Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Yamashita T

PROVIDER: S-EPMC11349424 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Yamashita Takeshi T Igawa Yoshiyuki Y Fukuzawa Masayuki M Hayashi Takuya T Hennig Stefanie S Okumura Ken K

Thrombosis and haemostasis 20240419 9

<h4>Background</h4> 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.<h4>Methods</h4> 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.<h4>Results</h4> ...[more]

PMID: 38641335

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Project description:ImportanceLong-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.ObjectiveTo 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 participantsThis 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.InterventionsEdoxaban (15 mg once daily) or placebo.Main outcomes and measuresThe 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.ResultsA 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 relevanceResults 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 registrationClinicalTrials.gov Identifier: NCT02801669.

Project description:ImportanceThe prevalence of atrial fibrillation (AF) increases with age and is more common in frail patients. However, data are lacking on outcomes of oral anticoagulants (OACs) in very elderly patients with AF with frailty, who are ineligible for standard anticoagulant treatment.ObjectiveTo compare very-low-dose edoxaban (15 mg daily) vs placebo across frailty status, including each of 5 frailty assessment parameters, among patients with AF involved in the ELDERCARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial.Design, setting, and participantsThis is a cohort study using data from ELDERCARE-AF, a multicenter, randomized, double-blind, placebo-controlled phase 3 study of Japanese patients with AF aged 80 years or older who were ineligible for OACs at doses approved for stroke prevention because of their high bleeding risks. Eligible patients were randomly assigned (1:1) to receive edoxaban or placebo. The study duration was from August 5, 2016, to November 5, 2019, with the last patient followed up on December 27, 2019. Data analysis was performed from February 2021 to February 2022.ExposureEdoxaban (15 mg) once daily or placebo.Main outcomes and measuresThe primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding.ResultsA total of 984 patients were randomly assigned to treatment (492 each to the edoxaban and placebo groups); 944 patients (402 frail patients [42.6%]; 542 nonfrail patients [57.4%]; mean [SD] age, 86.6 [4.3] years; 541 women [57.3%]) were included in this analysis. In the placebo group, the estimated event rates (SE) for stroke or systemic embolism were 7.1% (1.6%) per patient-year in the frail group and 6.1% (1.3%) per patient-year in the nonfrail group. Edoxaban was associated with lower event rates for stroke or systemic embolism with no interaction with frailty status or frailty assessment parameters. Major bleeding and major or clinically relevant nonmajor bleeding events were both numerically higher in the edoxaban group than in the placebo group, and no heterogeneity was observed with frailty status. Although both all-cause death and net clinical composite outcome occurred more frequently in the frail group than in the nonfrail group, there was no association with frailty status between the edoxaban and placebo groups.Conclusions and relevanceRegardless of frailty status, among Japanese patients with AF aged 80 years or older who were ineligible for standard OACs, once-daily 15-mg edoxaban was associated with reduced incidence of stroke or systemic embolism and may be a suitable treatment option for these patients.

Project description:Abstract Background 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. Methods 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. Results 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. Conclusions 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.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

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