Pulmonary vein isolation with radiofrequency ablation followed by cryotherapy: a novel strategy to improve clinical outcomes following catheter ablation of paroxysmal atrial fibrillation

Abstract

Introduction

Pulmonary vein (PV) isolation for atrial fibrillation (AF) often requires repeat procedures due to PV reconnection. We hypothesized that wide area cicumferential ablation using radiofrequency energy (RFA) followed by ostial PV ablation with a cryoablation balloon would reduce the rate of AF recurrence compared with either approach alone.

Methods and results

A retrospective study compared outcomes in the first 25 consecutive patients undergoing PV isolation for paroxysmal AF using the combined approach, to consecutive controls using either approach alone. Demographic and procedural data were collected from a prospective database. Kaplan–Meier curves were used to analyse AF free survival and curves were compared using the log-rank test. Twenty-five patients were included in each group. There were no major complications. Minor complications included two transient phrenic nerve palsies and a haematoma in both the combined groups and the cryoablation alone groups. In the RFA group the only complication was a grounding plate burn. Follow-up was 2.2 years in the RFA group, 1.0 years in the cryoablation group, and 1.4 years in the combined group. All recurrences but one occurred within one year. Freedom from AF was significantly greater in the combined group (80%) compared with the RFA alone group (52%) and the cryoablation alone group (56%, both P < 0.05).

Conclusion

The combined approach was safe and increased single procedure efficacy of PV isolation for AF compared with either technique alone.

AF, Catheter ablation, Outcome, Cryotherapy, Radiofrequency

Introduction

Cather ablation to isolate the pulmonary veins (PV) is a recognized and effective treatment for patients who suffer from paroxysmal atrial fibrillation (AF).^1,2 However, approximately half of these patients will have to undergo a second procedure to achieve this, usually as a result of PV reconnection.^3–5

Although techniques for catheter ablation of AF vary, guidelines suggest the procedural endpoints ought to include PV isolation with confirmation of electrical isolation for all patients.⁶ Pulmonary vein isolation has conventionally been achieved by placing radiofrequency ablation (RFA) lesions either at the PV ostia (segmental ostial isolation or SOI) or at a distance from the ostia to isolate PVs in ipsilateral pairs [wide area circumferential ablation (WACA)]. Each technique has advantages however achieving electrical isolation with wide lines is probably more efficacious.^7–9

Wide area circumferential ablation using a conventional ablation catheter is reliant upon placing contiguous lesions point-by-point to produce confluent linear lesions, which is technically challenging. Recovery of tissue forming gaps in these lines has been the Achilles heel of this technique. For this reason there has been considerable interest in the development of balloon-based technologies such as the cryoablation balloons, which should theoretically create a continuous circular lesion at the PV ostia with a single application.

We sought to evaluate the safety and efficacy of a novel approach using RFA to perform WACA with confirmation of PV electrical isolation, followed by selective PV ostial ablation with a cryoballoon creating two parallel lines of block. We hypothesized that this approach will improve the single procedure efficacy of catheter ablation for AF.

Methods

Single procedure efficacy of catheter ablation for paroxysmal AF using the combined approach was compared with consecutive historical controls using either technology alone between April 2006 and August 2009. All procedural data and baseline patient information were obtained from a prospective registry. All patients had symptomatic paroxysmal AF and had failed at least one antiarrhythmic drug. All patients underwent computed tomography scanning to allow three-dimensional (3D) reconstruction of the left atrium.

Periprocedural management

If patients were on warfarin this was stopped five days preprocedure and patients self-administered low molecular weight heparin (subcutaneous enoxaparin 1.5 mg/kg o.d.). Transoesophageal echocardiography within 24 h of their procedure was undertaken to exclude intracardiac thrombus. Five thousand units of unfractionated heparin was administered after insertion of sheaths, and a further 5000 units after transseptal puncture. Activated clotting time was checked every 30 min and maintained >300 s with further heparin boluses.

Patients were divided into three groups:

Radiofrequency ablationalone. Our technique has been described previously.¹ In brief, procedures were performed using local anaesthetic and conscious sedation using a combination of midazolam and diamorphine. Three right femoral venous sheaths were used to deliver a quadripolar catheter to the coronary sinus and perform two separate transseptal punctures (Mullin's sheath, Endry's needle; Cook Medical, IN, USA). A circular mapping catheter (Orbiter PV; Bard EP, Lowell, MA, USA) was used to map the PVs and confirm electrical isolation. Ablation was guided using Cartomerge as described previously¹⁰ and energy was delivered using an irrigated F curve 3.5 mm ablation catheter (Navistar Thermocool, Biosense Webster, Diamond Bar, CA, USA). Patients underwent WACA, with lesions placed 1–2 cm outside the PV ostia to isolate them in ipsilateral pairs, with electrical isolation as the procedural endpoint. Power was limited to 30 W and flow was adjusted from 2 mL/min up to 30 mL/min to achieve this.

Radiofrequency energy at a particular site was delivered either until electrogram amplitude was reduced by ≥80% or until a maximum of 60 s if the amplitude did not diminish to this extent.

