Effect of 15-mg Edoxaban on Clinical Outcomes in 3 Age Strata in Older Patients With Atrial Fibrillation

Kuroda, Minpei; Tamiya, E.; Nose, Taku; Ogimoto, Akiyoshi; Taura, Junki; Imamura, Yuki; Fukuzawa, Masahiro; Hayashi, Takuya; Akao, Masaharu; Yamashita, Takeshi; Lip, Gregory Y.H.; Okumura, Ken

doi:10.1001/jamacardio.2022.0480

Cited by 6 publications

(6 citation statements)

References 19 publications

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“… 4 In addition, subgroup analyses of ELDERCARE‐AF confirmed the consistent benefit of edoxaban 15 mg irrespective of age (80–84 years, 85–89 years, and ≥90 years) and renal function (creatinine clearance 15–<30 mL/min, 30–50 mL/min, and >50 mL/min). 5 , 6 …”

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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

Akao,

Yamashita,

Fukuzawa

et al. 2024

JAHA

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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.

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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

Akao,

Yamashita,

Fukuzawa

et al. 2024

JAHA

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“…Kuroda et al examined 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 Japanese patients with atrial fibrillation enrolled in the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE–AF) trial. In this prespecified substudy of patients who were not considered candidates for standard doses of oral anticoagulants, the authors demonstrated that a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism across all 3 age strata.…”

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JAMA Cardiology—The Year in Review, 2022

Bonow

2023

JAMA Cardiol

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“…We are seeing more trials exclusively designed to answer questions of importance to older adults. The Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial tested a very low dose of edoxaban (15 mg), a quarter of the recommended starting dose, in an older Japanese population with frailty characterized by low body weight (≤45 kg), very low creatinine clearance (<30 mL/min), history of bleeding, or medication use that increased the risk of bleeding . They randomized 984 patients with AF older than 80 years who were considered to be inappropriate candidates for standard-dose anticoagulation for stroke prevention to very low-dose edoxaban or placebo, which was feasible because no anticoagulation was the default in this group.…”

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“…The trade-offs are best informed by considering both absolute rates of stroke or systemic embolism (15 vs 44 events) and major bleeding (20 vs 11 events) with edoxaban or placebo, respectively. The article by Kuroda et al in this issue of JAMA Cardiology presents a prespecified age subgroup analysis of the ELDERCARE-AF trial across 3 age groups (80-84, 85-89, ≥90 years). As expected, event rates for bleeding and stroke increased with age; however, the main findings from the ELDERCARE-AF trial held in each subgroup, including among 127 nonagenarians.…”

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confidence: 99%

“…Age subgroups from pivotal trials provide reassurance but are ultimately arbitrary and not fully representative. To inform treatment for older adults with frailty and AF, dedicated studies like ELDERCARE-AF that test lower doses of anticoagulants, selected by pharmacokinetic studies, compared with placebo are most meaningful. Conversations that include pathways that could be taken and partnerships that would be needed for drug development for vulnerable populations are taking place at the US Food and Drug Administration .…”

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Meaningful Evidence for Anticoagulation in the Gray (Elder) Zone

Alexander

2022

JAMA Cardiol

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As more people are living longer lives, the number of older adults with atrial fibrillation (AF), a common age-associated condition, will increase. Advanced age coincides with changes in kidney and hepatic function, body mass and composition, and use of concomitant therapies with the potential for drug interactions. In recent years, helpful information for age-specific dosing has become more common, older adults are more likely to be included in clinical trials for AF, and subgroup analyses are routinely performed to confirm results apply to older subgroups. These shifts are timely and welcome. However, there remains a sizable group of elderly patients with frailty at risk for stroke from AF who are not prescribed anticoagulants. Hesitancy stems from concern about bleeding that outweighs any concern for stroke or systemic embolism. Independent predictors of not using anticoagulation include prior bleeding, history of fall, older age, polypharmacy, and frailty. [1][2][3] Many older adults with AF also have 1 or more geriatric syndromes (ie, falls, loss of independence, incontinence, and cognitive impairment), which also make it less likely they will be prescribed anticoagulation. 4 Older adults with frailty are mostly excluded from clinical trials but represent a unique group where decisions are fraught with angst. The stakes are high for stroke and for bleeding, but gaps in evidence tilt decisions toward the conservative path-not adding 1 more medication. So what evidence is needed to inform use of anticoagulation in a nonagenarian with frailty unlike those in the pivotal trials?The pivotal trials for direct oral anticoagulants, such as the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial, 5,6 which studied edoxaban, had no age exclusions and a sizeable proportion of participants were 75 years and older (approximately 40%). ENGAGE AF-TIMI 48 randomized patients into 3 arms: high-dose edoxaban (60 mg), low-dose edoxaban (30 mg), or warfarin. There were no interactions by age or weight in ENGAGE AF-TIMI 48, 5,7 nor in a large metaanalysis that looked across direct oral anticoagulants. 8 Statistical methods can confirm directionally similar findings in age groups, but age in trial populations is an imprecise proxy for age-associated vulnerability in practice. The protocol also recommended dose reduction if anticipated drug exposure would be increased based on reduced creatinine clearance or low body weight, and the majority of patients who met these dose reduction criteria were 75 years or older. 6 Extrapolations of data from trials is more complicated owing to dose adjustment based on subgroup criteria or within subgroups that include age. Prevention of stroke

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Effect of 15-mg Edoxaban on Clinical Outcomes in 3 Age Strata in Older Patients With Atrial Fibrillation

Abstract: This randomized clinical trial investigates the effect of 15-mg edoxaban in patients aged 80 years and older who are not candidates for standard-dose oral anticoagulants owing to bleeding risk.

Cited by 6 publications

References 19 publications

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

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

JAMA Cardiology—The Year in Review, 2022

Meaningful Evidence for Anticoagulation in the Gray (Elder) Zone

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