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Kim, Yang, and Joung: Optimal Rhythm Control Strategy in Patients With Atrial Fibrillation
State of the Art Review

Korean Circulation Journal 2022; 52(7): 496-512.

Published online: 7 June 2022

DOI: https://doi.org/10.4070/kcj.2022.0078

Optimal Rhythm Control Strategy in Patients With Atrial Fibrillation

Daehoon Kim, MD1, *, Pil-Sung Yang, MD2, *, Boyoung Joung, MD, PhD1

1Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea.

2Department of Cardiology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.

Correspondence to Boyoung Joung, MD, PhD. Division of Cardiology, Department of Internal Medicine, Yonsei Cardiovascular Hospital, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. cby6908@yuhs.ac

Equal contributor:

*The first two authors contributed equally to this work.

Received 12 March 2022       Revised 9 May 2022       Accepted 19 May 2022

Copyright © 2022. The Korean Society of Cardiology

The Korean Society of Cardiology

https://creativecommons.org/licenses/by-nc/4.0/
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Author's summary

In the recent EAST-AFNET 4 trial, early rhythm control reduced the risk of adverse cardiovascular events compared with usual care in patients recently diagnosed as atrial fibrillation (AF). Recent observational studies from Korean nationwide claim data confirmed and extended the findings from controlled trials. The beneficial effect of rhythm control on cardiovascular outcomes was not obvious in those who had been diagnosed with AF more than 1 year ago. Especially, early initiation of rhythm control was related to the lower risk of stroke and hospitalization due to heart failure. Finally, early rhythm control treatment was also effective in patients with asymptomatic AF but less effective in older adults. Therefore, in patients with AF, rhythm control should be considered at the earliest stage, regardless of symptom.

Abstract

For almost 20 years, data regarding the effect of rhythm control therapy for atrial fibrillation (AF) on cardiovascular prognosis in comparison with rate control therapy has not been conclusive. The safety of rhythm control and anticoagulation therapy has generally improved. Recently, it was revealed that a rhythm-control strategy reduced the risk of adverse cardiovascular events than usual rate control in patients with recent AF (diagnosed within 1 year). Within 1 year after the AF diagnosis, early initiation of rhythm control led to more favorable cardiovascular outcomes than rate control. Early rhythm control reduced the risks of stroke and heart failure-related admission than rate control. Moreover, rhythm control was associated with lower dementia risk than rate control. Finally, early rhythm control treatment was also effective in patients with asymptomatic AF but less effective in older adults. Therefore, in patients with AF, rhythm control should be considered at earlier stages, regardless of symptom.

Keywords: Atrial fibrillation, Rhythm control, Early treatment, Cardiovascular outcome, Cognitive outcome

INTRODUCTION

Atrial fibrillation (AF), the most common sustained arrhythmia among the general population,1)2)3)4) increases the risk of morbidity and mortality resulting from stroke, heart failure, and cognitive dysfunction, even among patients undergoing optimal anticoagulation and rate control therapy.5)6)7)8)9)10) Rhythm control, using antiarrhythmic drugs, electrical cardioversion, and AF ablation together with adequate rate control, is known to improve symptoms and quality of life in patients with symptomatic AF.11)12)13) No indication has been established for rhythm control therapy apart from improving AF-associated symptoms.1)12)13) Previous trials of rhythm control as compared with rate control in the 2000s, including the Atrial Fibrillation Follow-up Investigation of Sinus Rhythm Management (AFFIRM) and the RAte Control vs. Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) trials, showed no significant differences between the treatment strategies in regard to mortality and cardiovascular outcomes.14)15)16)17) However, there were important treatment-related factors associated with mortality during rhythm control therapy at that time, such as the safety of rhythm control and the continuation of anticoagulation. Dronedarone reduced the composite outcome of death and cardiovascular hospitalizations compared with placebo for patients with AF and additional risk factors for death.18) In the previous 20 years, AF catheter ablation has been developed, and the Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial confirmed the safety of AF ablation among contemporary AF patients with stroke risk.19) In AF patients with heart failure with reduced ejection fraction (HFrEF), AF catheter ablation improved outcomes compared with drug therapy combining rate control and antiarrhythmic drug therapy.20) Furthermore, long-term anticoagulation is generally maintained in contemporary patients with stroke risk after restoring the sinus rhythm using ablation.12)
The recently published Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4) demonstrated that rhythm control therapy reduced the risk of a composite of death from cardiovascular causes, stroke, hospitalization owing to worsening heart failure, or acute coronary syndrome by 21% among patients recently diagnosed with AF (within 1 year after diagnosis).21) Here, we summarize the evidence supporting the use of rhythm control treatment among patients with AF, suggest the potential implications for indications, and shed light on clinical evidence gaps.

