Clinical efficacy of irrigated catheter application of amiodarone during ablation of persistent atrial fibrillation

Abstract

Background

Pharmacological treatment during ablation of persistent atrial fibrillation (AF) is common, but utility of irrigated catheter application of amiodarone during ablation of persistent AF remains unclear.

Hypothesis

Irrigated catheter application of amiodarone improves quality of ablation and long‐term outcomes.

Methods

We enrolled 90 persistent AF patients who underwent catheter ablation. Patients were randomized to the amiodarone group (n = 45) or control group (n = 45). All patients underwent stepwise ablation beginning with isolation of the pulmonary veins. Next, we performed ablation of linear lesions and focal triggers until sinus rhythm (SR) was achieved. The primary endpoint was documented atrial arrhythmia during follow‐up. The secondary endpoint was cardioversion to SR during ablation.

Results

All pulmonary veins were successfully isolated. Conversion of AF to SR occurred more frequently in the amiodarone group than in the control group (33 vs 23 [73.3% vs 51.1%]; P = 0.03). The amiodarone group had lower procedure, radiofrequency, and fluoroscopy times than the control group (167.4 ± 22.5 min vs 186.7 ± 25.3 min; 78.3 ± 14.2 min vs 90.4 ± 15.5 min; and 6.5 ± 1.9 min vs 8.6 ± 2.4 min, respectively; P < 0.05). More importantly, the atrial arrhythmia recurrence‐free survival rates were 80% in the amiodarone group and 60% in the control group during the 14.7 ± 7.5‐month follow‐up (P = 0.043).

Conclusions

Irrigated catheter application of amiodarone during ablation for persistent AF resulted in higher cardioversion rates and lower procedure times and significantly reduced rates of atrial arrhythmia recurrence.

1. INTRODUCTION

Catheter ablation of atrial fibrillation (AF) is becoming increasingly common in clinical practice. In paroxysmal AF, the classical ablation method for circumferential lesions involves electrically isolating the pulmonary veins (PVs), where most AF triggers are located.1, 2, 3, 4, 5 Compared with ablation for paroxysmal AF, catheter ablation for persistent AF is more challenging and is associated with less favorable outcomes.6 In fact, ablation targeting the substrate that maintains fibrillation is often performed in addition to PV isolation.7, 8 The 2 most common techniques for substrate modification are the creation of linear lesions and ablation to eliminate complex fractionated atrial electrograms (CFAEs).2 The Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF) trial showed that additional ablations beyond isolated PVs did not improve outcomes in patients with persistent AF,4 as many of the CFAE areas may be passive bystanders that do not play a role in the potentiation of AF and, thus, may not require ablation.6, 9 Linear ablation is performed after PV isolation in a stepwise strategy. During linear ablation, high‐resolution mapping of the catheter and stimulation procedures, such as the administration of isoproterenol in incremental doses, are commonly used to aid in the identification of PV and non‐PV triggers.10 If a non‐PV trigger exists, that trigger should be mapped and ablated. For example, ablation is performed by isolating the superior vena cava or by ablating the endocardium of the vena coronaria.11 In this study, the stepwise ablation approach began with PV isolation and proceeded with the ablation of linear lesions. Trigger ablation was performed until sinus rhythm (SR) was achieved.

According to previous recommendations,6, 12 amiodarone and other antiarrhythmic drugs (AADs) are often used for the termination of AF and the maintenance of SR. Many studies have examined the use of periprocedural amiodarone during AF ablation6, 10, 13; however, little is known about the effect of irrigated catheter application of amiodarone on ablation outcomes in AF patients. Wang et al. reported that epicardial application of amiodarone‐releasing adhesive hydrogel is a less‐invasive, well‐tolerated, quick and effective therapeutic option for the prevention of postoperative AF, with minimal risks for extracardiac adverse side effects.14 Thus, we investigated the effect of irrigated catheter application of amiodarone in patients with persistent AF who underwent catheter ablation.

