https://orcid.org/0000-0001-9674-2540
Proposal for early rhythm control management of patients with atrial fibrillation (AF) irrespective of symptoms. The proposed time interval since first AF diagnosis is based on the median time reported in the EAST-AFNET 4 trial.5 Required cardiovascular conditions are defined as: age >75 years or post stroke/transient ischaemic attack or two of the following criteria: age >65 years, female sex, heart failure, hypertension, diabetes mellitus, severe coronary artery disease, chronic kidney disease (MDRD-based stage 3 or 4), and left ventricular hypertrophy (diastolic septal wall thickness >15 mm).5
This editorial refers to ‘Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 Trial’, by S. Willems et al., https://doi.org/10.1093/eurheartj/ehab593.
In December 1911, Sir Thomas Lewis wrote in his iconic book Clinical Disorders of the Heart Beat: ‘There is no ailment in which such success can be achieved, no other cardiac disease which can be so speedily benefited, as the well managed case of auricular fibrillation’.1
He probably did not expect that his intuitive, observational therapeutic enthusiasm would have needed more than a century to become cemented by solid scientific evidence. However, before achieving this goal, our approach in the last two decades has been rather nihilistic: we have managed patients with atrial fibrillation (AF) as though the benefits of rate and rhythm control strategies were similar. In other words, we have believed for quite a long time that in most patients with AF it is not worth struggling to restore and maintain sinus rhythm. This was the clinical message not only from the AFFIRM trial but also from other randomized trials, one of them conducted in patients with AF and heart failure—the CHF-AF trial.2 – 4
Last year the results of the EAST-AFNET 4 trial set a new landmark in our efforts to minimize adverse cardiovascular outcomes in patients with AF.5 This international, multicentre, randomized parallel-group trial enrolled 2789 patients with recent AF (diagnosed ≤1 year before enrolment with a median of 36 days). They were randomized to either early rhythm control or usual care. Early rhythm control was based on drugs and/or catheter ablation. In the usual care arm, rhythm control was driven only by arrhythmic symptoms. The strategy of initiating rhythm control soon after diagnosing AF (the authors introduce the term ‘early’ AF) was associated with a lower risk of the primary endpoint, a composite of death from cardiovascular causes, stroke, or hospitalization for heart failure or acute coronary syndrome, as compared with standard care over the following 5 years. Occurrence of the primary endpoint was 3.9 vs. 5.0 per 100 person-years in the early rhythm control arm and in the usual care arm, respectively [absolute difference 1.1 per 100 person-years; hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.66–0.94; P = 0.005].
In this issue of the European Heart Journal, Willems et al. report on a pre-specified analysis of the EAST-AFNET 4 trial comparing the outcome of a systematic rhythm control strategy for ‘early’ AF in patients with arrhythmia in relation to symptoms: symptomatic patients (EHRA class II–IV) vs. asymptomatic patients (EHRA class I).6 This analysis should be interpreted by the reader in the context of the main report5 and the recently published analyses by Metzner et al.7 Obviously, the aim of this analysis was to expand the currently limited evidence supporting a rhythm control strategy in asymptomatic patients and, if confirmed, to challenge current guideline-based practice to offer rhythm control mainly to symptomatic patients.
In the EAST-AFNET 4 trial, 30% of patients were asymptomatic at enrolment; of note, a similar proportion was observed in several other trials and registries such as the AFFIRM trial and GARFIELD-AF and ORBIT-AF registries.2 , 8 , 9 How did asymptomatic vs. symptomatic subgroups compare clinically? The mean CHA2DS2-VASc score of ∼3.0 was similar in each group. The typical patient in the EAST-AFNET 4 trial was an early septuagenarian, with asymptomatic patients being more often men, older, and less likely to have paroxysmal AF or heart failure. In half of asymptomatic patients, AF was classified as ‘first detected’ and, therefore, it is not surprising that they had (i) more strokes or transient ischaemic attacks and (ii) fewer attempts to restore sinus rhythm by cardioversion prior to randomization.
Asymptomatic and symptomatic patients received similar rhythm control therapies. Nevertheless, the overall rate of AF ablation was modest and similar in symptomatic and asymptomatic patients. Indeed, AF ablation was performed in 75/395 of asymptomatic patients (19.0%) and in 176/910 of symptomatic patients (19.3%). After a median follow-up of 5 years, ∼6% of patients assigned to the control group had reached the primary endpoint whether symptoms were present or not. Importantly, the benefit of an early rhythm control strategy vs. standard care was similar in symptomatic and asymptomatic patients (P for interaction 0.848).
