Impact of Age and Factor Xa Inhibitor Concentrations on Bleeding Risk in Patients with Atrial Fibrillation

Abstract

This study aimed to analyze differences in the exposure-response relationship for factor Xa inhibitors (FXaI) between patients aged ≥ 80 and < 80 years. Patients with atrial fibrillation (AF) taking rivaroxaban, apixaban, or edoxaban were enrolled, and a single steady-state trough concentration was measured. FXaI concentrations were compared with the expected range reported in clinical trials to define high or low drug levels. The primary outcome was major bleeding, and the secondary outcome was ischemic stroke or transient ischemic attack (IS/TIA). From 2016 to 2023, 1,037 patients aged from 30 to 105 years were enrolled (average, 75.4 ± 10.0 years; 33.8% were aged ≥ 80 years). During a median follow-up of 2.35 years, 48 major bleeding events and 32 IS/TIA events were observed. Although drug concentrations were similar between the two age groups, those aged ≥ 80 years with high FXaI levels experienced a greater increase in major bleeding risk compared to those aged < 80 years with high levels (aHR 6.47 [2.07, 20.28] vs. 3.45 [1.15, 10.30]). Additionally, patients aged ≥ 80 years without elevated FXaI levels also had a higher risk of major bleeding compared to those aged < 80 years without elevated levels (aHR 2.39 [1.20, 4.76]). While low FXaI concentrations were associated with IS/TIA, the risk was not significantly different across age groups. In conclusion, despite similar FXaI concentrations, patients aged ≥ 80 years have a higher baseline risk of major bleeding and experience a greater increase in bleeding risk at high drug levels compared to those aged < 80 years.

Figure 1

The flowchart of study population selection.

Figure 2

Concentration distribution across different age groups for each factor Xa inhibitor. (a) rivaroxaban, (b) apixaban and (c) edoxaban. The green bars represent the overall population within each factor Xa inhibitor group, the orange bars represent patients aged ≥ 80 years, and the blue bars represent patients aged < 80 years. The tables below display the median and interquartile range for each group. IQR, interquartile range; n, number; Y, year.

Figure 3

Kaplan–Meier survival curves for clinical outcomes. (a) Overall population categorized by age and factor Xa inhibitor (FXaI) concentration groups; (b) Patients receiving on‐label dosing regimens, categorized by age and FXaI dosing regimens. In (a), the solid line represents patients with high or low FXaI concentrations, while the dashed line represents patients without high or low FXaI concentrations. Orange lines represent elderly patients, while blue lines represent non‐elderly patients. In (b), the solid line represents patients receiving standard FXaI regimens, while the dashed line represents patients receiving reduced FXaI regimens. Pink lines represent elderly patients, while green lines represent non‐elderly patients. Elderly patients are defined as those aged ≥ 80 years. FXaI, factor Xa inhibitors; TIA, transient ischemic attack; Y, year.