2. METHODS

2.1. Study population

The study was approved by the ethics committee of Nanfang Hospital. This study enrolled 90 patients with persistent AF who were treated with ablation from January 2014 to February 2017. Patients were included only if the studied ablation was their first procedure. Patients with chronic hepatic disease, concomitant treatment with other class 1 or 2 AADs, severe pulmonary disease, or hyperthyroidism were excluded from the study. Patients were also excluded if they had undergone prior ablation procedures for AF. Written informed consent forms were obtained before patients were enrolled in the study. Patients were randomized to either the irrigated catheter application of amiodarone group (n = 45) or the control group (n = 45), in which ablation was performed without amiodarone administration. The randomization schema was created by a computer, and the operator and patients were blinded to the study details.

2.2. Procedural methods

Before the ablation procedure, all patients received either low‐molecular‐weight heparin for ≥7 days or continuous warfarin therapy for 1 month, and all patients underwent transthoracic and transesophageal echocardiography to exclude the presence of atrial thrombi. A decapolar electrode catheter was positioned in the coronary sinus for pacing and recording. In all patients, the left atrium (LA) was accessed using a transseptal puncture technique with a guidewire that was introduced by an 8.5‐F long sheath. After transseptal puncture, anticoagulation was achieved with heparin using a single 100‐IU/kg bolus followed by continuous intravenous (IV) infusion at 1000 IU/h. Another transseptal puncture was performed to place an additional 8.5‐F long sheath.

2.3. Mapping and radiofrequency ablation

A PentaRay catheter (Biosense Webster, Inc., Diamond Bar, CA) was introduced into the LA for electroanatomic mapping. The PentaRay catheter was localized to the PV using fluoroscopy and the CARTO‐3 mapping system (Biosense Webster). After careful mapping, the images were used to guide the ablation.

Before ablation, mild sedation was achieved using IV fentanyl and propofol. First, all patients underwent circumferential ablation of the PVs and PV isolation was confirmed. PV exit block was confirmed after PV ablation. A standard pacing technique was used to map the catheter inside the PV ostia and confirm the exit block at that point. If the PV‐LA conduction persisted, attempts were made to identify the conduction gaps and eliminate them by reapplying radiofrequency (RF) energy. If the AF terminated after isolation of all PVs, we attempted to induce AF by administering IV isoproterenol at 1.0‐20.0 μg/min. However, if AF persisted after complete PV isolation, substrate‐based ablations of the linear lesions were then initiated. Bidirectional block was confirmed during linear ablations. If SR was not achieved following linear ablation, we performed focal trigger mapping and ablation. Finally, synchronized electrical cardioversion was performed if the patient remained in AF at the end of the ablation procedure. After ablation, the isoproterenol challenge was performed to reveal non‐PV triggers or to reveal PV reconnection. The procedural endpoint was defined by complete elimination or dissociation of the pulmonary potentials and ablation of sustained or nonsustained premature atrial contractions (arising outside the PV antrum) induced during isoproterenol infusion.

A skilled operator performed the ablation procedure. RF ablation was delivered using an irrigated‐tip ST catheter with a power output of 30 to 35 W, and the temperature of the tip was maintained at <43°C. The contact force was 8 to 20 g, and the ablation time was 20 to 35 seconds at every ablation point. Heparinized 5% glucose was used to dilute amiodarone to a concentration of 300 μg/mL for the amiodarone group, whereas the catheter was irrigated using 0.9% heparin sodium chloride (normal saline) in the control group. Ablation was performed during irrigated catheter administration of amiodarone. In the control group, patients were not administered amiodarone before or during the ablation period. The average impedances were recorded at the beginning of ablation and every 10 seconds thereafter. Bipolar electrograms were recorded using a Siemens multichannel system at a bandpass between 30 Hz and 500 Hz.

2.4. Plasma concentrations of amiodarone

The total dose of endocardial amiodarone administration was calculated according to the consumption of normal saline. Plasma concentrations of amiodarone were also measured in blood drawn from a peripheral vein and the LA after the ablation procedure was completed. The standard method of high‐performance liquid chromatography (HP 1090 Series; Hewlett‐Packard, Palo Alto, CA) was used to perform the amiodarone assays.

