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Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.
Pivonello, R, Bancos, I, Feelders, RA, Kargi, AY, Kerr, JM, Gordon, MB, Mariash, CN, Terzolo, M, Ellison, N, Moraitis, AG
Frontiers in endocrinology. 2021;:662865
Abstract
INTRODUCTION/PURPOSE Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS). MATERIALS AND METHODS A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%). RESULTS 35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred. CONCLUSIONS The SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.
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Circulating tumor cells and palbociclib treatment in patients with ER-positive, HER2-negative advanced breast cancer: results from a translational sub-study of the TREnd trial.
Galardi, F, De Luca, F, Biagioni, C, Migliaccio, I, Curigliano, G, Minisini, AM, Bonechi, M, Moretti, E, Risi, E, McCartney, A, et al
Breast cancer research : BCR. 2021;(1):38
Abstract
BACKGROUND Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation. METHODS Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood samples were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. Samples with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR. RESULTS All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 (n = 26) had a worse PFS than those with 0 CTCs (n = 16) (p = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, (p = 0.004). Finally, patients with ≥ 5 CTCs at T2 (n = 6/23) who received chemotherapy as post-study treatment had a shorter TTF (p = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels. CONCLUSIONS CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied sample size.
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Effect of concomitant antiplatelet agents on clinical outcomes in the edoxaban vs warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSURE-AF) randomized trial.
Goette, A, Merino, JL, De Caterina, R, Huber, K, Heidbuchel, H, Jin, J, Lip, GYH
Clinical research in cardiology : official journal of the German Cardiac Society. 2020;(11):1374-1380
Abstract
AIMS: In ENSURE-AF (NCT02072434), the oral Factor Xa inhibitor edoxaban showed similar efficacy and safety vs enoxaparin-warfarin in patients undergoing electrical cardioversion of nonvalvular atrial fibrillation (AF). This ancillary analysis compares primary efficacy and safety end points for patients receiving vs not receiving concomitant antiplatelet therapy (APT) in ENSURE-AF. METHODS The primary efficacy end point was a composite of stroke, systemic embolic events, myocardial infarction, and cardiovascular death during 28 days on study drug after cardioversion plus 30 days of follow-up. The primary safety end point was the composite of major and clinically relevant non-major bleeding occurring between the first and the last dose of study drug. RESULTS Of 2199 patients enrolled, 1095 were randomized to edoxaban and 1104 to enoxaparin-warfarin. Patients receiving concomitant APT were older; more naïve to vitamin K antagonist; had lower creatinine clearance; and more likely to have history of coronary artery disease, hypertension, diabetes, or ischemic stroke/transient ischemic attack. In patients receiving vs not receiving concomitant APT, primary efficacy event rate was numerically higher (0.92% vs 0.60%, p = 0.64) and primary safety event rate was significantly higher (3.21% vs 0.92%, p = 0.0096). Stepwise logistic regression analysis identified age and APT as covariates correlated with bleeding. There was a trend toward increased bleeding risk in elderly patients receiving vs not receiving concomitant APT. CONCLUSION In ENSURE-AF, thromboembolic events were rare and absolute bleeding event rates were higher with concomitant APT. These findings may be relevant for AF-patients considered for dual therapy; even for a short treatment duration of 1 month.
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Edoxaban versus warfarin in vitamin K antagonist experienced and naïve patients from the edoxaban versus warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSURE-AF) randomised trial.