EFFICACY AND SAFETY OF RHYTHM CONTROL

Antiarrhythmic drug therapy

Table 1 summarizes the effects of rhythm control with contemporarily used antiarrhythmic drugs or catheter ablation on cardiovascular outcomes. There have been historical safety concerns of antiarrhythmic drug treatment.14)15) Amiodarone was associated with adverse outcomes among patients at high risk in non-randomized studies.22) Recent randomized trials found that the complication rates of drug treatment were similar to those of ablation therapy.19)23)24)25) In AF patients with heart failure, the risk of safety outcomes was similar between patients receiving amiodarone and rate control therapy.17) In the recent EAST-AFNET 4, there were no differences in the number of hospital stays and the risk of safety outcomes between the treatment strategies of rate control and rhythm control, which attenuates historical safety concerns.21) In the trial, 92% of rhythm-controlled patients underwent antiarrhythmic drug therapy initially, which replicated clinical practice patterns.
Table 1

Effects of contemporary rhythm control treatments compared to rate control in randomized controlled trials

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Variables AF-CHF17) (2008) ATHENA18) (2009) Flec-SL26) (2012) CTSN27) (2016) EAST-AFNET 421) (2020)
Number of patients 1,376 4,628 635 523 2,789
Female sex (%) 18 47 44 24.3 46.2
Mean age (years) 67 72 64 69 70
Inclusion Symptomatic HF (NYHA II–IV), LVEF <36% AF and >70 years with one comorbidity or >75 years Patients undergoing cardioversion New-onset AF after cardiac surgery Recent-onset AF (≤1 year before enrollment) with CV conditions (approximately ≥2 of CHA2DS2-VASc)
Type of AF >2/3 persistent NA Persistent Postoperative (persisted for more than 1 hour or recurrent AF within 7 days after surgery) Persistent: 26.0%
Duration between AF diagnosis and enrolment (years) <1 NA 2.3 NA 0.1
Intervention for rhythm control Amiodarone Dronedarone Flecainide for 4 weeks or 6 months Amiodarone Antiarrhythmic drugs or AF ablation
Comparator therapy Rate control Placebo No antiarrhythmic drug treatment Rhythm control Usual care
Primary endpoint CV death CV hospitalization or death Time to persistent AF or death Days of hospitalization A composite of CV death, stroke, hospitalization with worsening HF or ACS
SR maintenance Amiodarone: 70% vs. Control: 30% at 2 years visit Median time to first AF recurrence: 737 days (dronedarone) vs. 498 days (control) Flecainide: 60% vs. Control: 40% at 6 months Amiodarone: 97.9% vs. Control: 93.8% at 2 months Rhythm control: 82.1% vs. Control: 60.5% at 2 years
Outcomes No difference in mortality or QoL Lower mortality and less hospitalizations in patients randomized to dronedarone Lower mortality and recurrent AF at 4 weeks in patients randomized to flecainide No difference in the numbers of days of hospitalization Lower risk of the primary composite outcome in patients randomized to early rhythm control
ACS = acute coronary syndrome; AF = atrial fibrillation; CV = cardiovascular; HF = heart failure; HR = hazard ratio; LVEF = left ventricular ejection fraction; NA = not available; NYHA = New York Heart Association; QoL = quality of life; SR = sinus rhythm.
Dronedarone reduced cardiovascular deaths and cardiovascular hospitalizations compared to placebo.18) Flecainide reduced recurrent AF and all-cause death compared with no treatment following successful cardioversion in patients with persistent AF.26) By contrast, amiodarone failed to reduce death from cardiovascular causes in comparison with rate control for AF patients with HFrEF.17) Among patients with new-onset AF after cardiac surgery, amiodarone did not show a net clinical benefit over rate control.27)

Atrial fibrillation ablation therapy

Previous trials published more than a decade ago showed that AF ablation was better at maintaining sinus rhythm than antiarrhythmic drug treatment.28)29) A meta-analysis including 19 studies analyzing rhythm outcomes of at least 3 years after ablation revealed that the recurrence rate after a single procedure was approximately 47%.30) With multiple procedures, approximately 80% of patients were free from recurrent AF.30) In 20–50% of patients undergoing de novo AF ablation, redo ablation was performed.31) Dinshaw et al. reported that up to 90% and 60% of patients with paroxysmal and persistent AF undergoing ablation remained free from clinically relevant AF recurrences.32)
The CABANA trial confirmed the better efficacy of ablation therapy than antiarrhythmic drug treatment, although the primary composite outcome of death, disabling stroke, serious bleeding, or cardiac arrest did not differ with event rates of 8.0% and 9.2% in the ablation and drug therapy groups, respectively (p=0.30). The risk of AF recurrence was lower in the ablation group than in the antiarrhythmic drug group (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.45–0.60).19) A greater improvement in quality of life was observed in the ablation group than in the antiarrhythmic drug group.11) Rhythm control therapy was generally safe with low rates of complication in both treatment groups among the elderly study population (mean age: 68 years) of the CABANA trial. Periprocedural complications occurred in 4.8% of patients randomized to ablation, including tamponades (0.8%), hematomas (2.3%), and pseudoaneurysms (1.1%). In the arrhythmic drug therapy group, 0.8% and 1.6% of the patients experienced proarrhythmia and thyroid disorders, respectively.
The Early Aggressive Invasive Intervention for Atrial Fibrillation (EARLY-AF) and Cryoballoon Catheter Ablation in Antiarrhythmic Drug Naive Paroxysmal Atrial Fibrillation (STOP AF First) trials randomized 303 and 203 participants with symptomatic, untreated AF to early cryoballoon ablation or antiarrhythmic drug treatment, respectively.24)25) At 1-year follow-up with an implantable cardiac monitor in the EARLY-AF trial, the recurrence rates of atrial tachyarrhythmia were 42.9% and 67.8% in patients assigned to undergo ablation or to receive antiarrhythmic drugs, respectively.25) In the STOP AF First trial, 74.6% and 45.0% of the ablation and drug therapy groups were free from recurrence of atrial tachyarrhythmia.24) These results suggest that cryoballoon ablation as initial therapy provided a better efficacy of rhythm control than drug therapy among patients with paroxysmal AF.

