Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation.

BACKGROUND: Implementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis. RESULTS: A total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval [CI], 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P = 0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36). CONCLUSIONS: In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.).

A Portable Spectrometric System for Quantitative Prediction of the Soluble Solids Content of Apples with a Pre-calibrated Multispectral Sensor Chipset.

A portable spectrometric system for nondestructive assessment of the soluble solids content (SSC) of fruits for practical applications has been proposed and its performance has been examined by an experiment on quantitative prediction of the SSC of apples. Although the spectroscopic technique is a powerful tool for predicting the internal qualities of fruits, its practical applications are limited due to its high cost and complexity. In the proposed system, the spectra of apples were collected by a simple optical setup with a cheap pre-calibrated multispectral chipset. An optimal multiple linear regression model with five wavebands at 900, 760, 730, 680, and 535 nm revealed the best performance with the coefficient of determination of prediction and the root mean square error of prediction of 0.861 and 0.403 °Brix, respectively, which was comparable to that of the previous studies using dispersive spectrometers. Compared with previously reported systems using discrete filters or light emitting diodes, the proposed system was superior in terms of manufacturability and reproducibility. The experimental results confirmed that the proposed system had a considerable potential for practical, cost-effective applications of the SSC prediction, not only for apples but also for other fruits.

Edoxaban for the management of elderly Japanese patients with atrial fibrillation ineligible for standard oral anticoagulant therapies: Rationale and design of the ELDERCARE-AF study.

Edoxaban-a non-vitamin K antagonist oral anticoagulant (NOAC)- 60-mg and 30-mg once-daily dose regimens are noninferior versus well-managed warfarin for the prevention of stroke or systemic embolic events (SEE) with less major bleeding in patients with nonvalvular atrial fibrillation (NVAF). There are no published data from phase 3 clinical trials specifically evaluating the use of NOACs in elderly NVAF patients, especially those considered ineligible for available oral anticoagulants. The Edoxaban Low-Dose for EldeR CARE AF patients (ELDERCARE-AF) study is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study that will compare the safety and efficacy of once-daily edoxaban 15 mg versus placebo in Japanese patients with NVAF ≥80 years of age who are considered ineligible for standard oral anticoagulant therapy. A total of 800 patients (400 in each treatment group) are planned for randomization (1:1) to either edoxaban or placebo using a stratified randomization method with CHADS2 index score (2 points, ≥3 points) as a factor. The primary efficacy end point is the time to first onset of stroke or SEE. The net clinical outcome is the composite of stroke, SEE, major bleeding, and all-cause mortality. The primary safety end point is the incidence of major bleeding. The treatment period will continue until 65 patients with the primary efficacy events (ie, stroke or SEE) have been observed (2- to 2.5-year expected mean treatment period). The results of ELDERCARE-AF may provide clarity as to the efficacy and safety of edoxaban for the prevention of stroke or SEE in this high-risk population.

A Label-Free Fluorescent Array Sensor Utilizing Liposome Encapsulating Calcein for Discriminating Target Proteins by Principal Component Analysis.

A new fluorescent arrayed biosensor has been developed to discriminate species and concentrations of target proteins by using plural different phospholipid liposome species encapsulating fluorescent molecules, utilizing differences in permeation of the fluorescent molecules through the membrane to modulate liposome-target protein interactions. This approach proposes a basically new label-free fluorescent sensor, compared with the common technique of developed fluorescent array sensors with labeling. We have confirmed a high output intensity of fluorescence emission related to characteristics of the fluorescent molecules dependent on their concentrations when they leak from inside the liposomes through the perturbed lipid membrane. After taking an array image of the fluorescence emission from the sensor using a CMOS imager, the output intensities of the fluorescence were analyzed by a principal component analysis (PCA) statistical method. It is found from PCA plots that different protein species with several concentrations were successfully discriminated by using the different lipid membranes with high cumulative contribution ratio. We also confirmed that the accuracy of the discrimination by the array sensor with a single shot is higher than that of a single sensor with multiple shots.

Short-Term Safety and Plasma Concentrations of Edoxaban in Japanese Patients With Non-Valvular Atrial Fibrillation and Severe Renal Impairment.

