Enhanced safety advantage with DOAC in women with AF
Comparison of the Efficacy and Safety Outcomes of Edoxaban in 8040 Women Versus 13065 Men With Atrial Fibrillation in the ENGAGE AF-TIMI 48 Trial
Introduction and methods
Atrial fibrillation (AF) is linked to several risk factors and comorbidities that differ between men and women . Women with AF are less likely to have asymptomatic AF, but are more likely to experience atypical symptoms such as fatigue, in comparison with men [1-4]. Female sex is an independent risk factor for stroke and systemic embolic events (SEE) in patients with AF [4-6]. Moreover, VKA-naive women have higher pretreatment endogenous FXa activity (indicating a higher risk for thrombosis), compared with VKA-naive men .
The ENGAGE AF-TIMI 48 trial has previously shown that edoxaban - an oral factor Xa (FXa) inhibitor- is noninferior to well-managed warfarin in the prevention of stroke or SEE in patients with AF and a CHADS2 score ≥2 . Despite sex-differences in pretreatment endogenous FXa activity, the efficacy and safety of edoxaban in comparison with warfarin has not been explored in women versus men. This secondary analysis of the ENGAGE AF-TIMI 48 trial investigated the pharmacokinetics, pharmacodynamics, efficacy, and safety of edoxaban and warfarin in women versus men.
ENGAGE AF-TIMI 48 was a phase 3 multinational, double-blind, double-dummy, noninferiority trial in 21105 patients (38.1% women, n=8040) with AF and a CHADS2 score ≥2. Patients were randomized to a higher-dose edoxaban regimen (HDER, 60 mg once daily), a lower-dose edoxaban regimen (LDER, 30 mg once daily), or warfarin adjusted to an INR of 2.0 to 3.0. Edoxaban dose was reduced by 50% in patients with a body weight of ≤60 kg, an estimated creatinine clearance of ≤50 mL/min, or use of verapamil, quinidine, or dronedarone. Current analyses were focused on comparing HDER with warfarin, because only HDER is approved for clinical use in AF patients. The primary efficacy endpoint was first occurrence of stroke or SEE. Secondary efficacy endpoints were the composite of stroke, SEE and CV death; all-cause mortality; and each component separately. The primary safety endpoint was major bleeding. Prespecified secondary safety endpoints included fatal or life-threatening bleeding, intracranial hemorrhage, major or clinically relevant nonmajor bleeding, and all bleeding.
- Pretreatment (i.e. baseline) endogenous FXa activity was higher in warfarin-naïve women compared to warfarin-naïve men (women: 92.5%, IQR 84.3-102.3; men: 86.1%, IQR 78.8-94.5; P<0.001).
- Treatment with HDER led to greater change in endogenous FXa activity from baseline in women, compared to men. This resulted in similar levels of endogenous FXa activity between men and women 2 to 4 hours after dose on day 29. No significant difference was observed in change of endogenous FXa inhibition from baseline at the trough effect (i.e. just before the next dose) between men and women.
- Treatment with HDER resulted in higher peak-and trough edoxaban concentrations in women versus men on day 29 (peak: 235.0 versus 206.0 ng/mL, P<0.001; trough: 35.7 versus 32.4 ng/mL, P=0.025).
- There was no difference in risk of the primary efficacy endpoint with HDER versus warfarin in women compared to men (women: HR 0.87, 95%CI 0.69-1.11; men: HR 0.87, 95%CI 0.71-1.06; P for interaction=0.97).
- There was also no significant difference in risk of the primary safety endpoint of major bleeding with HDER versus warfarin in women compared to men (women: HR 0.74, 95%CI 0.59-0.92; men: HR 0.84, 95%CI 0.72-0.99; P for interaction=0.34). However, women experienced greater reductions with HDER versus warfarin in hemorrhagic stroke, life-threatening or fatal bleeding, intracranial bleeding, major or clinically relevant nonmajor bleeding and any bleeding, compared to men (hemorrhagic stroke: women HR 0.30, 95%CI 0.15-0.59 vs men HR 0.70, 95%CI 0.46-1.06, P for interaction=0.037; life-threatening or fatal bleeding: women HR 0.23, 95%CI 0.13-0.39 vs men HR 0.71, 95%CI 0.53-0.96, P for interaction<0.001; intracranial bleeding: women HR 0.20, 95%CI 0.10-0.39 vs men HR 0.63, 95%CI 0.44-0.89, P for interaction=0.003; major or clinically relevant nonmajor bleeding: women HR 0.76, 95%CI 0.68-0.85 vs men HR 0.92, 95%CI 0.84-1.00, P for interaction=0.011; any bleeding: women HR 0.78, 95%CI 0.70-0.87 vs men HR 0.92, 95%CI 0.85-1.00, P for interaction=0.010).
- Increase in major gastrointestinal bleeding with HDER versus warfarin was similar in women and men (women: HR 1.34, 95%CI 0.96-1.87; men: HR 1.19, 95%CI 0.94-1.50; P for interaction=0.59).
This secondary analysis of the ENGAGE AF-TIMI 48 trial investigated the efficacy and safety of edoxaban versus warfarin in women and men with AF and CHADS2 ≥2. Treatment with HDER versus warfarin resulted in similar risk of the primary efficacy endpoint (stroke or SEE) and primary safety endpoint (major bleeding) in women compared to men. However, HDER versus warfarin reduced risk of several bleeding outcomes, including hemorrhagic stroke, life-threatening or fatal bleeding, intracranial bleeding, major or clinically relevant nonmajor bleeding and any bleeding to a greater extend in women compared to men.