Atrial fibrillation ablation therapy in patients with heart failure

Restoring and maintaining sinus rhythm has been used to improve the outcomes of AF patients with heart failure. However, use of antiarrhythmic drug therapy or the presence of sinus rhythm is not associated with better clinical outcomes for AF patients with HFrEF in large randomized controlled trials.17)33)34) Relatively small-sized trials reported that AF ablation improved left ventricular systolic function, exercise performance, and brain natriuretic peptide levels in AF patients with HFrEF.35)36)37)38)39)
The Catheter Ablation for Atrial Fibrillation with Heart Failure (CASTLE-AF) trial compared AF ablation with medical therapy, including antiarrhythmic drug treatment and rate control in AF patients with HFrEF (left ventricular ejection fraction [LVEF] <35%).20) Approximately one-third of the patients in the medical therapy group were on antiarrhythmic drug treatments at their final follow-up. Catheter ablation reduced the risk of a composite outcome of all-cause death or hospitalization owing to worsening heart failure by 48%. Twenty-two percent of patients assigned to medical therapy had sinus rhythm at 60 months. In contrast, 63% of the patients in the ablation group had sinus rhythm. These findings are consistent with the findings from a recent study analyzing routine patient data from the Korean National Health Insurance Service (NHIS) database.40) The beneficial association of AF ablation with hard clinical outcomes is consistently observed in the post-hoc analysis of the CABANA trial that included 778 (35%) participants in the New York Heart Association (NYHA) class at least II.41) However, most patients did not have a reduced LVEF. Only 9.3% of the patients for whom the ejection fraction was available had an ejection fraction of <40%. A sub-study of the CASTLE-AF trial reported that lower NYHA classes (I and II) were associated with more favorable clinical outcomes after ablation when compared with higher NYHA classes.42) The benefit of catheter ablation was consistently observed independent of LVEF (<20% vs. 20–34%). These results suggest that catheter ablation might be helpful in the early stages of heart failure symptoms irrespective of LVEF. Further investigations are needed regarding the selection of adequate heart failure patients for AF ablation and the clinical outcomes after AF ablation in patients with heart failure with a preserved ejection fraction.

OPTIMAL TIMING OF RHYTHM CONTROL FOR CARDIOVASCULAR BENEFIT

Early rhythm control and adverse cardiovascular outcomes in atrial fibrillation

AF itself causes adverse electrical and structural atrial remodeling, contributing to the progressive nature of arrhythmia.43) Such AF-related atrial remodeling develops within a few weeks of AF.44)45) Conceptually, early intervention to prevent the remodeling associated with AF might reduce the risk of adverse cardiovascular events. The recently published EAST-AFNET 4 aimed to test the hypothesis that rhythm control therapy initiated early after the AF diagnosis could reduce the risk of adverse events compared with the current practice of delayed rhythm control.46) Two thousand two hundred ninety-six patients with early AF (defined as AF diagnosed ≤1 year before enrollment) and underlying cardiovascular conditions (approximately a congestive heart failure, hypertension, age, diabetes mellitus, prior ischemic stroke or transient ischemic attack or thromboembolism, vascular disease, age, sex category [CHA2DS2-VASc] score ≥2) were enrolled at the 36 median days after AF diagnosis. Patients randomized to the early rhythm control were treated with antiarrhythmic medications (87%) or AF ablation (8%) at initials, and 19% of those patients underwent AF ablation at the 2-year follow-up. The primary outcome was a composite of cardiovascular death, stroke, hospitalization owing to worsening heart failure, or acute coronary syndrome. After the 5.1 years of median follow-up, early rhythm control treatment reduced the risk of the primary composite outcome by 21% compared with usual care (95% CI, 0.66–0.94).21) The absolute reduction of adverse cardiovascular outcomes was 1.1 per 100 patient-years. Among the individual outcomes of the composite outcome, early rhythm control reduced the risks of death from cardiovascular causes (HR, 0.72; 95% CI, 0.52–0.98) and stroke (HR, 0.65; 95% CI, 0.44–0.97).
It is unclear whether the benefit of early rhythm control can be generalized to those in whom rhythm control is performed later after the AF diagnosis. Kim et al.47) investigated whether the results of rhythm control treatments depended on the duration between AF diagnosis and treatment initiation using a nationwide claim-based cohort comprising 22,635 AF adults on anticoagulant therapy in routine clinical practice. Among patients undergoing early AF treatment which was initiated within 1 year after diagnosis, compared with rate control, rhythm control was related to a 19% reduced risk of the primary composite end-point (absolute reduction 1.8 per 100 patient-years) (Figure 1A). However, this beneficial association was not observed in those who had AF for more than 1 year (Figure 1B).
Figure 1

Weighted cumulative incidence curves for individual components of the primary composite outcome in (A) early and (B) late atrial fibrillation treatments. Figure courtesy of Kim et al.47)

AF = atrial fibrillation; CI = confidence interval; HR = hazard ratio.
kcj-52-496-g001

Safety of rhythm control according to the timing of treatment initiation

Rhythm control may be related to clinically significant serious adverse events (SAEs), and concerns regarding SAEs can serve as a barrier for performing rhythm control. Data on the prognostic effect of rhythm control therapy are heterogeneous, without a clear signal for either benefit or harm.31) Kim et al.47) exploited a predictive model to determine the benefit-to-harm ratio of rhythm control compared to rate control. The benefit-to-harm ratio of rhythm control compared with rate control was over one within 1 year after AF diagnosis, suggesting that patients with early rhythm control would benefit than harm (Figure 2A). The benefit-to-harm ratio was decreased to under one when initiating rhythm control treatment later (Figure 2B).48)
Figure 2

