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Jeanne Mendell - One of the best experts on this subject based on the ideXlab platform.
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Edoxaban drug drug interactions with ketoconazole erythromycin and cyclosporine
British Journal of Clinical Pharmacology, 2016Co-Authors: Dolly A. Parasrampuria, Jeanne Mendell, Nobuko Matsushima, Minggao Shi, Hamim Zahir, Kenneth E. TruittAbstract:Aims Edoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P-glycoprotein (P-gp). Three Edoxaban drug–drug interaction studies examined the effects of P-gp inhibitors with varying degrees of CYP3A4 inhibition. Methods In each study, healthy subjects received a single oral dose of 60 mg Edoxaban with or without an oral dual P-gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, Edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, Edoxaban on day 7; or single dose of cyclosporine 500 mg with Edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study. Results Coadministration of ketoconazole, erythromycin, or cyclosporine increased Edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with Edoxaban alone. The half-life did not change appreciably. Exposure of M4, the major active Edoxaban metabolite, was consistent when Edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9-fold and peak exposure by 8.7-fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased Edoxaban exposure. No clinically significant adverse events were observed. Conclusions Administration of dual inhibitors of P-gp and CYP3A4 increased Edoxaban exposure by less than two-fold. This effect appears to be primarily due to inhibition of P-gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects.
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Edoxaban drug–drug interactions with ketoconazole, erythromycin, and cyclosporine
British journal of clinical pharmacology, 2016Co-Authors: Dolly A. Parasrampuria, Jeanne Mendell, Nobuko Matsushima, Minggao Shi, Hamim Zahir, Kenneth E. TruittAbstract:Aims Edoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P-glycoprotein (P-gp). Three Edoxaban drug–drug interaction studies examined the effects of P-gp inhibitors with varying degrees of CYP3A4 inhibition. Methods In each study, healthy subjects received a single oral dose of 60 mg Edoxaban with or without an oral dual P-gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, Edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, Edoxaban on day 7; or single dose of cyclosporine 500 mg with Edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study. Results Coadministration of ketoconazole, erythromycin, or cyclosporine increased Edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with Edoxaban alone. The half-life did not change appreciably. Exposure of M4, the major active Edoxaban metabolite, was consistent when Edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9-fold and peak exposure by 8.7-fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased Edoxaban exposure. No clinically significant adverse events were observed. Conclusions Administration of dual inhibitors of P-gp and CYP3A4 increased Edoxaban exposure by less than two-fold. This effect appears to be primarily due to inhibition of P-gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects.
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An open-label, phase 1 study to evaluate the effects of hepatic impairment on Edoxaban pharmacokinetics and pharmacodynamics.
The Journal of Clinical Pharmacology, 2015Co-Authors: Jeanne Mendell, Lisa Johnson, Shuquan ChenAbstract:Edoxaban, a once-daily, oral, direct factor Xa inhibitor, is approved for stroke prevention in nonvalvular atrial fibrillation and venous thromboembolism treatment. This study examined the effects of mild or moderate hepatic impairment on the pharmacokinetics of Edoxaban and its metabolite M4. Thirty-three subjects enrolled in 4 treatment cohorts—mild hepatic impairment (n = 8), moderate hepatic impairment (n = 9), and 2 cohorts of healthy controls matched for age, sex, and weight (each n = 8)—and received a single 15-mg dose of Edoxaban. Plasma pharmacokinetics for Edoxaban and M4, prothrombin time (PT), activated partial thromboplastin time (aPTT), and safety data were measured over 72 hours. Edoxaban and M4 exposures were similar in subjects with mild or moderate hepatic impairment compared with matched controls. Higher PT and aPTT values were observed at baseline and after Edoxaban dosing in the hepatic impairment groups compared with healthy controls. Edoxaban 15 mg was well tolerated in all cohorts. These results suggest that Edoxaban exposure does not significantly increase in patients with mild or moderate hepatic impairment. However, because of the potential for underlying coagulopathy, Edoxaban is not recommended for use in patients with moderate or severe hepatic impairment. No dose reduction is recommended for patients with mild hepatic impairment.
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The Effect of Rifampin on the Pharmacokinetics of Edoxaban in Healthy Adults
Clinical drug investigation, 2015Co-Authors: Jeanne Mendell, Shuquan Chen, Madhuri Desai, Dolly A. ParasramupriaAbstract:Background and Objective The oral direct factor Xa inhibitor Edoxaban is a P-glycoprotein (P-gp) substrate metabolized via carboxylesterase-1 and cytochrome P450 (CYP) 3A4/5. The effect of rifampin-induced induction of P-gp and CYP3A4/5 on transport and metabolism of Edoxaban through the CYP3A4/5 pathway was investigated in a single-dose Edoxaban study.
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bioavailability and safety of the factor xa inhibitor Edoxaban and the effects of quinidine in healthy subjects
Clinical pharmacology in drug development, 2013Co-Authors: Nobuko Matsushima, Frank Lee, Toshiyuki Sato, Daniel Weiss, Jeanne MendellAbstract:Background Edoxaban is an oral, once-daily, direct factor Xa inhibitor under investigation for stroke prevention in patients with atrial fibrillation and for treatment and secondary prevention of venous thromboembolism. This study evaluated Edoxaban absolute bioavailability and effects of the P-glycoprotein inhibitor quinidine on Edoxaban pharmacokinetics after intravenous Edoxaban administration. Methods Healthy volunteers received three treatments in a randomized sequence: single oral 60-mg Edoxaban dose, single intravenous 30-mg Edoxaban dose, and concomitant single intravenous 30-mg Edoxaban dose with quinidine 300 mg every 8 hours for 4 days. The primary objective was to determine absolute bioavailability of Edoxaban. Secondary objectives included pharmacokinetics and pharmacodynamics of Edoxaban after oral or intravenous administration, quinidine effect on intravenous Edoxaban pharmacokinetics, and safety. Results Thirty-six subjects were randomized; five discontinued (three for adverse events [AEs]). Edoxaban oral absolute bioavailability was 61.8%. With concomitant quinidine, total Edoxaban exposure increased ∼35% and total clearance decreased ∼25%. Coagulation parameters increased after Edoxaban administration in most subjects, but returned to baseline within 24 hours postdose. No deaths, serious AEs, or bleeding-related AEs occurred. Conclusions Absolute bioavailability of Edoxaban in healthy volunteers was established (61.8%). Edoxaban, administered orally or intravenously, appeared to be safe and well tolerated.
