Different Determinants of the Recurrence of Atrial Fibrillation and Adverse Clinical Events in the Mid-Term Period After Atrial Fibrillation Ablation

Abstract

Background: It is unclear whether there are differences in the clinical factors between atrial fibrillation (AF) recurrence and adverse clinical events (AEs), including stroke/transient ischemic attack (TIA), major bleeding, and death, after AF ablation.

Methods and Results: We examined the data from a retrospective multicenter Japanese registry conducted at 24 cardiovascular centers between 2011 and 2017. Of the 3,451 patients (74.1% men; 63.3±10.3 years) who underwent AF ablation, 1,046 (30.3%) had AF recurrence and 224 (6.5%) suffered AEs (51 strokes/TIAs, 71 major bleeding events, and 36 deaths) over a median follow-up of 20.7 months. After multivariate adjustment, female sex, persistent and long-lasting persistent AF (vs. paroxysmal AF), and stepwise increased left atrial diameter (LAd) quartiles were significantly associated with post-ablation recurrences. A multivariate analysis revealed that an age ≥75 years (vs. <65 years), body weight <50 kg, diabetes, vascular disease, left ventricular (LV) ejection fraction <40% (vs. ≥50%), Lad ≥44 mm (vs. <36 mm), and creatinine clearance <50 mL/min were independently associated with AE incidences, but not with recurrences.

Conclusions: This study disclosed different determinants of post-ablation recurrence and AEs. Female sex, persistent AF, and enlarged LAd were determinants of post-ablation recurrence, whereas an old age, comorbidities, and LV and renal dysfunction rather than post-ablation recurrence were AEs determinants. These findings will help determine ablation indications and post-ablation management.

Pulmonary vein isolation (PVI) is an accepted therapy for atrial fibrillation (AF),¹ and is widely performed worldwide. Development of ablation and mapping systems has increased the efficacy and safety of AF ablation.^2,3 Recent observational studies comparing matched or adjusted patients who did and did not undergo ablation,^4–6 and several randomized control trials^7–9 have reported that AF ablation not only relieves symptoms but also reduces the incidence of adverse clinical events (AEs) including strokes, heart failure (HF) readmissions, and death. Nonetheless, AF recurrence remains a major issue, with reported annual rates of 14–30% for paroxysmal AF and >30% for persistent and long-lasting persistent AF,^2,3,6 and it affects the beneficial clinical outcomes.^5,8 From this standpoint, many physicians and researchers have sought to explore the predictors of post-ablation AF recurrence,^10–12 but it remains unclear which factor for AEs is most robust: post-ablation AF recurrence itself, confounders related to AF recurrence, or other factors beyond AF recurrence. We therefore aimed to clarify the major determinants of both AF recurrence and AEs, including cardiovascular events, major bleeding, and death post-ablation.

Editorial p 243

Methods

Study Patients

Patients included in this substudy were enrolled in a retrospective multicenter Japanese AF registry called the “Atrial Fibrillation registry to Follow the long-teRm Outcomes and use of aNTIcoagulants aftER Ablation (AF Frontier Ablation Registry)”. The 3,530 patients who underwent AF catheter ablation at 24 cardiovascular centers in Japan were enrolled in August 2011 and followed up until July 2017 (UMIN Clinical Trials Registry: UMIN000026849).¹³ Data of consecutive patients (median number: 100 [range 47–443] patients) were collected in each center, amounting to 3,530 patients. Of these, 79 were lost to follow-up, leaving a total of 3,451 for inclusion in this study. The patients’ anonymized clinical data were used for research purposes by the opt-out method. The registry was approved by the Institutional Review Board (IRB) of Nihon University Itabashi Hospital, Clinical Research Judging Committee and the participating hospitals’ IRBs. This study was conducted in accordance with the principles of the Declaration of Helsinki, the Ethical Guidelines for Clinical Studies from the Japanese Ministry of Health, Labour and Welfare, and all applicable laws in Japan.

Data Collection

Registry records were reviewed for the following information: age, sex, body weight and body mass index (BMI), AF type, any comorbidity (hypertension, diabetes [defined as use of an oral hypoglycemic agent or insulin or a glycosylated hemoglobin (Hb) level ≥6.5%], history of a stroke/transient ischemic attack (TIA), HF, and vascular disease including coronary artery disease [CAD: previous myocardial infarction [MI] or angina pectoris], peripheral artery disease [PAD], and aortic atherosclerosis), oral anticoagulant [OAC] type, type of direct OAC [DOAC] used, use of an antiplatelet drug and/or antiarrhythmic drug [AAD], Hb concentration and creatinine clearance (CrCl) at the time of registry enrollment, number of ablation sessions (1 or ≥2), transthoracic echocardiography-derived LA diameter (LAd), left ventricular ejection fraction (LVEF), and ablation method (radiofrequency [RF], cryoballoon, or hotballoon ablation).