Kozieł, M, Al-Saady, N, Hjortshøj, SP, Goudev, A, Huber, K, Cohen, A, Jin, J, Melino, M, Winters, SM, Goette, A, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2020;(8):1018-1024
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BACKGROUND In ENSURE-AF study, edoxaban had similar efficacy and safety profile versus enoxaparin-warfarin (enox-warf) in patients undergoing electrical cardioversion of non-valvular atrial fibrillation. OBJECTIVES To evaluate the efficacy and safety of edoxaban versus enox-warf in patients who were vitamin K antagonists (VKA) naïve or experienced at time of randomisation into ENSURE-AF trial. METHODS The primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular death during the overall study period, 28 days on study drug after cardioversion and 30 days follow-up. The primary safety endpoint was the composite of major and clinically relevant nonmajor bleeding during the on-medication period from time of first dose to last dose of study drug taken + 3 days. RESULTS Of 2199 patients enrolled in ENSURE-AF, 1095 were randomised to edoxaban and 1104 to enox-warf. There were numerically fewer primary efficacy endpoint events with edoxaban than enox-warf irrespective of whether VKA experienced or naïve (0.5% vs. 0.9%, 0.3% vs. 1.4%, respectively). There were no significant differences in the primary safety endpoint [odds ratio (OR) 2.09, 95% confidence interval (CI) 0.72-6.81 in anticoagulant experienced patients, OR 0.77, 95% CI 0.15-3.60 in anticoagulant naïve patients] and in major bleeding rates regardless of treatment or VKA experience (OR 0.69, 95%CI 0.06-6.04, OR 0.48, 95% CI 0.01-9.25, respectively). CONCLUSIONS Edoxaban had comparable efficacy and safety to optimized anticoagulation with enox-warf. The primary efficacy and safety endpoint outcomes were broadly similar between VKA experienced or naïve patients.
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Cardiovascular- and Bleeding-Related Hospitalization Rates With Edoxaban Versus Warfarin in Patients With Atrial Fibrillation Based on Results of the ENGAGE AF-TIMI 48 Trial.
Vilain, K, Li, H, Kwong, WJ, Antman, EM, Ruff, CT, Braunwald, E, Cohen, DJ, Giugliano, RP, Magnuson, EA, ,
Circulation. Cardiovascular quality and outcomes. 2020;(11):e006511
Abstract
Background The ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) demonstrated noninferiority of once-daily 60 mg (30 mg dose-reduced) edoxaban compared with warfarin for prevention of stroke/systemic embolism in patients with atrial fibrillation. No previous analysis has explored the impact of treatment with edoxaban versus warfarin on rates of hospitalizations. Methods Detailed healthcare resource utilization data from ENGAGE AF-TIMI 48 for the 14 024 randomized patients who received at least one dose of study drug were used to compare the rates of bleeding- and cardiovascular-related hospitalizations for edoxaban versus warfarin. Hospitalization rates were calculated for each treatment group, and relative rates were estimated using Poisson regression. The influence of patient characteristics on the impact of edoxaban versus warfarin was evaluated through the inclusion of interaction terms. Results The overall rate of cardiovascular- or bleeding-related hospitalization was significantly lower for edoxaban than warfarin (relative rate [RR], 0.91 [95% CI, 0.85-0.97], P=0.003). Rates of hospitalizations for cardiovascular reasons (RR, 0.91 [95% CI, 0.85-0.97], P=0.004), stroke (RR, 0.80 [95% CI, 0.72-0.88], P<0.0001), and for each stroke subtype (ischemic: RR, 0.89 [95% CI, 0.81-0.99], P=0.03; hemorrhagic: RR, 0.60 [95% CI, 0.54-0.68], P<0.0001) were also lower for edoxaban. Notably, significantly greater reductions with edoxaban versus warfarin were seen for ischemic stroke-related hospitalizations in vitamin K antagonist naive patients and patients with CHADS2 scores 4 to 6, previous stroke or transient ischemic attack, age ≥75, and no previous coronary artery disease. For nonstroke bleeding-related hospitalizations, greater reductions with edoxaban were seen in vitamin K antagonist naive patients, patients with CHADS2 scores 4 to 6, and patients with moderate renal dysfunction. Conclusions Edoxaban 60 mg (30 mg dose-reduced) was associated with a significantly lower overall rate of cardiovascular- or bleeding-related hospitalization and significant reductions in the subcategories of cardiovascular-related, stroke-related, bleed-related, and nonstroke cardiovascular-related hospitalizations, when compared with warfarin. These results suggest the potential for cost offsets with edoxaban, with even greater reductions in higher-risk patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00781391.
