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

Abstract

Background A strategy of systematic, early rhythm control (ERC) improves cardiovascular outcomes in patients with atrial fibrillation (AF). It is not known which aspects of ERC contribute to outcome reduction. Methods Using the EAST – AFNET 4 trial data set, potential mediators of the effect of early rhythm control were identified in the total study population at 12-month follow-up and further interrogated by use of a 4-way decomposition of the treatment effect in an exponential model predicting future primary outcome events. Results 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 to 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%, respectively. There was no difference in outcomes in patients who underwent AF ablation compared to those who did not undergo AF ablation. Conclusions The effectiveness of early rhythm control therapy is mediated by the presence of sinus rhythm at 12 months in the EAST – AFNET 4 trial. Clinicians implementing early rhythm control should aim for rapid and sustained restoration of sinus rhythm in patients with recently diagnosed AF and cardiovascular comorbidities. Funded by AFNET, DZHK, EHRA, Deutsche Herzstiftung (DHS), Abbott Laboratories, Sanofi. EAST-AFNET 4 ISRCTN number, ISRCTN04708680; ClinicalTrials.gov number, NCT01288352; EudraCT number, 2010 -021258-20.

The burden of atrial fibrillation in patients with preserved or mildly reduced heart failure: a call to action for detecting atrial fibrillation and improving outcome

“…Unfortunately, the Get With The Guidelines‐Heart Failure registry does not include detailed information on the specific type of AF associated with HF. This limits the possibility to assess the potential role of strategies, such as cardioversion, use of antiarrhythmic drugs and AF ablation, targeted to rhythm control for maintaining sinus rhythm, whose benefit has been clearly outlined by the EAST‐AFNET 4 trial for patients, with or without HF, when treated within 1 year of diagnosis 12 . The registry 3 shows that antiarrhythmic drug use for rhythm control after HF hospitalization was quite low (18%), with a modest increase over time and was substantially focused only on amiodarone, which accounted for 71% of total antiarrhythmic drug prescriptions.…”

“…In light of EAST‐AFNET 4 results and current guideline recommendations, it is clear that there is the need for enhancing and refreshing the value of appropriate AF management with rhythm control in new‐onset AF, paroxysmal and persistent AF 12 taking into account the potential benefit of not limiting antiarrhythmic agents to only amiodarone, whose toxicity at long term is well known, but also to use pulmonary vein ablation, also in combination with antiarrhythmic drugs 13 . Dronedarone was employed only in a minority of patients enrolled in the Get With The Guidelines‐Heart Failure registry, but it is noteworthy that in the ATHENA randomized controlled trial, performed in patients with paroxysmal or persistent AF or atrial flutter, aged >70 years or with cardiovascular risk factors, a significant reduction of cardiovascular hospitalization or death was demonstrated, a benefit that is unique among currently available antiarrhythmic agents and that was confirmed also in the subgroups of patients with HFpEF and HFmrEF 14 .…”

“…The limited use of cardioversion and AF ablation (2.6% and 0.4% of patients with available data) in the study by Patel et al 3 should be interpreted in light of the complete change in paradigm that EAST-AFNET 4 proposed, moving from rhythm control as a strategy for improving patient symptoms when rate control fails, to a strategy targeted to improve patient outcomes through sinus rhythm maintenance. 12 Pulmonary vein ablation for controlling AF has been tested in various clinical settings, but a randomized trial focused on HFpEF and its different phenotypes is missing. 15 The available evidence is limited to observational studies and post-hoc analysis of randomized controlled trials.…”

Defining Anti-arrhythmic Efficacy in the Setting of Evolving Concepts About Atrial Fibrillation

“…More recently, additional, much larger trials examining the effect of earlier AF rhythm control have added confirmatory and expanded information to these datasets. [12][13][14][15][16][17] Because the data from these clinical trials and their implications for practice have already been reviewed extensively, 18,19 I will not detail them here. Nonetheless, they appear to show that, with our current treatment options, earlier rhythm control versus more conventional management approaches are associated not only with a greater ability to maintain sinus rhythm 12 but also potentially with improving cardiovascular outcomes, including cardiovascular death, stroke, and HF hospitalizations.…”

“…Moreover, such an outcome benefit has been reported (1) in patients across the spectrum of left ventricular ejection fraction, (2) in patients with symptomatic as well as asymptomatic AF, (3) in both younger and older patients and in those with a greater comorbidity burden, and (4) in patients both with paroxysmal as well as persistent AF presentations. [13][14][15][16][17] Finally, to a major degree, achieving sinus rhythm appears to be the key mediator of early rhythm control, leading to reduced cardiovascular complications. In the Early Treatment of Atrial Fibrillation for Stroke Prevention Trial 4 (EAST-AFNET 4), sinus rhythm at 12 months explained 81% of the treatment effect of early rhythm control compared to usual care during the remaining follow-up period of 4.1 years.…”