Ablation Protocol

For patients who underwent ablation, generally OACs were continued up to the time of the procedure, and the procedure itself was performed according to each institution’s particular protocol.¹³ A standard RF-based PVI was performed in 1,523 (44.1%) of the total patients who underwent ablation, with contact force-based RF ablation in 1,678 (48.6%), cryoballoon ablation with an Arctic Front Advance cryoballoon (Medtronic, Minneapolis, MN, USA) in 248 (7.2%), and hotballoon ablation (Toray Industries, Inc., Tokyo, Japan) in 2 (0.1%). Touch-up ablation for acute PV reconnections and dormant PV conduction provoked by adenosine triphosphate injections and any additional ablation (linear LA ablation and/or ECG-based ablation, cavotricuspid isthmus ablation and/or superior vena cava isolation, etc.) were performed at the physician’s discretion.

Follow-up

Follow-up was started on the day of the initial ablation or repeat ablation during the enrollment period at each center. Each patient in the ablation group was followed up at the attending hospital’s outpatient cardiology clinic, and follow-up examinations for AF monitoring and decisions regarding medical therapy were generally performed at 3, 6, 9, and 12 months, then once or twice per year thereafter. Patients also underwent routine follow-up examinations at their physician’s primary care outpatient clinic. AAD therapy was resumed during the 3-month post-ablation blanking period, and OAC therapy was continued during this period. Thereafter, the OAC and AAD therapies were discontinued, depending on the physicians’ discretion and patients’ preferences. The 24-h Holter recordings were obtained 3–6 months after ablation. An ECG-event recorder was used for any patient reporting cardiac symptoms. Any AF episodes >30 s in duration documented on standard ECG recordings, event-activated ECG recordings, or 24-h Holter recordings were considered as recurrence.

Study Endpoints

This study had 2 endpoints: the 1st was AF recurrence after ablation and the secondary endpoints were efficacy, assessed by the occurrences of stroke (ischemic or hemorrhagic stroke)/TIA, and safety, assessed by the occurrence of major bleeding (defined as a reduction in the Hb concentration of at least 2 g/dL, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ). Secondary endpoints were also cardiovascular events (hospitalization for HF, MI/unstable angina, other cardiovascular events [excluding stroke-related events, hospitalization for cardioversion, or repeat ablation], or cardiovascular death), and death from any cause (cardiovascular death, stroke-related death, or noncardiovascular death). AEs, defined as the sum of the incidence of strokes/TIAs, major bleeding, cardiovascular events, and death from any cause, were taken as a composite endpoint.

Statistical Analysis

Continuous variables are expressed as the mean±SD or median and interquartile range, and categorical variables as the number and percentage of patients. The incidences of clinical outcomes were estimated by the Kaplan-Meier method, and differences were analyzed by log-rank test. Cox proportional hazards modeling was performed to determine the risk of AF recurrence and each clinical outcome in the presence of a variable relative to the absence of a variable. Multivariate Cox modeling for AF recurrence was used to adjust for age, sex, and baseline variables with a P value <0.1 by univariate analysis. Stepwise multivariate Cox modeling for each clinical event outcome was used to adjust for age, sex, post-ablation AF recurrence, and baseline variables with a P value <0.1. The post-ablation AF recurrence and OAC continuation were analyzed as time-dependent covariates. Each variable for the post-ablation therapy was excluded in the multivariate models because it was not a predictive factor at enrollment or multicollinearity problem (AAD use and OAC continuation strongly depended on post-ablation AF recurrence and antiplatelet therapy for vascular disease). All statistical analyses were performed with JMP 12 (SAS Institute Inc., Cary, NC, USA) or SPSS Statistics 24 (IBM Corp., Armonk, NY, USA) software, and P<0.05 was considered significant.

Results

Clinical Characteristics of the Total Study Group

The patients’ characteristics are shown in Table 1. In brief, the number of males and females was 2,558 and 893, respectively, and the mean age was 63.3±10.3 years. AF was paroxysmal (lasting <7 days) in 2,157 (62.5%) patients, persistent (lasting ≥7 days to 12 months) in 1,036 (30.0%), and long-lasting persistent (lasting ≥12 months) in 258 (7.5%). The mean CHADS₂ and CHA₂DS₂-VASc scores were 1.2±1.1 and 2.1±1.5, respectively. The LAd was 40.0±6.6 mm and LVEF 63.6±9.6%. Of the total 3,451 patients, 3,038 (88.0%) underwent single AF ablation procedures, and the remaining 413 (12.0%) underwent ≥2 ablation procedures. During the post-ablation blanking period, warfarin was used in 711 (20.6%) patients and DOACs were used in 2,698 (78.2%), but the OAC type in 42 (1.2%) was not reported.

