A randomized, open-label trial of edoxaban in Japanese patients with severe renal impairment undergoing lower-limb orthopedic surgery.
ABSTRACT: 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.
Project description:Background and purpose - New oral anticoagulants have been developed to prevent venous thromboembolism (VTE) after knee or hip arthroplasty. Although there have been several network meta-analyses (NMA) to compare different regimens, an NMA including 2 different enoxaparin doses and edoxaban has not been performed. Methods - Standard NMA for fondaparinux, dabigatran, rivaroxaban, apixaban, edoxaban, and enoxaparin was performed. Outcome variables included a composite of total VTE and major/clinically relevant bleeding. The rank probabilities of each treatment outcome were summarized by the surface under the cumulative ranking curve. Results - Fondaparinux, rivaroxaban, and apixaban were associated with a reduced risk of VTE compared with enoxaparin, while dabigatran was not. None of these 3 drugs increased bleeding compared with enoxaparin 30?mg twice daily. However, fondaparinux and rivaroxaban increased bleeding compared with enoxaparin 40?mg once daily, while apixaban did not. Apixaban was even associated with decreased major/clinically relevant bleeding compared with enoxaparin 30?mg twice daily or 40?mg once daily. When edoxaban was included in the NMA, edoxaban decreased VTE and did not increase bleeding compared with enoxaparin. Interpretation - A higher efficacy of fondaparinux and rivaroxaban compared with enoxaparin was associated with increased bleeding tendency, while apixaban was superior to enoxaparin regarding both efficacy and safety. A clustered ranking plot showed that apixaban might be the most preferred regarding efficacy and safety. However, our results were driven by indirect statistical inference and were limited by the heterogeneity of the bleeding outcome definitions, drug initiation and continuation, and different surgery types.
Project description:Background:Direct oral anticoagulants are the first-line drugs for anticoagulation therapy in nonvalvular atrial fibrillation (NVAF). However, a real-world, large-scale, clinical study on edoxaban has not been performed. Our ongoing postmarketing surveillance, ETNA-AF-Japan (Edoxaban Treatment in routiNe clinical prActice in patients with non-valvular Atrial Fibrillation; UMIN000017011), was designed to collect such data. Methods:Enrollment started on 13 April 2015 and ended on 30 September 2017. Eligible patients were those diagnosed with NVAF who were to receive edoxaban for the first time and provided written consent for study participation. Baseline patient characteristics and adverse events (AEs) were collected. Results:A total of 11 569 patients were enrolled. Data for 8157 patients in the first 3 months were analyzed. Mean age, body weight, creatinine clearance (CLcr), and CHADS 2 score were 74.2 ± 10.0 years, 60.0 ± 12.6 kg, 64.0 ± 25.6 mL/min, and 2.2 ± 1.3, respectively. Female patients, and patients with age ?75 years, body weight ?60 kg, and CLcr <30 mL/min constituted 40.7%, 52.4%, 54.6%, and 4.7%, respectively. Patients with paroxysmal, persistent, and permanent AF constituted 46.1%, 38.7%, and 15.1%, respectively. Most patients (85.3%) received dosages according to the prescribing information, and 90.8% continued the medication for 3 months. Bleeding AEs occurred in 3.29%, including major bleeding in 0.29%. Conclusions:The majority (90.8%) of patients continued medication and no significant safety concerns related to edoxaban were reported during the first 3 months of treatment. Clearer safety and efficacy profiles of edoxaban await data analyses after the 2-year follow-up period.
