Comparative Effectiveness of Early Rhythm Control Versus Rate Control for Cardiovascular Outcomes in Patients With Atrial Fibrillation.

Background Rhythm control is associated with better cardiovascular outcomes than usual care among patients with recently diagnosed atrial fibrillation (AF). This study investigated the effects of rhythm control compared with rate control on the incidence of stroke, heart failure, myocardial infarction, and cardiovascular death stratified by timing of treatment initiation. Methods and Results We conducted a retrospective population-based cohort study including 22 635 patients with AF newly treated with rhythm control (antiarrhythmic drugs or ablation) or rate control in 2011 to 2015 from the Korean National Health Insurance Service database. Propensity overlap weighting was used. Compared with rate control, rhythm control initiated within 1 year of AF diagnosis decreased the risk of stroke. The point estimates for rhythm control initiated at selected time points after AF diagnosis are as follows: 6 months (hazard ratio [HR], 0.76; 95% CI, 0.66-0.87), 1 year (HR, 0.78; 95% CI, 0.66-0.93), and 5 years (HR, 1.00; 95% CI, 0.45-2.24). The initiation of rhythm control within 6 months of AF diagnosis reduced the risk of hospitalization for heart failure: 6 months (HR, 0.84; 95% CI, 0.74-0.95), 1 year (HR, 0.96; 95% CI, 0.82-1.13), and 5 years (HR, 2.88; 95% CI, 1.34-6.17). The risks of myocardial infarction and cardiovascular death did not differ between rhythm and rate control regardless of treatment timing. Conclusions Early initiation of rhythm control was associated with a lower risk of stroke and heart failure-related admission than rate control in patients with recently diagnosed AF. The effects were attenuated as initiating the rhythm control treatment later.

Atrial Fibrillation Follow‐up Investigation of Sinus Rhythm Management

A 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 Atrial Fibrillation/Atrial Flutter

Early Treatment of AF for Stroke Prevention Trial

National Health Insurance Service

Permanent Atrial Fibrillation Outcome Study

Clinical Perspective

What Is New?

In patients with atrial fibrillation and concomitant cardiovascular conditions, early initiation of rhythm control was associated with a lower risk of stroke and heart failure–related admission than rate control.

What Are the Clinical Implications?

The results call for shared decision‐making regarding the benefits of rhythm‐control therapy on cardiovascular outcomes in patients recently diagnosed with atrial fibrillation.

Atrial fibrillation (AF) increases the risk of mortality and morbidity caused by stroke and congestive heart failure (HF) and impairs quality of life. , , Previous randomized trials comparing rhythm‐control and rate‐control strategies, including the landmark AFFIRM (Atrial Fibrillation Follow‐up Investigation of Sinus Rhythm Management), have reported no significant differences between the treatment strategies with respect to mortality and stroke incidence. , , Similarly, a meta‐analysis of 5 randomized trials comparing the rhythm‐control strategy with the rate‐control strategy indicated no significant differences of the risk for all‐cause mortality, although the results appeared to favor the rate‐control strategy.

By contrast, recent studies have revealed that rhythm control is associated with a lower risk of adverse cardiovascular outcomes than usual care among patients with recently (within 1 year) diagnosed AF. , EAST‐AFNET 4 (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) revealed that patients randomly assigned to receive early rhythm control had a low risk of death attributable to cardiovascular causes, stroke, and hospitalization for the worsening of HF or acute coronary syndrome, as well as a low risk of individual components of death attributable to cardiovascular causes and stroke. Principally, a restored and maintained sinus rhythm with reduced AF burden is expected to reduce the risk of stroke, HF, and other cardiovascular outcomes and result in a good prognosis. , However, how early should we start rhythm control and which individual cardiovascular outcomes are improved by the early rhythm control are unclear. This study examined the comparative effectiveness of rhythm control versus rate control on cardiovascular outcomes stratified by the timing of treatment initiation.

