Two-year effectiveness and safety outcomes in 27,333 edoxaban-treated patients with and without a history of major bleeding from the Global ETNA-AF programme
Authors: Russo V , Wang C C , Unverdorben M , Yamashita T , Pecen L , Borrow A , Chen C , Kirchhof P , De Caterina R 
Published: October 2022

Abstract

Background
Atrial fibrillation patients with a history of major bleeding (MB) are at high risk of future bleeding events; this history was an exclusion criterion in pivotal phase 3 trials of anticoagulation for stroke prevention. Real-world edoxaban effectiveness and safety in patients with a history of MB were analysed from the global ETNA programme.

Purpose
To compare edoxaban effectiveness and safety in AF patients with or without an MB history.

Methods
The Global ETNA-AF programme (EU: NCT02944019, Japan: UMIN000017011, South Korea/Taiwan: NCT02951039) integrates data from multiple prospective, observational, noninterventional regional studies of AF patients treated with edoxaban for stroke prevention. This snapshot analysis summarises global baseline characteristics and 2-year annualised rates of all-cause death, cardiovascular death, stroke (haemorrhagic, ischaemic, any), and bleeding (including MB, major gastrointestinal bleeding [MGIB], intracranial haemorrhage [ICH], clinically relevant nonmajor bleeding, and any bleeding) in patients with or without MB history.

Results
Data from 27,333 patients (479 with MB history and 26,854 without) from Europe, Japan, South Korea, and Taiwan were analysed. Patients with MB history were significantly older (P&lt;0.0001) and more likely to be ≥75 years of age (P=0.0003), to be male (P=0.024), and to have a lower body weight and creatinine clearance (P&lt;0.0001 for both) (Table). Globally, antiplatelet use was significantly higher in patients with MB history compared with patients without (P=0.005). Patients with MB history were more likely to have previously diagnosed heart failure (HF, P=0.001) and to receive 30 mg vs 60 mg edoxaban at baseline (P&lt;0.0001). Hazard ratios for effectiveness and safety outcomes are shown in the Figure. Patients with MB history had significantly higher annualised rates of all-cause death (5.7% vs 3.1%; P&lt;0.0001), ischaemic stroke (1.8% vs 0.7%; P=0.002), and any stroke (3.1% vs 0.9%; P&lt;0.0001) than patients without MB history. Patients with MB history also had significantly higher annualised rates of MB (3.6% vs 1.0%; P&lt;0.0001), MGIB (1.5% vs 0.5%; P=0.001), ICH (1.5% vs 0.3%; P&lt;0.0001), fatal bleeding (0.9% vs 0.2%; P&lt;0.0001), and fatal ICH (0.5% vs 0.1%; P=0.0002). Among patients with MB history, the annualised rate of ICH did not differ between patients with ICH history (1.42%/yr) vs without (1.65%/yr); whereas the annualised rate of MGIB was significantly higher in patients with MGIB history vs without (4.14%/yr vs 1.08%/yr; P=0.0337).

Conclusions
Patients with AF receiving edoxaban and who have a history of MB are more likely elderly, male, and have comorbidities, including HF. These patients are also more susceptible to any adverse cardiovascular event. ICH event rates were not higher in patients with prior ICH than those with non-ICH major bleedings, whereas history of MGIB was associated with a high risk of MGIB recurrence.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo