Efficacy and Safety of Cryoballoon Ablation in Patients With Heart Failure and Reduced Left Ventricular Ejection Fraction　― A Multicenter Study ―

Abstract

Background: Second-generation cryoballoon (CB2)-based pulmonary vein isolation (PVI) has demonstrated encouraging results in the treatment of atrial fibrillation (AF). This study sought to assess data on the safety, efficacy and clinical success of CB2-based PVI in patients with heart failure (HF) and reduced ejection fraction (HFrEF).

Methods and Results: CB2-based PVI was performed in 551 consecutive patients in 3 highly experienced EP centers. Patients with HF and LVEF ≤40% were included (HFrEF group, n=50/551, 9.1%). Data were compared with propensity score-matched patients without HF and preserved left ventricular EF (LVEF) (n=50, control group). The median LVEF was HFrEF: 37% (35, 40) and control: 55% (55, 55), P<0.0001. Major periprocedural complications were registered in 4/50 (8%, HFrEF group) and 3/50 (6%, control group), P=0.695. The 12-month freedom from AF recurrence was 73.1% (95% confidence interval (CI): 61–88, HFrEF group) and 72.6% (95% CI: 61–87, control group), P=0.25. NYHA class decreased from 2.4±0.8 (baseline) to 1.7±0.8 at 12-month follow-up (P<0.0001). LVEF improved from a median of 37% (35, 40) prior to ablation to a median of 55% (40, 55), P<0.0001.

Conclusions: CB2-based PVI in patients with HFrEF appeared to be safe, was associated with comparable periprocedural complications and showed promising clinical success rates equal to those for patients with preserved LVEF. NYHA class and LVEF significantly improved at 12-month follow-up.

Atrial fibrillation (AF) and heart failure (HF) often coexist and AF increases the risk of hospitalization because of decompensated HF in those patients.^1–3 Pulmonary vein isolation (PVI) is the cornerstone of invasive AF treatment. Radiofrequency (RF)-based catheter ablation for HF patients, compared with amiodarone therapy, significantly reduces recurrent AF and improves left ventricular ejection fraction (LVEF) in selected cases.⁴ Although current guidelines recommend ablation therapy to maintain sinus rhythm (SR) for symptomatic AF patients, recommendations for HF patients with reduced LVEF (HFrEF) are deliberative because of the limited data. Recently, the CASTLE-AF study showed that RF-based catheter ablation for AF in patients with reduced LVEF was associated with lower rates of all-cause mortality and hospitalization for worsening HF.⁵ Point-by-point ablation by RF often results in a favorable clinical outcome, but its complexity demands a long learning curve and relatively long procedural duration. In this context the 2nd-generation cryoballoon (CB2, Arctic Front Advance, Medtronic Inc., Minneapolis, MN, USA) for PVI has demonstrated high procedural success rates, shorter procedural duration, high durability of PVI and convincing clinical success rates for patients with paroxysmal (PAF) and persistent AF (PersAF). The “Fire And Ice” trial proved the non-inferiority of CB2- to RF-based PVI in patients with PAF.⁶ As a consequence, the latest AF guidelines state that PVI should be performed using either RF or CB catheters.⁷ Despite the serious consequences of AF, data focusing on the role of CB2-based PVI in patients with HFrEF are limited. The aim of this study was to investigate safety profile and efficacy of CB2 ablation in HFrEF patients.

Methods

Inclusion and Exclusion Criteria

Data for all patients referred to 3 experienced EP centers in Germany (University Heart Center Luebeck; Asklepios Klinik St. Georg Hamburg; Asklepios Klinik Harburg) from July 2012 to March 2017) were analyzed retrospectively. Patients with PAF or PersAF and HF with LVEF ≤40% scheduled for CB2-based PVI were included. Exclusion criteria were prior left atrial (LA) ablation, LA diameter >60 mm, severe valvular heart disease or long-standing PersAF (AF duration >12 months). Transesophageal echocardiography (TEE) was performed prior to ablation to assess the LA diameter and to rule out intracardiac thrombi. Procedural data and clinical follow-up of patients with LVEF ≤40% who underwent CB2-based PVI (HFrEF group) were analyzed and compared with propensity score-matched patients with no HF, no structural heart disease and preserved LVEF (control group). All patient data were generated from the institutional databases.^8,9 HFrEF was defined in line with current guidelines for patients with HF and LVEF ≤40%.^10,11 All patients gave written informed consent to the procedure. The study was approved by the local ethics board and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Preprocedural Management