METHODS

This study is a retrospective analysis based on the national health claims database established by the National Health Insurance Service (NHIS) of Korea. All data and materials have been made publicly available at the NHIS of Korea. The data can be accessed on the National Health Insurance Data Sharing Service homepage of the NHIS (http://nhiss.nhis.or.kr). Applications to use the NHIS data will be reviewed by the inquiry committee of research support and, once approved, raw data will be provided to the authorized researcher for a fee at several permitted sites. A majority (97.1%) of the Korean population mandatorily subscribes to the NHIS, which is a single insurer managed by the Korean government, with the remaining 3% categorized as medical aid patients. As the database also includes information of the medical aid population, it can be considered to represent the entire Korean population. This study was approved by the institutional review board of the Yonsei University Health System (4‐2016‐0179). The requirement for informed consent was waived because personal identification information was removed after cohort generation, in accordance with strict confidentiality guidelines. The NHIS database includes information on drug prescriptions for the entire Korean population from January 1, 2002, which provides a minimum look‐back period of 9.5 years before each individual’s date of inclusion (the earliest date of inclusion was July 28, 2011).

Cohort Design and Study Population

The details of the study protocol are presented in Table S1. We identified adults (age ≥18 years) with AF who were treated with rhythm‐ or rate‐control strategies between July 28, 2011, and December 31, 2015, and who were aged >75 years, had a history of a transient ischemic attack or stroke, or met 2 of the following criteria: age >65 years, female sex, HF, hypertension, diabetes, previous myocardial infarction (MI), or chronic kidney disease, using a similar inclusion period and criteria as EAST‐AFNET 4. AF was defined according to the International Classification of Diseases, Tenth Revision (ICD‐10), code I48. The diagnosis of AF has previously been validated in the NHIS database with a positive predictive value of 94.1%. We used a new‐user and intention‐to‐treat design for rhythm‐ or rate‐control treatments. New users were defined as those with no previous records of prescriptions or procedures of interest in the database. Intention to treat with rhythm control was defined as a prescription of a >90‐day supply of any rhythm‐control drugs in the 180‐day period since the first prescription or performance of an ablation procedure for AF. Intention‐to‐treat with rate control was defined as a prescription of a >90‐day supply of any rate‐control drugs in the 180‐day period since the first prescription, with no prescriptions of rhythm‐control drugs and ablation within this period. Patients who were prescribed rhythm‐control drugs for >90 days or who underwent ablation within the 180‐day period since the initiation of rate‐control drugs were classified into the intention‐to‐treat with rhythm control group (n=8350). Rhythm‐ and rate‐control drugs and claim codes for ablation procedures are presented in Table S2. This study excluded patients without a prescription of a >90‐day supply of warfarin or a direct oral anticoagulant within the 180‐day period since the initiation of rhythm‐ or rate‐control drugs or the performance of an ablation procedure for AF and those who died within 180 days of the first record of a prescription or procedure (Figure 1A).

Figure 1

Flowchart of the enrollment and analysis of the study population (A) and initial choice of rhythm‐control treatments (B).

*Older than 75 years, had a previous transient ischemic attack or stroke, or met 2 of the following criteria: age >65 years, female sex, heart failure, hypertension, diabetes, history of myocardial infarction, and chronic kidney disease. †Patients prescribed rhythm control drugs for >90 days or those who underwent ablation within the 180‐day period since the initiation of rate‐control drugs were classified as intention to treat with rhythm control. ‡Ablations performed within 180 days after the initial prescription of rhythm‐control drugs were classified as initial choices for rhythm control. AF indicates atrial fibrillation.

Outcome and Covariates

We investigated the individual components of the primary composite outcome of EAST‐AFNET 4: ischemic stroke, hospitalization cause by HF, acute MI, and cardiovascular death. Detailed definitions of the outcomes are presented in Table S3. The study outcomes were followed up from 180 days after the first recorded prescription or procedure. Patients were followed up until the occurrence of study outcomes, death, or the end of the study period (December 31, 2016), whichever came earliest. Each clinical outcome was analyzed independently of the other without being censored.