BACKGROUND: The short-term safety and plasma concentrations of edoxaban 15 mg once daily in Japanese patients with non-valvular atrial fibrillation (NVAF) and severe renal impairment (SRI; creatinine clearance [CLCR] ≥15 to <30 ml/min) were compared with those in NVAF patients with normal renal function or mild renal impairment (normal/MiRI; CLCR≥50 ml/min) treated with edoxaban 30 or 60 mg. METHODS AND RESULTS: In this Phase 3 multicenter open-label 3 parallel-group study, SRI patients received once-daily edoxaban 15 mg (n=50), whereas normal/MiRI patients were randomized to receive either once-daily edoxaban 30 or 60 mg (n=22 and 21, respectively) for 12 weeks. Plasma edoxaban concentrations and biomarkers of blood coagulation and fibrinolysis were measured. Adverse events and thromboembolic events were recorded throughout the study. Rates of any bleeding were comparable between SRI patients receiving edoxaban 15 mg (20.0%) and normal/MiRI patients receiving edoxaban 30 or 60 mg (22.7% and 23.8%, respectively). No major bleeding or thromboembolic events occurred in any treatment group. Similar plasma concentrations and biomarker profiles were observed in SRI patients receiving edoxaban 15 mg and normal/MiRI patients receiving edoxaban 30 or 60 mg. CONCLUSIONS: In this 12-week short-term study in Japanese NVAF patients with SRI, edoxaban 15 mg once daily exhibited similar safety, plasma concentration, and biomarker profiles as did the 30-mg and 60-mg doses in patients with normal/MiRI.

Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty: STARS J-V.

BACKGROUND: In the absence of thromboprophylaxis, patients undergoing total hip arthroplasty (THA) are at increased risk for venous thromboembolism (VTE). The objective of this study was to compare the efficacy and safety of edoxaban with enoxaparin for the prevention of VTE after THA in Japan. METHODS: This was a phase 3, double-blind, double-dummy, noninferiority study. Patients undergoing elective, unilateral primary THA were randomized to receive edoxaban 30 mg once daily (n = 307) or enoxaparin 2000 IU (equivalent to 20 mg) twice daily (n = 303) for 11 to 14 days. The primary efficacy endpoint was the incidence of VTE. Safety endpoints included the incidence of major or clinically relevant nonmajor (CRNM) bleeding. RESULTS: The incidence of VTE, based on venography and clinical surveillance, was 2.4 % in the edoxaban group and 6.9 % in the enoxaparin group (P <0.001). The absolute difference in the incidence of VTE was -4.5 % (95 % confidence interval [CI]: -8.6, -0.9), which was within the noninferiority margin set at 8 % for the difference and established the noninferiority of edoxaban to enoxaparin. Since the upper limit of the 95 % CI of the absolute difference was less than 0 %, the superiority of edoxaban over enoxaparin was demonstrated. The incidence of major or CRNM bleeding was 2.6 % in the edoxaban group and 3.7 % in the enoxaparin group (P = 0.475). CONCLUSIONS: Oral edoxaban 30 mg once daily was superior to subcutaneous enoxaparin 2000 IU twice daily in the prevention of VTE following THA without increasing the risk for major or CRNM bleeding.

A randomized, open-label trial of edoxaban in Japanese patients with severe renal impairment undergoing lower-limb orthopedic surgery.

BACKGROUND: Edoxaban is an oral, direct, factor Xa inhibitor approved in Japan for thromboembolic prophylaxis after lower-limb orthopedic surgery (LLOS), but contraindicated in patients with severe renal impairment (SRI; creatinine clearance [CLCR] ≥15 to <30 mL/min). METHODS: This open-label study compared the safety of edoxaban 15 mg once daily in Japanese patients with SRI to that of edoxaban 30 mg in patients with mild renal impairment (MiRI; CLCR ≥50 to ≤80 mL/min; N = 30) undergoing LLOS. Patients with CLCR ≥20 to <30 mL/min were randomized to receive edoxaban 15 mg (N = 22) or subcutaneous fondaparinux 1.5 mg once daily (N = 21). All patients with CLCR ≥15 to <20 mL/min received edoxaban 15 mg (N = 7). Treatment was administered for 11 to 14 days. RESULTS: Major or clinically relevant non-major bleeding occurred in 6.7%, 3.4%, and 5.0% of patients in the MiRI edoxaban 30-mg, SRI edoxaban 15-mg, and SRI fondaparinux groups, respectively; there were no major bleeding events. No thromboembolic events occurred. At all time points assessed, edoxaban plasma concentrations and changes in coagulation biomarkers were similar between the SRI and MiRI groups. CONCLUSIONS: These results suggest edoxaban 15 mg once daily is well tolerated in Japanese patients with SRI undergoing LLOS. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01857583.