Benefit-to-harm ratios of rhythm control compared with rate control according treatment timing. The ratios >1 indicate positive net benefit. Figure courtesy of Kim et al.47)

AF = atrial fibrillation; CI = confidence interval.
kcj-52-496-g002

Optimal treatment timing for better cardiovascular outcomes

Kim et al.47) explored questions about the optimal timing for initiating rhythm control in overall periods beyond the enrollment criteria of EAST-AFNET 4. There was a linearly increasing relationship between rhythm control and worse cardiovascular outcomes with later timing of treatment initiation compared with rate control (Figure 3). Rhythm control was associated with a lower risk of the primary composite outcome when initiated earlier timing after AF diagnosis compared to rate control whereas the HR exceeded one between the treatment timing at 1 and 2 years after AF diagnosis (Figure 3A). Within 1 year since the diagnosis of AF, more earlier treatment timing of rhythm control showed a more favorable outcome relative to rate control (Figure 3B). In contrast, the risk of safety outcomes was not different between the rhythm and rate control treatments, regardless of the treatment timing (Figure 3A and B).
Figure 3

Relation between treatment timing and risk of clinical outcomes for rhythm control or rate control in (A) overall period and (B) within 1 year after the first diagnosis of AF. Figure courtesy of Kim et al.47)

The x-axis shows the timing of treatment initiation since the first diagnosis of AF; the y-axis, HRs associated with rhythm control compared with rate control. The black horizontal lines indicate HR=1, which corresponds to an equal risk of outcomes in patients treated with rhythm and rate control. Dashed black lines show the 95% CI.
AF = atrial fibrillation; CI = confidence interval; HR = hazard ratio.
kcj-52-496-g003

Early rhythm control and individual outcomes

Conceptually, a reduced AF burden may reduce the risk of AF-related adverse cardiovascular outcomes including stroke, heart failure, and myocardial infarction.49)50) However, how early rhythm control should be initiated and for which outcomes we benefit from early rhythm control are unknown. Kim et al.47) recently reported that early rhythm control may reduce the risks of stroke and hospitalization due to heart failure compared with rate control using the Korean NHIS database. They further investigated comparative efficacy of rhythm control versus rate control for reducing individual adverse outcomes stratified by the treatment timing.48) Compared with rate control, rhythm control initiated within 1 year of AF diagnosis decreased the risk of stroke (Figure 4A). The HRs of stroke for rhythm control initiated at selected timings after AF diagnosis were as follows: HR 0.76 at 6 months, HR 0.78 at 1 year, HR 1.00 at 5 years. This result is consistent with that of a post-hoc study of the Placebo-controlled, Double-blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of Cardiovascular Hospitalization or Death from any Cause in Patients with AF/Atrial Flutter (ATHENA) trial, which demonstrated that dronedarone treatment reduced the risk of ischemic and hemorrhagic stroke compared with placebo.18) Two observational studies revealed that rhythm control with antiarrhythmic drugs or catheter ablation was associated with a lower risk of stroke/transient ischemic attack compared with rate control.50)51) The rhythm control performed within 6 months of AF diagnosis was associated with a reduced risk of hospitalization due to heart failure: HR 0.84 at 6 months, HR 0.96 at 1 year, HR 2.88 at 5 years (Figure 4B). There were no differences in the risks of myocardial infarction and death from cardiovascular causes between the strategies of rhythm and rate control, irrespective of the treatment timing (Figure 4C and D).
Figure 4

Relation between treatment timing and risk of ischemic stroke (A), hospitalization owing to heart failure (B), acute myocardial infarction (C), and cardiovascular death (D) for rhythm control or rate control. Figure courtesy of Kim et al.48)

The x-axis shows the timing of treatment initiation since the first diagnosis of atrial fibrillation; the y axis, HRs associated with rhythm control compared with rate control. The skyblue horizontal dotted lines indicate HR=1, which corresponds to an equal risk of outcomes in patients treated with rhythm and rate control. Dashed black lines show the 95% CI.
CI = confidence interval; HR = hazard ratio.
kcj-52-496-g004

OPTIMAL PATIENT SELECTION FOR EARLY RHYTHM CONTROL

Age and the effects of rhythm control

Whether the beneficial effects of early rhythm control can be generalized to older adults is unclear. A subgroup analysis of the AFFIRM trial showed a reduction in mortality associated with rate control than rhythm among those aged between 65 and 80 years.15) Shariff et al.52) performed a propensity score-matched study of the AFFIRM trial participants aged 70–80 years to investigate the comparative effect of rate versus rhythm control strategies on outcomes. They suggested that rate controlled patients were at lower risks of mortality and hospitalization than those with rhythm control among septuagenarians with AF.52) Although there is no specific age discrimination determining the treatment options of rhythm or rate control, including cardioversion and AF catheter ablation in the current guidelines,12)53) age is an independent predictor of procedure-related complications, AF recurrence, adverse cardiac outcomes in patients undergoing ablation procedures.54)55)56)
Kim et al.57) studied whether the benefits from early rhythm control differed with age. There was a linear decrease of the protective effects of early rhythm control over rate control on adverse cardiovascular outcomes with age (Figure 5). A significant interaction between age and early rhythm control was observed at 75 years (p=0.045). Compared with rate control, early rhythm control was associated with a 20% reduced risk of the composite outcome of death from cardiovascular causes, stroke, heart failure-related admission, or myocardial infarction in patients aged <75 years (Figure 6A) but not in patients aged ≥75 years (Figure 6B). This result suggests that early initiation of rhythm control can be adopted preferentially, especially in patients with AF aged <75 years.
Figure 5