We obtained information regarding selected baseline comorbid conditions for the look‐back period from January 1, 2002, up to the start of therapy from inpatient and outpatient hospital diagnoses and pharmacy claims. The patients were considered to have comorbidities when the condition was a discharge diagnosis or was confirmed at least twice in an outpatient setting (Table S2). The Hospital Frailty Risk score was calculated retrospectively using 109 ICD‐10 diagnostic codes, which were found to be associated with frailty. The baseline relative economic status was determined based on the health insurance premiums in the index year. Concurrent use of medication was verified by identifying NHIS database claims and defined as a prescription of a >90‐day supply of the medication within the 180 days of the first record of a prescription or procedure for rhythm‐ or rate‐control therapies.

Statistical Analysis

Descriptive statistics were used to describe baseline characteristics. Overlap weighting based on a propensity score was used to assess the differences in baseline characteristics between the rhythm‐control and rate‐control groups. The propensity score, which represents the probability of receiving rhythm control, was estimated using logistic regression based on sociodemographic factors, time from AF diagnosis, year of therapy initiation, level of care at which the prescription was provided, clinical risk scores, medical history, and concurrent medication use (variables in Table). Continuous variables were modeled as cubic spline functions. The distribution of propensity scores before and after overlap weighting is shown in Figure S1. The overlap weight was calculated as 1 minus the propensity score for patients who received rhythm control, and as the propensity score for patients who received rate control, to obtain estimates representing the average treatment effects in the population with a minimized asymptotic variance of the treatment effect and desirable exact balance property. The balance between the treatment populations was evaluated by standardized differences of all baseline covariates using a threshold of 0.1 to indicate imbalance. Competing risk regression by Fine and Gray was used to consider all‐cause death as a competing event when estimating the relative hazards of clinical outcomes. Cofactors that had not been balanced by weighting were included as covariates in the competing risk regression. The proportional hazards assumption was tested based on Schoenfeld residuals. To explore the treatment timing–dependent effect of rhythm control on the cardiovascular outcomes, Cox proportional hazards models were fit to the entire weighted study population using an interaction term for treatment timing after AF diagnosis (modeled as a natural spline) and treatment (rhythm‐control or rate‐control strategy). Standard errors were computed using 1000 bootstrap replicates. Two‐sided P values of <0.05 were considered significant. Statistical analyses were conducted using SAS version 9.3 (SAS Institute Inc) and R version 3.6.0 (The R Foundation, www.R‐project.org).

Table 1

Baseline Characteristics of Patients Receiving Rhythm‐ and Rate‐Control Treatments Before and After Overlap Weighting