Tetsuya Kimura - One of the best experts on this subject based on the ideXlab platform.
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Plasma Concentration and Pharmacodynamics of Edoxaban in Patients with Nonvalvular Atrial Fibrillation and Acute Heart Failure
Clinical Pharmacokinetics, 2021Co-Authors: Takeru Nabeta, Tetsuya Kimura, Keisuke Kida, Miwa Ishida, Takaaki Shiono, Norio Suzuki, Shunichi Doi, Maya Tsukahara, Yuki Ohta, Keita YamaguchiAbstract:Objective The objective of this study was to assess the pharmacokinetic and pharmacodynamic profiles and safety of Edoxaban in patients with nonvalvular atrial fibrillation (NVAF) who were hospitalized with acute heart failure (AHF). Methods The trough plasma concentrations of Edoxaban, and the coagulation biomarkers prothrombin fragments 1 and 2 (F1+2) and d -dimer, were determined. Twenty-six patients received Edoxaban 60 mg (30 mg when dose adjustment was required) and blood samples were collected immediately before oral Edoxaban administration for 7 consecutive days after hospitalization and on the day of discharge. Results The mean observation period was 13 (range 7–46) days. Trough plasma concentrations of Edoxaban were constant from day 2 onwards. On day 1, the variation was greater owing to the differing intervals between the last Edoxaban dose and day 1 blood collection. Trough plasma concentrations were higher in patients with reduced creatinine clearance (≤ 50 mL/min). Median values for F1+2 and d -dimer remained within normal ranges throughout the study. There were no drug discontinuations, and no serious adverse events were reported. Conclusions This is the first study of Edoxaban pharmacokinetics and pharmacodynamics in patients with NVAF and AHF, and shows that the pharmacokinetic and pharmacodynamic profiles of Edoxaban were constant during hospitalization. Thus, even in patients with NVAF and AHF, Edoxaban anticoagulation therapy with guided dose adjustment is considered to be a safe and appropriate intervention. In particular, patients with reduced creatinine clearance should adhere to dose adjustment criteria. Clinical Trial Registration jRCTs031190006 (Japan Registry of Clinical Trials), 5 April, 2019 retrospectively registered.
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Plasma Concentration and Pharmacodynamics of Edoxaban in Patients with Nonvalvular Atrial Fibrillation and Acute Heart Failure.
Clinical pharmacokinetics, 2021Co-Authors: Takeru Nabeta, Tetsuya Kimura, Keisuke Kida, Miwa Ishida, Takaaki Shiono, Norio Suzuki, Shunichi Doi, Maya Tsukahara, Yuki Ohta, Keita YamaguchiAbstract:The objective of this study was to assess the pharmacokinetic and pharmacodynamic profiles and safety of Edoxaban in patients with nonvalvular atrial fibrillation (NVAF) who were hospitalized with acute heart failure (AHF). The trough plasma concentrations of Edoxaban, and the coagulation biomarkers prothrombin fragments 1 and 2 (F1+2) and D-dimer, were determined. Twenty-six patients received Edoxaban 60 mg (30 mg when dose adjustment was required) and blood samples were collected immediately before oral Edoxaban administration for 7 consecutive days after hospitalization and on the day of discharge. The mean observation period was 13 (range 7-46) days. Trough plasma concentrations of Edoxaban were constant from day 2 onwards. On day 1, the variation was greater owing to the differing intervals between the last Edoxaban dose and day 1 blood collection. Trough plasma concentrations were higher in patients with reduced creatinine clearance (≤ 50 mL/min). Median values for F1+2 and D-dimer remained within normal ranges throughout the study. There were no drug discontinuations, and no serious adverse events were reported. This is the first study of Edoxaban pharmacokinetics and pharmacodynamics in patients with NVAF and AHF, and shows that the pharmacokinetic and pharmacodynamic profiles of Edoxaban were constant during hospitalization. Thus, even in patients with NVAF and AHF, Edoxaban anticoagulation therapy with guided dose adjustment is considered to be a safe and appropriate intervention. In particular, patients with reduced creatinine clearance should adhere to dose adjustment criteria. jRCTs031190006 (Japan Registry of Clinical Trials), 5 April, 2019 retrospectively registered.
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Effects of concomitant use of prasugrel with Edoxaban on bleeding time, pharmacodynamics, and pharmacokinetics of Edoxaban in healthy elderly Japanese male subjects: a clinical pharmacology study.