Table 1. Clinical Characteristics of the Total Patients

	Total (n=3,451)
Age (years)	63.3±10.3
<65	1,869 (52.9)
65–74	1,200 (34.8)
≥75	425 (12.3)
Female sex	893 (25.9)
Body weight (kg)	66.5±13.0
<50	300 (8.7)
50–79.9	2,671 (77.4)
≥80	480 (13.9)
BMI (kg/m2)	24.0
<18.5	156 (4.5)
18.5–24.9	2,106 (61.0)
≥25	1,189 (34.4)
Type of AF
Paroxysmal	2,157 (62.5)
Persistent	1,036 (30.0)
LL persistent	258 (7.5)
≥2 ablation sessions	413 (12.0)
2nd session	357 (10.3)
3rd session	43 (1.2)
4th session	12 (0.3)
5th session	1 (0.03)
Comorbidities
Hypertension	1,891 (54.8)
Diabetes	561 (16.3)
History of stroke/TIA	275 (8.0)
Heart failure	601 (17.4)
Vascular disease	302 (8.8)
Coronary artery disease	222 (6.4)
Peripheral artery disease	39 (1.1)
Aortic atherosclerosis	66 (1.9)
CHADS2 score	1.2±1.1
CHA2DS2-VASc score	2.1±1.5
CHA2DS2-VASc score ≥3	197 (38)
Echo variables
LVEF (%)	63.6±9.6
≥50	3,142 (92.8)
40–49.9	153 (4.5)
<40	90 (2.7)
Not reported	66 (1.9)
LAd (mm)	40.0±6.6
<36	831 (24.5)
36–39.9	747 (22.1)
40–43.9	816 (24.1)
≥44	993 (29.3)
Not reported	64 (1.9)
Hb (mg/dL)	14.2±1.5
≥13	2,735 (80.2)
<13	676 (19.8)
Not reported	40 (1.2)
CrCl (mL/min)	73.4±25.7
≥50	2,921 (84.9)
<50	520 (15.1)
Not reported	10 (0.3)
Post-ablation therapy
OAC type
Warfarin	711 (20.6)
Dabigatran	654 (19.0)
Rivaroxaban	828 (24.0)
Apixaban	884 (25.6)
Edoxaban	332 (9.6)
Not reported	42 (1.2)
Antiplatelet therapy	240 (7.0)
Antiarrhythmic drug use at final follow-up	1,113 (32.3)

Values are shown as the mean±SD or n (%). AF, atrial fibrillation; BMI, body mass index; CHADS₂, congestive heart failure, hypertension, age ≥75 years, diabetes, and stroke/TIA; CHA₂DS₂-VASc, congestive heart failure, hypertension, age ≥75 years, diabetes, stroke/TIA, vascular disease, age 65–74 years, and female sex; CrCl, creatinine clearance; Echo, echocardiographic; Hb, hemoglobin; LAd, left atrial diameter; LL, long-lasting; LVEF, left ventricular ejection fraction; OAC, oral anticoagulant; TIA, transient ischemic attack.

AF Recurrence After Ablation

During the median follow-up period of 20.7 (12.7–33.2) months, 2,405 (69.7%) of the 3,451 patients were arrhythmia-free, with 565 (23.5%) of those patients still taking AADs. OACs were discontinued in 1836 (53.2%) patients after ablation. Table 2 shows the major determinants of AF recurrence after ablation. In the univariate analysis, body weight had a positive relationship (hazard ratio [HR] for per kg increase; 1.01), and persistent and long-lasting persistent AF (HR 1.36 and 2.00, respectively, vs. paroxysmal AF) had a significant association with the incidence of post-ablation AF recurrence, but not with age, sex, hypertension, diabetes, HF, vascular disease, LVEF, Hb level, or CrCL. The Kaplan-Meier curves for the incidence of recurrence between the age and body weight categories, AF types, and LAd quartile groups are shown in Figure 1. There was no difference in the age categories regarding the incidence of post-ablation AF recurrence (P=0.88 by log-rank test), but they increased significantly more for body weight ≥80 kg than for 50–79.9 kg and <50 kg (P=0.013). The incidence of post-ablation AF recurrence increased significantly in a stepwise manner from paroxysmal to persistent AF and to long-lasting persistent AF, and as the LAd quartile increased (P<0.001 for both). Regarding the post-ablation therapy, the use of AADs at the final follow-up and OAC continuation were significantly associated with post-ablation AF recurrence. After multivariate adjustment, female sex, persistent AF and long-lasting persistent AF (HR 1.28 and 1.82, respectively vs. paroxysmal AF) and an increased LAd quartile remained significantly associated with post-ablation recurrence.

