Phase III Trial Shows Older Patients with Atrial Fibrillation May Benefit From Lower-Dose Anticoagulants

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Patients aged 80 years and above with atrial fibrillation (AF) may gain a benefit from treatment with lower-dose anticoagulants regardless of existing dose-reduction criteria, according to the results of a Phase III trial published by JAMA Cardiology.^1,2 Investigators noted that older patients with AF prescribed anticoagulants to prevent stroke have a greater likelihood of bleeding compared to younger patients, which leads physicians to frequently prescribe the medication in doses lower than recommended despite limited data supporting the practice.

“Older individuals with (AF) who are taking oral anticoagulants are at high risk for bleeding for numerous reasons, including chronic kidney disease, frailty, polypharmacy, multimorbidity, and risk of falls, and the risk increases with a greater number of high-risk features,” the study authors wrote. “As bleeding risk increases with age, clinicians often use lower than recommended doses of anticoagulants or even avoid anticoagulation altogether, placing older individuals at higher risk of ischemic events. Notably, although older patients have high rates of AF and widespread use of alternative doses in clinical practice, there are limited randomized data comparing the efficacy and safety of lower doses of anticoagulants in this patient population to inform decision-making.”¹

The multicenter, three-group, double-blind, double-dummy, randomized ENGAGE AF-TIMI 48 trial (NCT00781391) previously reported results of two dosing regimens of edoxaban in 21,105 patients with AF. Patients were randomly assigned on a 1:1:1 to receive higher-dose edoxaban (HDER) at 60/30 mg, lower-dose edoxaban (LDER) at 30/15 mg, or warfarin once daily. Investigators lowered the edoxaban dose in both the HDER and LDER cohorts by 50% in patients with creatinine clearance of 50 mL/min or less, body weight of 60 kg or less, or who were administered strong permeability glycoprotein inhibitors at the time of randomization or during treatment.

For the current analysis, researchers evaluated 2966 patients aged 80 years and above (mean [SD] age, 83 [2.7] years; 1295 female [44%]; 1671 male [56%]). The trial included 1700 patients without dose-reduction criteria who were randomly assigned to receive edoxaban 30 mg (LDER; n = 578); edoxaban 60 mg (HDER; n = 560); or warfarin (n = 562), and 1266 patients with dose-reduction criteria were randomly assigned to edoxaban, 30 mg (HDER with dose reduction; n = 623), or warfarin (n = 643).

The study’s primary efficacy endpoint was any stroke or systemic embolic event (SEE), with a principal safety endpoint of major bleeding defined by the International Society on Thrombosis and Hemostasis. The trial’s secondary endpoints included ischemic stroke, intracranial hemorrhage, all-cause death, and predefined primary net clinical outcome of stroke, SEE, major bleeding, or death from any cause.

Among 1138 patients without dose-reduction criteria, patients administered edoxaban, 60 mg vs 30 mg, experienced a greater number of major bleeding events (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03)—specifically gastrointestinal hemorrhage (HR, 2.24; 95% CI, 1.29-3.90; P = .004)—with no significant difference in the efficacy endpoints. Among 2406 patients with or without dose-reduction criteria, those administered edoxaban 30 mg experienced lower rates of the primary net clinical outcome (HR, 0.78; 95% CI, 0.68-0.91; P = .001), major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001), and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046) compared to warfarin; however, there were comparable rates of stroke or systemic embolism.

“Our analyses show that patients 80 years and older without dose-reduction criteria treated with edoxaban, 30 mg, instead of 60 mg experienced approximately 9 fewer major gastrointestinal bleeding events for each additional ischemic stroke,” the study authors wrote. “Furthermore, preventing bleeding may have long-term implications for efficacy: in the ENGAGE AF-TIMI 48 trial, patients who interrupted oral anticoagulation after a bleeding event were at a markedly higher risk of ischemic events and death. 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 with AF at increased risk of bleeding, regardless of the presence or absence of currently labeled dose-reduction criteria.”¹

References

1. Zimerman A, Braunwald E, Steffel J, et al. Dose Reduction of Edoxaban in Patients 80 Years and Older With Atrial Fibrillation: Post Hoc Analysis of the ENGAGE AF-TIMI 48 Randomized Clinical Trial. JAMA Cardiol. Published online July 10, 2024. doi:10.1001/jamacardio.2024.1793

2. Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation (EngageAFTIMI48). ClinicalTrials.gov. March 5, 2019. https://clinicaltrials.gov/study/NCT00781391