Thrombosis journal, 2020Co-Authors: Ippei Ikushima, Yoshiyuki Morishima, Takaaki Akasaka, Atsushi Takita, Tomoko Motohashi, Tetsuya KimuraAbstract:Dual therapy with a direct oral anticoagulant (DOAC) plus a P2Y12 receptor inhibitor is recommended in patients with nonvalvular atrial fibrillation who undergo percutaneous coronary intervention. Thus, we evaluated the effects of DOAC Edoxaban plus P2Y12 receptor inhibitor prasugrel on bleeding time (BT), and pharmacodynamics (PD) and pharmacokinetics (PK) of Edoxaban in healthy elderly Japanese male subjects. A single-center, clinical pharmacology study with randomized, open-label, repeated dosing enrolled 24 participants in two groups of 12 receiving 30 mg Edoxaban once daily for 3 days; then 30 mg Edoxaban plus 2.5 mg prasugrel (Group 1) or 30 mg Edoxaban plus 3.75 mg prasugrel (Group 2) once daily for 5 days. Primary endpoint was BT by the Ivy method. Secondary endpoints were the PD parameters of prothrombin time (PT), activated partial thromboplastin time (aPTT), prothrombin fragment F1 + 2 (F1 + 2), and P2Y12 reaction units (PRU), and PK profiles of Edoxaban alone and in combination with prasugrel. Geometric least squares mean of BT ratios (vs. baseline) for 3-day Edoxaban treatment were 1.097 (90% confidence interval (CI) 0.911–1.321) in Group 1 and 1.327 (90% CI 1.035–1.703) in Group 2; for 5-day Edoxaban plus 2.5 mg and 3.75 mg prasugrel, they were 1.581 (90% CI 1.197–2.087) and 1.996 (90% CI 1.482–2.690), respectively. Contributions of prasugrel to the effects (Edoxaban + prasugrel/Edoxaban) were 1.442 (90% CI 1.096–1.897) in Group 1 and 1.504 (90% CI 1.172–1.930) in Group 2. Edoxaban prolonged PT and aPTT and decreased F1 + 2. Adding on prasugrel did not appreciably change PT, aPTT, or F1 + 2. Prasugrel reduced PRU, whereas Edoxaban had no effect on PRU. We recorded 26 adverse events; 23 were treatment-emergent (positive fecal occult blood test). All participants with adverse events recovered during follow-up. Coadministration of 2.5 mg and 3.75 mg prasugrel with 30 mg Edoxaban prolonged BT in healthy elderly Japanese male subjects. The effect was dependent on the dose of prasugrel. Prasugrel did not affect PD or PK profiles of Edoxaban. Edoxaban had no effect on PD of prasugrel. Japan Registry of Clinical Trials No. jRCTs071190006; registration date, 26-April-2019.
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Sensory evaluation of Edoxaban orally disintegrating tablets: an open-label interventional study (secondary publication)
Thrombosis Journal, 2019Co-Authors: Takeshi Yamashita, Yoshiyuki Morishima, Takaaki Akasaka, Joji Hagii, Takuyuki Matsumoto, Tetsuya KimuraAbstract:Background This study involved a sensory evaluation of Edoxaban orally disintegrating (OD) tablets in patients with nonvalvular atrial fibrillation who had been receiving the existing Edoxaban film-coated tablets before the study. Methods Edoxaban OD tablets 30 or 60 mg were prescribed for patients who had been receiving the existing 30- or 60-mg Edoxaban film-coated tablets before the study. Each dose group was randomized into groups taking the tablets with or without water. After ingestion of the Edoxaban OD tablet, each patient was asked to complete a sensory evaluation questionnaire (12 items). Results In the evaluation of satisfaction with Edoxaban OD tablets, 52.8% of the patients perceived “no difference” from the existing Edoxaban film-coated tablets and 34.9% indicated that they were more satisfied with the OD tablets, thus demonstrating a relatively high degree of satisfaction. When asked about convenience and reliability in using Edoxaban OD tablets, about half of the patients perceived “no difference” from the existing Edoxaban film-coated tablets and the remaining half indicated preference for the OD tablets. Responses about taste, flavor, ease of ingestion, and motivation to continue taking Edoxaban indicated the overall acceptance of the OD tablets. Recognition of Edoxaban OD tablets was rated as “easy” by about half of the patients and “difficult” by the remaining half. Among all patients, 49.5% preferred a change to Edoxaban OD tablets. The degree of satisfaction with taste, flavor, and ease of ingestion, as well as overall satisfaction, tended to be greater when the OD tablets were taken with rather than without water, and the percentage of patients who preferred a change was higher in the group taking the OD tablets with water. Conclusions This study indicated that the degree of satisfaction with taste, flavor, ease of ingestion, and convenience, as well as overall satisfaction, in addition to motivation to continue drug intake and sense of confidence were greater for OD tablets than for the existing Edoxaban film-coated tablets. Edoxaban OD tablet is a promising formulation for inducing greater patient adherence to medication and therefore ensures better treatment response. Trial registration UMIN-CTR UMIN000028788 , registered 23-Aug-2017.
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efficacy and safety of Edoxaban in elderly patients with atrial fibrillation in the engage af timi 48 trial
Journal of the American Heart Association, 2016Co-Authors: Eri Toda Kato, Tetsuya Kimura, Yukihiro Koretsune, Takeshi Yamashita, Christian T Ruff, Sabina A Murphy, Robert P. Giugliano, Francesco Nordio, Robert Gabor Kiss, James JinAbstract:Background Elderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the ENGAGE AF‐TIMI 48 trial, we evaluate clinical outcomes with Edoxaban versus warfarin according to age. Methods and Results Twenty‐one thousand one‐hundred and five patients enrolled in the ENGAGE AF‐TIMI 48 trial were stratified into 3 prespecified age groups: <65 (n=5497), 65 to 74 (n=7134), and ≥75 (n=8474) years. Older patients were more likely to be female, with lower body weight and reduced creatinine clearance, leading to higher rates of Edoxaban dose reduction (10%, 18%, and 41% for the 3 age groups, P <0.001). Stroke or systemic embolic event (1.1%, 1.8%, and 2.3%) and major bleeding (1.8%, 3.3%, and 4.8%) rates with warfarin increased across age groups ( P trend<0.001 for both). There were no interactions between age group and randomized treatment in the primary efficacy and safety outcomes. In the elderly (≥75 years), the rates of stroke/systemic embolic event were similar with Edoxaban versus warfarin (hazard ratio 0.83 [0.66–1.04]), while major bleeding was significantly reduced with Edoxaban (hazard ratio 0.83 [0.70–0.99]). The absolute risk difference in major bleeding (−82 events/10 000 pt‐yrs) and in intracranial hemorrhage (−73 events/10 000 pt‐yrs) both favored Edoxaban over warfarin in older patients. Conclusions Age has a greater influence on major bleeding than thromboembolic risk in patients with atrial fibrillation. Given the higher rates of bleeding and death with increasing age, treatment of elderly patients with Edoxaban provides an even greater absolute reduction in safety events over warfarin, compared to treatment with Edoxaban versus warfarin in younger patients. Clinical Trial Registration URL: . Unique identifier: NCT00781391.