Pharmacokinetics of Edoxaban 15 mg in Very Elderly Patients with Nonvalvular Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Study.

BACKGROUND: We evaluated the pharmacokinetics (PK) of low-dose (15 mg) edoxaban in very elderly patients (≥80 years) with nonvalvular atrial fibrillation (NVAF) and high bleeding risk. METHODS: This subanalysis of the phase 3, randomized, double-blind, placebo-controlled, multicenter ELDERCARE-AF study evaluated edoxaban plasma concentrations and compared them with the Japanese population of the ENGAGE AF-TIMI 48 and Japanese severe renal impairment (SRI) studies. RESULTS: The PK analysis population included 451 patients, 53.8% of whom concomitantly used antiplatelet drugs, 41.0% had SRI, and 38.0% had low body weight. Edoxaban plasma concentrations at trough and 1 to 3 hours post-dose in ELDERCARE-AF were 17.3 ± 13.9 (n = 427) and 93.3 ± 57.8 ng/mL (n = 447), respectively. These values were slightly higher than the 15 mg group in ENGAGE AF-TIMI 48 (n = 79; 12.4 ± 12.1 and n = 115; 78.7 ± 45.0 ng/mL, respectively), lower than the ENGAGE AF-TIMI 48 high-dose reduced to 30 mg group (n = 83; 25.1 ± 36.6 and n = 111; 150 ± 91.6 ng/mL, respectively), but similar to the Japanese SRI study (n = 39; 18.4 ± 11.2 and n = 40; 96.8 ± 48.3 ng/mL, respectively). ELDERCARE-AF patients with SRI and low body weight (≤45 kg) had higher concentrations than those without, and those taking antiplatelet drugs had lower concentrations than those who were not. CONCLUSION: PK data support edoxaban 15 mg once daily for very elderly NVAF patients with high bleeding risk, with caution for patients with SRI and/or low body weight.

Efficacy and Safety of Low-Dose Edoxaban by Body Weight in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the Randomized ELDERCARE-AF Trial.

BACKGROUND: The ELDERCARE-AF trial showed that low-dose edoxaban benefits elderly patients with nonvalvular atrial fibrillation considered ineligible for standard oral anticoagulants due to high bleeding risk, but whether this applied to patients with extremely low body weight was unclear. METHODS AND RESULTS: This was a prespecified subanalysis by body weight (≤45, >45 kg) of the phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven ELDERCARE-AF trial, which compared low-dose edoxaban (15 mg once daily) with placebo in Japanese patients considered ineligible for oral anticoagulants at the recommended therapeutic strength or the approved doses. The primary efficacy and safety end points were stroke or systemic embolism and major bleeding (International Society on Thrombosis and Hemostasis definition), respectively. The ≤45-kg weight group included 374/984 patients (38.0%), and the >45-kg group included 610/984 patients (62.0%). The stroke or systemic embolism rate was lower with edoxaban than placebo in both weight groups (≤45 kg: hazard ratio [HR], 0.36 [95% CI, 0.16-0.80]; >45 kg: HR, 0.31 [95% CI, 0.13-0.73]; interaction P=0.82). Major bleeding incidence was numerically higher with edoxaban than placebo (≤45 kg: HR, 3.05 [95% CI, 0.84-11.11]; >45 kg: HR, 1.40 [95% CI, 0.56-3.48), with no interaction with body weight (interaction P=0.33). All-cause mortality was higher in the ≤45-kg group, with no significant difference between treatment groups. CONCLUSIONS: The benefit of edoxaban 15 mg was consistent in elderly patients with atrial fibrillation and extremely low body weight, though clinicians must remain vigilant about the risk of major bleeding, especially gastrointestinal bleeding. REGISTRATION INFORMATION: ClinicalTrials.gov. Identifier: NCT02801669.