Relationship between age at treatment initiation and the risk of the primary composite outcome in early rhythm control and rate control groups. Figure courtesy of Kim et al.57)

The x-axis shows the age at treatment initiation and the y-axis shows HRs associated with rhythm control when compared with rate control. The purple horizontal line indicates HR=1, which corresponds to an equal risk of outcomes in patients treated with rhythm control and rate control. The dashed black lines indicate the 95% CI.
CI = confidence interval; HR = hazard ratio.
kcj-52-496-g005
Figure 6

Weighted cumulative incidence curves for the primary composite outcome in patients aged <75 years (A) and ≥75 years (B) who were recently (within 1 year) diagnosed with atrial fibrillation. Figure courtesy of Kim et al.57)

CI = confidence interval; HR = hazard ratio.
kcj-52-496-g006

The association between the effects of rhythm control and the CHA2DS2-VASc score

The EAST-AFNET 4 included patients with early AF and a CHA2DS2-VASc score of approximately ≥2. We compared the effect of early rhythm control on adverse cardiovascular outcomes between eligible and ineligible patients (CHA2DS2-VASc approximately 0–1) for EAST-AFNET 4 using a nationwide claim database of routine clinical practice to investigate whether the results can be generalized for patients with low stroke risk. Of the included 54,216 participants, 69.3% were eligible for the EAST-AFNET 4 trial (median age: 70 years, median CHA2DS2-VASc: 4), among whom early rhythm control reduced the risk of the primary composite outcome than rate control (HR, 0.86; 95% CI, 0.81–0.92). Among the patients with low risk (30.7%) who failed to meet the inclusion criteria (median age: 54 years, median CHA2DS2-VASc: 1), early rhythm control was consistently associated with a reduced risk of the primary composite outcome (HR, 0.80; 95% CI, 0.66–0.97) (Unpublished data). In routine clinical practice, the beneficial association between early rhythm control and cardiovascular complications was consistent among low-risk patients, regardless of trial eligibility.

The association between the effects of rhythm control and frailty

Frailty is a state of vulnerability defined as an age-associated decline in physiological reserve and function across multiple organ systems, leading to an increasing hazard of adverse outcomes, especially in the elderly.58)59) Frailty is important for estimating risks and aiding diagnosis and care planning in older patients.60) However, it is unclear whether the results of the rate versus rhythm control trials can be generalized for frail elderly adults. We evaluated whether frailty affected the outcomes of early rhythm control in older patients. Although the beneficial association between early rhythm control and cardiovascular outcomes was attenuated with increasing frailty, early rhythm control showed consistent trends toward a lower risk of adverse cardiovascular outcomes without an increased risk of safety outcomes across the different frailty groups (Unpublished data).

The association between the effects of rhythm control and symptom status

In current guidelines, rhythm control therapy is restrictively recommended only among patients with symptomatic AF. In the EAST-AFNET 4, 30% of the patients were asymptomatic at enrollment.21) A similar proportion has been observed in other trials and registries, such as the AFFIRM trial and Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) and Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registries.15)61)62) Recently, Willems et al.63) showed that the benefit of early rhythm control was consistently observed regardless of symptom status in the participants of the EAST-AFNET.

RHYTHM CONTROL AND PREVENTION OF DEMENTIA

Data on the efficacy of various treatments for preventing cognitive decline among patients with AF are unclear. In patients with incident AF, oral anticoagulant use was associated with a 39% lower incidence of dementia.9) Interestingly, Kim et al. reported that compared with warfarin users, direct oral anticoagulant users were at a 22% lower risk of dementia.10) Integrated AF management controlling risk factors was also shown to be associated with a lower risk of dementia.64)65)66)67)

Association of a rhythm control strategy and dementia risk

The effect of rhythm control treatment for AF on cognitive outcomes has been unclear.67)68) A sub-analysis of the AFFIRM trial reported no difference in cognitive function between treatment strategies of rate or rhythm control.69) However, several observational investigations have suggested that AF ablation may improve cognitive function and reduce dementia risk.70)71)72)73)
Recently, Kim et al.74) compared subsequent dementia risk between rhythm control (antiarrhythmic drugs or ablation) and rate control treatment using a Korean nationwide cohort including 41,135 AF participants on anticoagulant therapy. Rhythm control was associated with a 14% lower risk of all-cause dementia, irrespective of overt stroke (absolute reduction 4.0 per 1,000 patient-years) (Figure 7). The beneficial effect of rhythm control on the risk of dementia decreased linearly with increasing age (Figure 8). Performing rhythm control in patients aged under 80 years showed a reduced dementia risk compared with rate control. The protective association between rhythm control and dementia risk was also pronounced in those without heart failure and those with lower CHA2DS2-VASc scores. These results suggest that rhythm control in those with fewer risk factors may help minimize the risk of dementia.
Figure 7

Weighted cumulative incidence curves for all-cause dementia in (A) overall and (B) after censoring stroke. Figure courtesy of Kim et al.74)

CI = confidence interval; sHR = subdistribution hazard ratio.
kcj-52-496-g007
Figure 8

Relation between age at treatment initiation and risk of dementia for rhythm control or rate control. Figure courtesy of Kim et al.74)