Robert P. Giugliano - One of the best experts on this subject based on the ideXlab platform.
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clinical outcomes Edoxaban concentration and anti factor xa activity of asian patients with atrial fibrillation compared with non asians in the engage af timi 48 trial
European Heart Journal, 2019Co-Authors: Shih-ann Chen, Christian T Ruff, Rose A Hamershock, Michele Mercuri, Elliott M Antman, Eugene Braunwald, Tzefan Chao, Robert P. GiuglianoAbstract:Aims Prior studies suggested that the risks of ischaemic stroke and bleeding in patients of Asian race with atrial fibrillation (AF) may be higher than that of non-Asians. In the analysis of ENGAGE AF-TIMI 48 trial, we compared clinical outcomes, Edoxaban concentration, and anti-factor Xa (anti-FXa) activity, between Asian and non-Asian races. Methods and results There were 2909 patients of Asian race and 18 195 non-Asian race in the ENGAGE AF-TIMI 48 trial. The risks of thromboembolism and bleeding events were compared for Asians and non-Asians treated with warfarin. The trough levels of Edoxaban concentration and anti-FXa activity were also compared and correlated with the efficacy and safety of Edoxaban vs. warfarin. Compared to non-Asian patients, the Asian population was on average 2 years younger and 20 kg lighter. In the warfarin group, the adjusted risk of ischaemic stroke did not differ significantly for patients of Asian and non-Asian race [adjusted hazard ratio (aHR) = 1.12, P = 0.56). Asians treated with warfarin had a higher-adjusted risk of intracranial haemorrhage (ICH: aHR 1.71, P = 0.03) compared with non-Asians. The trough Edoxaban concentration and anti-FXa activity were 20-25% lower for Asians compared with non-Asians. Compared to warfarin, higher dose Edoxaban significantly reduced ICH while preserving the efficacy of stroke prevention in both Asians and non-Asians. Two of three net clinical outcomes appeared to be more favourably reduced with Edoxaban in Asians compared with non-Asians (Pint = 0.063 for primary, 0.037 for secondary, and 0.032 for third net clinical outcomes, respectively). Conclusion Compared to warfarin, higher dose Edoxaban preserved the efficacy for stroke prevention and was associated with a favourable safety profile for Asians, which may be due to the lower trough Edoxaban concentration and anti-FXa activity achieved in patients of Asian race.
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mortality in patients with atrial fibrillation randomized to Edoxaban or warfarin insights from the engage af timi 48 trial
The American Journal of Medicine, 2016Co-Authors: Robert P. Giugliano, Minggao Shi, Christian T Ruff, Sabina A Murphy, Michele Mercuri, Elliott M Antman, Stephen D Wiviott, Francesco Nordio, Johannes A N Kappelhof, Eugene BraunwaldAbstract:Abstract Background When compared with warfarin, Edoxaban significantly reduced cardiovascular mortality in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial. We studied the possible reasons leading to this reduction. Methods ENGAGE AF-TIMI 48 was a double-blind, double-dummy comparison of warfarin with 2 regimens of once-daily Edoxaban in 21,105 patients with atrial fibrillation followed for 2.8 years (median). Causes of deaths in the intention-to-treat population were classified as cardiovascular (including fatal bleeding and ischemic stroke), malignancy, or noncardiovascular/nonmalignancy by an independent, blinded, clinical endpoint committee. Deaths also were adjudicated as directly due to bleeding (ie, fatal), or bleeding contributing to death, or neither. Results There were 839 total deaths (4.35%/y) in the warfarin arm, compared with 773 (3.99%/y, P = .08) with the higher-dose Edoxaban regimen, and 737 (3.80%/y, P = .006) with the lower-dose Edoxaban regimen. No significant differences between treatments were observed in (1) any of the 3 most common causes of cardiovascular death (sudden cardiac, heart failure, ischemic stroke), (2) fatal malignancies, (3) other noncardiovascular death. There were 124 fatal bleeds, 65 with warfarin, significantly fewer with the higher-dose (n = 35, P = .003) and lower-dose (n = 24, P P = .001) and lower-dose (n = 54, P Conclusions Fewer total and cardiovascular deaths were observed with Edoxaban as compared with warfarin in the ENGAGE AF-TIMI 48 trial, and this predominantly resulted from the significantly lower rate of major bleeding with Edoxaban. Edoxaban reduces mortality both directly (less fatal bleeding) and indirectly (fewer bleeding-related complications and interruptions in therapy after nonfatal bleeding).
