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A Randomized Phase II Study of Androgen Deprivation Therapy with or without Palbociclib in RB-positive Metastatic Hormone-Sensitive Prostate Cancer.
Palmbos, PL, Daignault-Newton, S, Tomlins, SA, Agarwal, N, Twardowski, P, Morgans, AK, Kelly, WK, Arora, VK, Antonarakis, ES, Siddiqui, J, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(11):3017-3027
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Abstract
PURPOSE Palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, blocks proliferation in a RB and cyclin D-dependent manner in preclinical prostate cancer models. We hypothesized that cotargeting androgen receptor and cell cycle with palbociclib would improve outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC). PATIENTS AND METHODS A total of 60 patients with RB-intact mHSPC were randomized (1:2) to Arm 1: androgen deprivation (AD) or Arm 2: AD + palbociclib. Primary endpoint was PSA response rate (RR) after 28 weeks of therapy. Secondary endpoints included safety, PSA, and clinical progression-free survival (PFS), as well as PSA and radiographic RR. Tumors underwent exome sequencing when available. Circulating tumor cells (CTC) were enumerated at various timepoints. RESULTS A total of 72 patients with mHSPC underwent metastatic disease biopsy and 64 had adequate tissue for RB assessment. A total of 62 of 64 (97%) retained RB expression. A total of 60 patients initiated therapy (Arm 1: 20; Arm 2: 40). Neutropenia was the most common grade 3/4 adverse event in Arm 2. Eighty percent of patients (Arm 1: 16/20, Arm 2: 32/40; P = 0.87) met primary PSA endpoint ≤4 ng/mL at 28 weeks. PSA undetectable rate at 28 weeks was 50% and 43% in Arms 1 and 2, respectively (P = 0.5). Radiographic RR was 89% in both arms. Twelve-month biochemical PFS was 69% and 74% in Arms 1 and 2, respectively (P = 0.72). TP53 and PIK3 pathway mutations, 8q gains, and pretreatment CTCs were associated with reduced PSA PFS. CONCLUSIONS Palbociclib did not impact outcome in RB-intact mHSPC. Pretreatment CTC, TP53 and PIK3 pathway mutations, and 8q gain were associated with poor outcome.
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Evaluation of [18F]-JNJ-64326067-AAA tau PET tracer in humans.
Baker, SL, Provost, K, Thomas, W, Whitman, AJ, Janabi, M, Schmidt, ME, Timmers, M, Kolb, HC, Rabinovici, GD, Jagust, WJ
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2021;(12):3302-3313
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Abstract
The [18F]-JNJ-64326067-AAA ([18F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer's disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [11C]-PIB amyloid PET scan, and a tau [18F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [18F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P < 0.05). Only AD participants showed elevated retention in the entorhinal cortex. There was off-target signal in the putamen, pallidum, thalamus, midbrain, superior cerebellar gray, and white matter. [18F]-JNJ-067 significantly correlated (p < 0.05) with Mini-Mental State Exam in entorhinal cortex and temporal meta regions. There is clear binding of [18F]-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests [18F]-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.
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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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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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Edoxaban-based versus vitamin K antagonist-based antithrombotic regimen after successful coronary stenting in patients with atrial fibrillation (ENTRUST-AF PCI): a randomised, open-label, phase 3b trial.
Vranckx, P, Valgimigli, M, Eckardt, L, Tijssen, J, Lewalter, T, Gargiulo, G, Batushkin, V, Campo, G, Lysak, Z, Vakaliuk, I, et al
Lancet (London, England). 2019;(10206):1335-1343
Abstract
BACKGROUND We aimed to assess the safety of edoxaban in combination with P2Y12 inhibition in patients with atrial fibrillation who had percutaneous coronary intervention (PCI). METHODS ENTRUST-AF PCI was a randomised, multicentre, open-label, non-inferiority phase 3b trial with masked outcome evaluation, done at 186 sites in 18 countries. Patients had atrial fibrillation requiring oral anticoagulation, were aged at least 18 years, and had a successful PCI for stable coronary artery disease or acute coronary syndrome. Participants were randomly assigned (1:1) from 4 h to 5 days after PCI using concealed, stratified, and blocked web-based central randomisation to either edoxaban (60 mg once daily) plus a P2Y12 inhibitor for 12 months or a vitamin K antagonist (VKA) in combination with a P2Y12 inhibitor and aspirin (100 mg once daily, for 1-12 months). The edoxaban dose was reduced to 30 mg per day if one or more factors (creatinine clearance 15-50 mL/min, bodyweight ≤60 kg, or concomitant use of specified potent P-glycoprotein inhibitors) were present. The primary endpoint was a composite of major or clinically relevant non-major (CRNM) bleeding within 12 months. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of their assigned study drug. This trial is registered with ClinicalTrials.gov, NCT02866175, is closed to new participants, and follow-up is completed. FINDINGS From Feb 24, 2017, through May 7, 2018, 1506 patients were enrolled and randomly assigned to the edoxaban regimen (n=751) or VKA regimen (n=755). Median time from PCI to randomisation was 45·1 h (IQR 22·2-76·2). Major or CRNM bleeding events occurred in 128 (17%) of 751 patients (annualised event rate 20·7%) with the edoxaban regimen and 152 (20%) of 755 patients (annualised event rate 25·6%) patients with the VKA regimen; hazard ratio 0·83 (95% CI 0·65-1·05; p=0·0010 for non-inferiority, margin hazard ratio 1·20; p=0·1154 for superiority). INTERPRETATION In patients with atrial fibrillation who had PCI, the edoxaban-based regimen was non-inferior for bleeding compared with the VKA-based regimen, without significant differences in ischaemic events. FUNDING Daiichi Sankyo.