The x-axis shows the age at the time of treatment initiation; the y-axis, HR associated with rhythm control compared with rate control. The purple horizontal line indicates HR=1, which corresponds to an equal risk of outcomes in patients treated with rhythm and rate control. Dashed black lines show the 95% CI.
CI = confidence interval; HR = hazard ratio.
kcj-52-496-g008

CONCLUSIONS

The safety of rhythm control treatment has been confirmed in recent randomized trials, including CASTLE-AF, CABANA, and EAST-AFNET 4 and observational studies. Initiating rhythm control early after AF diagnosis was shown to reduce the risk of adverse cardiovascular events compared with rate control; however, this effect of rhythm control was not shown among patients who had AF for more than 1 year. Within 1 year after AF diagnosis, performing rhythm control as early as possible might result in more favorable outcomes, especially in reducing the risks of stroke and hospitalization owing to heart failure. The favorable effects of rhythm control versus rate control were observed irrespective of the estimated stroke risk, frailty, or the symptoms of AF and were more prominent in younger age groups. Furthermore, rhythm control might help prevent dementia incidence compared to rate control, especially for younger AF patients with fewer risk factors. Therefore, rhythm control should be considered at the earliest stage and at a younger age, regardless of the existence of AF-related symptoms.

Notes

Funding: This research was supported by a grant of Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HC19C0130).

Conflict of Interest: The authors have no financial conflicts of interest.

Data Sharing Statement: The data generated in this study are available from the corresponding author(s) upon reasonable request.

Author Contributions:

  • Data curation: Yang PS.

  • Formal analysis: Yang PS.

  • Investigation: Kim D, Joung B.

  • Methodology: Kim D, Yang PS.

  • Resources: Kim D.

  • Supervision: Yang PS, Joung B.

  • Validation: Joung B.

  • Writing - original draft: Kim D, Joung B.

  • Writing - review & editing: Kim D, Yang PS, Joung B.