The intraprocedural management has been described in detail in previous studies.^8,9 TEE was performed in all patients prior to the procedure. If reduced LVEF was detected additional transthoracic echocardiography (TTE) was conducted to assess structural abnormality, LVEF, LA diameter, and valvular disease. Apart from echocardiography, no additional preprocedural imaging was performed. Assessment of LVEF was performed in AF or SR according to the individual patient’s rhythm status. In patients on vitamin K antagonists, anticoagulation was continued throughout the procedure, aiming at an international normalized ratio (INR) of 2–3. In patients treated with novel oral anticoagulants (NOACs), the drug was discontinued 12–24 h prior to the procedure and re-initiated 6 h post-ablation at half the regular dose, and then at full dose on the following day.⁹

Cryoballoon-Based PVI

All procedures were performed under deep sedation using midazolam, fentanyl, and propofol.^8,9 One diagnostic catheter was introduced via the right femoral vein and positioned within the coronary sinus. A single transseptal puncture was performed via the right femoral vein under fluoroscopic guidance, using a modified Brockenbrough technique and an 8.5Fr transseptal sheath (SL1, St. Jude Medical, Inc., St Paul, MN, USA) or PREFACE (Biosense Webster, Inc. Irvine, CA, USA). Heparin was administered after transseptal puncture to maintain an activated clotting time ≥300 s. The transseptal sheath was then exchanged over a guidewire with a 12Fr steerable sheath (Flexcath Advance, Medtronic, Inc.). In order to identify all PV ostia, selective PV angiography was performed. In all patients, an esophageal temperature probe (Sensitherm, St. Jude Medical, Inc. or CIRCA S-CATH^TM) was inserted and positioned according to the individual CB position to facilitate esophageal temperature monitoring during energy delivery. The 2nd-generation 28-mm CB was advanced into the LA via the 12Fr steerable sheath and a spiral mapping catheter (20-mm diameter; Achieve, Medtronic, Inc.) was advanced into the target PV to record electrical activity. The CB was inflated proximal to the PV ostium and gently pushed against the ostium to facilitate complete antral sealing. Contrast medium injected through the central lumen of the CB was used to verify complete occlusion of the PV ostium. The order of PV treatment was always in a clockwise rotation starting with the LSPV.

Different ablation protocols were applied: 5 consecutive patients (n=5 for the control group, P=0.999) were treated by a “bonus-freeze” protocol (freeze-cycle duration of 240 s followed by an additional bonus freeze-cycle of 240 s duration after PVI); another 30 consecutive patients (n=35 for the control group, P=0.294) were treated with a “no-bonus-freeze” protocol (freeze-cycle duration of 180 or 240 s without an additional bonus freeze-cycle following PVI);⁸ 9 consecutive patients (n=15 for the control group, P=0.160) were treated based on a “time-to-effect” guided ablation protocol.^12,13 In patients demonstrating AF at the time of the procedure, electrical cardioversion was performed after the final freeze-cycle and PVI was reconfirmed in SR. During energy delivery along the septal PVs, continuous phrenic nerve pacing at maximum output and pulse width (12 mA, 2.9 ms) at a cycle length of 1,000 ms was performed, using a diagnostic catheter positioned in the superior vena cava. Phrenic nerve capture was monitored by intermittent fluoroscopy and by tactile feedback of diaphragmatic contraction by the operator’s hand positioned on the patient’s abdomen. In addition, the continuous motor action potential (CMAP) was monitored. Refrigerant delivery was stopped by double-stop technique immediately if there was weakening or loss of diaphragmatic movement, or a 30% reduction of CMAP amplitude was noted. If phrenic nerve palsy (PNP) occurred, no additional freeze-cycle was applied along the septal PVs. Cavotricuspid isthmus ablation (CTI) using an open-irrigated RF catheter (Celsius ThermoCool or ThermoCool SF, Biosense Webster Inc.) was solely performed in patients with documented or induced common type atrial flutter.