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Evaluation of the safety and efficacy of an edoxaban-based antithrombotic regimen in patients with atrial fibrillation following successful percutaneous coronary intervention (PCI) with stent placement: Rationale and design of the ENTRUST-AF PCI trial.
Vranckx, P, Lewalter, T, Valgimigli, M, Tijssen, JG, Reimitz, PE, Eckardt, L, Lanz, HJ, Zierhut, W, Smolnik, R, Goette, A
American heart journal. 2018;:105-112
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Abstract
BACKGROUND The optimal antithrombotic treatment after percutaneous coronary intervention (PCI) with stenting in patients with atrial fibrillation (AF) is unknown. In the ENGAGE AF-TIMI 48 trial, edoxaban was noninferior to a vitamin K antagonist (VKA) with respect to the prevention of stroke or systemic embolism and was associated with significantly lower rates of bleeding and cardiovascular death in patients with nonvalvular AF. The effects of edoxaban in combination with single- or dual-antiplatelet therapy in the setting of PCI are unexplored. DESIGN The ENTRUST-AF PCI trial is a multinational, multicenter, randomized, open-label phase 3b trial with blinded end point evaluation involving 1,500 patients on oral anticoagulation for AF. Patients are randomized between 4 hours and 5 days after successful PCI to either an edoxaban-based strategy (experimental arm; 60 mg [or 30 mg according to dose reduction criteria] once daily plus a P2Y12 antagonist [default clopidogrel, 75 mg once daily] for 12 months) or a VKA-based strategy (control arm; VKA plus a P2Y12 antagonist [as above] plus acetylsalicylic acid [100 mg once daily] for 30 days to 12 months). The primary safety end point is the incidence of International Society on Thrombosis and Haemostasis-defined major or clinically relevant nonmajor bleeding. The main efficacy end point is the composite of cardiovascular death, stroke, systemic embolic events, spontaneous myocardial infarction, and definite stent thrombosis. SUMMARY The ENTRUST-AF PCI trial tests the hypothesis that an edoxaban-based antithrombotic strategy reduces the risk of bleeding complications after PCI compared with VKA plus conventional dual-antiplatelet therapy in patients with AF in need of oral anticoagulation. The relative risk of ischemic events between groups will be compared.
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Pilot Dose Comparison of Apatinib in Chinese Patients With Progressive Radioiodine-Refractory Differentiated Thyroid Cancer.
Zhang, X, Wang, C, Lin, Y
The Journal of clinical endocrinology and metabolism. 2018;(10):3640-3646
Abstract
CONTEXT Apatinib has shown overwhelming efficacy in progressive radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) starting at a 750-mg dosing protocol; however, a relatively high incidence of treatment-associated adverse events (TAAEs) was observed, which reduced quality of life and interrupted the treatment. OBJECTIVES To evaluate the efficacy and safety of apatinib with two different dosing schedules [750 or 500 mg once a day (q.d.)] in RAIR-DTC. PARTICIPANTS AND METHODS Twenty patients were sequentially recruited to receive apatinib beginning at 750 (n = 10) or 500 (n = 10) mg q.d. Efficacy and safety were compared in each 28-day cycle at the beginning two cycles and every two cycles thereafter. RESULTS After six treatment cycles, the best disease control rates were 100% for the 750- and 500-mg schedules, respectively, and the best objective response rates were 90.0% and 70.0% (P = 0.58), respectively. The two dosing schedules did not differ regarding greatest reduction in target lesion size (-42.7% vs -40.5% for the 750- vs 500-mg schedule, P = 0.48) and thyroglobulin level (-82.5% vs -94.3% for the 750- vs 500-mg schedule, P = 0.14). All patients experienced TAAEs, and the two dosing schedules showed similar incidence in TAAEs of grade ≥3 (100% vs 70% for 750 vs 500 mg, P = 0.21). However, the frequency of TAAEs was much higher in the 750-mg schedule (26.8 ± 6.5 vs 18.1 ± 6.5 in any grades, P = 0.01; 5.2 ± 3.0 vs 1.6 ± 1.3 in grade ≥3, P < 0.01). CONCLUSION Within six cycles of follow-up, the 500-mg starting dose protocol might be less toxic than the 750-mg protocol, whereas the efficacy was similar between the two dosages.