References

1. Joung B, Lee JM, Lee KH, et al. 2018 Korean guideline of atrial fibrillation management. Korean Circ J. 2018; 48:1033–1080. PMID: 30403013.
crossref
2. Timmis A, Townsend N, Gale CP, et al. European Society of Cardiology: cardiovascular disease statistics 2019. Eur Heart J. 2020; 41:12–85. PMID: 31820000.
3. Lee H, Kim TH, Baek YS, et al. The trends of atrial fibrillation-related hospital visit and cost, treatment pattern and mortality in Korea: 10-year nationwide sample cohort data. Korean Circ J. 2017; 47:56–64. PMID: 28154592.
crossref
4. Kim D, Yang PS, Jang E, et al. 10-year nationwide trends of the incidence, prevalence, and adverse outcomes of non-valvular atrial fibrillation nationwide health insurance data covering the entire Korean population. Am Heart J. 2018; 202:20–26. PMID: 29802976.
crossref
5. Schnabel RB, Yin X, Gona P, et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: a cohort study. Lancet. 2015; 386:154–162. PMID: 25960110.
crossref
6. Kim D, Yang PS, Jang E, et al. Increasing trends in hospital care burden of atrial fibrillation in Korea, 2006 through 2015. Heart. 2018; 104:2010–2017. PMID: 29666179.
crossref
7. Marijon E, Le Heuzey JY, Connolly S, et al. Causes of death and influencing factors in patients with atrial fibrillation: a competing-risk analysis from the randomized evaluation of long-term anticoagulant therapy study. Circulation. 2013; 128:2192–2201. PMID: 24016454.
crossref
8. Camm AJ, Amarenco P, Haas S, et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J. 2016; 37:1145–1153. PMID: 26330425.
crossref
9. Kim D, Yang PS, Yu HT, et al. Risk of dementia in stroke-free patients diagnosed with atrial fibrillation: data from a population-based cohort. Eur Heart J. 2019; 40:2313–2323. PMID: 31212315.
crossref
10. Kim D, Yang PS, Jang E, et al. Association of anticoagulant therapy with risk of dementia among patients with atrial fibrillation. Europace. 2021; 23:184–195. PMID: 33063123.
crossref
11. Mark DB, Anstrom KJ, Sheng S, et al. Effect of catheter ablation vs medical therapy on quality of life among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA. 2019; 321:1275–1285. PMID: 30874716.
crossref
12. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): the Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021; 42:373–498. PMID: 32860505.
13. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation. 2019; 140:e125–e151. PMID: 30686041.
crossref
14. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002; 347:1834–1840. PMID: 12466507.
crossref
15. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002; 347:1825–1833. PMID: 12466506.
crossref
16. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol. 2003; 41:1690–1696. PMID: 12767648.
crossref
17. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008; 358:2667–2677. PMID: 18565859.
crossref
18. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009; 360:668–678. PMID: 19213680.
crossref
19. Packer DL, Mark DB, Robb RA, et al. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA. 2019; 321:1261–1274. PMID: 30874766.
20. Marrouche NF, Brachmann J, Andresen D, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med. 2018; 378:417–427. PMID: 29385358.
crossref
21. Kirchhof P, Camm AJ, Goette A, et al. Early rhythm-control therapy in patients with atrial fibrillation. N Engl J Med. 2020; 383:1305–1316. PMID: 32865375.
crossref
22. Adelstein EC, Althouse AD, Davis L, et al. Amiodarone is associated with adverse outcomes in patients with sustained ventricular arrhythmias upgraded to cardiac resynchronization therapy-defibrillators. J Cardiovasc Electrophysiol. 2019; 30:348–356. PMID: 30575185.
crossref
23. Cosedis Nielsen J, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med. 2012; 367:1587–1595. PMID: 23094720.
crossref
24. Wazni OM, Dandamudi G, Sood N, et al. Cryoballoon ablation as initial therapy for atrial fibrillation. N Engl J Med. 2021; 384:316–324. PMID: 33197158.
crossref
25. Andrade JG, Wells GA, Deyell MW, et al. Cryoablation or drug therapy for initial treatment of atrial fibrillation. N Engl J Med. 2021; 384:305–315. PMID: 33197159.
crossref
26. Kirchhof P, Andresen D, Bosch R, et al. Short-term versus long-term antiarrhythmic drug treatment after cardioversion of atrial fibrillation (Flec-SL): a prospective, randomised, open-label, blinded endpoint assessment trial. Lancet. 2012; 380:238–246. PMID: 22713626.
crossref
27. Gillinov AM, Bagiella E, Moskowitz AJ, et al. Rate control versus rhythm control for atrial fibrillation after cardiac surgery. N Engl J Med. 2016; 374:1911–1921. PMID: 27043047.
28. Pappone C, Augello G, Sala S, et al. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: the APAF Study. J Am Coll Cardiol. 2006; 48:2340–2347. PMID: 17161267.
crossref
29. Jaïs P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation. 2008; 118:2498–2505. PMID: 19029470.
30. Ganesan AN, Shipp NJ, Brooks AG, et al. Long-term outcomes of catheter ablation of atrial fibrillation: a systematic review and meta-analysis. J Am Heart Assoc. 2013; 2:e004549. PMID: 23537812.
crossref
31. Willems S, Meyer C, de Bono J, et al. Cabins, castles, and constant hearts: rhythm control therapy in patients with atrial fibrillation. Eur Heart J. 2019; 40:3793–3799c. PMID: 31755940.
crossref
32. Dinshaw L, Schäffer B, Akbulak Ö, et al. Long-term efficacy and safety of radiofrequency catheter ablation of atrial fibrillation in patients with cardiac implantable electronic devices and transvenous leads. J Cardiovasc Electrophysiol. 2019; 30:679–687. PMID: 30821012.
crossref
33. Talajic M, Khairy P, Levesque S, et al. Maintenance of sinus rhythm and survival in patients with heart failure and atrial fibrillation. J Am Coll Cardiol. 2010; 55:1796–1802. PMID: 20413028.
crossref
34. Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. N Engl J Med. 1999; 341:857–865. PMID: 10486417.
crossref
35. Khan MN, Jaïs P, Cummings J, et al. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med. 2008; 359:1778–1785. PMID: 18946063.
crossref
36. Jones DG, Haldar SK, Hussain W, et al. A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure. J Am Coll Cardiol. 2013; 61:1894–1903. PMID: 23500267.
crossref
37. Hunter RJ, Berriman TJ, Diab I, et al. A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial). Circ Arrhythm Electrophysiol. 2014; 7:31–38. PMID: 24382410.
crossref
38. Di Biase L, Mohanty P, Mohanty S, et al. Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: results from the AATAC multicenter randomized trial. Circulation. 2016; 133:1637–1644. PMID: 27029350.
39. Prabhu S, Taylor AJ, Costello BT, et al. Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction: the CAMERA-MRI study. J Am Coll Cardiol. 2017; 70:1949–1961. PMID: 28855115.