Table 2. Univariate and Multivariate Cox Hazard Models for Predicting AF recurrence

	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Age (+1 year)	1.00 (0.99–1.00)	0.12
<65	Reference		Reference
65–74	0.97 (0.85–1.11)	0.63	0.98 (0.86–1.13)	0.81
≥75	0.95 (0.79–1.15)	0.62	0.98 (0.80–1.21)	0.88
Female	1.04 (0.91–1.19)	0.58	1.20 (1.03–1.40)*	0.019*
Body weight (+1 kg)	1.01 (1.00–1.01)*	0.022*
<50	0.84 (0.66–1.05)	0.13	0.83 (0.65–1.07)	0.16
50–79.9	Reference		Reference
≥80	1.22 (1.03–1.44)*	0.022*	1.09 (0.91–1.30)	0.36
BMI (+1 kg/m2)	1.02 (1.00–1.03)	0.07
<18.5	0.82 (0.58–1.12)	0.22
18.5–24.9	Reference
≥25	1.09 (0.95–1.23)	0.21
AF type
Paroxysmal	Reference		Reference
Persistent	1.36 (1.19–1.55)*	<0.001*	1.28 (1.11–1.47)*	0.001*
LL persistent AF	2.00 (1.64–2.45)*	<0.001*	1.82 (1.48–2.25)*	<0.001*
≥2 ablation sessions	1.18 (0.98–1.42)	0.08	1.24 (1.03–1.50)*	0.024*
Comorbidities
Hypertension	0.95 (0.84–1.08)	0.46
Diabetes	0.97 (0.82–1.14)	0.67
Heart failure	0.95 (0.81–1.12)	0.56
Stroke/TIA	1.08 (0.87–1.33)	0.51
Vascular disease	1.09 (0.89–1.34)	0.38
CHA2DS2-VASc	1.00 (0.96–1.04)	0.83
Echo variables
LVEF (+1%)	1.00 (0.99–1.00)	0.20
≥50%	Reference
40–49.9%	0.98 (0.73–1.34)	0.92
<40%	1.33 (0.93–1.89)	0.12
LAd (+1 mm)	1.03 (1.02–1.04)*	<0.001*
<36	Reference		Reference
36–39.9	1.28 (1.05–1.56)*	0.015*	1.24 (1.01–1.51)*	0.038*
40–43.9	1.47 (1.22–1.78)*	<0.001*	1.36 (1.13–1.65)*	0.001*
≥44	1.75 (1.47–2.08)*	<0.001*	1.51 (1.25–1.82)*	<0.001*
Hb (mg/dL)	0.99 (0.96–1.04)	0.80
≥13	Reference
<13	1.03 (0.88–1.20)	0.72
CrCl (mL/min)	1.00 (1.00–1.00)	0.60
≥50	Reference
<50	1.02 (0.86–1.21)	0.77
Post-ablation therapy
Warfarin (vs. DOAC)	1.11 (0.96–1.28)	0.15
Antiplatelet therapy	0.90 (0.71–1.13)	0.38
AAD use	3.19 (2.82–3.60)*	<0.001*
OAC continuation (time-dependent)	2.53 (2.14–3.00)*	<0.001*

*P value <0.05. AAD use, antiarrhythmic drug use at final follow-up; CI, confidence interval; DOAC, direct oral anticoagulant; HR, hazard ratio; other abbreviations are as in Table 1.

Figure 1.

Kaplan-Meier curves of the AF recurrence-free survival after ablation among the age categories, body weight, type of AF, and LAd quartile groups. AF, atrial fibrillation; LAd, left atrial diameter; LL, long-lasting.