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PET response assessment in apatinib-treated radioactive iodine-refractory thyroid cancer.
Wang, C, Zhang, X, Yang, X, Li, H, Cui, R, Guan, W, Li, X, Zhu, Z, Lin, Y
Endocrine-related cancer. 2018;(6):653-663
Abstract
This work evaluated the use of the positron emission tomography (PET)/computed tomography (CT) technique to assess the early therapeutic response and predict the prognosis of patients with radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) who underwent apatinib therapy. Standardised uptake value (SUV), metabolic tumour volume (MTV) and total lesion glycolysis (TLG), derived from 18F-FDG PET/CT and SUV from 68Ga-NOTA-PRGD2 PET/CT were evaluated. Tumour response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Sixteen of 20 patients achieved partial response (PR) and four of 20 had stable disease (SD) after apatinib therapy. Six progression-free survival (PFS) events occurred. A strong correlation was observed between the best change in the sum of the longest diameters of target lesions (ΔCT%) and 18F-FDG PET/CT indices after the completion of the first treatment cycle (ΔMTV% (P = 0.0019), ΔTLG% (P = 0.0021) and ΔSUVmax% (P = 0.0443)). A significant difference in PFS was observed between patients with ΔMTV% <-45% and ≥-45% (P = 0.0019) and between patients with ΔTLG% <-80% and ≥-80% (P = 0.0065). Ten of 11 patients presented a decrease in SUVmax on 68Ga-NOTA-PRGD2 PET/CT after two cycles of apatinib therapy and showed PR, whereas one patient presenting an increase in SUVmax only showed SD as the best response. When a cut-off value of the target/background ratio at -20% was used, two PFS curves showed a significant difference (P = 0.0016). Hence, early assessment by 18F-FDG and 68Ga-NOTA-PRGD2 PET/CT was effective in the prediction and evaluation of RAIR-DTC treated with apatinib.
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Edoxaban Management in Diagnostic and Therapeutic Procedures (EMIT-AF/VTE)-Trial design.
Colonna, P, von Heymann, C, Santamaria, A, Matsushita, Y, Unverdorben, M
Clinical cardiology. 2018;(9):1123-1129
Abstract
Non-vitamin K dependent oral anticoagulants (NOAC) are now widely used in patients with nonvalvular atrial fibrillation (NVAF) for stroke prevention and in patients with venous thromboembolism (VTE) for the treatment and secondary prevention of the disease. Among NOAC, edoxaban demonstrated noninferiority to warfarin for stroke prevention in NVAF and for VTE treatment, with superior safety. EMIT-AF/VTE (Edoxaban Management in Diagnostic and Therapeutic Procedures) (NCT02950168) is a multicenter, prospective, and noninterventional registry study designed to collect detailed information on the periprocedural management of patients with NVAF and VTE receiving edoxaban. The primary objective of EMIT-AF/VTE is to document the periprocedural management of patients receiving edoxaban and to collect data on safety and other outcomes in these patients. The primary safety outcome is the rate of major bleeding. Other assessments include the evaluation of efficacy outcomes, periprocedural dosing, and timing of edoxaban. The observation period will start 5 days prior to the procedure and end 30 days post-procedure. EMIT-AF/VTE will aim to prospectively enroll up to approximately 1400 procedures from Europe. Enrollment commenced in December 2016 and will be completed in July 2018. As of July 2018, before database lock and with several procedure forms still temporarily inserted, a preliminary number of 1204 patients have been enrolled, who underwent a total of 1453 procedures. The prospective EMIT-AF/VTE registry program will expand the knowledge of periprocedural management of patients with NVAF and VTE receiving edoxaban in clinical practice.