Variables	Before overlap weighting			After overlap weighting
	Rhythm control (n=13 653)	Rate control (n=8982)	ASD, %	Rhythm control (n=13 653)	Rate control (n=8982)	ASD, %
Sociodemographic
Age, y	68 (60–75)	72 (64–78)	25.5	70 (62–76)	71 (62–77)	<0.1
<65 y	4795 (35.1)	2334 (26.0)	19.9	29.7	29.7	<0.1
65–74 y	5279 (38.7)	3160 (35.2)	7.2	37.1	37.1	<0.1
≥75 y	3579 (26.2)	3488 (38.8)	27.2	33.1	33.1	<0.1
Men	7364 (53.9)	4836 (53.8)	0.2	54.7	54.7	<0.1
AF duration, mo	1.3 (0.0–31.5)	0.0 (0.0–5.3)	28.2	0.6 (0.0–13.6)	0.1 (0.0–14.7)	<0.1
Early AF (initiating treatment within 1 y after diagnosis)	9246 (67.7)	7077 (78.8)	25.2	74.2	73.6	1.3
Enrollment year
2011	941 (6.9)	581 (6.5)	1.7	6.3	6.3	<0.1
2012	2352 (17.2)	1697 (18.9)	4.3	18.1	18.1	<0.1
2013	2859 (20.9)	1974 (22.0)	2.5	21.4	21.4	<0.1
2014	3288 (24.1)	2032 (22.6)	3.5	23.1	23.1	<0.1
2015	4213 (30.9)	2698 (30.0)	1.8	31.1	31.1	<0.1
High tertile of income	6563 (48.1)	3840 (42.8)	10.7	44.8	44.8	<0.1
No. of OPD visits ≥12 per y	11 812 (86.5)	6968 (77.6)	23.4	81.7	81.7	<0.1
Living in metropolitan areas	6473 (47.4)	3778 (42.1)	10.8	44.7	44.7	<0.1
Level of care initiating treatment
Tertiary	8570 (62.8)	3633 (40.4)	45.8	50.1	50.1	<0.1
Secondary	4661 (34.1)	4604 (51.3)	35.1	44.6	44.6	<0.1
Primary	422 (3.1)	745 (8.3)	22.6	5.3	5.3	<0.1
Risk scores
CHA2DS2‐VASc	4 (3–5)	4 (3–5)	4.3	4 (3–5)	4 (3–5)	<0.1
HAS‐BLED*	3 (2–3)	3 (2–3)	19.7	3 (2–3)	3 (2–3)	<0.1
Charlson comorbidity index	4 (3–6)	3 (2–5)	33.9	4 (2–6)	4 (2–6)	<0.1
Hospital Frailty Risk Score	2.8 (0.3–6.8)	2.8 (0.1–7.0)	2.4	3.0 (0.5–7.1)	2.9 (0.3–7.1)	<0.1
Medical history
HF	7431 (54.4)	4933 (54.9)	1.0	54.9	54.9	<0.1
Previous hospitalization for HF	1835 (13.4)	1368 (15.2)	5.1	14.5	14.5	<0.1
Hypertension	11 923 (87.3)	6094 (67.8)	48.0	80.3	80.3	<0.1
Diabetes	4336 (31.8)	2310 (25.7)	13.4	29.6	29.6	<0.1
Dyslipidemia	11 990 (87.8)	6934 (77.2)	28.2	83.4	83.4	<0.1
Ischemic stroke	4423 (32.4)	3295 (36.7)	9.0	35.8	35.8	<0.1
Transient ischemic attack	1643 (12.0)	785 (8.7)	10.8	10.4	10.4	<0.1
Hemorrhagic stroke	387 (2.8)	249 (2.8)	0.4	2.9	2.9	<0.1
MI	1510 (11.1)	605 (6.7)	15.2	8.6	8.6	<0.1
Peripheral arterial disease	2363 (17.3)	1076 (12.0)	15.1	14.6	14.6	<0.1
Valvular heart disease	1568 (11.5)	1047 (11.7)	0.5	11.5	11.5	<0.1
Chronic kidney disease	1113 (8.2)	428 (4.8)	13.8	6.3	6.3	<0.1
Proteinuria	1041 (7.6)	613 (6.8)	3.1	7.5	7.5	<0.1
Hyperthyroidism	2074 (15.2)	751 (8.4)	21.3	10.8	10.8	<0.1
Hypothyroidism	2177 (15.9)	905 (10.1)	17.5	12.4	12.4	<0.1
Malignancy	3467 (25.4)	2067 (23.0)	5.6	24.7	24.7	<0.1
Chronic obstructive pulmonary disease	4471 (32.7)	2776 (30.9)	4.0	32.3	32.3	<0.1
Chronic liver disease	6330 (46.4)	3388 (37.7)	17.6	41.9	41.9	<0.1
Hypertrophic cardiomyopathy	311 (2.3)	94 (1.0)	9.6	1.5	1.5	<0.1
Osteoporosis	4930 (36.1)	3154 (35.1)	2.1	35.6	35.6	<0.1
Sleep apnea	99 (0.7)	34 (0.4)	4.7	0.5	0.5	<0.1
Concurrent medication
Oral anticoagulant	13 653 (100.0)	8982 (100.0)	<0.1	100.0	100.0	<0.1
Warfarin	10 950 (80.2)	7525 (83.8)	9.3	82.4	82.4	<0.1
Direct oral anticoagulant	3464 (25.4)	1955 (21.8)	8.5	23.3	23.3	<0.1
β‐Blocker	6524 (47.8)	6481 (72.2)	51.4	69.2	69.2	<0.1
Nondihydropyridine CCB	1759 (12.9)	1377 (15.3)	7.0	16.3	16.3	<0.1
Digoxin	1106 (8.1)	2927 (32.6)	63.9	18.3	18.3	<0.1
Aspirin	3015 (22.1)	1662 (18.5)	8.9	20.3	20.3	<0.1
P2Y12 inhibitor	1279 (9.4)	759 (8.5)	3.2	9.3	9.3	<0.1
Statin	6213 (45.5)	3952 (44.0)	3.0	46.0	46.0	<0.1
Dihydropyridine CCB	2897 (21.2)	1170 (13.0)	21.9	16.4	16.4	<0.1
ACEI/ARB	7329 (53.7)	4767 (53.1)	1.2	53.3	53.3	<0.1
Loop/thiazide diuretics	5536 (40.5)	4715 (52.5)	24.1	46.8	46.8	<0.1
K+‐sparing diuretics	1970 (14.4)	2105 (23.4)	23.1	19.0	19.0	<0.1
α‐Blocker	290 (2.1)	169 (1.9)	1.7	1.9	1.9	<0.1