Postprocedural Management

Following ablation, all patients underwent TTE to rule out pericardial effusion. Low-molecular-weight heparin was administered to patients on vitamin K antagonists and an INR <2.0 until a therapeutic INR of 2–3 was achieved. NOACs were re-initiated 6 h post-ablation. Anticoagulation was recommended for at least 3 months and thereafter according to the individual CHA₂ DS₂-VASc scores. Previously ineffective antiarrhythmic drugs were continued for 3 months post-ablation. All patients were treated with proton-pump inhibitors for 6 weeks. All HFrEF patients were treated with optimal medical treatment according to the latest guidelines.^10,11

Clinical Follow-up and Study Endpoints

Following a blanking period of 3 months, patients completed outpatient clinic visits at 3, 6 and 12 months and at 6-month intervals thereafter including ECG and 24 h-Holter ECG. In addition, regular telephone interviews were performed. Additional outpatient clinic visits were immediately initiated in cases of symptoms suggestive of recurrent arrhythmia. Repeat ablation was offered to the patient in cases of symptomatic AF/AT recurrence after the blanking period or symptomatic drug-refractory recurrent AF/AT within the blanking period that could not be managed without intervention. In HFrEF patients the LVEF was systematically evaluated at baseline and at follow-up on TTE. The primary endpoint of this study was any episode of documented AF/AT recurrence lasting longer than 30 s after a 3-month blanking period. Secondary endpoints were procedural data and procedure-related complications such as bleeding, PNP, cerebral embolism, pericardial effusion/tamponade or atrioesophageal fistula. Additionally the NYHA score, LVEF and deaths were assessed.

Statistical Analysis

The primary aim of this retrospective analysis was the 1-year efficacy (recurrence-free survival) of 100 patients treated with CB2. Overall, 50 patients with LVEF ≤40% (HFrEF group) were matched to 50 patients with normal LVEF (control group). Propensity score matching was based on age, sex, type of AF, hypertension, diabetes mellitus, LA size, coronary artery disease and prior transient ischemic attack (TIA)/stroke. Continuous data are summarized as mean±standard deviation or as median [25^th and 75^th percentiles] as appropriate. Categorical data are presented as N (%). An F-test of overall significance was performed to examine differences in the baseline variables between the groups. Differences in procedural data between groups were analyzed with an unpaired t-test and the Wilcoxon-Mann Whitney test as appropriate. Differences in complications between the groups were analyzed using the Chi-squared test. Recurrence-free survival was estimated with the Kaplan-Meier method. Differences in recurrence-free survival were analyzed with the log-rank test. All P-values were two-sided and P<0.05 was considered significant. All calculations were performed with the statistical analysis software R (R Core Team, 2018).

Results

Patients’ Characteristics

A total of 551 patients were included in the analysis; 50/551 (9.1%) patients had LVEF ≤40% (HFrEF group). The control group was selected by propensity score matching from patients with preserved LVEF. It was based on a logistic regression model including age, sex, type of AF, hypertension, diabetes mellitus, LA size, coronary artery disease and prior TIA/stroke. Baseline characteristics are summarized in Table 1. As expected, the number of patients with HFrEF, the median LVEF and EHRA score were different between groups. Assessment of LVEF at baseline was performed in SR in 42 patients (84%) of the HFrEF group and in 40 patients (80%) of the control group.