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efficacy and safety of Edoxaban in elderly patients with atrial fibrillation in the engage af timi 48 trial
Journal of the American Heart Association, 2016Co-Authors: Eri Toda Kato, Tetsuya Kimura, Yukihiro Koretsune, Takeshi Yamashita, Christian T Ruff, Sabina A Murphy, Robert P. Giugliano, Francesco Nordio, Robert Gabor Kiss, James JinAbstract:Background Elderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the ENGAGE AF‐TIMI 48 trial, we evaluate clinical outcomes with Edoxaban versus warfarin according to age. Methods and Results Twenty‐one thousand one‐hundred and five patients enrolled in the ENGAGE AF‐TIMI 48 trial were stratified into 3 prespecified age groups: <65 (n=5497), 65 to 74 (n=7134), and ≥75 (n=8474) years. Older patients were more likely to be female, with lower body weight and reduced creatinine clearance, leading to higher rates of Edoxaban dose reduction (10%, 18%, and 41% for the 3 age groups, P <0.001). Stroke or systemic embolic event (1.1%, 1.8%, and 2.3%) and major bleeding (1.8%, 3.3%, and 4.8%) rates with warfarin increased across age groups ( P trend<0.001 for both). There were no interactions between age group and randomized treatment in the primary efficacy and safety outcomes. In the elderly (≥75 years), the rates of stroke/systemic embolic event were similar with Edoxaban versus warfarin (hazard ratio 0.83 [0.66–1.04]), while major bleeding was significantly reduced with Edoxaban (hazard ratio 0.83 [0.70–0.99]). The absolute risk difference in major bleeding (−82 events/10 000 pt‐yrs) and in intracranial hemorrhage (−73 events/10 000 pt‐yrs) both favored Edoxaban over warfarin in older patients. Conclusions Age has a greater influence on major bleeding than thromboembolic risk in patients with atrial fibrillation. Given the higher rates of bleeding and death with increasing age, treatment of elderly patients with Edoxaban provides an even greater absolute reduction in safety events over warfarin, compared to treatment with Edoxaban versus warfarin in younger patients. Clinical Trial Registration URL: . Unique identifier: NCT00781391.
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Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the us food and drug administration approval population an analysis from the effective anticoagulation with factor xa next generation in atrial fibrillation thrombolysis in myoc
American Heart Journal, 2016Co-Authors: Alon Eisen, Christian T Ruff, Michele Mercuri, Robert P. Giugliano, Howard Rutman, Francesco Nordio, Harinder S Gogia, Vivek R Awasty, David A Henderson, Elliott M AntmanAbstract:Background Edoxaban is a specific anti-Xa inhibitor that, in comparison to warfarin, has been found to be noninferior for the prevention of stroke or systemic embolism (SSE) and to reduce bleeding significantly in patients with nonvalvular atrial fibrillation (AF). The US Food and Drug Administration (FDA) approved the higher-dose Edoxaban regimen (60/30 mg) in patients with AF and a creatinine clearance of ≤95 mL/min. We report for the first time the clinical characteristics, efficacy, and safety of the FDA-approved population in the ENGAGE AF–-TIMI 48 trial. Methods The patients included had been treated with either warfarin or Edoxaban 60/30 mg and had a creatinine clearance of ≤95 mL/min. The primary efficacy was SSE, and the principal safety end point was major bleeding (International Society on Thrombosis and Haemostasis classification). Median follow-up was 2.8 years. Results Patients in the FDA-approved cohort were older, were more likely female, and had higher CHADS 2 and HAS-BLED scores, as compared with patients not included in the FDA label. The primary end point occurred in 1.63%/y with Edoxaban vs 2.02%/y with warfarin (hazard ratio [HR] 0.81, 95% CI 0.67-0.97, P = .023). Edoxaban significantly reduced the rate of hemorrhagic stroke (HR 0.47, 95% CI 0.31-0.72, P P = .015). Ischemic stroke rates were similar between the treatment groups (1.31%/y vs 1.39%/y, P = .97). Major bleeding was significantly lower with Edoxaban (3.16%/y vs 3.77%/y; HR 0.84, 95% CI 0.72-0.98, P = .023). Conclusion In the FDA-approved cohort of the ENGAGE AF–-TIMI 48 trial, treatment with Edoxaban 60/30 mg was superior to warfarin in the prevention of SSE and significantly reduced cardiovascular death and bleeding, especially fatal bleeding and hemorrhagic stroke.
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cost effectiveness of Edoxaban vs warfarin in patients with atrial fibrillation based on results of the engage af timi 48 trial
American Heart Journal, 2015Co-Authors: Elizabeth A Magnuson, Christian T Ruff, Elliott M Antman, Robert P. Giugliano, Katherine Vilain, Kaijun Wang, Winghan Jacqueline Kwong, David J CohenAbstract:Background In 21,105 patients with atrial fibrillation (AF), the ENGAGE AF–TIMI 48 trial demonstrated that both higher dose (60mg/30mg dose reduced) and lower dose (30mg/15mg dose reduced) once-daily regimens of Edoxaban were non-inferior to warfarin for the prevention of stroke or systemic embolism (SE), with significantly lower rates of bleeding and cardiovascular death. Higher dose Edoxaban was associated with a greater reduction in the risk of ischemic stroke than lower dose Edoxaban, and the FDA approved higher dose Edoxaban in patients with creatinine clearance ≤95mL/min. This study evaluated the economic value of higher dose Edoxaban vs warfarin based on data from patients in ENGAGE within the FDA-approved population. Methods We assessed the cost-effectiveness of Edoxaban vs warfarin over a lifetime horizon from the US healthcare system perspective using a Markov model based on a combination of ENGAGE AF–TIMI 48 trial data, US life tables, and published literature on the costs and long-term outcomes of non-fatal cardiovascular and bleeding events. Data from the ENGAGE AF–TIMI 48 trial were used to calculate age-adjusted event rates for warfarin and hazard ratios (HRs) for the relative impact of Edoxaban on embolic and bleeding complications. Based on the wholesale acquisition price, Edoxaban and warfarin were assumed to cost $9.24 and $0.36/day, respectively. Results For Edoxaban vs warfarin, lifetime incremental costs and QALYs were $16,384 and 0.444, respectively, yielding an incremental cost-effectiveness ratio (ICER) of $36,862/QALY gained, using data from patients with creatinine clearance ≤95mL/min in ENGAGE AF–TIMI 48. ICERs were more favorable for patients without compared to those with prior warfarin use; ICERs differed minimally by CHADS 2 score. Conclusions Despite its higher acquisition cost, Edoxaban is an economically attractive alternative to warfarin for the prevention of stroke and SE in patients with atrial fibrillation and creatinine clearance ≤95mL/min. These results were robust to variation of key model parameters, including assumptions regarding the cost and quality-of-life impact of stroke and bleeding events, and were favorable across both CHADS 2 score stroke-risk categories.