Coronary events in elderly patients with non-valvular atrial fibrillation: a prespecified sub-analysis of the ANAFIE registry.

Real-world data on coronary events (CE) in elderly patients with atrial fibrillation (AF) are lacking in the direct oral anticoagulant era. This prespecified sub-analysis of the ANAFIE Registry, a prospective observational study in > 30,000 Japanese patients aged ≥ 75 years with non-valvular AF (NVAF), investigated CE incidence and risk factors. The incidence and risk factors for new-onset CE (a composite of myocardial infarction [MI] and cardiac intervention for coronary heart diseases other than MI), MI, and cardiac intervention for coronary heart diseases other than MI during the 2-year follow-up were assessed. Bleeding events in CE patients were also examined. Among 32,275 patients, the incidence rate per 100 patient-years was 0.48 (95% confidence interval (CI): 0.42-0.53) for CE during the 2-year follow-up, 0.20 (0.16-0.23) for MI, and 0.29 (0.25-0.33) for cardiac intervention for coronary heart diseases other than MI; that of stroke/systemic embolism was 1.62 (1.52-1.73). Patients with CE (n = 287) likely had lower creatinine clearance (CrCL) and higher CHADS2 and HAS-BLED scores than patients without CE (n = 31,988). Significant risk factors associated with new-onset CE were male sex, systolic blood pressure of ≥ 130 mmHg, diabetes mellitus (glycated hemoglobin ≥ 6.0%), CE history, antiplatelet agent use, and CrCL < 50 mL/min. Major bleeding incidence was significantly higher in patients with new-onset CE vs without CE (odds ratio [95% CI], 3.35 [2.06-5.43]). In elderly patients with NVAF, CE incidence was lower than stroke/systemic embolism incidence. New-onset CE (vs no CE) was associated with a higher incidence of major bleeding.Trial registration: UMIN000024006.

Effect of 15-mg Edoxaban on Clinical Outcomes in 3 Age Strata in Older Patients With Atrial Fibrillation: A Prespecified Subanalysis of the ELDERCARE-AF Randomized Clinical Trial.

Importance: Long-term use of oral anticoagulants (OACs) is necessary for stroke prevention in patients with atrial fibrillation (AF). The effectiveness and safety of OACs in extremely older patients (ie, aged 80 years or older) with AF and at high risk of bleeding needs to be elucidated. Objective: To examine the effects of very low-dose edoxaban (15 mg) vs placebo across 3 age strata (80-84 years, 85-89 years, and ≥90 years) among patients with AF who were a part of the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial. Design, Setting, and Participants: This prespecified subanalysis of a phase 3, randomized, double-blind, placebo-controlled trial was conducted from August 5, 2016, to December 27, 2019. Patients with AF aged 80 years or older who were not considered candidates for standard-dose OACs were included in the study; reasons these patients could not take standard-dose OACs included low creatinine clearance (<30 mL per minute), low body weight (≤45 kg), history of bleeding from critical organs, continuous use of nonsteroidal anti-inflammatory drugs, or concomitant use of antiplatelet drugs. Eligible patients were recruited randomly from 164 hospitals in Japan and were randomly assigned 1:1 to edoxaban or placebo. Interventions: Edoxaban (15 mg once daily) or placebo. Main Outcomes and Measures: The primary efficacy end point was the composite of stroke or systemic embolism. The primary safety end point was International Society on Thrombosis and Hemostasis-defined major bleeding. Results: A total of 984 patients (mean [SD] age: age group 80-84 years, 82.2 [1.4] years; age group 85-89 years, 86.8 [1.4] years; age group ≥90 years, 92.3 [2.1] years; 565 women [57.4%]) were included in this study. In the placebo group, estimated (SE) event rates for stroke or systemic embolism increased with age and were 3.9% (1.2%) per patient-year in the group aged 80 to 84 years (n = 181), 7.3% (1.7%) per patient-year in the group aged 85 to 89 years (n = 184), and 10.1% (2.5%) per patient-year in the group aged 90 years or older (n = 127). A 15-mg dose of edoxaban consistently decreased the event rates for stroke or systemic embolism with no interaction with age (80-84 years, hazard ratio [HR], 0.41; 95% CI, 0.13-1.31; P = .13; 85-89 years, HR, 0.42; 95% CI, 0.17-0.99; P = .05; ≥90 years, HR, 0.23; 95% CI, 0.08-0.68; P = .008; interaction P = .65). Major bleeding and major or clinically relevant nonmajor bleeding events were numerically higher with edoxaban, but the differences did not reach statistical significance, and there was no interaction with age. There was no difference in the event rate for all-cause death between the edoxaban and placebo groups in all age strata. Conclusions and Relevance: Results of this subanalysis of the ELDERCARE-AF randomized clinical trial revealed that among Japanese patients aged 80 years or older with AF who were not considered candidates for standard OACs, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism consistently across all 3 age strata, including those aged 90 years or older, albeit with a higher but nonstatistically significant incidence of bleeding. Trial Registration: ClinicalTrials.gov Identifier: NCT02801669.