Table 1. Baseline Characteristics of the Study Patients

	All	HFrEF	Control	P value
Patients (n)	100	50	50
Age (years)	65.8±10	66.0±11	65.6±9	0.997
Left atrial diameter (mm)	45.6±7	45.1±7	46.1±7	0.997
Persistent AF, n (%)	27 (27)	14 (28)	13 (26)	0.997
Duration of AF (months)	12 (4, 36)	12 (4, 36)	11.5 (4, 42)	0.681
Female sex, n (%)	31 (31)	16 (32)	15 (30)	0.997
Arterial hypertension, n (%)	77 (77)	38 (76)	39 (78)	0.997
Coronary artery disease, n (%)	28 (28)	15 (30)	13 (26)	0.997
HFrEF, n (%)	50 (50)	50 (100)	0 (0)	<0.0001
LVEF (%)	41 (55, 55)	37 (35, 40)	55 (55, 55)	<0.0001
Heart failure etiology
DCM		23 (46)
ICM		15 (30)
TCM		8 (20)
HCM		4 (8)
Implantable cardiac device, n (%)	15 (15)	12 (24)	3 (6)	0.012
Diabetes mellitus type II, n (%)	22 (50)	11 (50)	11 (50)	0.997
Prior TIA/stroke, n (%)	11 (11)	6 (12)	5 (10)	0.997
COPD, n (%)	2 (2)	1 (2)	1 (2)	0.999
CHA2DS2-VASc score	3 (2, 4)	3 (2, 4)	2 (1, 4)	0.027
HAS-BLED score	2 (1, 3)	2 (1, 3)	2 (2, 3)	0.363
EHRA score	2 (2, 3)	3 (2, 3)	2 (1, 3)	0.008

Continuous data are summarized as mean±standard deviation or as median [25^th and 75^th percentiles]. Categorical data are presented as n (%). Test of no regression P=0.997 based on age, sex, type of AF, hypertension, diabetes mellitus, left atrial size, coronary artery disease and prior TIA/stroke. AF, atrial fibrillation; COPD, chronic obstructive pulmonary disease; DCM, dilated cardiomyopathy; EHRA, European Heart Rhythm Association; HCM, hypertrophic cardiomyopathy; HFrEF, heart failure with reduced ejection fraction; ICM, ischemic cardiomyopathy; LVEF, left ventricular ejection fraction; TCM, tachycardia-induced cardiomyopathy; TIA, transient ischemic attack.

In 16 (40%) HFrEF patients, optimal medical treatment according to the latest HF guidelines was started before discharge.^10,11 The number of patients with β-blockers at discharge was 45/50 (90%), while angiotensin-converting enzyme inhibitors were prescribed in 33/50 (66%) patients, AT1-antagonists in 17/50 (34%) patients and diuretics in 29/50 (58%) patients.

Acute Ablation Results

Periprocedural data and complications are presented in Table 2. In 100 patients a total of 396 PVs were identified and targeted. Two RSPV (HFrEF group: n=1, control group: n=1) were not isolated, because of PNP during CB application along the ipsilateral RIPV. All other PVs were successfully isolated. Total procedural and fluoroscopy times were: HFrEF group: 131±39 min vs. control group: 126±33 min (P=0.420), and HF group: 21 (14, 27) min vs. control group: 24 (17, 30) min (P=0.079), respectively.

Table 2. Procedural Data

	All	HFrEF	Control	P value
No. of PVs	396	198	198
No. of isolated PVs	394/396 (99)	197/198 (99)	197/198 (99)	0.999
Procedure duration (min)	128±36	131±39	126±33	0.420
Fluoroscopy time (min)	22 (14, 28)	21 (14, 27)	24 (17, 30)	0.079
Contrast medium (mL)	120 (110, 150)	130 (112, 150)	120 (107, 150)	0.090
Additional CTI block, n (%)	10 (10)	7 (14)	3 (6)	0.182
Major complications, n (%)	7 (7)	4 (8)	3 (6)	0.695
PNP, n (%)	6	3	3	0.999
Transient PNP, n (%)	2	1	1	0.999
Severe hematoma, n (%)	2	1	1	0.999
Pericardial tamponade, n (%)	1	1	0	0.320
Pericardial effusion, n (%)	0	0	0	0.999
Periprocedural TIA/stroke, n (%)	0	0	0	0.999
Procedure-related death, n (%)	0	0	0	0.999

Continuous data are summarized as mean±standard deviation or as median [25^th and 75^th percentiles]. Categorical data are presented as n (%). CTI, cavotricuspid isthmus; HFrEF, heart failure with reduced ejection fraction; PNP, phrenic nerve palsy; PV, pulmonary vein; TIA, transient ischemic attack.