2.5. Follow‐up

After the ablation procedure, patients were hospitalized overnight with telemetry monitoring. Oral anticoagulation with warfarin was administered the day after the procedure with a target international normalized ratio of 2.0 to 3.0. IV amiodarone was not continuously administered unless the AF was persistent or recurrent. During the 3‐month blanking period, oral amiodarone was prescribed to all patients. The method of oral amiodarone administration was 600 mg/d for 10 days, then 400 mg/d for 10 days and, finally, 200 mg/d for 70 days. Oral amiodarone was discontinued in every patient after the blanking period. Any atrial arrhythmia episodes that occurred during the blanking period after the procedure were not considered as recurrences. The patients returned for clinical evaluations at 3, 6, and 12 months after the ablation procedure and every 6 months thereafter for cardiovascular evaluation. Patients were instructed to call a clinical coordinator if they experienced symptoms that were suggestive of arrhythmia. The follow‐up screening included (1) symptoms of AF; (2) a 12‐lead electrocardiogram (ECG) at each follow‐up visit; and (3) 24‐hour Holter monitoring, if necessary. Recurrence of atrial arrhythmia was defined as AF, atrial flutter (AFL), or atrial tachycardia (AT) with a > 30‐second duration. The desired outcome was that the patient was free of atrial arrhythmia during follow‐up.

2.6. Statistical analysis

Continuous variables are expressed as mean ± SD. The Student t test was used to compare the 2 groups. Categorical variables were compared using χ² analysis. The time to atrial arrhythmia recurrence was estimated by the Kaplan–Meier method, and comparisons were made with the log‐rank test. Univariate Cox proportional hazards models were used to identify significant predictors of atrial arrhythmia recurrence. A 2‐sided P value <0.05 indicated statistical significance. Data were analyzed using the SPSS statistical package for Windows, version 20.0 (IBM Corp., Armonk, NY).

3. RESULTS

3.1. Patient characteristics

Ninety persistent AF patients were studied, with 45 patients in the amiodarone group and 45 patients in the control group (Table 1). Overall, the patients were 58.1 ± 13.1 years of age and were mostly male (64.4%). The mean duration of AF episodes was 17.9 ± 16.4 months. Hypertension was present in 46.7% of the patients, whereas coronary heart disease (30%) and diabetes mellitus (25.6%) were less common; additionally, 24.4% of the patients had a previous history of stroke. The average left ventricular ejection fraction was 51.7% ± 7.8%, and the average left atrial dimension (LAD) was 41.2 ± 4.6 mm. The average CHA₂DS₂‐VASc score was 2.3 ± 1.1. Baseline characteristics were not significantly different between the 2 groups.

Table 1.

Comparison of baseline characteristics between the 2 groups

	Amiodarone Group, n = 45	Control Group, n = 45	P Value
Age, y	57.0 ± 12.6	59.2 ± 13.6	0.427
Sex, M/F, n	29/16	29/16	1.000
BMI, kg/m2	23.5 ± 2.8	23.2 ± 2.7	0.577
Duration of AF, mo	16.8 ± 14.5	19.0 ± 16.2	0.534
LAD, mm	40.4 ± 3.8	42.0 ± 5.1	0.105
LVEF, %	51.4 ± 7.1	52.0 ± 8.6	0.709
HTN	19 (42.2)	23 (51.1)	0.404
DM	11 (24.4)	12 (26.7)	0.812
CAD	12 (26.7)	15 (33.3)	0.496
Stroke	10 (22.2)	12 (26.7)	0.628
CHA2DS2‐VASc score	2.2 ± 1.2	2.4 ± 1.0	0.294
Antiarrhythmic drugs
β‐Blockers	24 (53.3)	26 (57.8)	0.676
CCB	8 (17.8)	13 (28.9)	0.217
Digoxin	12 (26.7)	9 (20)	0.460

Abbreviations: BMI, body mass index; CAD, coronary artery disease; CCB, calcium channel blockers; CHA₂DS₂‐VASc, congestive HF, HTN, age > 75 y, DM, stroke/TIA, vascular disease, age 65–74 y, sex category (female); DM, diabetes mellitus; F, female; HF, heart failure; HTN, hypertension; LAD, left atrial dimension; LVEF, left ventricular ejection fraction; M, male; SD, standard deviation; TIA, transient ischemic attack.