Values are presented as median (interquartile range) or number (percentage) unless otherwise indicated. ACEI indicates angiotensin‐converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; ASD, absolute standardized difference; CCB, calcium channel blocker; HF, heart failure; MI, myocardial infarction; and OPD, outpatient department.

A liable international normalized ratio was not assessed.

Sensitivity Analysis

First, we performed analyses in analogy to the on‐treatment principle by censoring patients who switched to another treatment strategy or discontinued their treatment (censored at the time of switch or discontinuation). Second, one‐to‐one propensity score matching (without replacement with a calliper of 0.01) was used instead of overlap weighting. The balance of covariates after matching is shown in Table S4. Third, we performed stratified analysis based on whether the patients undergoing rhythm control were treated with catheter ablation or antiarrhythmic drugs, comparing each group with the patients undergoing rate control. Fourth, we conducted a separate propensity score overlap weighting analysis on restricted patients with access to anticoagulants covering at least 80% of the time at risk during follow‐up. Fifth, we performed “falsification analysis” to measure systematic bias in this study by employing 45 prespecified falsification end points, with true hazard ratios (HRs) of 1. Detailed definitions of the falsification end points are presented in Table S5.

RESULTS

Patient Characteristics

In total, 9246 of 13 653 (67.7%) patients started receiving rhythm‐control therapy within 1 year of AF diagnosis (early rhythm control). In contrast, 7077 of 8982 (78.8%) patients started receiving rate‐control therapy within 1 year of AF diagnosis (early rate control) (Table). The most commonly used rhythm‐control drug was the class III drug amiodarone (40.4%), followed by class Ic drugs (Figure 1B). Ablation was the initial rhythm‐control strategy in 5.7% of patients and was eventually performed during follow‐up in 11.0% of the patients in the rhythm‐control group.

Patients in the rhythm‐control group were more likely to have comorbidities such as hypertension, diabetes, vascular disease, and chronic kidney disease and less likely to have a history of HF‐related admission and ischemic stroke than patients in the rate‐control group. After overlap weighting, all baseline characteristics were similar between the 2 groups (Table).

Stroke

During the mean follow‐up of 2.3±1.3 years, 1419 patients experienced stroke: 715 (5.2%) in the rhythm‐control group and 704 (7.8%) in the rate‐control group. The rhythm‐control strategy was associated with a reduction in stroke incidence compared with the rate‐control strategy (2.80 versus 3.65 events per 100 person‐years; HR, 0.77 [95% CI, 0.65–0.92]; P=0.004) (Figure 2). The rhythm‐control strategy was consistently associated with a reduction in stroke incidence compared with the rate‐control strategy in on‐treatment analysis and after propensity score matching (Figure 2). The weighted cumulative incidence curves showed that the cumulative incidence of stroke was significantly lower in the rhythm‐control group than in the rate‐control group (log‐rank P<0.001) (Figure 3A).