Heart rate control by carvedilol in Japanese patients with chronic atrial fibrillation: The AF Carvedilol study.

BACKGROUND: ß-Blockers are used to control heart rate (HR) in patients with atrial fibrillation (AF). However, the appropriate dosage and efficacy of carvedilol in Japanese AF patients are yet to be clarified. METHODS: In this multicenter, randomized, double-blind study, Japanese patients with persistent or permanent AF received carvedilol for 6 weeks in the following three dosage-regimen groups: 5-mg fixed-dose (n=42), 10-mg dose-escalation (n=42), or 20-mg dose-escalation (n=43). To evaluate the efficacy of each dosage regimen and the dose-response relationship, changes in 24-h mean HR (mHR) on Holter electrocardiograms from baseline to weeks 2, 4, and 6 were determined as primary endpoints. The effects on circadian changes in HR, the proportion of patients achieving target HR, clinical symptoms, and adverse events were also examined. RESULTS: After 2 weeks, carvedilol 5mg decreased 24-h mHR significantly [6.6 (95% CI: 5.2-8.0)beats/min, p<0.0001]. After 6 weeks, carvedilol showed a trend of dose-dependent HR reduction (p=0.0638): 7.6 (5.4-9.8) in the 5-mg fixed-dose group; 8.9 (6.7-11.1) in the 10-mg dose-escalation group; and 10.6 (8.4-12.8)beats/min in the 20-mg dose-escalation group. There were no serious adverse events related to carvedilol. CONCLUSIONS: In Japanese patients with persistent or permanent AF, carvedilol at 5mg once daily demonstrated a significant HR reduction, and step-wise dose escalation from 5mg to 20mg showed a trend of dose-dependent HR reduction.

Simulative operation on congenital heart disease using rubber-like urethane stereolithographic biomodels based on 3D datasets of multislice computed tomography.

OBJECTIVE: Stereolithographic biomodelling is a technique where photosensitive liquid resin is polymerised with a pinpoint laser beam controlled by three-dimensional (3D) datasets. This study was designed to assess whether a stereolithographic biomodelling technique is applicable for precise anatomical diagnosis and simulation surgery of complicated congenital heart disease. METHODS: Twelve stereolithographic biomodels were manufactured with multislice computed tomography (MSCT)-based 3D datasets. They were made of photosensitive liquid epoxy or urethane. RESULTS: All the solid epoxy and rubber-like urethane biomodels reproduced the complex anatomical structures of the arteries and veins in congenital heart diseases. Furthermore, the rubber-like urethane biomodels allowed the surgeon to cut and suture, thus facilitating the simulation of the surgical operation. CONCLUSIONS: Stereolithographic biomodelling is a promising technique for the preoperative practice and simulation of individual surgery. This technique would be useful in the planning of novel and innovative surgical procedures of congenital heart disease.