Data are presented as n (%) or mean ± SD.

3.2. Ablation outcomes

The study profile of catheter ablation for persistent AF is shown in Figure 1. All PVs were successfully isolated in all patients. After PV isolation alone, 18 patients in the amiodarone group and 11 patients in the control group converted to SR (P = 0.114). Linear ablations were performed in the remaining 61 patients, and 14 patients converted to SR, including 8 patients in the amiodarone group and 6 patients in the control group (P = 0.058). Then, trigger mapping and ablation were performed in the remaining 47 patients. Finally, 7 patients in the amiodarone group and 6 patients in the control group converted to SR after trigger ablation (P = 0.03). The remaining 34 patients, including 12 patients in the amiodarone group and 22 patients in the control group, were successfully electrically converted to SR by the end of the procedure.

Figure 1.

Study profile detailing the outcomes of the 90 patients who underwent catheter ablation for persistent AF. Abbreviations: AF, atrial fibrillation; PV, pulmonary vein; SR, sinus rhythm

The total procedure, catheter ablation, and fluoroscopy times were shorter in the amiodarone group than in the control group (167.4 ± 22.5 min vs 186.7 ± 25.3 min; 78.3 ± 14.2 min vs 90.4 ± 15.5 min; and 6.5 ± 1.9 min vs 8.6 ± 2.4 min, respectively; P < 0.05). The total average impedances were significantly different between the 2 groups at every recording time point (145.4 ± 2.5 Ω vs 140.7 ± 2.3 Ω; 142.2 ± 2.8 Ω vs 137.3 ± 1.9 Ω; 137.5 ± 2.2 Ω vs 134.5 ± 2.7 Ω; and 134.8 ± 2.5 Ω vs 132.5 ± 3.7 Ω, respectively; P < 0.05).

Two patients in the control group experienced recurrent AF after ablation in hospital. IV amiodarone was used continuously until the AF converted to SR. None of the patients in the amiodarone group experienced recurrent AF while in the hospital.

3.3. Plasma concentration of amiodarone

The total dose of amiodarone applied via an irrigated catheter was 432 ± 76 mg. In the amiodarone group, the blood concentration of amiodarone in the LA (1.6 ± 0.5 μg/mL) was much higher than that in the peripheral plasma (0.8 ± 0.3 μg/mL; P < 0.01). In the control group, no amiodarone was used during the procedure, and the plasma concentration of amiodarone was not tested.

3.4. Primary endpoint at follow‐up

At the 14.7 ± 7.5‐month (3–36‐month) follow‐up, the atrial arrhythmia recurrence‐free survival rates were 80% in the amiodarone group and 60% in the control group (P = 0.043). Atrial arrhythmia recurrence occurred in 9 patients (20%) in the amiodarone group and 18 patients (40%) in the control group, including 6 recurrent AF, 1 AFL, and 2 AT cases in the amiodarone group and 9 AF, 5 AFL, and 4 AT cases in the control group. The Kaplan–Meier curve comparing the cumulative freedom from atrial arrhythmia recurrence without AADs is shown in Figure 2. The results were confirmed by ECG or 24‐hour Holter monitoring. Baseline variables were fitted to a univariate Cox model to assess their prognostic role regarding atrial arrhythmia recurrence during long‐term follow‐up. Amiodarone administration, duration of AF, LAD, and β‐blocker administration were significantly associated with the endpoint of recurrence‐free survival (Table 2).

Figure 2.

Kaplan–Meier curves comparing atrial arrhythmia recurrence‐free survival between study groups after ablation

Table 2.