AEs After Ablation

By the time of the final follow-up examination, stroke/TIA had occurred in 51 (1.5%, 0.7 [95% confidence interval (CI) 0.5–0.9] events per 100-person years), major bleeding in 71 (2.1%, 1.0 [0.8–1.3] events per 100-person years), cardiovascular events in 106 (3.1%, 1.5 [1.3–1.8] events per 100-person years), and 36 patients (1.0%, 0.5 [0.4–0.7] events per 100-person years) died, and subsequently, AEs occurred in 224 patients (6.5%, 3.3 [2.7–3.7] events per 100-person years). The major determinants of AEs are shown in Table 3. Patients aged 65–74 years and >75 years (HR 1.70 and 3.37, respectively vs. <65 years), body weight <50 kg (HR 1.88), each of the CHA₂DS₂-VASc score components (except for stroke/TIA), LVEF <40% (HR 4.27 vs. ≥50%), LAd ≥44 mm (HR 2.08 vs. <36 mm), Hb <13 g/dL (HR 2.08), and CrCL <50 mL/min (HR 3.48) were shown to be significantly associated with the incidence of AEs. Persistent AF (vs. paroxysmal AF) and post-ablation AF recurrence tended to be related to the incidence of AEs but not to female sex or ≥2 ablation sessions. The Kaplan-Meier curves for the incidence of AEs between the age and body weight categories, AF type, and LAd quartile group are shown in Figure 2. The incidence of AEs increased significantly in a stepwise manner from patients aged <65 years, to 65–74 years, and to ≥75 years, and for body weight <50 kg to 50–79.9 kg and ≥80 kg (P<0.01 for both), but did not differ among the 3 types of AF. The incidence of AEs increased significantly only in the 4th quartile (greatest) LAd ≥44 mm group, but not in the other 3 quartile LAd groups (P<0.001). Regarding the post-ablation therapy, the use of warfarin (vs. DOAC), antiplatelet therapy, AAD use, and OAC continuation were significantly associated with the incidence of AEs. After multivariate adjustment, age >75 years (HR 1.91 vs. <65 years), body weight <50 kg (HR 1.86), diabetes (HR 1.43), vascular disease (HR 2.60), LVEF <40% (HR 2.85 vs. ≥50%), LAd ≥44 mm (HR 1.58 vs. <36 mm), and CrCL <50 mL/min (HR 1.78) were independently associated with the incidence of AEs, but not with post-ablation AF recurrence.

Table 3. Univariate and Multivariate Cox Hazard Models for Predicting Adverse Clinical Events

	Univariate analysis		Multivariate analysis
	HR (95% CI)	P value	HR (95% CI)	P value
Age (+1 year)	1.06 (1.04–1.07)*	<0.001*
<65	Reference		Reference
65–74	1.70 (1.25–2.31)*	<0.001*	1.34 (0.96–1.87)	0.09
≥75	3.37 (2.41–4.73)*	<0.001*	1.91 (1.27–2.88)*	0.002*
Female	0.99 (0.74–1.34)	0.99	0.80 (0.55–1.15)	0.22
Body weight (+1 kg)	0.99 (0.98–0.996)*	0.009*
<50	1.88 (1.30–2.70)*	0.001*	1.86 (1.19–2.89)*	0.006*
50–79.9	Reference		Reference
≥80	0.94 (0.63–1.42)	0.78*	1.11 (0.71–1.73)	0.65
BMI (+1 kg/m2)	0.98 (0.94–1.02)	0.27
<18.5	1.46 (0.82–2.40)	0.19
18.5–24.9	Reference
≥25	0.91 (0.68–1.21)	0.52
AF type
Paroxysmal	Reference		Reference
Persistent	1.31 (0.99–1.73)	0.06	1.03 (0.76–1.39)	0.84
LL persistent	1.20 (0.72–1.98)	0.49	1.15 (0.67–1.98)	0.60
≥2 ablation sessions	1.11 (0.71–1.74)	0.66
Comorbidities
Hypertension	1.57 (1.19–2.08)*	0.002*	1.05 (0.78–1.41)	0.75
Diabetes	2.14 (1.60–2.86)*	<0.001*	1.43 (1.05–1.94)*	0.023*
Heart failure	2.23 (1.67–2.96)*	<0.001*	1.35 (0.96–1.89)	0.08
Stroke/TIA	1.43 (0.94–2.16)	0.09	1.03 (0.67–1.58)	0.90
Vascular disease	4.08 (3.06–5.46)*	<0.001*	2.60 (1.90–3.57)*	<0.001*
CHA2DS2-VASc	1.44 (1.33–1.54)*	<0.001*
Echo variables
LVEF (+1%)	0.97 (0.96–0.98)*	<0.001*
≥50%	Reference		Reference
40–49.9%	1.64 (0.95–2.82)	0.07	1.10 (0.62–1.95)	0.74
<40%	4.27 (2.66–6.86)*	<0.001*	2.85 (1.66–4.88)*	<0.001*
LAd (+1 mm)	1.06 (1.04–1.08)*	<0.001*
<36	Reference		Reference
36–39.9	1.11 (0.71–1.72)	0.66	1.14 (0.73–1.78)	0.58
40–43.9	1.08 (0.70–1.66)	0.74	0.98 (0.63–1.52)	0.91
≥44	2.08 (1.44–2.99)*	<0.001*	1.58 (1.05–2.37)*	0.027*
Hb (mg/dL)	0.77 (0.71–0.84)*	<0.001*
≥13	Reference		Reference
<13	2.08 (1.56–2.73)*	<0.001*	1.30 (0.95–1.76)	0.10
CrCl (mL/min)	0.98 (0.97–0.99)*	<0.001*
≥50	Reference		Reference
<50	3.48 (2.64–4.55)*	<0.001*	1.78 (1.27–2.49)*	0.001*
AF recurrence (time-dependent)	1.37 (0.98–1.91)	0.07	1.27 (0.90–1.78)	0.17
Post-ablation therapy
Warfarin (vs. DOAC)	1.86 (1.41–2.46)*	<0.001*
Antiplatelet therapy	3.89 (2.84–5.25)*	<0.001*
AAD use	1.45 (1.11–1.90)*	0.007*
OAC continuation (time-dependent)	1.81 (1.29–2.53)*	0.001*

