medwireNews: In people with atrial fibrillation (AF) aged 80 years or older, edoxaban 30 mg significantly reduces major bleeding events without increasing ischemic events compared with the recommended dose of 60 mg or warfarin, suggests a post-hoc analysis of the ENGAGE AF-TIMI 48 trial.
The results showed that patients aged 80 years or older with AF who did not meet dose-reduction criteria and received edoxaban 60 mg/day experienced a 57% higher rate of major bleeding and a 124% higher rate of major gastrointestinal bleeding than their peers who received edoxaban 30 mg/day.
Writing in JAMA Cardiology, Robert Giugliano (Harvard Medical School, Boston, Massachusetts, USA) and team say: “In the context of prior studies, these results suggest that edoxaban, 30 mg, once daily may represent a reasonable approach in patients 80 years and older AF at increased risk of bleeding, regardless of the presence or absence of currently labeled dose-reduction criteria.”
The ENGAGE AF-TIMI 48 trial was a parallel design, double-blind clinical trial, which enrolled 21,105 patients in 46 countries between 2008 and 2010. Eligible participants had AF within the past year and a CHADS2 score of 2 points or higher, and required anticoagulation for thromboembolism prevention.
For the current analysis, 2966 patients aged 80 years and older with AF were randomly assigned to receive either edoxaban 30 mg/day, edoxaban 60 mg/day, or warfarin. The assigned edoxaban dose was reduced by 50% in patients meeting one or more of the following criteria: creatinine clearance of 50 mL/min or less, body weight of 60 kg or less, or use of strong P-glycoprotein inhibitors.
Comparisons between edoxaban 30 mg (n=1201) and warfarin (n=1205) included all patients, regardless of dose-reduction criteria. Further comparisons among patients taking edoxaban 30 mg (n=578), edoxaban 60 mg (n=560), and warfarin (n=562) focused on those who did not meet dose-reduction criteria.
The median age of the participants was 83 years, 56% were men, and the largest ethnicity group was White, at 87%.
The primary net clinical outcome was a composite of death, stroke or systemic embolism, and major bleeding, with secondary outcomes including ischemic stroke and all-cause death.
The researchers report that among patients who did not meet dose-reduction criteria, those who received edoxaban 60 mg had significantly higher rates of major bleeding than those who received 30 mg (hazard ratio [HR]=1.57)
Major gastrointestinal bleeding rates were also significantly greater with edoxaban 60 mg than with 30 mg (HR=2.24). There were no significant differences in all-cause death or ischemic stroke rates between the two doses.
In patients who did and did not meet dose-reduction criteria, edoxaban 30 mg significantly lowered the risk for net clinical outcomes by 22% and all-cause death by 17% compared with warfarin. Ischemic stroke rates were similar and intracranial hemorrhage was 51% lower with edoxaban 30 mg.
“These findings were supported by pharmacokinetic and pharmacodynamic analyses demonstrating that patients 80 years and older achieved higher edoxaban concentrations and inhibition of endogenous FXa, indicating that the same dose of edoxaban had a more pronounced anticoagulant effect in older patients than in younger patients,” write the researchers.
Giugliano et al conclude that “patients (and clinicians) may weigh the consequences of ischemic and bleeding events differently. The present analyses provide data that are a step in the direction of precision dosing of anticoagulants in older patients.”
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