Project description:Venous thromboembolism (VTE) is a common and potentially fatal complication of arthroplasty.We reviewed randomized trials to determine which anticoagulant has the best safety and efficacy in hip and knee arthroplasty patients. We searched PubMed, MEDLINE, and EMBASE through January 2016.Compared to enoxaparin (most commonly dosed 40 mg once daily), the relative risk (RR) of VTE was lowest for edoxaban 30 mg once daily (0.49; 95% confidence interval [CI], 0.32-0.75), fondaparinux 2.5 mg once daily (0.53; 95% CI, 0.45-0.63), and rivaroxaban 10 mg once daily (0.55; 95% CI, 0.46-0.66), and highest for dabigatran 150 mg once daily (1.19; 95% CI; 0.98-1.44). The RR of major/clinically relevant bleeding was lowest for apixaban 2.5 mg twice daily (0.84; 95% CI; 0.70-0.99) and highest for rivaroxaban (1.27; 95% CI, 1.01-1.59) and fondaparinux (1.64; 95% CI, 0.24-11.35). Fondaparinux was the only agent that was more effective than enoxaparin 30 mg twice daily (VTE RR = 0.58; 95% CI, 0.43-0.76).With the possible exception of apixaban, newer anticoagulants that lower the risk of postoperative VTE increase bleeding.
Project description:A retrospective analysis of the randomized controlled DART (Development of AntiRetroviral Therapy in Africa; ISRCTN13968779) trial in HIV-1-positive adults initiating antiretroviral therapy with co-formulated zidovudine/lamivudine plus either tenofovir, abacavir, or nevirapine was conducted to evaluate the safety of initiating standard lamivudine dosing in patients with impaired creatinine clearance (CLcr). Safety data collected through 96 weeks were analyzed after stratification by baseline CLcr (estimated using Cockcroft-Gault) of 30-49 mL/min (n = 168) versus ?50 mL/min (n = 3,132) and treatment regimen. The Grade 3-4 adverse events (AEs) and serious AEs (for hematological, hepatic and gastrointestinal events), maximal toxicities for liver enzymes, serum creatinine and bilirubin and maximum treatment-emergent hematology toxicities were comparable for groups with baseline CLcr 30-49 versus CLcr?50 mL/min. No new risks or trends were identified from this dataset. Substantial and similar increases in the mean creatinine clearance (>25 mL/min) were observed from baseline though Week 96 among participants who entered the trial with CLcr 30-49 mL/min, while no increase or smaller median changes in creatinine clearance (<7 mL/min) were observed for participants who entered the trial with CLcr ?50 mL/min. Substantial increases (> 150 cells/ mm3) in mean CD4+ cells counts from baseline to Week 96 were also observed for participants who entered the trial with CLcr 30-49 mL/min and those with baseline CLcr ?50 mL/min. Though these results are descriptive, they suggest that HIV-positive patients with CLcr of 30-49 mL/min would have similar AE risks in comparison to patients with CLcr ?50 mL/min when initiating antiretroviral therapy delivering doses of 300 mg of lamivudine daily through 96 weeks of treatment. Overall improvements in CLcr were observed for patients with baseline CLcr 30-49 mL/min.
Project description:Abstract <h4>Background</h4> Direct oral anticoagulants (DOACs) are the recommended first‐line therapy for ischemic stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). However, the safety and effectiveness of edoxaban for this indication requires monitoring over the long term in real‐world settings. <h4>Methods</h4> ETNA‐AF‐Japan (trial no. UMIN000017011) was a prospective, multicenter observational study (part of postmarketing surveillance in Japan). NVAF patients due to receive edoxaban to prevent ischemic stroke were enrolled between 13 April 2015 and 30 September 2017. <h4>Results</h4> A total of 11 569 patients were enrolled. For the 11 111 patients (female, 40.6%) whose data comprised the safety analysis set, age, body weight, creatinine clearance (CLcr), and CHADS2 score were 74.2 ± 10.0 years, 60.0 ± 12.7 kg, 63.9 ± 25.8 mL/min, and 2.2 ± 1.3, respectively (mean ± SD). The majority (86.3%) received edoxaban in accordance with package insert information. The mean duration of treatment was 561.9 ± 261.2 days. The annual incidence (95% confidence interval) of all bleeding events and major bleeding events was 5.60% (5.25%–5.98%) and 1.02% (0.88%–1.18%), respectively. The annual incidence of ischemic stroke (excluding transient ischemic attack, TIA) or systemic embolism was 1.08% (0.93%–1.25%). Multivariate analysis showed low body weight, low CLcr, history of gastrointestinal bleeding, anemia, and use of an antiplatelet agent to be associated with major bleeding, and history of ischemic stroke or TIA, vascular disease, and antiplatelet agent use to be associated with ischemic stroke (excluding TIA) or systemic embolism. <h4>Conclusions</h4> These results provide real‐world evidence for the long‐term good safety and effectiveness profile of edoxaban in Japanese NVAF patients under clinical practice. This prospective, multicenter observational study was carried out to evaluate the safety and effectiveness of edoxaban as first‐line therapy to prevent ischemic stroke in Japanese patients with nonvalvular atrial fibrillation (NVAF). Annual incidence (95% confidence interval) of all bleeding events, major bleeding events, and ischemic stroke (excluding transient ischemic attack, TIA) or systemic embolism was 5.60% (5.25%–5.98%), 1.02% (0.88%–1.18%), and 1.08% (0.93%–1.25%), respectively (safety analysis set, 11 111; effectiveness analysis set, 11 063; mean duration of treatment, 561.9 ± 261.2 days). These results add to the evidence for the long‐term good safety and effectiveness profile of edoxaban in Japanese patients with NVAF in a real‐world clinical setting.