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Uninterrupted edoxaban vs. vitamin K antagonists for ablation of atrial fibrillation: the ELIMINATE-AF trial.
Hohnloser, SH, Camm, J, Cappato, R, Diener, HC, Heidbüchel, H, Mont, L, Morillo, CA, Abozguia, K, Grimaldi, M, Rauer, H, et al
European heart journal. 2019;(36):3013-3021
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AIMS: Edoxaban is a direct factor Xa inhibitor approved for stroke prevention in atrial fibrillation (AF). Uninterrupted edoxaban therapy in patients undergoing AF ablation has not been tested. METHODS AND RESULTS The ELIMINATE-AF trial, a multinational, multicentre, randomized, open-label, parallel-group study, was conducted to assess the safety and efficacy of once-daily edoxaban 60 mg (30 mg in patients indicated for dose reduction) vs. vitamin K antagonists (VKAs) in AF patients undergoing catheter ablation. Patients were randomized 2:1 to edoxaban vs. VKA. The primary endpoint (per-protocol population) was time to first occurrence of all-cause death, stroke, or International Society of Thrombosis and Haemostasis-defined major bleeding during the period from the end of the ablation procedure to end of treatment (90 days). Overall, 632 patients were enrolled, 614 randomized, and 553 received study drug and underwent ablation; 177 subjects underwent brain magnetic resonance imaging to assess silent cerebral infarcts. The primary endpoint (only major bleeds occurred) was observed in 0.3% (1 patient) on edoxaban and 2.0% (2 patients) on VKA [hazard ratio (95% confidence interval): 0.16 (0.02-1.73)]. In the ablation population (modified intent-to-treat population including patients with ablation), the primary endpoint was observed in 2.7% of edoxaban (N = 10) and 1.7% of VKA patients (N = 3) between start of ablation and end of treatment. There were one ischaemic and one haemorrhagic stroke, both in patients on edoxaban. Cerebral microemboli were detected in 13.8% (16) patients who received edoxaban and 9.6% (5) patients in the VKA group (nominal P = 0.62). CONCLUSION Uninterrupted edoxaban therapy represents an alternative to uninterrupted VKA treatment in patients undergoing AF ablation.
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Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study.
Lowery, MA, Burris, HA, Janku, F, Shroff, RT, Cleary, JM, Azad, NS, Goyal, L, Maher, EA, Gore, L, Hollebecque, A, et al
The lancet. Gastroenterology & hepatology. 2019;(9):711-720
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BACKGROUND Isocitrate dehydrogenase-1 (IDH1) is mutated in up to 25% of cholangiocarcinomas, especially intrahepatic cholangiocarcinoma. Ivosidenib is an oral, targeted inhibitor of mutant IDH1 (mIDH1) approved in the USA for the treatment of mIDH1 acute myeloid leukaemia in newly diagnosed patients ineligible for intensive chemotherapy and patients with relapsed or refractory disease. Ivosidenib is under clinical evaluation in a phase 1 study that aims to assess its safety and tolerability in patients with mIDH1 solid tumours. Here we report data for the mIDH1-cholangiocarcinoma cohort. METHODS We did a phase 1 dose-escalation and expansion study of ivosidenib monotherapy in mIDH1 solid tumours at 12 clinical sites in the USA and one in France. The primary outcomes were safety, tolerability, maximum tolerated dose, and recommended phase 2 dose. Eligible patients had a documented mIDH1 tumour based on local testing, an Eastern Cooperative Oncology Group performance status of 0 or 1, one or more previous lines of therapy, and evaluable disease by Response Evaluation Criteria in Solid Tumors version 1.1. During dose escalation, ivosidenib was administered orally at 200-1200 mg daily in 28-day cycles in a standard 3 + 3 design; during expansion, patients received the selected dose on the basis of pharmacodynamic, pharmacokinetic, safety, and activity data from dose escalation. Safety and clinical activity analyses were reported for all patients with mIDH1-cholangiocarcinoma who were enrolled and received at least one dose of study