*P value <0.05. Abbreviations as in Tables 1 and 2.

Figure 2.

Kaplan-Meier curves for AEs (sum of strokes/transient ischemic attacks, major bleeding, cardiovascular events, and death) among the age categories, body weight, type of AF, and LAd quartile groups. AF, atrial fibrillation; AEs, adverse clinical events; LAd, left atrial diameter; LL, long-lasting.

The major determinants of stroke/TIA, major bleeding, cardiovascular events, and death are shown in Supplementary Table 1 and Supplementary Table 2. Multivariate Cox hazard analysis revealed that age >75 years (vs. <65 years), long-lasting persistent AF (vs. paroxysmal AF), vascular disease, and LVEF <40% (vs. ≥50%) remained significant predictors for the incidence of stroke/TIA; age 65–75 and ≥75 years (vs. <65 years) and diabetes for the incidence of major bleeding events; age >75 years (vs. 65 years), body weight <50 kg, diabetes, vascular disease, LVEF <40% (vs. ≥50%), and Lad >44 mm (vs. <36 mm) for the incidence of cardiovascular events; and vascular disease, LVEF <40% (vs. ≥50%), and CrCL <50 mL/min for the incidence of death.

Discussion

We found different determinants of post-ablation AF recurrence and AEs; that is, by multivariable adjustment, female sex, persistent AF and long-lasting persistent AF (vs. paroxysmal AF), and LAd quartile increase remained significantly associated with the incidence of post-ablation recurrence but not with comorbidities, whereas age >75 years, low body weight, diabetes, vascular disease, reduced LVEF, greatest quartile LAd, and low CrCL rather than post-ablation AF recurrence remained independently associated with the incidence of AEs.

Determinants of AF Recurrence and Clinical AEs After Ablation

Our data disclosed different determinants of AF recurrence and AEs, including stroke, bleeding, cardiovascular events, and death, after ablation. Age category was not associated with post-ablation recurrence, but patients aged >75 years (vs. <65 years) were independently associated with AEs. The similar AF recurrence rates among the young and old age categories were well in line with the findings from recent studies and meta-analyses,^14–17 which suggested that the decision to perform AF ablation should be independent of an older age. In contrast, we found that after multivariate adjustment, patients aged >75 years were independently associated with 3 AEs (stroke/TIA, major bleeding, and cardiovascular events), as many other studies have reported.^{7,8,13,18–20}