Shintaro Tachibana - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty stars j v
Thrombosis Journal, 2015Co-Authors: Takeshi Fuji, Tetsuya Kimura, Masayuki Fukuzawa, Kenji Abe, Satoru Fujita, Yohko Kawai, Mashio Nakamura, Shintaro TachibanaAbstract: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. 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. 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). 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.
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safety and efficacy of Edoxaban an oral factor xa inhibitor versus enoxaparin for thromboprophylaxis after total knee arthroplasty the stars e 3 trial
Thrombosis Research, 2014Co-Authors: Takeshi Fuji, Tetsuya Kimura, Kenji Abe, Satoru Fujita, Yohko Kawai, Chingjen Wang, Mashio Nakamura, Kei Ibusuki, Hitoshi Ushida, Shintaro TachibanaAbstract:Abstract Introduction This phase 3 trial compared the safety and efficacy of Edoxaban, an oral direct factor Xa inhibitor, with enoxaparin sodium (enoxaparin) for thromboprophylaxis after total knee arthroplasty (TKA) in patients in Japan and Taiwan. Materials and methods In this randomized, double-blind, double-dummy study, patients received oral Edoxaban 30mg once daily beginning 6 to 24hours postsurgery or enoxaparin 2000IU (equivalent to 20mg) subcutaneously twice daily beginning 24 to 36hours postsurgery for 11 to 14days. The primary efficacy endpoint was the composite of symptomatic pulmonary embolism and symptomatic and asymptomatic deep vein thrombosis. Safety endpoints included the incidence of major bleeding, clinically relevant non-major (CRNM) bleeding, major bleeding or CRNM bleeding, all bleeding events, adverse events, and adverse drug reactions. Results Of 716 patients enrolled, 360 and 356 were randomized to receive Edoxaban or enoxaparin, respectively. The primary efficacy outcome occurred in 22/299 (7.4%) and 41/295 (13.9%) patients in the Edoxaban and enoxaparin groups, respectively (relative risk reduction=46.8%), indicating non-inferiority ( P P =0.010) of Edoxaban versus enoxaparin. In the Edoxaban and enoxaparin groups, major bleeding occurred in 4/354 (1.1%) versus 1/349 (0.3%) patients ( P =0.373); major or CRNM bleeding occurred in 22/354 (6.2%) versus 13/349 (3.7%) patients ( P =0.129), respectively. Conclusions Edoxaban 30mg once daily was more effective for thromboprophylaxis than subcutaneous enoxaparin 2000IU twice daily following TKA and demonstrated a similar incidence of bleeding events.
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Safety and efficacy of Edoxaban in patients undergoing hip fracture surgery
Thrombosis research, 2014Co-Authors: Takeshi Fuji, Tetsuya Kimura, Kenji Abe, Satoru Fujita, Yohko Kawai, Mashio Nakamura, Yuichi Kiuchi, Shintaro TachibanaAbstract:Abstract Introduction Edoxaban is an oral, direct, once-daily factor Xa inhibitor. This study evaluated the safety and efficacy of Edoxaban compared to subcutaneous enoxaparin in Japanese patients undergoing hip fracture surgery. Materials and methods In this multicenter, randomized, open-label, active-comparator, phase 3 trial, 92 patients were randomized 2:1 to receive Edoxaban 30 mg once daily (n = 62) or enoxaparin sodium (enoxaparin) 2000 IU (equivalent to 20 mg) twice daily (n = 30) for 11 to 14 days. The primary endpoints were the incidence of major or clinically relevant non-major (CRNM) bleeding and incidence of any bleeding events (major, CRNM, or minor bleeding). Secondary efficacy endpoints included the incidence of thromboembolic events, venous thromboembolism-related deaths, and all-cause deaths. Additional adverse events were recorded throughout the study. Results In the Edoxaban and enoxaparin treatment groups, the incidence of major or CRNM bleeding was 3.4% and 6.9%, respectively, while any bleeding event occurred in 25.4% and 17.2% of patients, respectively. The incidence of thromboembolic events was 6.5% in the Edoxaban group and 3.7% in the enoxaparin group. All events were asymptomatic deep vein thrombosis. The incidence of adverse events was 72.9% and 82.8% in the Edoxaban and enoxaparin groups, respectively. Conclusions Compared to subcutaneous enoxaparin 2000 IU twice daily, oral Edoxaban 30 mg once daily demonstrated similar safety and efficacy in the prevention of thromboembolic events in Japanese patients undergoing hip fracture surgery. Clinical trials registration number: NCT01181141.
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Edoxaban in Patients Undergoing Total Hip Arthroplasty: A Phase IIb Dose-Finding Study.