Figure 2

Cardiovascular outcomes in patients receiving rhythm‐ and rate‐control treatments.

Event rates are per 100 person‐years. *Incidences and hazard ratios are overlap weighted.

Figure 3

Weighted cumulative incidence curves for ischemic stroke (A) and hospitalization for heart failure (B).

 

Cox proportional hazard models using an interaction term showed that compared with rate control, rhythm control initiated within 16 months after AF diagnosis decreased the risk of ischemic stroke. No difference in the risk of stroke was found between the rhythm‐ and rate‐control strategies initiated after the 16 months of AF diagnosis (Figure 4A). Compared with rate control, rhythm control showed the following point estimates at selected time points after AF diagnosis: 6 months (HR, 0.76; 95% CI, 0.66–0.87), 1 year (HR, 0.78; 95% CI, 0.66–0.93), and 5 years (HR, 1.00; 95% CI, 0.45–2.24) (Figures 4A and 5). The benefit of early rhythm control for stroke risk was consistently observed in on‐treatment analysis and after propensity score matching (Figure 5 and Figure S2A).

Figure 4

Relationship between treatment timing and risk of ischemic stroke (A) and hospitalization owing to heart failure (B) for rhythm control or rate control.

The x‐axis shows the timing of treatment initiation since the first diagnosis of atrial fibrillation, and the y‐axis, the hazard ratios (HRs) associated with rhythm control compared with rate control. The sky blue horizontal dotted lines indicate an HR of 1, which corresponds to an equal risk of outcomes in patients treated with rhythm and rate control. Dashed black lines show the 95% CI.

Figure 5

Point estimates of rhythm control compared with rate control for cardiovascular outcomes according to timing of treatment initiation.

AF indicates atrial fibrillation. Values are presented as hazard ratios (95% CIs).

HF‐Related Hospitalization

After overlap weighting, 608 (2.7%) patients were found to have been hospitalized owing to HF during follow‐up: 285 (1.3%) in the rhythm‐control group and 323 (1.4%) in the rate‐control group. The rhythm‐control strategy was associated with a reduction in HF‐related hospitalization incidence compared with the rate‐control strategy (3.62 versus 4.20 events per 100 person‐years; HR, 0.84 [95% CI, 0.75–0.94]; P=0.002) (Figure 2). This finding was consistently observed in on‐treatment analysis and after propensity score matching (Figure 2). The weighted cumulative incidence curves showed that the cumulative incidence of HF‐related hospitalization was significantly lower in the rhythm‐control group than in the rate‐control group (log‐rank P=0.009) (Figure 3B).

Cox proportional hazard models using an interaction term showed that rhythm control initiated within 7 months of AF diagnosis decreased the incidence of HF‐related hospitalization compared with rate control (Figure 4B). Rhythm control showed the following point estimates at selected time points after AF diagnosis: 6 months (HR, 0.84; 95% CI, 0.74–0.95), 1 year (HR, 0.96; 95% CI, 0.82–1.13), and 5 years (HR, 2.88; 95% CI, 1.34–6.17) (Figures 4B and 5). The benefit of initiating rhythm control within 6 months of AF diagnosis was consistently observed in on‐treatment analysis and after propensity score matching (Figure 5 and Figure S2B).

MI and Cardiovascular Death

In the overall weighted patients, rhythm control was not associated with a reduced risk of acute MI or cardiovascular death (Figure 2). Rhythm control initiated within 3 months of AF diagnosis was associated with a reduced risk of acute MI, with an HR of 0.59 (95% CI, 0.37–0.94) at 1 month after AF diagnosis (Figures 5 and 6A); however, the benefit of early rhythm control was not consistently observed in on‐treatment analysis and propensity score–matched analysis (Figure 5). Early rhythm control did not reduce the incidence of cardiovascular death compared with early rate control (Figures 5 and 6B).

Figure 6

Weighted cumulative incidence curves and relation between treatment timing and risk of acute myocardial infarction (A) and cardiovascular death (B).

HR indicates hazard ratio.