The rhythm control therapies were safe: 37/2789 (1.3%) patients suffered adverse events from antiarrhythmic drugs, with one patient who suffered non-fatal polymorphic ventricular tachycardia and two who suffered non-fatal cardiac arrest.5 Most patients were treated with beta-blockers as background rate control therapy, which might have reduced proarrhythmic effects of class IC antiarrhythmics. In addition, and importantly, all adverse events directly related to catheter ablation in 12/367 patients were non-life threatening.5
Surprisingly, no precise data on electrical cardioversion are presented in the cluster of EAST-AFNET 4 publications. It is a highly effective method of rhythm control for patients with symptomatic persistent AF, irrespective of prior attempts to achieve sinus rhythm by antiarrhythmic drugs.10 In the AFFIRM trial, 769/2033 patients (38%) in the rhythm control arm underwent at least one electrical cardioversion.2 Data from international registries reveal that patients with AF undergo an attempt to restore sinus rhythm by electric cardioversion infrequently (e.g. only in 8% in the ORBIT-AF registry).11 Electric cardioversion followed, if necessary, by long-term antiarrhythmic drug therapy is widely available (in contrast to catheter ablation) and it would be of great interest to obtain data on its contribution to a successful early rhythm control strategy.
The EAST-AFNET 4 trial clearly demonstrates that a systematic, early (i.e. proactive) rhythm control strategy in patients with recent AF reduces cardiovascular events. In addition, the prognostic benefit is also evident in asymptomatic patients, as shown in the post-hoc analysis of Willems et al.6 Another interesting lesson we can learn from this study stems from the observation that the overall rate of cardiovascular events was 4.4/100 person-years, much lower than observed in previous trials comparing rate vs. rhythm strategies (annual incidence of cardiovascular events between 6% and 9%).3 This nicely demonstrates the major therapeutic advances with effective stroke prevention, upstream therapy, and better management of comorbidities, the quintessence of the ESC 2020 guidelines for the diagnosis and management of AF.10
In the EAST-AFNET 4, trial the use of recommended therapies was excellent: the vast majority of patients continued to take oral anticoagulants during follow-up whether or not they had returned to sinus rhythm, 80% were on beta-blockers, and >70% on renin–angiotensin system inhibitors. For comparison, anticoagulation could be stopped if AF was not detected on follow-up visits during >12 weeks in the AFFIRM trial.12 Recent registry data confirm that unwarranted discontinuation of anticoagulation increases the HRs for death, stroke, and myocardial infarction significantly (1.62, 2.21, and 1.84, respectively).8 A systematic approach to therapy may ultimately be responsible for the good outcome of patients in EAST-AFNET 4. It is worth noting that the ALL-IN cluster randomized trial published in this Journal in 2020 demonstrated a stunning 45% reduction of all-cause mortality over 2 years in patients with AF who were randomized to integrated care from family physicians, specialists, and nurses as compared with standard care.13 These remarkable improvements were achieved in a population with a mean age of 77 years.
In summary, the EAST-AFNET 4 results demonstrate that applying a systematic holistic therapeutic approach based on anticoagulation, rate control, and upstream therapy very early after diagnosis—irrespective of arrhythmia symptoms—creates a more favourable milieu for an effective concomitant rhythm control strategy with, possibly, an increasing role for catheter ablation (Graphical Abstract). These results potentially emphasize the role of screening for AF in order to initiate therapy as soon as possible. However, at least two important questions remain to be resolved in order to implement this approach in clinical practice. (i) Are the benefits of early rhythm control limited only to ‘early’ AF (i.e. diagnosed within the previous 4–6 weeks) or can they be extrapolated to AF of longer duration? This is of utmost practical importance since most countries do not have the capacity to offer specialized care (including catheter ablation) to patients with incident AF within 4–6 weeks after initial diagnosis. (ii) Which feature of the proposed strategy of rhythm control is the decisive one: the systematic medical treatment, the early rhythm control, the systematic ablation if antiarrhythmic drugs fail, or all of them?
Even with such unresolved issues, Sir Thomas Lewis would probably be pleased to see that we can further improve the outcome of ‘auricular fibrillation’ but we must implement all appropriate evidence-based therapies speedily and regardless of symptoms.
Conflict of interest: R.H. reports disclosures outside the present work: Abbott, AbbVie, Amgen, Bayer AG, Medtronic, Merck, Sharp & Dohme, Novartis, Novo-Nordisk, Pfizer, Servier, and the Slovak Research and Development Agency.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
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