Project description:Plazomicin is a new FDA-approved aminoglycoside antibiotic for complicated urinary tract infections (cUTI). In the product labeling, trough-based therapeutic drug management (TDM) is recommended for cUTI patients with renal impairment to prevent elevated trough concentrations associated with serum creatinine increases of ?0.5?mg/dl above baseline. Herein, the utility of the Hartford nomogram to prevent plazomicin trough concentrations exceeding the TDM trough of 3??g/ml and optimize the area under the curve (AUC) was assessed. The AUC reference range was defined as the 5th to 95th percentile AUC observed in the phase 3 cUTI trial (EPIC) (121 to 368 ?g · h/ml). Observed 10-h plazomicin concentrations from patients in EPIC (n?=?281) were plotted on the nomogram to determine an eligible dosing interval (every 24 h [q24h], q36h, q48h). Based on creatinine clearance (CLcr), a 15- or 10-mg/kg of body weight dose was simulated with the nomogram-derived interval. The nomogram recommended an extended interval (q36h and q48h) in 31% of patients. Compared with the 15?mg/kg q24h regimen received by patients with CLcr of ?60 ml/min in EPIC, the nomogram-derived interval reduced the proportion of patients with troughs of ?3 ?g/ml (q36h, 27% versus 0%, P?=?0.021; q48h, 57% versus 0%, P?=?0.002) while significantly increasing the number of patients within the AUC range. Compared with the 8 to 12 mg/kg q24h regimen (received by patients with CLcr of >30 to 59?ml/min in EPIC), the nomogram-derived interval significantly reduced the proportion of troughs of ?3?g/ml in the q48h cohort (72% versus 0%, P?<?0.001) while maintaining a similar proportion of patients in the AUC range. Simulated application of the Hartford nomogram optimized plazomicin exposures in patients with cUTI while reducing troughs to <3 ?g/ml.
Project description:Background: Non-vitamin K antagonist oral anticoagulants (NOACs) depend on some degree of renal excretion, and no head-to-head comparisons based on renal function is available. This study mainly investigated the trade-off property of NOACs in nonvalvular atrial fibrillation (NVAF) with varying degrees of renal function. Methods: A comprehensive search of Medline, Embase, Cochrane Library, and Clinical Trials.gov Website was performed for eligible randomized controlled trials (RCTs) that reported the efficacy and safety outcomes according to renal function of NOACs. Primary efficacy outcome was any Stroke or systemic embolism (S/SE). Major bleeding was considered as a primary safety outcome. Risk ratios (RRs) with their confidence intervals (CIs), the surface under the cumulative ranking curve (SUCRA), and trade-off analysis were conducted by renal function. Results: Finally, 5 phase III Clinical Trials (72961 NVAF patients) comparing NOACs with warfarin in NVAF patients were included. In terms of normal renal function, dabigatran-150 mg was ranked first for efficacy (SUCRA: 90.3), and edoxaban-30 mg was ranked first for safety (SUCRA: 93.3). Dabigatran-110 mg/150 mg, and apixaban-5 mg were regarded as the most effective and reasonably safe interventions in the trade-off analysis. Regarding mild renal impairment, edoxaban-60 mg was ranked first for efficacy (SUCRA: 97.8), and edoxaban-30 mg was ranked first for safety (SUCRA: 99.5). Edoxaban-60 mg and dabigatran-150 mg were accounted as the most effective and reasonably safe interventions. With regards to moderate renal impairment, dabigatran-150 mg was ranked first for efficacy (SUCRA: 95.1), and edoxaban-15 mg was ranked first for safety (SUCRA: 98.2). Apixaban-2.5 mg and Edoxaban-30 mg was considered as the reasonably effective and the safest interventions. Conclusions: Dabigatran-150 mg seems the most effective therapy in patients with normal renal function and moderate renal impairment, and edoxaban-60 mg in patients with mild renal impairment. Low dose edoxaban (15 and 30 mg) seems the safest intervention. Apixaban-2.5 mg and edoxaban-30 mg might be the best trade-off property in moderate renal insufficiency. HIGHLIGHTS? Dabigatran-150 mg seems the most effective therapy for normal renal function and moderate renal impairment patients, edoxaban-60 mg for mild renal impairment patients.Low-dose edoxaban can be considered as a good choice in NVAF patients at high risk of bleeding.Apixaban-2.5 mg and edoxaban-30 mg might be the balanced option in NVAF patients with moderate renal insufficiency.STUDY REGISTRATION:? PROSPERO Identifier, CRD42017054235.
Project description:<h4>Aims</h4>To characterize the pharmacokinetics of deferiprone in healthy subjects using a model-based approach and to assess the effect of demographic and physiological factors on drug exposure.<h4>Methods</h4>Data from 55 adult healthy subjects receiving deferiprone (solution 100?mg?ml(-1)) were used for model building purposes. A population pharmacokinetic analysis was performed using nonmem v.7.2. The contribution of gender, age, weight and creatinine clearance (CLcr) on drug disposition was evaluated according to standard forward inclusion, backward deletion procedures. Model selection criteria were based on graphical and statistical summaries.<h4>Results</h4>A one compartment model with first order oral absorption was found to describe best the pharmacokinetics of deferiprone. Simulated exposure values were comparable with previously published data. Mean AUC estimates were 45.8 and 137.4?mg?l(-1) ?h, whereas Cmax increased from 17.6 to 26.5?mg?l(-1) after administration of 25 and 75?mg?kg(-1) doses, respectively. Gender differences in the apparent volume of distribution (20%) have been identified, which are unlikely to be of clinical relevance. Furthermore, simulation scenarios reveal that dose adjustment is required for patients with reduced CLcr . Doses of 60, 40 and 25?mg?kg(-1) for patients showing mild, moderate and severe renal impairment are proposed based on CLcr values of 60-89, 30-59 and 15-29?ml?min(-1), respectively.<h4>Conclusions</h4>Our analysis has enabled the assessment of the impact of gender and CLcr on the pharmacokinetics of deferiprone. Moreover, it provides the basis for dosing recommendations in renal impairment. The implication of these covariates on systemic exposure is currently not available in the prescribing information of deferiprone.
Project description:<h4>Background</h4>Studies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban.<h4>Methods</h4>With data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15-50?ml/min, weight ?60?kg, and/or use of strong p?glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC).<h4>Results</h4>Of all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA<sub>2</sub>DS<sub>2</sub>-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30?mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30?mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30?mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC.<h4>Conclusion</h4>There were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation.<h4>Trial registration</h4>NCT02944019; Date of registration 24 October 2016.
Project description:<h4>Aims</h4>The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy.<h4>Methods</h4>A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CLcr) = 50-79 ml min(-1) ], moderate [CLcr = 30-49 ml min(-1) ], severe [CLcr <30 ml min(-1) ]).<h4>Results</h4>Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m(-2) day(-1) , given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m(-2) day(-1) for patients with moderate renal impairment (suggested dose 1.9 mg m(-2) day(-1) for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m(-2) day(-1) in this cohort.<h4>Conclusions</h4>Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.