were independently measured in a blinded fashion at an imaging core laboratory, and the neurological and clinical outcomes were prespecified with the use of standardized definitions and adjudicated by an independent blinded clinical events committee. Second, the ADAPT-TAVR trial has adopted surrogate imaging outcomes as the primary and key secondary end points. Therefore, its limited sample size was too small to allow a sufficient correlation of imaging findings with adverse clinical events. In addition, our trial was underpowered to detect any meaningful differences in clinical efficacy and safety outcomes. Third, the hypoattenuated leaflet thickening that we observed could be associated with subclinical leaflet thrombosis. However, our study is limited by the absence of pathological confirmation. Fourth, because the appearance or resolution of leaflet thrombosis has been reported to be a dynamic process11,12 and the follow-up period of our trial is relatively short, the long-term effect of leaflet thrombosis or different antithrombotic strategies on bioprosthetic valve durability is still unknown. Last, we excluded patients with an established indication for OAC, which might be at least one-third of the TAVR population. Thus, our findings cannot be directly extrapolated to this population.

Conclusions

In patients without an established indication for long-term anticoagulation after successful TAVR, there was a trend in favor of the edoxaban group compared with the DAPT group in the incidence of subclinical leaflet thrombosis on CT scans, which was not statistically significant. The effect on the reduction of leaflet thrombosis was not associated with a reduction of new cerebral lesions and a new development of neurological or neurocognitive dysfunction. In addition, there was no association between subclinical leaflet thrombosis and temporally related changes of new cerebral thromboembolic lesions and neurological end points. However, the study had insufficient statistical power to allow a conclusive interpretation. Hence, further research is needed in this area.

Article Information

Supplemental Material

Expanded Methods
Tables S1–S15
Figures S1–S4

Acknowledgments

Conception and design: D.-W.P., S.-J.P. Analysis and interpretation of data: D.-W.P., S.-C.Y., S.-J.P. Drafting of the manuscript: D.-W.P., J.-M.A., D.-Y.K., S.-C.Y., S.-J.P. Critical revision of the manuscript for important intellectual content: D.-W.P., J.-M.A., D.-Y.K., K.W.K., H.J.K., D.H.Y., S.C.J., B.K., Y.T.A.W., C.C.S.L., W.-H.Y., J.W., Y.-T.L., H.-L.K., M.-S.L., T.-Y.K., W.-J.K., S.H.K., S.-C.Y., S.-A.L., E.K., H.P., D.-H.K., J.-W.K., J.-H.L., S.-J.P. Final approval of the manuscript: D.-W.P., J.-M.A., D.-Y.K., K.W.K., H.J.K., D.H.Y., S.C.J., B.K., Y.T.A.W., C.C.S.L., W.-H.Y., J.W., Y.-T.L., H.-L.K., M.-S.L., T.-Y.K., W.-J.K., S.H.K., S.-C.Y., S.-A.L., E.K., H.P., D.-H.K., J.-W.K., J.-H.L., S.-J.P. Statistical expertise: S.-C.Y. Obtaining research funding: D.-W.P., S.-J.P. Administrative, technical, or logistic support: D.-W.P., J.-M.A., D.-Y.K., K.W.K., H.J.K., D.H.Y., S.C.J., B.K., Y.T.A.W., C.C.S.L., W.-H.Y., J.W., Y.-T.L., H.-L.K., M.-S.L., T.-Y.K., W.-J.K., S.H.K., S.-C.Y., S.-A.L., E.K., H.P., D.-H.K., J.-W.K., J.-H.L., S.-J.P. Acquisition of data: D.-W.P., J.-M.A., D.-Y.K., K.W.K., Y.T.A.W., C.C.S.L., W.-H.Y., J.W., Y.-T.L., H.-L.K., M.-S.L., T.-Y.K., W.-J.K., S.H.K., E.K., S.-J.P. The authors thank the staff members of the ADAPT-TAVR trial; the cardiologists, radiologists, imaging specialists, and neurologists at the participating centers; and all research coordinators for their efforts in collecting clinical data and ensuring the accuracy and completeness of the data.

Footnote

Nonstandard Abbreviations and Acronyms

ADAPT-TAVR
Anticoagulation Versus Dual Antiplatelet Therapy for Prevention of Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement
CT
computed tomography
DAPT
dual antiplatelet therapy
ENVISAGE-TAVI AF
Edoxaban Versus Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation–Atrial Fibrillation
MRI
magnetic resonance imaging
NOAC
non–vitamin K direct anticoagulant
OAC
oral anticoagulation
TAVR
transcatheter aortic-valve replacement

Supplemental Material

File (10.1161.circulationaha.122.059512 supplement.pdf)
File (circ_circulationaha-2022-059512_supp1.pdf)

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Published In

Go to Circulation
Go to Circulation
Circulation
Volume 146 • Number 6 • 9 August 2022
Pages: 466 - 479
PubMed: 35373583

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© 2022 American Heart Association, Inc.

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History

Received: 2 February 2022
Accepted: 15 March 2022
Published online: 4 April 2022
Published in print: 9 August 2022

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Keywords

  1. anticoagulants
  2. aortic valve stenosis
  3. thromboembolism
  4. thrombosis
  5. transcatheter aortic valve replacement

Subjects

  1. Aortic Valve Replacement/Transcatheter Aortic Valve Implantation

Authors

Affiliations

Duk-Woo Park, MD https://orcid.org/0000-0001-6643-0239 [email protected]
Division of Cardiology (D.-W.P., J.-M.A., D.-Y.K., S.-A.L., E.K., D.-H.K., S.-J.P.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Jung-Min Ahn, MD https://orcid.org/0000-0003-4031-391X
Division of Cardiology (D.-W.P., J.-M.A., D.-Y.K., S.-A.L., E.K., D.-H.K., S.-J.P.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Do-Yoon Kang, MD
Division of Cardiology (D.-W.P., J.-M.A., D.-Y.K., S.-A.L., E.K., D.-H.K., S.-J.P.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Kyung Won Kim, MD
Asan Image Metrics, Clinical Trial Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea (K.W.K.).
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Hyun Jung Koo, MD
Department of Radiology Research Institute of Radiology (H.J.K., D.H.Y., S.C.J., J.-W.K.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Dong Hyun Yang, MD https://orcid.org/0000-0001-5477-558X
Department of Radiology Research Institute of Radiology (H.J.K., D.H.Y., S.C.J., J.-W.K.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Seung Chai Jung, MD
Department of Radiology Research Institute of Radiology (H.J.K., D.H.Y., S.C.J., J.-W.K.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Byungjun Kim, MD
Department of Radiology, Anam Hospital, Korea University College of Medicine, Seoul (B.K.).
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Yiu Tung Anthony Wong, MD https://orcid.org/0000-0001-9321-5067
Division of Cardiology, Department of Medicine, University of Hong Kong, Queen Mary Hospital (Y.T.A.W., C.C.S.L.).
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Cheung Chi Simon Lam, MD
Division of Cardiology, Department of Medicine, University of Hong Kong, Queen Mary Hospital (Y.T.A.W., C.C.S.L.).
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Wei-Hsian Yin, MD
Heart Center, Cheng Hsin General Hospital, Taipei, Taiwan (W.-H.Y., J.W., Y.-T.L.).
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Jeng Wei, MD
Heart Center, Cheng Hsin General Hospital, Taipei, Taiwan (W.-H.Y., J.W., Y.-T.L.).
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Yung-Tsai Lee, MD
Heart Center, Cheng Hsin General Hospital, Taipei, Taiwan (W.-H.Y., J.W., Y.-T.L.).
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Hsien-Li Kao, MD https://orcid.org/0000-0002-5278-3540
Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei (H.-L.K., M.-S.L.).
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Mao-Shin Lin, MD
Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei (H.-L.K., M.-S.L.).
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Tsung-Yu Ko, MD
Division of Cardiology, Department of Internal Medicine, Hsin-Chu Branch, National Taiwan University Hospital (T.-Y.K.).
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Won-Jang Kim, MD
Department of Cardiology, CHA Bundang Medical Center, Seongnam, Korea (W.-J.K., S.H.K.).
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Se Hun Kang, MD
Department of Cardiology, CHA Bundang Medical Center, Seongnam, Korea (W.-J.K., S.H.K.).
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Sung-Cheol Yun, PhD
Division of Biostatistics (S.-C.Y.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Seung-Ah Lee, MD https://orcid.org/0000-0002-4093-7928
Division of Cardiology (D.-W.P., J.-M.A., D.-Y.K., S.-A.L., E.K., D.-H.K., S.-J.P.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Euihong Ko, MD
Division of Cardiology (D.-W.P., J.-M.A., D.-Y.K., S.-A.L., E.K., D.-H.K., S.-J.P.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Hanbit Park, MD
Division of Cardiology, GangNeung Asan Hospital (H.P.), University of Ulsan College of Medicine, Korea.
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Dae-Hee Kim, MD https://orcid.org/0000-0002-8275-4871
Division of Cardiology (D.-W.P., J.-M.A., D.-Y.K., S.-A.L., E.K., D.-H.K., S.-J.P.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Joon-Won Kang, MD
Department of Radiology Research Institute of Radiology (H.J.K., D.H.Y., S.C.J., J.-W.K.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Jae-Hong Lee, MD https://orcid.org/0000-0001-7368-4560
Department of Neurology (J.-H.L.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Seung-Jung Park, MD https://orcid.org/0000-0002-9187-5405
Division of Cardiology (D.-W.P., J.-M.A., D.-Y.K., S.-A.L., E.K., D.-H.K., S.-J.P.), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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for the ADAPT-TAVR Investigators
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Notes

Circulation is available at www.ahajournals.org/journal/circ
For Sources of Funding and Disclosures, see page 478.
Correspondence to: Duk-Woo Park, MD, and Seung-Jung Park, MD, Division of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea. Email [email protected] or [email protected]

Disclosures

Disclosures Dr D.-W. Park reports grants from Daiichi-Sankyo, ChongKunDang Pharm, and Daewoong Pharm; personal fees from Edwards and Medtronic; and grants and personal fees from Abbott Vascular outside the submitted work. Dr S.-J. Park reports grants and personal fees from Abbott Vascular and Edwards, as well as grants from Daiichi-Sankyo, ChongKunDang Pharm, and Daewoong Pharm, outside the submitted work. The other authors report no conflicts.

Sources of Funding

This study was an investigator-initiated trial and was funded by the CardioVascular Research Foundation (Seoul, Korea) and Daiichi Sankyo Korea Co, Ltd. The funders assisted in the design of the protocol but had no role in the conduct of the trial or in the analysis, interpretation, or reporting of the results.

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Edoxaban Versus Dual Antiplatelet Therapy for Leaflet Thrombosis and Cerebral Thromboembolism After TAVR: The ADAPT-TAVR Randomized Clinical Trial
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