Association of genetic risk and outcomes in patients with atrial fibrillation: interactions with early rhythm control in the EAST-AFNET4 trial.

The randomized Early Treatment of Atrial Fibrillation for Stroke Prevention Trial found that early rhythm control reduces cardiovascular events in patients with recently diagnosed atrial fibrillation (AF) compared with usual care. How genetic predisposition to AF and stroke interacts with early rhythm-control therapy is not known. Array genotyping and imputation for common genetic variants were performed. Polygenic risk scores (PRS) were calculated for AF (PRS-AF) and ischaemic stroke risk (PRS-stroke). The effects of PRS-AF and PRS-stroke on the primary outcome (composite of cardiovascular death, stroke, and hospitalization for acute coronary syndrome or worsening heart failure), its components, and recurrent AF were determined.A total of 1567 of the 2789 trial patients were analysed [793 randomized to early rhythm control; 774 to usual care, median age 71 years (65-75), 704 (44%) women]. Baseline characteristics were similar between randomized groups. Early rhythm control reduced the primary outcome compared with usual care [HR 0.67, 95% CI: (0.53, 0.84), P < 0.001]. The randomized intervention, early rhythm control, did not interact with PRS-AF (interaction P = 0.806) or PRS-stroke (interaction P = 0.765). PRS-AF was associated with recurrent AF [HR 1.08 (01.0, 1.16), P = 0.047]. PRS-stroke showed an association with the primary outcome [HR 1.13 (1.0, 1.27), P = 0.048], driven by more heart failure events [HR 1.23 (1.05-1.43), P = 0.010] without differences in stroke [HR 1.0 (0.75, 1.34), P = 0.973] in this well-anticoagulated cohort. In a replication analysis, PRS-stroke was associated with incident AF [HR 1.16 (1.14, 1.67), P < 0.001] and with incident heart failure in the UK Biobank [HR 1.08 (1.06, 1.10), P < 0.001]. The association with heart failure was weakened when excluding AF patients [HR 1.03 (1.01, 1.05), P = 0.001]. Early rhythm control is effective across the spectrum of genetic AF and stroke risk. The association between genetic stroke risk and heart failure calls for research to understand the interactions between polygenic risk and treatment. ISRCTN04708680, NCT01288352, EudraCT2010-021258-20, www.easttrial.org.

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© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

Déclaration de conflit d'intérêts

Conflict of interest: P.K. receives research support for basic, translational, and clinical research projects from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Center for Cardiovascular Research, from several drug and device companies active in AF, and has received honoraria from several such companies in the past, but not in the last 3 years. L.F. and P.K. are listed as inventors on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). L.F. has received institutional research grants and non-financial support from European Union, DFG, British Heart Foundation, Medical Research Council (UK), NIHR, and several biomedical companies. K.W. reports grants from AFNET, during the conduct of the study; grants from Biotronik; personal fees from Biotronik; and personal fees from Boston Scientific, from Resmed, and from Novartis, outside the submitted work. J.P.P. has consulted for Maze Therapeutics. P.E. has received sponsored research support from Bayer AG, IBM Health, Bristol Meyers Squibb, and Pfizer; he has also served on advisory boards or consulted for Bayer AG, MyoKardia, and Novartis. R.B.S. has received lecture fees and advisory board fees from BMS/Pfizer outside this work. The other authors report no conflicts. A.S. reports grants from AFNET, during the conduct of the study, and grants from BIOTRONIK, outside the submitted work. C.R. is supported by a grant from Bayer AG to the Broad Institute focused on the development of therapeutics for cardiovascular disease. T.Z. is listed as a co-inventor of an international patent on the use of a computing device to estimate the probability of myocardial infarction (International Publication Number WO2022043229A1).