LA size/volume and persistent and long-lasting persistent AF as counterparts to paroxysmal AF are widely known as strict markers for predicting AF recurrence after ablation.^11,12 We also showed a stepwise increased risk of AF recurrence after ablation with an increase in the LAd quartile, and from paroxysmal to persistent to long-lasting persistent AF. These data strongly support the clinical importance of atrial remodeling on post-ablation recurrence. In contrast, we found different effects of LA size and type of AF on AEs. Recent Japanese registry-based studies indicated the prognostic importance of LA size¹⁹ and persistent and/or long-lasting persistent AF,^20,21 but post-ablation data are lacking, possibly because of fewer post-ablation AEs in the relatively healthy patients who would undergo ablation. In this large-scale study, there was no difference in the risk of AEs between the 1st, 2nd, and 3rd quartile LAd groups; only the 4th quartile (greatest) group with LAd ≥44 mm was independently associated with the incidence of AEs. The type of AF was not independently associated with AEs, but long-lasting persistent AF (vs. paroxysmal AF) was independently associated with the incidence of stroke/TIA. Therefore, the clinical significance of LA size or type of AF on AEs might be less, especially in the ablation cohort. Unexpectedly, in this study, associations between post-ablation recurrence and the incidence of AEs, stroke/TIA, bleeding, cardiovascular events, and death were absent after adjusting for other relevant factors. Taken together, the findings suggested that the mechanisms of post-ablation AEs such as stroke/TIA and death may be multifactorial and not solely dependent on AF recurrence or atrial remodeling reflected by LA size or the type of AF. This study could partially answer the question regarding prognostic factors. Regarding comorbidities, there were no associations between AF recurrence and each comorbidity such as hypertension, diabetes, HF, stroke/TIA, and vascular disease, but diabetes and vascular disease were independently associated with AEs. Diabetes and vascular disease including CAD or PAD are representative of atherosclerosis, resulting in LV dysfunction, increased LA pressures, and/or atrial ischemia, which all eventually cause LA remodeling.^22–26 Nonetheless, the association between diabetes and CAD and AF recurrence after ablation remains controversial.^25,26 Hiraya et al showed that CAD patients had a significantly higher AF recurrence rate than those without CAD,²⁷ but other prior observational studies showed a contradicting result that the presence of CAD or coronary atherosclerosis was not associated with AF recurrence.^28,29 Our study sheds light on the prognostic effect of diabetes and vascular disease after AF ablation. In particular, diabetes was strongly associated with major bleeding and cardiovascular events, and vascular disease (which mostly consisted of CAD) was strongly associated with strokes/TIAs, cardiovascular events, and death. It is well-known that concomitant diabetes or CAD is a high risk for cardiovascular events and death in AF patients.^13,30–32 Given the retrospective observational study design, we could not find the exact mechanisms of the AEs outside of less AF detected. However, our data suggested that the prognostic role of the progression of atherosclerosis, inflammation and/or oxidative stress^25,26 driven by diabetes, CAD, and advancing age were striking risk factors of AEs after AF ablation.

We found an interesting association between body weight and AF recurrence and AEs. In the univariate analysis, body weight ≥80 kg was a dependent predictor of AF recurrence, while body weight <50 kg was an independent predictor of AEs, and this group was at high risk for major bleeding and cardiovascular events. Similarly, many recent studies have indicated that increased BMI is associated with a higher recurrence rate after ablation,^33–36 but a recent meta-analysis of AF patients who underwent ablation showed a higher risk of AEs in patients with high BMI.³⁶ The untoward effects of a high BMI on AEs in that study was unclear, but may be due to a higher distribution of severe obesity than that in our Japanese study subjects. Nevertheless, the association between being underweight and the clinical outcomes was relatively consistent. For example, very large Japanese studies of AF patients who did not undergo ablation showed the highest risk of death or cardiovascular events in those who were underweight,^20,21 and Bunch et al also reported that underweight patients remained at high risk for cardiovascular events after AF ablation.³⁷ Low body weight patients are often older females with reduced CrCL and Hb levels, and less muscle mass, which are all well-known risk factors for major bleeding, cardiovascular events, and death.^13,18,38 Again, this indicated that low body weight patients may have multiple risk factors of AEs outside of AF recurrence.

Clinical Implications

Post-ablation AF recurrence and only the greatest LAd group were modestly associated with AEs, but most determinants of AEs differed from those for AF recurrence. Therefore, the decision on the indication for AF ablation should be made while considering the benefit–risk balance based on AF-related symptoms, AF recurrence factors such as LA size and type of AF, and the determinants for AEs identified in this study. Another implication is that, if ablation is performed in very elderly patients or those at high risk for AEs, careful monitoring after the ablation procedure is of utmost importance. Comorbidities such as diabetes mellitus, HF with reduced EF (HFrEF) or vascular disease should be carefully managed, concomitant use of antiplatelet drugs should be avoided, and discontinuation of OAC drugs should be carefully controlled. Optimal medical therapy for HFrEF such as angiotensin-converting enzyme inhibitors and β-blockers, etc., should be continued even if sinus rhythm is maintained after ablation.

Study Limitations

Our study was observational, so no causal relationships could be established. Registry-based studies are subject to patient selection bias, and the diagnosis and therapies/interventions are not controlled for. In particular, the time-course changes in the post-ablation AF recurrence and medications such as AADs or OACs, etc. were complexly related to each other, which may affect AEs. Continuation of AADs/OACs was strongly associated with AF recurrence, so we, at least, considered AF recurrence, and it was entered as a time-dependent covariable into the multivariate model. Identification of post-ablation recurrence during routine follow-up may underestimate actual recurrences. We acknowledge that the follow-up period was relatively short to clarify strokes/TIAs and other clinical events, and this short follow-up time might have affected our results. Despite those limitations, the study was based on routine clinical baseline and follow-up data in a relatively large number of patients from multiple centers in Japan, and thus we believe that our findings will help clinicians understand the clinical outcomes that can be expected for Japanese patients who undergo AF ablation.