Cox regression analyses for predictors of long‐term recurrence of atrial arrhythmia

	HR	95% CI	P Value
Age, y	1.02	0.99–1.05	0.214
Male sex	1.30	0.59–2.84	0.513
BMI	1.05	0.92–1.21	0.452
Duration of AF	1.04	1.02–1.06	<0.001
Duration of AF ≥12 mo	3.73	1.56–8.91	0.003
LAD	1.09	1.01–1.19	0.036
LAD ≥41 mm	2.34	1.06–5.17	0.036
LVEF	1.00	0.92–1.01	0.155
HTN	1.12	0.56–2.55	0.653
DM	1.17	0.46–2.95	0.745
CAD	1.57	0.58–4.24	0.370
Stroke	1.02	0.42–2.43	0.977
CHA2DS2‐VASc score	0.78	0.53–1.17	0.232
β‐Blockers	0.34	0.13–0.84	0.02
Amiodarone vs control	2.21	1.01–4.95	0.045
Conversion to SR during ablation	1.34	0.66–2.72	0.425

Abbreviations: AF, atrial fibrillation; BMI, body mass index; CAD, coronary artery disease; CHA₂DS₂‐VASc, congestive HF, HTN, age > 75 y, DM, stroke/TIA, vascular disease, age 65–74 y, sex category (female); CI, confidence interval; DM, diabetes mellitus; HF, heart failure; HR, hazard ratio; HTN, hypertension; LAD, left atrial dimension; LVEF, left ventricular ejection fraction; SR, sinus rhythm; TIA, transient ischemic attack.

3.5. Adverse events

All periprocedural adverse events in patients who underwent any ablation procedure were recorded. Nine patients (10%) experienced side effects that were potentially related to the ablation procedure, including 7 patients in the amiodarone group and 2 patients in the control group (P = 0.079). One sedation‐related complication occurred in the amiodarone group, and 1 occurred in the control group. Three patients in the amiodarone group presented with sinus bradycardia during ablation, which was reversed before discharge. Two patients in the amiodarone group presented with hypotension during the ablation, which was mitigated with dopamine. Serious adverse events included 1 instance of cardiac tamponade that occurred in the amiodarone group after ablation and 1 instance of transient ischemic attack that occurred in the control group during ablation.

During follow‐up, Holter monitoring and 12‐lead ECG identified 1 patient with asymptomatic episodes of second‐degree atrioventricular block type 2 and 1 patient with asymptomatic nodal rhythm in the amiodarone group. Both patients recovered after amiodarone was discontinued. No major complications were observed during follow‐up.

4. DISCUSSION

This is the first prospective randomized study to evaluate the novel approach of irrigated catheter application of amiodarone for patients with persistent AF who underwent ablation. The novel strategy of ablation for persistent AF was both safe and efficient. Moreover, the present study determined that (1) irrigated catheter application of amiodarone resulted in a higher ratio of conversion to SR during the ablation procedure; (2) the amiodarone group had lower procedural, RF, and fluoroscopy times than did the control group; and (3) at the 14.7 ± 7.5‐month follow‐up, the amiodarone group exhibited a higher success rate, as indicated by atrial arrhythmia recurrence‐free survival.

4.1. Acute role of irrigated catheter application of amiodarone

First, the main findings of the present study were that the new ablation approach could increase the rate of conversion to SR during ablation (Figure 1). This result is similar to that of a previous study in which periprocedural amiodarone treatment was associated with a higher termination rate during ablation.6 Several reasons may account for these findings. The plasma concentration of amiodarone in the LA was higher than that in the peripheral plasma, which may be related to the delivery of amiodarone through an irrigated catheter. Amiodarone also prolonged the effective refractory period of atrial myocytes, which was dependent on the dose of amiodarone and the duration of AF.15 However, the mechanism of action has not yet been established. Wang et al. reported that the bilateral atrial epicardial application of amiodarone‐releasing hydrogel significantly reduced the incidence of postoperative AF compared with the control group.14 This method of application specifically increased the concentration of amiodarone in the atrial tissue and was locally effective in the atria. Therefore, the efficacy of amiodarone, in this case, was due to a high concentration of localized amiodarone during intracardial diffusion. The methodology used in our study was similar to that of the study by Wang. In addition, irrigated catheter application of amiodarone can result in close contact of the drug with the PVs, and amiodarone may be able to penetrate PV tissues. Second, in our study, amiodarone administration was associated with lower procedural, RF, and ablation times due to fewer ablation targets. This result is similar to that from previous periprocedural amiodarone studies.6, 10

Furthermore, some patients in the amiodarone group presented with sinus bradycardia and hypotension during ablation. All episodes were reversed by dopamine treatment, which indicates the influence of amiodarone.