Overall, the beneficial association of rhythm control with stroke and HF‐related hospitalization compared with rate control was more prominent for patients undergoing catheter ablation than for patients treated with antiarrhythmic drugs (Table S6). Regardless of the initial choice of rhythm‐control treatments (catheter ablation or antiarrhythmic drugs), we consistently observed trends toward lower risks of outcomes for rhythm control initiated earlier (Figure S3). Enrolling only patients taking oral anticoagulants, at least 80% of their follow‐up period (67.0% of the study population) showed consistent findings with the main results (Table S7 and Figure S4). In the analyses of 45 falsification end points, the 95% CIs of the associations of rhythm‐control with each end point covered 1 in 45 (100%) end points (Table S8).

DISCUSSION

In this study, the initiation of rhythm control, rather than that of rate control, within 1 year of AF diagnosis was associated with a decreased risk of ischemic stroke. The initiation of rhythm control within 6 months of AF diagnosis was associated with a decreased risk of HF‐related hospitalization. Furthermore, no differences were found in the incidence of acute MI and cardiovascular death between the 2 groups, regardless of the timing of treatment.

Lower Risks of Stroke and HF Hospitalization by Early Rhythm Control

In EAST‐AFNET 4, early rhythm control lowered the risk of stroke by 35% compared with usual care. Consistently, Kim et al reported that the risk of stroke can be decreased 26% by early rhythm‐control therapy rather than by rate‐control therapy. In this study, rhythm control was associated with less frequent stroke events and a lower risk of stroke when initiated within 16 months of AF diagnosis. This result is in line with that of a post hoc analysis of ATHENA (A 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 Atrial Fibrillation/Atrial Flutter), which demonstrated that dronedarone use was associated with a significant reduction in the risk of ischemic and hemorrhagic stroke. In population‐based observational cohort studies, rhythm control with antiarrhythmic drugs or catheter ablation was associated with lower rates of stroke/transient ischemic attack than rate‐control therapy. ,

In EAST‐AFNET 4, early rhythm control showed a trend of reduction in the incidence of hospitalization for worsening of HF, without statistical significance. Kim et al assessed real‐world data and reported that early rhythm control might be associated with a reduction in the risk of hospitalization for HF. In this study, rhythm control was associated with a lower risk of hospitalization for HF when initiated within 7 months of AF diagnosis. A large US cohort study reported that patients with AF who undergo ablation have a significantly lower risk of long‐term HF than those who do not undergo ablation. In a randomized controlled trial, catheter ablation for AF was associated with significantly lower rates of a composite end point of all‐cause death and hospitalization for worsening HF in patients with HF and reduced ejection fraction. The association between antiarrhythmic drug treatment and HF is not well known. However, dronedarone use was associated with a decreased incidence of hospitalization for HF in ATHENA, without statistical significance, owing to the small number of events. In contrast, the results of PALLAS (Permanent Atrial Fibrillation Outcome Study) using dronedarone in addition to standard therapy indicated that dronedarone use increased the rates of HF, stroke, and death attributable to cardiovascular causes in patients with permanent AF at risk for major vascular events. Consistently, we observed trends in favor of the rate‐control strategy when therapy initiation was delayed.

The association between early rhythm control and lower cardiovascular mortality in this study was less prominent than that in EAST‐AFNET 4, which might be explained by a relatively shorter follow‐up period (median, 2.5 versus 5.1 years in EAST‐AFNET 4). Also, the low proportion of ablation as the initial choice for rhythm control (5.7%) in this study might contribute to the discrepant findings. The association between early rhythm control and acute MI has not been observed in previous studies. ,

