Clinical outcomes in patients with atrial fibrillation and frailty: insights from the ENGAGE AF-TIMI 48 trial

Chris Wilkinson,Kenneth Rockwood,Jianhua Wu,Oliver Todd,Andrew Clegg,Vijay Kunadian,Chris P Gale,Marlous Hall,Samuel D Searle

doi:10.1186/s12916-020-01870-w

Abstract

BackgroundAtrial fibrillation (AF) is common in older people with frailty and is associated with an increased risk of stroke and systemic embolism. Whilst oral anticoagulation is associated with a reduction in this risk, there is a lack of data on the safety and efficacy of direct oral anticoagulants (DOACs) in people with frailty. This study aims to report clinical outcomes of patients with AF in the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial by frailty status.MethodsPost hoc analysis of 20,867 participants in the ENGAGE AF-TIMI 48 trial, representing 98.8% of those randomised. This double-blinded double-dummy trial compared two once-daily regimens of edoxaban (a DOAC) with warfarin. Participants were categorised as fit, living with pre-frailty, mild-moderate, or severe frailty according to a standardised index, based upon the cumulative deficit model. The primary efficacy endpoint was stroke or systemic embolism and the safety endpoint was major bleeding.ResultsA fifth (19.6%) of the study population had frailty (fit: n = 4459, pre-frailty: n = 12,326, mild-moderate frailty: n = 3722, severe frailty: n = 360). On average over the follow-up period, the risk of stroke or systemic embolism increased by 37% (adjusted HR 1.37, 95% CI 1.19–1.58) and major bleeding by 42% (adjusted HR 1.42, 1.27–1.59) for each 0.1 increase in the frailty index (four additional health deficits). Edoxaban was associated with similar efficacy to warfarin in every frailty category, and a lower risk of bleeding than warfarin in all but those living with severe frailty.ConclusionsEdoxaban was similarly efficacious to warfarin across the frailty spectrum and was associated with lower rates of bleeding except in those with severe frailty. Overall, with increasing frailty, there was an increase in stroke and bleeding risk. There is a need for high-quality, frailty-specific population randomised control trials to guide therapy in this vulnerable population.Trial registrationClinicalTrials.gov NCT00781391. First registered on 28 October 2008

Highlights

Atrial fibrillation (AF) is common in older people with frailty and is associated with an increased risk of stroke and systemic embolism
There was a similar number of participants in each treatment arm, and the distribution of frailty category was comparable between treatment arms (Fig. 1)
Primary outcomes Across the three treatment arms, 997 patients experienced stroke or systemic embolism

Summary

Introduction

Atrial fibrillation (AF) is common in older people with frailty and is associated with an increased risk of stroke and systemic embolism. Whilst oral anticoagulation is associated with a reduction in this risk, there is a lack of data on the safety and efficacy of direct oral anticoagulants (DOACs) in people with frailty. The incidence and prevalence of AF increases with age [2] and is more common in patients with frailty [3, 4], a condition characterised by a decline in a person’s biological reserves and deterioration in physiological mechanisms that render them vulnerable to a range of adverse outcomes [5,6,7,8,9]. There is overlap between the two approaches [15]

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