treatment. Enrolment is complete, and the study is ongoing. This trial is registered at ClinicalTrials.gov, number NCT02073994. FINDINGS Between March 14, 2014 and May 12, 2017, 73 patients with mIDH1-cholangiocarcinoma were enrolled and received ivosidenib. No dose-limiting toxicities were reported and maximum tolerated dose was not reached; 500 mg daily was selected for expansion. Common (≥20%) adverse events, regardless of cause, were fatigue (31 [42%]; two [3%] grade ≥3), nausea (25 [34%]; one [1%] grade ≥3), diarrhoea (23 [32%]), abdominal pain (20 [27%]; two [3%] grade ≥3), decreased appetite (20 [27%]; one [1%] grade ≥3), and vomiting (17 [23%]). Common grade 3 or worse adverse events were ascites (four [5%]) and anaemia (three [4%]); the only treatment-related grade 3 or worse adverse event in more than one patient was fatigue (two [3%]). Two (3%) patients had serious adverse events leading to on-treatment death (Clostridioides difficile infection and procedural haemorrhage); neither was assessed by the investigator as related to treatment. 46 (63%) patients had adverse events deemed related to ivosidenib, of which four (5%) were grade 3 or higher (two [3%] for fatigue; one [1%] each for decreased blood phosphorus and increased blood alkaline phosphatase). One serious adverse event was considered possibly related to treatment (grade 2 supraventricular extrasystoles). Four (5%; 95% CI 1·5-13·4) patients had a partial response. Median progression-free survival was 3·8 months (95% CI 3·6-7·3), 6-month progression-free survival was 40·1% (28·4-51·6), and 12-month progression-free survival was 21·8% (12·3-33·0). Median overall survival was 13·8 months (95% CI 11·1-29·3); however, data were censored for 48 patients (66%). INTERPRETATION Ivosidenib might offer a well tolerated option for patients with mIDH1-cholangiocarcinoma. An ongoing, global phase 3 study is evaluating ivosidenib versus placebo in patients with previously treated nonresectable or metastatic mIDH1-cholangiocarcinoma. FUNDING Agios Pharmaceuticals, Inc.
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Real-life Performance of Edoxaban in Elderly Patients With Atrial Fibrillation: a Multicenter Propensity Score-Matched Cohort Study.
Russo, V, Attena, E, Mazzone, C, Melillo, E, Rago, A, Galasso, G, Riegler, L, Parisi, V, Rotunno, R, Nigro, G, et al
Clinical therapeutics. 2019;(8):1598-1604
Abstract
PURPOSE The purpose of the current study was to compare the efficacy and safety of edoxaban versus vitamin K antagonist (VKA) therapy among a cohort of elderly patients (ie, those aged ≥75 years) with atrial fibrillation (AF) in a real-life setting. METHODS A propensity score-matched cohort observational study was performed comparing the safety and efficacy of edoxaban versus VKA therapy among a cohort of elderly (aged ≥75 years) patients with AF in a real-life setting. Follow-up data were obtained through outpatient visits at 1, 3, and every 6 months. The primary safety outcome was major bleeding. The primary efficacy outcome was the composite of stroke, transient ischemic attack, and systemic embolism. FINDINGS A total of 130 patients receiving edoxaban 60 mg (EDO) treatment were compared with the same number of VKA recipients. The mean follow-up was 16 (2.6) months. The cumulative incidence of thromboembolic events in the EDO and VKA groups was 1.5% (2 of 130) and 2.3% (3 of 130), respectively (P < 0.6). The cumulative incidence of major bleeding events was 1.5% (2 of 130) in the EDO group and 3.1% (4 of 130) in the VKA group (P < 0.4). The total anticoagulant therapy discontinuation rate was 2.3% (3 of 130) in the EDO group and 4.6% (6 of 130) in the VKA group (P < 0.3). A nonsignificant trend in improved adherence was observed between the EDO and VKA groups (81% vs 78%; P = 0.6). IMPLICATIONS Edoxaban therapy showed a good real-life performance among elderly patients (aged ≥75 years) with AF.
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Edoxaban in atrial fibrillation patients with established coronary artery disease: Insights from ENGAGE AF-TIMI 48.
Zelniker, TA, Ruff, CT, Wiviott, SD, Blanc, JJ, Cappato, R, Nordio, F, Mercuri, MF, Lanz, H, Antman, EM, Braunwald, E, et al
European heart journal. Acute cardiovascular care. 2019;(2):176-185
Abstract
BACKGROUND The relative efficacy and safety profile of the oral Factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation and established coronary artery disease (CAD) has not been analyzed. MATERIALS AND METHODS In the ENGAGE AF-TIMI 48 trial, two edoxaban regimens were compared with warfarin in 21,105 patients with atrial fibrillation and CHADS2 ⩾2. We analyzed the primary trial endpoints (efficacy: stroke or systemic embolic event, safety: International Society on Thrombosis and Haemostasis major bleeding) in patients with versus without CAD, and used interaction testing to assess for treatment effect modification. RESULTS The 4510 patients (21.4%) with known CAD were older, more likely male, on aspirin, with lower creatinine clearance and higher CHADS2 and HAS-BLED scores ( p <0.001 for each). Treatment with the higher-dose edoxaban regimen (versus warfarin) in patients with known CAD tended to have a greater reduction in stroke/systemic embolic event compared with patients without CAD (CAD: hazard ratio 0.65 (0.46-0.92) versus no CAD: hazard ratio 0.94 (0.79-1.12), p-INT 0.062) and also in myocardial infarction (CAD: hazard ratio 0.69 (0.49-0.98) versus no CAD: hazard ratio 1.24 (0.89-1.72), p-INT 0.017), while there was a similar reduction in bleeding irrespective of CAD status (hazard ratio 0.81 and 0.80, p-INT 0.97). Presence or absence of CAD did not modify the efficacy or safety profile of the lower-dose edoxaban regimen (versus warfarin). CONCLUSION The reduction in ischemic events with the higher-dose edoxaban regimen versus warfarin was greater in patients with CAD, while bleeding was significantly reduced with edoxaban regardless of CAD status. The efficacy and safety profile of the lower-dose edoxaban regimen relative to warfarin was unaffected by CAD status.
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Edoxaban Versus standard of care and their effects on clinical outcomes in patients having undergone Transcatheter Aortic Valve Implantation in Atrial Fibrillation-Rationale and design of the ENVISAGE-TAVI AF trial.
Van Mieghem, NM, Unverdorben, M, Valgimigli, M, Mehran, R, Boersma, E, Baber, U, Hengstenberg, C, Shi, M, Chen, C, Saito, S, et al
American heart journal. 2018;:63-69
Abstract
Transcatheter aortic valve implantation, also called transcatheter aortic valve replacement (TAVR), is the treatment of choice for patients with severe aortic stenosis and intermediate to high operative risk. A significant portion of TAVR patients have atrial fibrillation (AF) requiring chronic oral anticoagulation. In moderate- to high-risk AF patients, the direct factor Xa inhibitor edoxaban is noninferior to vitamin K antagonists (VKAs) for prevention of stroke or systemic embolism with less bleeding and cardiovascular deaths. ENVISAGE-TAVI AF (NCT02943785) is a multinational, multicenter, prospective, randomized, open-label, blinded end point evaluation study comparing edoxaban to VKA-based therapy in approximately 1,400 patients with an indication for chronic oral anticoagulation after successful transfemoral TAVR. The coprimary end points are to assess the differential effects of the 2 treatments (a) on net adverse clinical events (the composite of all-cause death, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, and major bleeding events) and (b) on major bleeding. Twelve hours to 5 days after successful TAVR, patients will be randomized to 60 mg daily oral edoxaban or any VKA (international normalized ratio: 2.0-3.0 or 1.6-2.6 [numbers inclusive] in Japan if age ≥ 70 years). Antiplatelet therapy may be administered per physician's discretion. Randomization will be stratified by edoxaban dose reduction (per local label). Treatment duration will be up to 36 months. The study is powered (80%) to detect noninferiority (margin for the hazard ratio: 1.38) for the composite primary end points, followed by superiority testing.