Conclusions

This study disclosed that the major determinants of post-ablation AF recurrence mostly differed from those of AEs including stroke/TIA, major bleeding, cardiovascular events, and death. Female sex, persistent and long-lasting persistent AF as counterparts to paroxysmal AF, and a large LA size were major predictive factors of post-ablation AF recurrence, while age ≥75 years, low body weight, LAd ≥44 mm, diabetes, vascular disease, reduced LVEF, and CrCL rather than post-ablation AF recurrence were independent AE determinants. These findings will help with ablation indications and management after ablation, especially in high-risk patients.

Acknowledgments

The authors wish to thank all of the centers that participated in this study and all patients who provided consent to the use of their data. We thank Mr. John Martin for his encouragement and assistance with reporting our findings in English.

Disclosures

The following authors have potential conflicts of interest: Y.O. has received research funding from Bayer Healthcare, Daiichi Sankyo and Bristol-Meyers Squibb, has accepted remuneration from Bayer Healthcare and Daiichi Sankyo, and belongs to the endowed departments of Boston Scientific Japan, Abbott Medical Japan, Japan LifeLine, Medtronic Japan, and Nihon Kohden. N.M. has received research funding from Daiichi Sankyo. S.S. received research funding from Daiichi Sankyo and Mitsubishi-Tanabe. A.H. has received accepted remuneration from Nippon Boehringer Ingelheim, Bayer Healthcare, Bristol-Myers Squibb, and Daiichi Sankyo. M.K. has received accepted remuneration from Johnson & Johnson K.K., Medtronic Japan, and Bayer Healthcare. H.F. has received lecture fees from Nippon Boehringer Ingelheim, Daiichi Sankyo, Bayer Healthcare, Abbott Medical Japan, and Japan LifeLine. S.N. has received lecture fees from Daiichi Sankyo, Bayer Healthcare, Nippon Boehringer Ingelheim, and Japan Lifeline. T.K. has received research grant from Daiichi Sankyo, and lecture fees from Bristol-Myers Squibb, Daiichi Sankyo and Nippon Boehringer Ingelheim, and honoraria for writing promotional material for Bristol-Myers Squibb. W.S. has received research funding from Bristol-Myers Squibb, Daiichi Sankyo, and Nippon Boehringer Ingelheim, patent royalties/licensing fees from Daiichi Sankyo, Pfizer Japan, Bristol-Myers Squibb, Bayer Healthcare, and Nippon Boehringer Ingelheim, and he is a member of Circulation Journal’s Editorial Team. T.H. serves as a consultant to Medtronic Japan and has received lecture fees from Daiichi Sankyo. I.N. has received a scholarship from the Japanese Heart Rhythm Society and received speaking honoraria from Medtronic Japan. K.O. has received remuneration from Nippon Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, and Medtronic Japan. M. Tokuda serves as a consultant to Medtronic Japan. T.Y. has received speaker honoraria from Daiichi Sankyo, Nippon Boerringer Ingelheim, Abbott Medical Japan, Bristol-Myers Squibb, Medtronic Japan, and Japan LifeLine, and research grants from Nippon Boehringer Ingelheim. K.T. has received lecture fees from Daiichi Sankyo, Nippon Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer Japan, and Bayer Healthcare. K. Soejima has received research funding from Daiichi Sankyo and Nippon Boehringer Ingelheim, and accepted remuneration from Medtronic Japan, Jonson & Jonson, and Abbott Medical Japan, and she is a member of Circulation Journal’s Editorial Team. N.H. has received accepted remuneration from Nippon Boehringer Ingelheim, Bristol-Myers Squibb, Bayer Healthcare, and research funding from Bayer Healthcare, Nippon Boehringer Ingelheim, Daiichi Sankyo, and he is a member of Circulation Journal’s Editorial Team. M.H. has lecture fee from Nippon Boehringer Ingelheim and Bristol-Myers Squibb. K. Satomi and Y.Y. have received research funding from BIOTRONIK Japan. Other authors have no conflicts of interest.

This study was supported by a research grant from Bristol-Meyers Squibb.

IRB Information

Nihon University Itabashi Hospital, Clinical Research Judging Committee (No. RK-161213-06).

Data Availability

The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0326

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