Peri- and Postprocedural Complications

Severe groin complications requiring blood transfusion without surgical intervention occurred in 2 patients (1 per group, 2%). A total of 6 PNP occurred in (n=3 per group 6%) patients during the ablation of the right-sided pulmonary veins. PNP resolved in 2/6 (33.3%) during the procedure, 2 days later in 1/6 (17%) patients and after a maximum of 12 months in 3/6 (50%) of patients. One patient experienced pericardial tamponade, but recovered after drainage. No other adverse events, such as symptomatic PV stenosis, cerebral embolism, or atrioesophageal fistula, were noted.

Follow-up and Clinical Success

The Kaplan-Meier plot (Figure 1) demonstrated the relative proportion of patients in stable SR following index PVI using CB2. After 1 year of follow-up and a single CB2-based PVI procedure, Kaplan-Meier estimates of patients in stable SR were 73.1% (95% confidence interval (CI): 61–88, HFrEF group) and 72.6% (95% CI: 61–87, control group), P=0.25). No significant differences were observed in the duration of follow-up (median time to event HF group: 1.1 (0.4–2.0) years, median time to event control group: 1.2 (0.6–2.5) years, P=0.25). NYHA class improved from 2.4±0.8 at baseline to 1.7±0.8 at 12-month follow-up (P<0.0001) (Figure 2). No patient died during follow-up. Among the patients in the HFrEF group, preprocedural TTE detected a median LVEF of 37% (35, 40), while at follow-up LVEF increased to a median of 55% (40, 55), P<0.0001). The median improvement in LVEF was 15% (6, 20).

Figure 1.

Clinical success. The Kaplan-Meier estimates demonstrate the relative proportion of patients in stable sinus rhythm following index PVI using the 2nd-generation cryoballoon. A log-rank test was used to compare the AF/AT-free survival between the groups (P=0.25). AF, atrial fibrillation; AT, atrial tachycardia; HF, heart failure with reduced ejection fraction; PVI, pulmonary vein isolation.

Figure 2.

NYHA class before and after PVI in patients with heart failure with reduced ejection fraction. After 12 months of follow-up a significant improvement in NYHA class was observed (P<0.0001). PVI, pulmonary vein isolation.

Discussion

To the best of our knowledge, this is the first study to present the periprocedural and long-term outcome data of patients with HFrEF compared with a control group of patients with preserved LVEF treated with CB2. The data suggested that CB2-based PVI is comparably feasible and safe in patients with HFrEF and a normal LVEF. A total of 99% of PVs could be isolated in both groups and procedural and fluoroscopy times were similar. In our series of patients, serious procedure-related complications occurred in the same proportion of both groups. Similar rates (2.0–7.5%) are reported in the literature.^14–17

HF often coexists with AF, although it has been demonstrated that AF predisposes to HF, and vice versa. It has been estimated that development of AF is associated with reduced cardiac output followed by acute HF and an increased risk of death among HFrEF patients.³ Especially in HFrEF subjects undergoing cardiac resynchronization therapy (CRT-D) and implantable cardioverter defibrillators (ICD), AF can have additional devastating consequences such as ineffective biventricular pacing and triggering of inadequate ICD interventions.

