By Michael H. Crawford, MD, Editor
SYNOPSIS: In patients age 80 years and older with atrial fibrillation who were not considered for oral anticoagulants because of serious comorbidities, one-quarter of the recommended daily dose of edoxaban was superior to placebo for preventing thromboembolic events.
SOURCE: 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;e220480. doi: 10.1001/jamacardio.2022.0480. [Online ahead of print].
Despite guideline recommendations to prescribe full-dose direct oral anticoagulants to older patients with atrial fibrillation (AF), there are concerns about the higher risk of bleeding in patients age 80 years and older and the relative paucity of relevant data for this age group. This subanalysis of the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial is of interest. The authors of the ELDERCARE-AF trial studied the effect of once-daily edoxaban 15 mg vs. placebo in Japanese AF patients age 80 years and older who were not considered candidates for the standard 60 mg/day dose. These reasons included a CHADS2 score of greater than or equal to 2, creatinine clearance 15-30 mL/min, history of bleeding, low body weight (≤ 45 kg), or use of anti-inflammatory or anti-platelet drugs. The investigation showed edoxaban was superior to placebo for preventing stroke or systemic embolism (SE), but the risk of major bleeding was higher on edoxaban (although not significantly).
In the prespecified subanalysis, the authors examined the risk of SE events and major bleeding across three age strata: age 80-84 years, age 85-89 years, and age 90 years and older. The net clinical outcome was a composite of SE, major bleeding, or all-cause death. Of 984 patients (43% men), 36% were in the age 80-84 years group, 38% in the age 85-89 years group, and 26% in the age 90 years and older group. Clinical characteristics of the three age groups between the edoxaban and placebo cohorts were similar.
Edoxaban consistently lowered the risk of stroke or systemic embolism similarly in the three age groups: age 80-84 years group (HR = 0.41), age 85-90 years group (HR = 0.42), and age 90 years and older group (HR = 0.23; interaction P = 0.65). Major bleeding was numerically higher with edoxaban, but was not statistically significant, and there was no interaction with age. Also, all-cause death was not different between the edoxaban and placebo cohorts in the three age groups. The authors concluded among Japanese patients age 80 years and older with AF who were not considered candidates for the recommended full dose of direct oral anticoagulants, 15 mg of edoxaban daily was superior to placebo for preventing SE consistently. However, there was a higher incidence rate (albeit nonsignificant) of major bleeding in the edoxaban cohort.
COMMENTARY
Potentially beneficial therapies often are withheld from older adults because of the fear of serious complications that could be triggered by their comorbidities. Indeed, in the ELDERCARE-AF trial, the incidence of bleeding or death increased with age in the placebo and edoxaban cohorts. However, withholding potentially beneficial therapy solely because of age may not be the best approach, because there may be a relatively safe dose at which some benefit is obtained.
These investigators are to be congratulated for trying to find a safe dose of edoxaban to prevent SE. The SE relative risk reduction with low-dose edoxaban was 66%, but the relative increase in major bleeding was 87%. However, in this situation, it is informative to look at the actual numbers. SE decreased from 44 in the placebo cohort to 15 in the low-dose edoxaban cohort, although the incidence of SE with this low dose of edoxaban are higher than that in younger patients on full dose. The number of major bleeding episodes increased from 11 in the placebo cohort to 20 in the edoxaban cohort. The incidence rates of major bleeding per patient-year in each age group were: placebo youngest age group, 0.4%; middle group, 3%; oldest group, 2.1%; edoxaban youngest group, 2.2%; middle group, 2.2%; and oldest group, 6.5%. Also, there were no fatal bleeds.
ELDERCARE-AF was a double-blind, randomized, placebo-controlled trial with a reasonably large patient population. Researchers focused on the relevant population: patients age 80 years and older with such significant comorbidities that they were not considered candidates for oral anticoagulants. In addition, 127 patients were nonagenarians. On the other hand, this was a pure Japanese population with low body weights and a high risk for SE and bleeding. A large portion of the study population did not complete the trial for various reasons, but excluding these patients did not affect the results. Additionally, this study was not powered for subgroup analysis, and the event rates were low.
I have observed other physicians putting older, frail patients on lower doses of oral anticoagulants and thought this was a questionable practice. However, this study has opened my eyes to the possible merits of such an approach — but we need more data on this issue before we can make firm conclusions.
In patients age 80 years and older with atrial fibrillation who were not considered for oral anticoagulants because of serious comorbidities, one-quarter of the recommended daily dose of edoxaban was superior to placebo for preventing thromboembolic events.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content