Early Rhythm Control Therapy in Patients With Atrial Fibrillation and Heart Failure

Andreas Rillig, Christina Magnussen, Ann-Kathrin Ozga, Anna Suling, Axel Brandes, Günter Breithardt, A John Camm, Harry J G M Crijns, Lars Eckardt, Arif Elvan, Andreas Goette, Michele Gulizia, Laurent Haegeli, Hein Heidbuchel, Karl-Heinz Kuck, Andre Ng, Lukasz Szumowski, Isabelle van Gelder, Karl Wegscheider, Paulus Kirchhof, Andreas Rillig, Christina Magnussen, Ann-Kathrin Ozga, Anna Suling, Axel Brandes, Günter Breithardt, A John Camm, Harry J G M Crijns, Lars Eckardt, Arif Elvan, Andreas Goette, Michele Gulizia, Laurent Haegeli, Hein Heidbuchel, Karl-Heinz Kuck, Andre Ng, Lukasz Szumowski, Isabelle van Gelder, Karl Wegscheider, Paulus Kirchhof

Abstract

Background: Even on optimal therapy, many patients with heart failure and atrial fibrillation experience cardiovascular complications. Additional treatments are needed to reduce these events, especially in patients with heart failure and preserved left ventricular ejection fraction.

Methods: This prespecified subanalysis of the randomized EAST-AFNET4 trial (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) assessed the effect of systematic, early rhythm control therapy (ERC; using antiarrhythmic drugs or catheter ablation) compared with usual care (allowing rhythm control therapy to improve symptoms) on the 2 primary outcomes of the trial and on selected secondary outcomes in patients with heart failure, defined as heart failure symptoms New York Heart Association II to III or left ventricular ejection fraction [LVEF] <50%.

Results: This analysis included 798 patients (300 [37.6%] female, median age 71.0 [64.0, 76.0] years, 785 with known LVEF). The majority of patients (n=442) had heart failure and preserved LVEF (LVEF≥50%; mean LVEF 61±6.3%), the others had heart failure with midrange ejection fraction (n=211; LVEF 40%-49%; mean LVEF 44 ± 2.9%) or heart failure with reduced ejection fraction (n=132; LVEF<40%; mean LVEF 31±5.5%). Over the 5.1-year median follow-up, the composite primary outcome of cardiovascular death, stroke, or hospitalization for worsening of heart failure or for acute coronary syndrome occurred less often in patients randomly assigned to ERC (94/396; 5.7 per 100 patient-years) compared with patients randomly assigned to usual care (130/402; 7.9 per 100 patient-years; hazard ratio, 0.74 [0.56-0.97]; P=0.03), not altered by heart failure status (interaction P value=0.63). The primary safety outcome (death, stroke, or serious adverse events related to rhythm control therapy) occurred in 71 of 396 (17.9%) patients with heart failure randomly assigned to ERC and in 87 of 402 (21.6%) patients with heart failure randomly assigned to usual care (hazard ratio, 0.85 [0.62-1.17]; P=0.33). LVEF improved in both groups (LVEF change at 2 years: ERC 5.3±11.6%, usual care 4.9±11.6%, P=0.43). ERC also improved the composite outcome of death or hospitalization for worsening of heart failure.

Conclusions: Rhythm control therapy conveys clinical benefit when initiated within 1 year of diagnosing atrial fibrillation in patients with signs or symptoms of heart failure. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01288352. URL: http://www.controlled-trials.com; Unique identifier: ISRCTN04708680. URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2010-021258-20.

Keywords: acute coronary syndrome; anti-arrhythmia agents; atrial fibrillation; atrial fibrillation ablation; controlled clinical trial; death; heart failure; stroke.

Figures

Figure 1.
Figure 1.
Consort flow chart of the EAST-AFNET4 heart failure subanalysis. A total of 798 patients with heart failure were included in this analysis; 396 were randomly assigned to early rhythm control, and 402 were randomly assigned to usual care. During follow-up, in the early rhythm control group 201 of 2049 total follow-up years were lost (147 follow-up years lost because 31 patients withdrew; 54 follow-up years lost because 36 patients were lost to follow-up) and 159 of 2070 total follow-up years were lost in the usual care group (108 follow-up years lost because 26 patients withdrew; 51 follow-up years lost because 33 patients were lost to follow-up). Screening and randomization are replicated from the main article. AF indicates atrial fibrillation; EAST-AFNET4, Early Treatment of Atrial Fibrillation for Stroke Prevention Trial; fu, follow-up; and LVEF, left ventricular ejection fraction.
Figure 2.
Figure 2.
Primary outcome in EAST-AFNET4 patients with heart failure by randomized groups. Aalen-Johansen cumulative-incidence curves for the effects of early rhythm control on the primary outcome. Primary outcome is defined as a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome. A, All patients with heart failure. B, Heart failure with reduced ejection fraction. C, Heart failure with midrange ejection fraction. D, Heart failure with preserved ejection fraction. EAST-AFNET4 indicates Early Treatment of Atrial Fibrillation for Stroke Prevention Trial; and LVEF, left ventricular ejection fraction.
Figure 3.
Figure 3.
Left ventricular function and changes in left ventricular function of EAST-AFNET4 patients with heart failure by randomized groups. Changes in LVEF between baseline and 2 years are given in the overall heart failure population (all patients, Left) and split by LVEF groups (reduced, midrange, and preserved). The numeric changes in LVEF, split by randomized group, were early rhythm control, reduced LVEF 17.28±13.45; usual care, reduced LVEF 18.10±10.73, mean difference –0.83 (–4.44 to 2.79; P=0.66); early rhythm control, midrange LVEF 9.25±10.44; usual care, midrange LVEF 8.68±8.97 (mean difference 0.66 [–1.99 to 3.31]; P=0.63); early rhythm control, preserved LVEF 0.33±8.33; usual care, preserved LVEF –0.93±8.34 (mean difference 0.98 [(–0.83 to 2.79]; P=0.29). EAST-AFNET4 indicates Early Treatment of Atrial Fibrillation for Stroke Prevention Trial; and LVEF, left ventricular ejection fraction.

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