In patients with both AF and HFrEF, the mortality rate significantly increases,³ and the restoration of SR in these patients by catheter ablation may increase the survival rate. However, follow-up duration was limited in our analysis and patient numbers were not powered to calculate mortality benefit. The recently published CASTLE-AF trial proved that RF-based catheter ablation for AF in patients with HF was associated with a significantly lower rate of the composite endpoint of death from any cause or hospitalization for worsening HF compared with medical therapy.⁵

Additionally, it has been shown that the arrhythmia burden influence outcomes in HFrEF patients.¹⁸ Although a retrospective analysis, our findings on CB2-based PVI in HFrEF patients are in line with previous results and we found an improved NYHA class and increased LVEF during follow-up.¹⁹ The reported rates for improved LVEF range between 4% and 22%.^20,21

As previously reported for RF-based PVI in HF, patients with reduced LVEF without evidence of structural heart disease seem to benefit most from catheter ablation with regards to freedom of AF and improvement of LVEF.²² Especially, in patients with baseline LVEF <35%, the clinical implication of LVEF improvement to >35% gains further importance because ICD implantation as primary prevention might therefore no longer be necessary.^10,11

As a consequence of the findings of the “Fire And Ice” trial, latest AF guidelines state that PVI should be performed using either RF or CB catheters.^6,7 It is important to state patients treated with the CB had significantly fewer repeat ablations and cardiovascular rehospitalizations during follow-up.¹⁵ Furthermore the total procedure duration was significantly shorter for CB-based PVI, although most patients in the CB group were treated with a bonus-Freeze, which previously was omitted.⁸ Advantages of CB-based PVI in patients with HF compared with RF might be a shorter procedure time, lower periprocedural volume load, lower rates of repeat ablation and cardiovascular rehospitalization.

Study Limitations

Patients with HF and moderately reduced EF (41–49%) were not included in this analysis. In addition, patients with preserved EF were not further subclassified as patients with HF and preserved LVEF (HFpEF) and without HF. As the current guidelines state, diagnosing HFpEF is challenging.^10,11 Because ofthe retrospective design of this analysis, HFpEF could not be precisely diagnosed in all patients. This study was retrospective, but the analysis was performed using data from 3 high-volume centers and patient groups were matched according to baseline characteristics from a large database. Although in a certain number of patients, follow-up was based on pacemakers, ICD or CRT interrogation, which allowed for continuous rhythm monitoring, follow-up assessment of AF recurrence consisted of 24-h Holter ECG monitoring in most patients. Thus, the clinical success rate might be overestimated and asymptomatic episodes of atrial tachyarrhythmia might have been missed. Only LVEF assessed by TTE was utilized to detect patients with HFrEF. No systematic measurements of biomarkers or MRI were performed, which limits our data. Initialization of optimal medical treatment before discharge may have additionally improved LVEF during follow-up. Because 24% of patients had previously implanted cardiac devices, a high ventricular pacing rate in patients in AF before catheter ablation and a lower pacing rate in patients in stable SR afterwards might also increase LVEF. The majority of patients suffered from PAF and some from PersAF, so the current findings may not be meaningful for patients with long-standing PersAF.

Conclusions

In this population of HFrEF patients, acute success, periprocedural complications and long-term clinical success rates are comparable to those for patients without structural heart disease, when using CB2-based PVI for the treatment of PAF or PersAF. Additionally, significant improvements of NYHA class and LVEF were observed.

Disclosures

C.-H.H. received travel grants and research grants by Medtronic, Claret Medical, SentreHeart, Biosense Webster and Cardiofocus. KHK received travel grants and research grants from Biosense Webster, Stereotaxis, Prorhythm, Medtronic, Edwards, Cryocath, and is a consultant to St. Jude Medical, Biosense Webster, Prorhythm, and Stereotaxis. He received speaker’s honoraria from Medtronic. R.R.T. received travel grants from St. Jude Medical, Topera, Biosense Webster, Daiichi Sankyo, SentreHeart and Speaker’s Bureau Honoraria from Biosense Webster, Biotronik, Pfizer, Topera, Bristol-Myers Squibb; Bayer, Sano Aventis and research grants by Cardiofocus. AM received speaker’s honoraria and travel grants from Medtronic, Biosense Webster and Cardiofocus. K.Y. received an educational and research grant by the Turkish Society of Cardiology. C.E. received travel grants and educational grants by Medtronic. All other authors have no relevant disclosures.

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