Attaining sinus rhythm mediates improved outcome with early rhythm control therapy of atrial fibrillation: the EAST-AFNET 4 trial

Abstract

Aims: A strategy of systematic, early rhythm control (ERC) improves cardiovascular outcomes in patients with atrial fibrillation (AF). It is not known how this outcome-reducing effect is mediated.

Methods and results: Using the Early treatment of Atrial Fibrillation for Stroke prevention Trial (EAST-AFNET 4) data set, potential mediators of the effect of ERC were identified in the total study population at 12-month follow up and further interrogated by use of a four-way decomposition of the treatment effect in an exponential model predicting future primary outcome events. Fourteen potential mediators of ERC were identified at the 12-month visit. Of these, sinus rhythm at 12 months explained 81% of the treatment effect of ERC compared with usual care during the remainder of follow up (4.1 years). In patients not in sinus rhythm at 12 months, ERC did not reduce future cardiovascular outcomes (hazard ratio 0.94, 95% confidence interval 0.65-1.67). Inclusion of AF recurrence in the model only explained 31% of the treatment effect, and inclusion of systolic blood pressure at 12 months only 10%. There was no difference in outcomes in patients who underwent AF ablation compared with those who did not undergo AF ablation.

Conclusion: The effectiveness of early rhythm control is mediated by the presence of sinus rhythm at 12 months in the EAST-AFNET 4 trial. Clinicians implementing ERC should aim for rapid and sustained restoration of sinus rhythm in patients with recently diagnosed AF and cardiovascular comorbidities.

Trial registration: ClinicalTrials.gov NCT01288352.

Keywords: AF ablation; Antiarrhythmic drugs; Atrial fibrillation; Mediator analysis; Randomized trials; Rhythm control; Stroke.

Conflict of interest statement

Conflict of interest: L.E. discloses consultant fees, speaking honoraria, and travel expenses from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boehringer, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Pfizer, and Sanofi Aventis. Research has been supported by German Research Foundation (DFG) and German Heart Foundation outside the submitted work. S.S. reports grants from AFNET, during the conduct of the study; grants from Biotronik, personal fees from Boston Scientific and grants from ResMed, outside the submitted work. A.S. reports grants from AFNET, during the conduct of the study; grants from BIOTRONIK and grants from ResMed, outside the submitted work. K.B. declares that there is no conflict of interest. G.B. reports no potential conflicts of interest with regard to the present substudy of EAST. H.J.G.M.C. reports support from The Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON 2014-9: reappraisal of atrial fibrillation: interaction between hypercoagulability, electrical remodelling, and vascular destabilization in the progression of AF (RACE V), outside this work. A.G. reports speaker and consulting fees from Bayer Health Care, Berlin Chemie, Boehringer Ingelheim, BMS/Pfizer, Boston Scientific, Daiichi Sankyo, Medtronic, Omeicos, and Menarini; grants from EU Horizon 2020 [grant no. 965286] and grants from AFNET, Sanofia-Aventis, and St Jude Medical during the conduct of the study. K.W. reports grants from AFNET, during the conduct of the study; grants from Biotronik, personal fees from Biotronik, personal fees from Boston Scientific, grants from ResMed and personal fees from Novartis, outside the submitted work. A.Z. reports grants from AFNET, during the conduct of the study; grants from Biotronik, personal fees from Boston Scientific and grants from ResMed, outside the submitted work. A.J.C. reports personal fees from Abbott and Sanofi and institutional grants from Abbott for work unrelated to the EAST trial. A.M. reports consulting fees from Medtronic and Biosense Webster; speaker fees from Medtronic, Biosense Webster, Boston Scientific, and Bayer; travel support from Medtronic and Boston Scientific. P.K. reports grants and nonfinancial support from BMBF (German Ministry of Education and Research), grants from Sanofi, grants from Abbott, grants and nonfinancial support from EHRA, grants from German Heart Foundation, grants from DZHK (German Center for Cardiovascular Research), during the conduct of the study; grants from European Union, grants from British Heart Foundation, grants from Leducq Foundation, grants from Medical Research Council (UK), non-financial support from German Centre for Heart Research, outside the submitted work. In addition, P.K. has a patent Atrial Fibrillation Therapy WO 2015140571 issued to University of Birmingham, and a patent Markers for Atrial Fibrillation WO 2016012783 issued to University of Birmingham.

© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.

Figures

Structured graphical abstract

The EAST-AFNET 4 trial data set was analysed for potential mediators of the outcome-reducing effect of the early rhythm control strategy in the trial. All factors that were different between randomized groups at the 12-month visit were considered. Attaining sinus rhythm explained most of the treatment effect in a landmark analysis considering the remaining 4.1 follow-up years. In conclusion, clinicians aiming to implement early rhythm control should try to attain sinus rhythm.

Figure 1

CONSORT diagram of the analyses. (A) Objective 1: Population analysis for the mediator analysis at the 12-month visit and follow-up time for future events (landmark analysis). (B) Objectives 2 and 3: Population analysis for the effect of atrial fibrillation ablation as a component of early rhythm control.

Figure 2

Strong mediating and moderating effect of sinus rhythm at 12 months on the first primary outcome of the EAST-AFNET 4 trial. The presence of sinus rhythm at 12 months explains about 81% of the effect of early rhythm control on the first primary outcome, a composite of cardiovascular death, stroke, or hospitalization for heart failure, or acute coronary syndrome. This can be appreciated in the first horizontal line in the graph (natural effect). There is hardly any effect of early rhythm control in patients who are not in sinus rhythm at the 12-month visit, visible in lack of a controlled direct effect in patients not in sinus rhythm at 12 months. Atrial fibrillation recurrence at any time up to the 12-month visit, in contrast, only explains 31% of the effect of early rhythm control, due to the small differences between the effects of the two subgroups (controlled effect in patients without AF recurrence and patients with AF recurrence). The analysis is adjusted for baseline characteristics that may confound the treatment effects on the mediator or the mediator effect on the outcome. Total effect indicates the adjusted treatment effect on the outcome; natural direct effect indicates the adjusted treatment effect due to the observed distribution of the mediator; controlled direct effect indicates the adjusted treatment effect for subgroups of patients with and without sinus rhythm or with and without atrial fibrillation recurrence at 12 months.

Figure 3

Time to recurrent atrial fibrillation and number of patients with recurrent atrial fibrillation in patients randomized to early rhythm control by rhythm status at 12 months. (A) The survival curves show the time to recurrent atrial fibrillation from randomization to 12 months in patients randomized to early rhythm control who were in sinus rhythm at 12 months and for patients who were not in sinus rhythm at 12 months. Patients who reached a primary outcome event or died in the first 12 months were not included. Recurrent atrial fibrillation was documented by triggered visits due to atrial fibrillation in the telemetric echocardiography or by an unscheduled visit due to clinically documented atrial fibrillation. (B) The tabulated data show the proportion of patients without recurrent atrial fibrillation and with recurrent atrial fibrillation who were in sinus rhythm at the 12-month visit: 58.3% (105/180) of patients not in sinus rhythm at 12 months had a scheduled or unscheduled visit due to recurrent atrial fibrillation, while only 28.5% (288/1009) of those in sinus rhythm at 12 months had such a visit.

Figure 4

Association of atrial fibrillation ablation and primary outcome for all patients: results of an adjusted Cox model with ablation as a time-dependent predictor and its interaction with treatment, and random effect for centre (n = 2789, events = 565).

Figure 5

Association of early, late, or no atrial fibrillation ablation and primary outcome for patients randomized to early rhythm control: results of an adjusted Cox model with two time-dependent variables for early and late ablation as predictors and random effect for centre (n = 1395, events = 249).