Mechanism

Precise mechanisms by which early rhythm control confers benefits were not assessed in this clinical observational study; however, early rhythm control may be associated with an early impact on electrical and substrate remodeling. In addition, patients receiving rhythm control may have had a more careful, structured follow‐up; however, in that case, we would have observed benefits in both the early and late rhythm‐control subgroups. Contemporary rhythm‐control treatments use antiarrhythmic drugs that are better tolerated and safer than those used (ie, class Ia agents) in trials comparing rate‐control versus rhythm‐control strategies 2 to 3 decades ago. Yang et al reported that no difference in survival, cardiovascular hospitalization incidence, or ischemic stroke incidence was found between patients with diagnosed AF within 6 months of study enrollment who were treated with rate control and rhythm control in AFFIRM. In addition, they concluded that the superiority of the rhythm‐control strategy reported in recent AF trials may be more attributable to the refinement of AF therapies and less related to the timing of intervention. Although rhythm control included all major antiarrhythmic drugs and ablation in this study, both dronedarone and ablation are not popular choices for treatment of AF (dronedarone, 1.9%; ablation, 5.7%) (Figure 1B). These findings suggest that the favorable outcomes of rhythm control, which were only observed in patients with AF who started treatment shortly after diagnosis, could not be fully explained by the use of a promising drug or ablation, which may not have been available in previous trials, and might be associated with the timing of treatment.

Study Limitations

The present study has several limitations. In this study, data from a claims‐based database were used; hence, the burden of AF (rhythm status) was not evaluated. Thus, the role of AF burden, a contributor to outcomes, remains unknown. We defined AF diagnoses and ablation cases using only ICD‐10 or claim codes, and, therefore, data regarding AF type (paroxysmal versus nonparoxysmal) or symptoms (symptomatic versus asymptomatic) were not available. The findings from this observational study cannot be used to establish causal relationships, and residual confounding may persist even after propensity score weighting or matching. However, the results of the falsification analysis revealed that the presence of significant systematic bias was less likely. We were unable to determine the exact reasons for the selection of the rhythm‐control strategy over the rate‐control strategy, which may introduce potential bias, and the unmeasured confounders (quality of anticoagulation therapy and lifestyle factors such as obesity, alcohol intake, and physical activity) may have influenced the findings. Nonetheless, we identified sufficient overlap of propensity scores between the groups, which represents the existence of equipoise between the 2 therapies. The proportion of ablation as the initial choice for rhythm control was low. Ablation is permitted and reimbursed by national health insurance only in patients with documented AF after undergoing antiarrhythmic drug treatment for more than 6 weeks. As first‐line treatment, ablation is reimbursed only in those who cannot tolerate antiarrhythmic drugs owing to tachycardia‐bradycardia syndrome or other conditions. Thus, the proportion of patients treated with catheter ablation at baseline (within 180 days after the initiation of rhythm control) is low (5.7%). The proportion was increased, however, to 11.0% at the end of follow‐up, which was comparable to the 7% (as an initial choice) and 19.4% (at 2 years after randomization) in EAST‐AFNET 4. Because of the active‐comparator design of this study, asymptomatic patients with AF who did not require therapy may have been excluded. In addition, because of the new‐user design, according to which prevalent drug users at the time of AF diagnosis were excluded, the proportions of treatment strategies selected for patients with AF in this study may not fully reflect the preferences in real‐world clinical practice. Last, this study enrolled only high‐risk patients with a median CHA2DS2‐VASc score of 4 using similar inclusion criteria as EAST‐AFNET 4. Thus, further investigation is warranted to shed light on the effects of early rhythm control in patients with low risk.

CONCLUSIONS

In this population‐based sample of patients with AF, the initiation of early rhythm control was found to reduce the incidence of ischemic stroke and HF‐related hospitalization in patients with AF compared with that of rate control. However, the effects of rhythm control were attenuated when initiating the treatments later.

Sources of Funding

This research was supported by a grant from the Patient‐Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (grant numbers: HI19C0481, HC19C013, and HI15C1200).

Disclosures

Dr Lip has served as a consultant for Bayer/Janssen, BMS/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Novartis, Verseon, and Daiichi‐Sankyo; and as a speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi‐Sankyo. No fees have been directly or personally received. Dr Joung has served as a speaker for Bayer, BMS/Pfizer, Medtronic, and Daiichi‐Sankyo; and received research funds from Medtronic and Abbott. No fees have been directly or personally received. The remaining authors have no disclosures to report.

Tables S1–S8

Figures S1–S4

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