Study: Early rhythm control is safe, effective in atrial fibrillation patients irrespective of genetic predisposition

A sub-study analysis of the EAST—AFNET 4 trial revealed how genetic risk for atrial fibrillation (AF) and stroke interacts with early rhythm control therapy: Early rhythm control reduces cardiovascular events in patients with AF across the spectrum of genetic AF and stroke risks. The findings were published in the journal Cardiovascular Research.

The EAST—AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention) trial demonstrated that rhythm control therapy—with antiarrhythmic drugs or atrial fibrillation ablation—delivered within one year after AF diagnosis improves outcomes in patients with AF and comorbidities.

Early rhythm control (ERC) with antiarrhythmic drugs and/or AF ablation reduced the primary outcome, a composite of cardiovascular death, stroke, and hospitalization for worsening heart failure or acute coronary syndrome, in 2789 patients with early AF and cardiovascular risk factors compared to usual care (UC) over a 5-year follow-up time.

The causes for atrial fibrillation and stroke are manifold and also comprise a heritable component. The genetic risk can be quantified by polygenic risk scores (PRS) using data from large genome-wide association studies. In a collaboration with the Broad Institute of MIT and Harvard in Cambridge, U.S., these PRS were tested in the EAST—AFNET 4 study.

Dr. Shinwan Kany, University Medical Center Hamburg Eppendorf, Hamburg, Germany, explained, "Prior studies suggest that patients with a genetic predisposition to AF may suffer more recurrent AF on rhythm control therapy. Additionally, studies using PRS for stroke identified AF patients with an increase in stroke risk when otherwise classified as low risk by CHA2DS2-VASc. This information suggests that early rhythm control therapy could be less effective or less safe in patients with an elevated genomic risk for AF. To assess this, we analyzed the association between genetic AF and stroke risk and cardiovascular events in the EAST—AFNET 4 bio-sample study."

In the EAST—AFNET 4 bio-sample sub-study, patients were asked to donate a blood sample for later analyses. For the present analysis, blood samples from 1567 of the 2789 trial patients were analyzed. Of these patients, 793 were randomized to early rhythm control, 774 to usual care. They had a median age of 71 years and comprised 44% women. Baseline characteristics were similar between randomized groups.

Consistent with the EAST—AFNET 4 main trial, early rhythm control reduced the primary outcome compared with usual care in the bio-sample sub-population (HR 0.67, p<0.001). The randomized intervention, early rhythm control, did not interact with genetic risk for AF (PRS-AF: interaction p=0.806) or stroke (PRS-Stroke: interaction p=0.765).

As expected, genetic AF risk was associated with recurrent AF, but the attributable risk was modest (HR 1.08), illustrating the effectiveness of modern rhythm control therapy across the spectrum of genetic AF risk. Unexpectedly, genetic stroke risk was associated with a higher risk for heart failure events (HR 1.23, p=0.010) without differences in stroke (HR 1.0, p=0.973) in this well-anticoagulated cohort.

The association of genetic stroke risk with heart failure hospitalization was validated in the UK Biobank, a prospective cohort study of over 500,000 participants from the United Kingdom. In the replication analysis, PRS-Stroke was associated with incident AF (HR 1.16, p<0.001) and with incident heart failure (HR 1.08, p<0.001). The association with heart failure was weakened when excluding AF patients (HR 1.03, p=0.001).

EAST—AFNET 4 principal investigator, Professor Paulus Kirchhof, University Medical Center Hamburg Eppendorf, Hamburg, Germany, concluded, "Our bio-sample study shows: Early rhythm control is effective and safe across the spectrum of genetic AF and stroke risks. Our findings support the use of early rhythm control therapy irrespectively of genetic risks for AF and stroke. The association between genetic stroke risk and heart failure calls for research to understand the interactions between polygenic risks, cardiovascular diseases, and treatment."

Since the publication of the main study result in 2020, different subgroup analyses of the EAST—AFNET 4 study data have been performed. One described the different, variable treatment patterns of antiarrhythmic drugs and AF ablation used in the trial, applied within guideline recommendations.

Other subgroup analyses demonstrated the prognostic benefit of early rhythm control in patients with AF and heart failure, in patients with asymptomatic AF, in patients with different AF patterns, in patients with high comorbidity burden and in patients with prior stroke. A mediator analysis identified sinus rhythm as key factor for the effectiveness of early rhythm control. A cost-effectiveness analysis revealed: the health benefits of early rhythm control come at reasonable additional costs.