Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients - ELDERCARE-AF

May 20, 2022
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Daiichi Sankyo
Date Presented:
08/30/2020
Date Published:
04/13/2022
Date Updated:
05/20/2022
Original Posted Date:
08/30/2020
References

Contribution To Literature:

Highlighted text has been updated as of May 20, 2022.

The ELDERCARE-AF trial showed that very low dose edoxaban (15 mg) was superior to placebo in reducing stroke or systemic embolism among Japanese AF patients ≥80 years of age.

Description:

The goal of the trial was to assess the safety and efficacy of low-dose edoxaban among Japanese patients ≥80 years of age who had nonvalvular atrial fibrillation (AF) and in whom standard oral anticoagulants were not recommended.

Study Design

Patients were randomized in a 1:1 fashion to either edoxaban 105 mg (n = 492) or placebo (n = 492). Patients were stratified according to CHADS2 score (2 points or ≥3 points).

  • Total number of enrollees: 984
  • Duration of follow-up: 36 months
  • Mean patient age: 86.6 years
  • Percentage female: 57%

Inclusion criteria:

  • Age ≥80 years
  • History of nonvalvular AF documented on an electrocardiogram or on a monitor recording obtained within 1 year
  • CHADS2 score of 2 or higher
  • Inappropriate candidates for oral anticoagulants (i.e., warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban) at the recommended therapeutic strength (in the case of warfarin) or at approved doses for one or more of the following reasons:
    • A low creatinine clearance (15-30 ml/min)
    • A history of bleeding from a critical area or organ or gastrointestinal (GI) bleeding
    • Low body weight (≤45 kg)
    • Continuous use of nonsteroidal anti-inflammatory drugs
    • Current use of an antiplatelet drug

Other salient features/characteristics:

  • Paroxysmal AF: 47%
  • Median weight: 50.6 kg
  • Mean creatinine clearance: 36.3 ml/min
  • Mean CHADS2 score: 3.1; CHA2DS2-VASc score: 4.9
  • HAS-BLED score: 2.3
  • History of falls within past year: 35%
  • Trial discontinuation: 151 for edoxaban vs. 150 for placebo

Principal Findings:

The primary efficacy endpoint, stroke or systemic embolism for edoxaban vs. placebo, was 2.3% vs. 6.7% (hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.19-0.61, p < 0.001).

  • Stroke: 1.8% vs. 6.0% (p < 0.001)
  • Ischemic stroke: 1.8% vs. 5.9% (p < 0.001)
  • Hemorrhagic stroke: 0 vs. 0.3%

Primary safety endpoint:

  • Major bleeding: 3.3% vs. 1.8% (p = 0.09)
  • Intracranial bleeding: 0.3% vs. 0.6%
  • GI bleeding: 2.3% vs. 0.8%

Secondary outcomes:

  • Major adverse cardiac events (cardiovascular death, myocardial infarction, stroke, bleeding): 7.7% vs. 11.0% (HR 0.70, 95% CI 0.49-1.01)
  • All-cause mortality: 9.9% vs. 10.2% (p > 0.05)
  • Major or clinically relevant nonmajor bleeding: 17.7% vs. 10.7% (HR 1.65, 95% CI 1.20-2.27)

Age stratification (number of patients aged 80-84 years: 354, 85-89 years: 374, ≥90 years: 256):

  • Stroke or systemic embolism for edoxaban vs. placebo for patients aged 80-84 years: 1.6% vs. 3.9%, 85-89 years: 2.8% vs. 7.3%, ≥90 years: 2.4% vs. 10.1% (p for interaction = 0.65)
  • Major or clinically relevant nonmajor bleeding for edoxaban vs. placebo for patients aged 80-84 years: 13% vs. 7.8%, 85-89 years: 15% vs. 7.4%, ≥90 years: 26% vs. 16.2% (p for interaction > 0.99)

Interpretation:

The results of this trial indicate that very low dose edoxaban (15 mg) was superior to placebo in reducing stroke or systemic embolism among Japanese AF patients ≥80 years of age. The primary safety endpoint of major bleeding was similar, although bleeding was overall higher with edoxaban, primarily GI bleeding. Event rates of stroke/systemic embolism increased in the placebo arm with increasing age, with preserved efficacy of edoxaban among older-age strata. Similarly, bleeding with edoxaban also increased with increasing age. Mortality rates were high and similar between the two arms. Trial discontinuation rates were quite high (nearly one-third).

These were all very elderly patients with a high proportion of frail patients; nearly one-third had sustained a fall within the year prior to enrollment. The dose of edoxaban used in this trial is one-fourth the usual stroke prophylaxis dose approved for AF (60 mg). Typically, when estimated glomerular filtration rate is <50, the dose is reduced to 30 mg daily for this indication. The current trial suggests that an even lower dose may be efficacious and could be considered in selected elderly patients. One caveat is that the median body weight in this trial was ~50 kg and all patients were east Asian. It is unclear if this dose would have the same efficacy among similar elderly patients in the United States.

References:

Kuroda M, Tamiya E, Nose T, et al. Effect of 15-mg Edoxaban on Clinical Outcomes in 3 Age Strata in Older Patients With Atrial Fibrillation: A Prespecified Subanalysis of the ELDERCARE–AF Randomized Clinical Trial. JAMA Cardiol 2022;Apr 13:[Epub ahead of print].

Okumura K, Akao M, Yoshida T, et al., on behalf of the ELDERCARE-AF Committees and Investigators. Low-Dose Edoxaban in Very Elderly Patients With Atrial Fibrillation. N Engl J Med 2020;383:1735-45.

Presented by Dr. Ken Okumura at the European Society of Cardiology Virtual Congress, August 30, 2020.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Geriatric Cardiology, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias

Keywords: ESC Congress, ESC20, Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Embolism, Frail Elderly, Geriatrics, Hemorrhage, Myocardial Infarction, Secondary Prevention, Stroke, Vascular Diseases


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