Blood, 2009Co-Authors: Takashi Fuji, Chen-jen Wang, Satoru Fujita, Shintaro Tachibana, Yohko KawaiAbstract:Abstract 2098 Poster Board II-75 Introduction: Edoxaban (the free base of DU-176b) is an oral, selective, reversible direct factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim of this study was to evaluate the efficacy, safety, and dosage regimen of Edoxaban in patients undergoing total hip arthroplasty (THA) in Japan and Taiwan. Patients and Methods: This was a randomized, enoxaparin-controlled, multicenter, parallel group study. Double-blind Edoxaban 15 mg or 30 mg once daily or open-label, subcutaneous enoxaparin 20 mg BID was administered for 11 to 14 days. Treatment of Edoxaban was started within 6 to 24 hours and treatment of enoxaparin was started within 24 to 36 hours after surgery. The primary efficacy endpoint was the incidence of thromboembolic events (composite of asymptomatic deep vein thrombosis [DVT], symptomatic pulmonary embolism [PE], or symptomatic DVT). Bilateral venography was performed at the end of the study and centrally adjudicated. The primary safety endpoint was the incidence of major and clinically relevant non-major bleeding. Prothombin time (PT), PT/international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) and Edoxaban plasma concentration was also assessed. Results: A total of 264 patients were randomized. There were no clinically relevant differences in demographic or baseline characteristics between the treatment groups. The incidence of thromboembolic events was 3.8% (3/78), 2.8% (2/72), and 4.1% (3/74) in 15 mg, 30 mg Edoxaban, and enoxaparin groups, respectively. The thromboembolic events were all distal asymptomatic DVT. PT, prothrombin PT-INR, and aPTT were prolonged at 1 to 3 hours post-dose on Day 7 in both Edoxaban dose groups. The prolongation observed in the Edoxaban dose groups was directly proportional to the plasma Edoxaban concentration. No prolongation in PT, PT-INR, or aPTT was observed in the enoxaparin group. The incidence of major and clinically relevant non-major bleeding was 2.2% (2/89) in the 15 mg Edoxaban group, 1.2% (1/85) in the 30 mg Edoxaban group, and 2.3% (2/87) in the enoxaparin group. There was one major bleeding event in the 30 mg Edoxaban group classified as clinically overt bleeding accompanied by a decrease in hemoglobin > 2g/dL. The incidence of adverse drug reactions was 18.0% (16/89) in the 15 mg group, 25.9% (22/85) in the 30 mg of Edoxaban group, and 52.9% (46/87) in the enoxaparin group. Conclusions: Oral administration of Edoxaban 15 mg and 30 mg showed potential efficacy similar to enoxaparin for the prevention of thromboembolic events in patients undergoing total hip arthroplasty. The incidence of major and clinically relevant non-major bleeding was comparable to that of enoxaparin. Disclosures: Fuji:Daiichi Sankyo: Consultancy; Astellas: Consultancy; Showa Ikakogyo: Consultancy. Wang:Daiichi Sankyo: Consultancy. Fujita:Daiichi Sankyo: Consultancy; Astellas: Consultancy; GlaxoSmithKline: Consultancy. Tachibana:Daiichi Sankyo: Consultancy. Kawai:Daiichi Sankyo: Consultancy; Toyama Chemical: Consultancy.
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efficacy and safety of Edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty stars j v
Thrombosis Journal, 2015Co-Authors: Takeshi Fuji, Tetsuya Kimura, Masayuki Fukuzawa, Kenji Abe, Satoru Fujita, Yohko Kawai, Mashio Nakamura, Shintaro TachibanaAbstract: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. 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. 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). 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.
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safety and efficacy of Edoxaban an oral factor xa inhibitor versus enoxaparin for thromboprophylaxis after total knee arthroplasty the stars e 3 trial
Thrombosis Research, 2014Co-Authors: Takeshi Fuji, Tetsuya Kimura, Kenji Abe, Satoru Fujita, Yohko Kawai, Chingjen Wang, Mashio Nakamura, Kei Ibusuki, Hitoshi Ushida, Shintaro TachibanaAbstract:Abstract Introduction This phase 3 trial compared the safety and efficacy of Edoxaban, an oral direct factor Xa inhibitor, with enoxaparin sodium (enoxaparin) for thromboprophylaxis after total knee arthroplasty (TKA) in patients in Japan and Taiwan. Materials and methods In this randomized, double-blind, double-dummy study, patients received oral Edoxaban 30mg once daily beginning 6 to 24hours postsurgery or enoxaparin 2000IU (equivalent to 20mg) subcutaneously twice daily beginning 24 to 36hours postsurgery for 11 to 14days. The primary efficacy endpoint was the composite of symptomatic pulmonary embolism and symptomatic and asymptomatic deep vein thrombosis. Safety endpoints included the incidence of major bleeding, clinically relevant non-major (CRNM) bleeding, major bleeding or CRNM bleeding, all bleeding events, adverse events, and adverse drug reactions. Results Of 716 patients enrolled, 360 and 356 were randomized to receive Edoxaban or enoxaparin, respectively. The primary efficacy outcome occurred in 22/299 (7.4%) and 41/295 (13.9%) patients in the Edoxaban and enoxaparin groups, respectively (relative risk reduction=46.8%), indicating non-inferiority ( P P =0.010) of Edoxaban versus enoxaparin. In the Edoxaban and enoxaparin groups, major bleeding occurred in 4/354 (1.1%) versus 1/349 (0.3%) patients ( P =0.373); major or CRNM bleeding occurred in 22/354 (6.2%) versus 13/349 (3.7%) patients ( P =0.129), respectively. Conclusions Edoxaban 30mg once daily was more effective for thromboprophylaxis than subcutaneous enoxaparin 2000IU twice daily following TKA and demonstrated a similar incidence of bleeding events.