40. Yang PS, Kim D, Sung JH, et al. Reduction of mortality by catheter ablation in real-world atrial fibrillation patients with heart failure. Sci Rep. 2021; 11:4694. PMID: 33633286.
crossref
41. Packer DL, Piccini JP, Monahan KH, et al. Ablation versus drug therapy for atrial fibrillation in heart failure: results from the CABANA trial. Circulation. 2021; 143:1377–1390. PMID: 33554614.
crossref
42. Sohns C, Zintl K, Zhao Y, et al. Impact of left ventricular function and heart failure symptoms on outcomes post ablation of atrial fibrillation in heart failure: CASTLE-AF trial. Circ Arrhythm Electrophysiol. 2020; 13:e008461. PMID: 32903044.
crossref
43. Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ Arrhythm Electrophysiol. 2008; 1:62–73. PMID: 19808395.
44. Kirchhof P, Bax J, Blomstrom-Lundquist C, et al. Early and comprehensive management of atrial fibrillation: executive summary of the proceedings from the 2nd AFNET-EHRA consensus conference ‘research perspectives in AF’. Eur Heart J. 2009; 30:2969–2977c. PMID: 19535417.
crossref
45. Kumagai K, Nakashima H, Urata H, Gondo N, Arakawa K, Saku K. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol. 2003; 41:2197–2204. PMID: 12821247.
crossref
46. Kirchhof P, Breithardt G, Camm AJ, et al. Improving outcomes in patients with atrial fibrillation: rationale and design of the Early treatment of Atrial fibrillation for Stroke prevention Trial. Am Heart J. 2013; 166:442–448. PMID: 24016492.
crossref
47. Kim D, Yang PS, You SC, et al. Treatment timing and the effects of rhythm control strategy in patients with atrial fibrillation: nationwide cohort study. BMJ. 2021; 373:n991. PMID: 33975876.
crossref
48. Kim D, Yang PS, You SC, et al. Comparative effectiveness of early rhythm control versus rate control for cardiovascular outcomes in patients with atrial fibrillation. J Am Heart Assoc. 2021; 10:e023055. PMID: 34889116.
crossref
49. Rolf S, Kornej J, Dagres N, Hindricks G. What can rhythm control therapy contribute to prognosis in atrial fibrillation? Heart. 2015; 101:842–846. PMID: 25792720.
crossref
50. Yang PS, Sung JH, Jang E, et al. Catheter ablation improves mortality and other outcomes in real-world patients with atrial fibrillation. J Am Heart Assoc. 2020; 9:e015740. PMID: 32427022.
crossref
51. Tsadok MA, Jackevicius CA, Essebag V, et al. Rhythm versus rate control therapy and subsequent stroke or transient ischemic attack in patients with atrial fibrillation. Circulation. 2012; 126:2680–2687. PMID: 23124034.
crossref
52. Shariff N, Desai RV, Patel K, et al. Rate-control versus rhythm-control strategies and outcomes in septuagenarians with atrial fibrillation. Am J Med. 2013; 126:887–893. PMID: 24054956.
crossref
53. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2019; 74:104–132. PMID: 30703431.
54. Shah RU, Freeman JV, Shilane D, Wang PJ, Go AS, Hlatky MA. Procedural complications, rehospitalizations, and repeat procedures after catheter ablation for atrial fibrillation. J Am Coll Cardiol. 2012; 59:143–149. PMID: 22222078.
crossref
55. Srivatsa UN, Danielsen B, Anderson I, et al. Risk predictors of stroke and mortality after ablation for atrial fibrillation: the California experience 2005-2009. Heart Rhythm. 2014; 11:1898–1903. PMID: 25048442.
crossref
56. Bunch TJ, May HT, Bair TL, et al. The impact of age on 5-year outcomes after atrial fibrillation catheter ablation. J Cardiovasc Electrophysiol. 2016; 27:141–146. PMID: 26443666.
crossref
57. Kim D, Yang PS, You SC, et al. Age and outcomes of early rhythm control in patients with atrial fibrillation: nationwide cohort study. JACC Clin Electrophysiol. 2022; 8:619–632. PMID: 35589174.
crossref
58. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet. 2013; 381:752–762. PMID: 23395245.
crossref
59. Villacampa-Fernández P, Navarro-Pardo E, Tarín JJ, Cano A. Frailty and multimorbidity: two related yet different concepts. Maturitas. 2017; 95:31–35. PMID: 27889050.
crossref
60. Rockwood K, Theou O, Mitnitski A. What are frailty instruments for? Age Ageing. 2015; 44:545–547. PMID: 25824236.
crossref
61. Gibbs H, Freedman B, Rosenqvist M, et al. Clinical outcomes in asymptomatic and symptomatic atrial fibrillation presentations in GARFIELD-AF: implications for AF screening. Am J Med. 2021; 134:893–901.e11. PMID: 33607088.
crossref
62. Steinberg BA, Gao H, Shrader P, et al. International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries. Am Heart J. 2017; 194:132–140. PMID: 29223431.
crossref
63. Willems S, Borof K, Brandes A, et al. Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial. Eur Heart J. 2022; 43:1219–1230. PMID: 34447995.
crossref
64. Yang PS, Sung JH, Jang E, et al. The effect of integrated care management on dementia in atrial fibrillation. J Clin Med. 2020; 9:9.
crossref
65. Joung B. Risk factor management for atrial fibrillation. Korean Circ J. 2019; 49:794–807. PMID: 31456373.
crossref
66. Kim D, Yang PS, Jang E, et al. Blood pressure control and dementia risk in midlife patients with atrial fibrillation. Hypertension. 2020; 75:1296–1304. PMID: 32172620.
crossref
67. Kim D, Yang PS, Joung B. Prevention of dementia in patients with atrial fibrillation. Korean Circ J. 2021; 51:308–319. PMID: 33821580.
crossref
68. Kim D, Yang PS, Joung B. Lower dementia risk with anticoagulation and ablation in patients with atrial fibrillation. International Journal of Arrhythmia. 2021; 22:17.
crossref
69. Chung MK, Shemanski L, Sherman DG, et al. Functional status in rate- versus rhythm-control strategies for atrial fibrillation: results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Functional Status Substudy. J Am Coll Cardiol. 2005; 46:1891–1899. PMID: 16286177.
crossref
70. Jin MN, Kim TH, Kang KW, et al. Atrial fibrillation catheter ablation improves 1-year follow-up cognitive function, especially in patients with impaired cognitive function. Circ Arrhythm Electrophysiol. 2019; 12:e007197. PMID: 31442075.
crossref
71. Kim D, Yang PS, Sung JH, et al. Less dementia after catheter ablation for atrial fibrillation: a nationwide cohort study. Eur Heart J. 2020; 41:4483–4493. PMID: 33022705.
crossref
72. Bunch TJ, Crandall BG, Weiss JP, et al. Patients treated with catheter ablation for atrial fibrillation have long-term rates of death, stroke, and dementia similar to patients without atrial fibrillation. J Cardiovasc Electrophysiol. 2011; 22:839–845. PMID: 21410581.
crossref
73. Kirchhof P, Haeusler KG, Blank B, et al. Apixaban in patients at risk of stroke undergoing atrial fibrillation ablation. Eur Heart J. 2018; 39:2942–2955. PMID: 29579168.
crossref
74. Kim D, Yang PS, You SC, et al. Association of rhythm control with incident dementia among patients with atrial fibrillation: a nationwide population-based cohort study. Age Ageing. 2022; 51:afab248. PMID: 35061873.
crossref
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