4.2. Long‐term outcomes

This was the first study to prospectively validate the impact of irrigated catheter application of amiodarone therapy on long‐term outcomes following AF ablation. Although there are many ablation strategies for persistent AF, PV isolation is the basic method.16 In a meta‐analysis, Voskoboinik et al. reported that the 12‐month arrhythmia‐free survival was 66.7% among persistent AF patients who only underwent PV isolation.17 In this study, the atrial arrhythmia recurrence‐free survival rate was 60% in the control group, which was similar to that in a previous report. Interestingly, the atrial arrhythmia recurrence‐free survival rate was higher in the amiodarone group than in the control group (80% vs 60%; P = 0.043). One substantial reason may account for this finding: patients in the control group had more recurrences of atrial arrhythmia, which might be because substrate ablation was performed more frequently in the control group than in the amiodarone group. It is well known that incomplete lines create a substrate for post‐ablation AFL and tachycardia, even when ablation is performed by a very experienced surgeon.

Many studies have described the protective effects of amiodarone when administered during AF ablation. Additionally, periprocedural amiodarone can reduce ablation times,6 terminate AF,13 and halve atrial arrhythmia rates related to hospitalization and cardioversion rates (without long‐term effects).18 Mohanty et al. reported that periprocedural amiodarone was associated with a higher termination rate during ablation and lower RF ablation and procedural times.10 However, periprocedural amiodarone increased the late recurrence rate by masking non‐PV triggers. In this study, irrigated catheter application of amiodarone was associated with a better atrial arrhythmia recurrence‐free survival rate, which was very different from that in previous reports. The mechanism underlying this association is unclear. Several factors may explain our findings. First, osmolarity irrigation and ablation impedance were different between groups. Nguyen et al. reported that decreased sodium in the irrigation fluid may lead to increased, deeper, and more effective RF lesions due to impedance mismatches.19 Indeed, in our study, the impedance was lower in the amiodarone group. To the best of our knowledge, the recurrence of arrhythmia after PV isolation was predominantly caused by PV reconduction.20 Therefore, deeper lesions may lead to better outcomes. Second, the application method of amiodarone was different. Only oral amiodarone was prescribed to patients in previous reports, whereas in our study, irrigated catheter application of amiodarone was performed during ablation. Thus, the effect may have been largely driven by the new approach of amiodarone administration during ablation. Finally, a stepwise approach was adopted to achieve the desired endpoint of termination of AF; compared with the amiodarone group, the control group underwent additional ablation that led to more unnecessary and potentially proarrhythmic ablation.

4.3. Predictors for atrial arrhythmia recurrence

There were many predictors of atrial arrhythmia recurrence after AF ablation, such as the LAD, the duration of AF and, especially, long‐standing persistent AF. The duration of AF, the LAD, and β‐blocker and amiodarone administration were significantly associated with the endpoint of recurrence‐free survival in the univariate Cox model. We concluded that irrigated catheter application of amiodarone may be a predictor of atrial arrhythmia recurrence‐free survival.

5. CONCLUSION

Irrigated catheter application of amiodarone was both safe and efficient during ablation for persistent AF. Irrigated catheter application of amiodarone was associated with an increased rate of conversion to SR during stepwise ablation for persistent AF and with a higher rate of atrial arrhythmia recurrence‐free survival. Based on these findings, irrigated catheter application of amiodarone should be considered for persistent AF ablation.

Conflicts of interest

The authors declare no potential conflicts of interest.

Huang X, Chen Y, Huang Y, et al. Clinical efficacy of irrigated catheter application of amiodarone during ablation of persistent atrial fibrillation. Clin Cardiol. 2017;40:1333–1338. 10.1002/clc.22835