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Safety and efficacy of Edoxaban in patients undergoing hip fracture surgery
Thrombosis research, 2014Co-Authors: Takeshi Fuji, Tetsuya Kimura, Kenji Abe, Satoru Fujita, Yohko Kawai, Mashio Nakamura, Yuichi Kiuchi, Shintaro TachibanaAbstract:Abstract Introduction Edoxaban is an oral, direct, once-daily factor Xa inhibitor. This study evaluated the safety and efficacy of Edoxaban compared to subcutaneous enoxaparin in Japanese patients undergoing hip fracture surgery. Materials and methods In this multicenter, randomized, open-label, active-comparator, phase 3 trial, 92 patients were randomized 2:1 to receive Edoxaban 30 mg once daily (n = 62) or enoxaparin sodium (enoxaparin) 2000 IU (equivalent to 20 mg) twice daily (n = 30) for 11 to 14 days. The primary endpoints were the incidence of major or clinically relevant non-major (CRNM) bleeding and incidence of any bleeding events (major, CRNM, or minor bleeding). Secondary efficacy endpoints included the incidence of thromboembolic events, venous thromboembolism-related deaths, and all-cause deaths. Additional adverse events were recorded throughout the study. Results In the Edoxaban and enoxaparin treatment groups, the incidence of major or CRNM bleeding was 3.4% and 6.9%, respectively, while any bleeding event occurred in 25.4% and 17.2% of patients, respectively. The incidence of thromboembolic events was 6.5% in the Edoxaban group and 3.7% in the enoxaparin group. All events were asymptomatic deep vein thrombosis. The incidence of adverse events was 72.9% and 82.8% in the Edoxaban and enoxaparin groups, respectively. Conclusions Compared to subcutaneous enoxaparin 2000 IU twice daily, oral Edoxaban 30 mg once daily demonstrated similar safety and efficacy in the prevention of thromboembolic events in Japanese patients undergoing hip fracture surgery. Clinical trials registration number: NCT01181141.
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randomized multicenter warfarin controlled phase ii study of Edoxaban in japanese patients with non valvular atrial fibrillation
Circulation, 2012Co-Authors: Takeshi Yamashita, Yukihiro Koretsune, Masahiro Yasaka, Yohko Kawai, Hiroshi Inoue, Takenori Yamaguchi, Shinichiro Uchiyama, Masayasu Matsumoto, Satoshi OgawaAbstract:Background: Edoxaban is a once-daily (QD) oral, direct factor Xa inhibitor in clinical development for the prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to evaluate the safety of Edoxaban in Japanese patients with NVAF. Methods and Results: A total of 536 NVAF patients (CHADS2 ≥1) were randomized to receive double-blinded Edoxaban 30, 45, or 60mg QD or open-label warfarin (international normalized ratio [INR] 2.0-3.0 for age <70 years; 1.6-2.6 for age ≥70 years) for 12 weeks. The primary endpoint was the incidence of all bleeding events (major, clinically relevant non-major, and minor bleeds). Patients underwent CT and/or MRI to assess asymptomatic intracranial hemorrhage (ICH). Secondary endpoints included thromboembolic events and pharmacodynamic indices. The mean incidence of all bleeding events for Edoxaban 30, 45, and 60mg, and warfarin was 18.5%, 22.4%, 27.7%, and 20.0%, respectively. There were no statistically significant differences among the Edoxaban groups and no significant differences from the warfarin group. There were no asymptomatic ICH events in any group. One episode of cerebral infarction was observed in the Edoxaban 45-mg group. Subgroup analysis suggested low body weight (≤60kg) was associated with higher bleeding risk. Conclusions: Edoxaban 30, 45, and 60mg QD in patients with NVAF was associated with a numerical increase in all bleeding across the dose range, but this was not statistically significant, nor was any dose compared with warfarin. (Circ J 2012; 76: 1840–1847)
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a dose ranging study evaluating the oral factor xa inhibitor Edoxaban for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty
Journal of Thrombosis and Haemostasis, 2010Co-Authors: T Fuji, S Fujita, S Tachibana, Yohko KawaiAbstract:Summary. Background: Edoxaban (the free base of DU-176b) is an oral, direct factor (F)Xa inhibitor in clinical development for the prevention and treatment of thromboembolic events. Objectives: The aim of the present study was to evaluate the efficacy and safety of Edoxaban for the prevention of venous thromboembolism (VTE) in patients undergoing total knee arthroplasty (TKA). Patients/methods: This was a randomized, double-blind, placebo-controlled, multicenter study conducted in Japan. A total of 523 Japanese patients were assigned to receive Edoxaban 5, 15, 30 or 60 mg once daily or placebo for 11–14 days. A placebo control was used as neither low-molecular-weight heparin (LMWH) nor fondaparinux had been approved for thromboprophylaxis at the time of the study in Japan. The primary efficacy outcome was the incidence of VTE (lower-extremity deep vein thrombosis, symptomatic pulmonary embolism or symptomatic deep vein thrombosis). The primary safety outcome was the incidence of major and clinically relevant non-major bleeding. Results: Edoxaban produced a significant dose-related reduction in VTE: the incidence of VTE was 29.5%, 26.1%, 12.5% and 9.1% in the Edoxaban 5-, 15-, 30- and 60-mg treatment groups vs. 48.3% in the placebo group. The incidence of major and clinically relevant non-major bleeding was similar across all groups without any significant differences among Edoxaban doses or between Edoxaban and placebo. Conclusions: Edoxaban demonstrated significant dose-dependent reductions in VTE in patients undergoing TKA with a bleeding incidence similar to placebo. [This trial is registered with JAPIC, JapicCTI-060283 (ja).]