Cryoablation alone. Patients underwent cryoablation of all PVs using an appropriately sized cryoablation balloon (Arctic Front, Medtronic, CA, USA). The technique has been described in detail previously.¹¹ As in the RFA group, three femoral venous sheaths were placed, with a quadripolar catheter placed in the coronary sinus and a circular mapping catheter introduced to the left atrium after transseptal puncture. A second transseptal puncture was made, and a 15Fr FlexCath sheath (CryoCath, Medtronic, CA, USA) was exchanged into the left atrium over an extra stiff 180 cm long 0.032 guide wire. This was used to deliver either a 23 or 28 mm cryoablation balloon. Either a 28 or 23 mm balloon (or both) was used depending on PV angiography. Adequate PV occlusion was demonstrated by retrograde PV angiography. At least two 5 min freezes were performed in each PV. Temperatures of ≤40°C were considered adequate for cryoablation. During ablation of the right-sided veins, the quadripolar catheter in the coronary sinus was moved to the superior vena cava and used to pace the phrenic nerve, so that cryoablation could be halted early in the event of phrenic nerve injury. Electrical isolation was determined by the circular mapping catheter. Further freezes were delivered if the veins were not isolated, and if required, focal lesions were applied with a focal 8 mm Cryo catheter (Freezor Max, Cryocath)

Radiofrequency ablation followed by cryoablation.Patients initially underwent WACA as in the RFA group, with electrical isolation demonstrated using the circular mapping catheter. A 0.032 180 cm stiff guide wire was then used to exchange one Cook Mullin's sheath for the FlexCath sheath, which was used to deliver the cryoablation balloon. Two successful freezes achieving temperatures of less than −40°C and lasting 5 min were performed in all PVs (see above). Electrical isolation of each PV was confirmed again at the end of the case.

At the end of cases, in all three groups, PV angiography was performed to exclude PV stenosis.

Follow-up and study endpoints

Patients were discharged the day after the procedure, having stopped all antiarrhythmic medication. While reloading warfarin patients were given daily enoxaparin injections (1.5 mg/kg) until their INR was therapeutic (>2.0). Anticoagulation was continued for a minimum of 3 months and ongoing anticoagulation advised if the CHADS2 score was ≥2 (regardless of rhythm). Patients were followed up at 3 months, and again at 6 months with a 7 day Holter monitor. There was open access to arrhythmia nurse specialists subsequently and further monitoring prompted by symptoms. All patients were contacted for final follow-up. Success was defined as freedom from AF or any other atrial tachyarrhythmia (AT) lasting ≥30 s, and is reported after a single procedure. As early recurrences often settle spontaneously, a 3-month blanking period was observed during which recurrences managed medically and were not counted as failures as per guidelines.⁶

Cost analysis

The procedural costs were estimated for each group to allow comparison between groups and examine the economic feasibility of the combined approach. Many of the procedural costs are equal between groups have been excluded (the coronary sinus catheter, the pulmonary vein mapping catheter, the transoesophageal echocardiogram, the cost of a hospital bed and time in the catheter laboratory). Cost is therefore presented in terms of incremental cost with each approach, rather than total cost which will vary substantially between centres and countries. Cost is presented in pounds sterling, but at the time of writing 1 pound sterling = 1.60 US dollars or 1.15 euros.

Statistical analysis

Continuous data are presented as mean ± standard deviation if normally distributed or as median (range) if not. Differences between groups were tested using the Student's t-test or χ² test as appropriate. Kaplan–Meier curves were used to analyse AF free survival and curves were compared using the log-rank test. A P value of less than 0.05 was considered to be statistically significant.

Results

There were 25 patients in each group. No differences in the baseline factors of the three groups were found, although follow-up was longer in patients in the RFA alone group (Table 1).

Table 1

Baseline characteristics. Patient demographics, procedural details, and outcome

	RFA only	Cryo only	RFA & Cryo
Patient demographics
Number	25	25	25
Male	13 (52)	18 (72)	21 (84)a
Age	56 ± 10 years	56 ± 10 years	56 ± 12 years
AF duration	68 ± 61 months	68 ± 56 months	61 ± 53 months
Hypertension	7 (28)	8 (32)	8 (32)
Diabetes	2 (8)	2 (8)	0 (0)
IHD	0 (0)	3 (12)	1 (4)
Stroke	1 (4)	0 (0)	1 (4)
High cholesterol	1 (4)	3 (12)	3 (12)
LVSD	3 (16)	2 (8)	0 (0)
Procedural details
Procedure time (min)	197 (110–394)	185 (115–273)	229 (160–439)
Fluoroscopy time (min)	35 (16–72)	45 (13–73)	36.5 (20–110)
28 mm balloon used		22(88)	21(84)
23 mm balloon used		5(20)	5(20)
Outcome
Follow-up	2.2 (0.8–4.4) yearsa	1 (0.6–3.2) years	1.4 (1.0–2.1) years
Freedom from AF (off drugs)	52 (48)%	56 (52)%	80 (80)%a
Recurrence AF/AT	8/4	9/2	3/2

^aStatistical significance with P < 0.05, and was observed for gender between RFA only and Cryo & RFA groups, for length of follow-up between RFA only group and both other groups, and for freedom from AF between RFA & Cryo group and other two groups. Categorical values as n (%). RFA, radiofrequency ablation; Cryo, cryotherapy; AF, atrial fibrillation, IHD, ischaemic heart disease; LVSD, left ventricular systolic dysfunction; AT, atrial tachycardia.

Procedure

All PVs in all patients were successfully electrically isolated acutely during the index procedure. In the RFA alone and combination groups this was achieved during WACA. In six patients, all veins could not be isolated with the cryoballoon alone and hence point lesions were added. In total, 11 veins could not be isolated with the cryoballoon (up to three in one patient), including three left superior PVs, five left inferior PVs, and three right inferior PVs (all right superior PVs were isolated with the balloon). Total procedure and X-ray time was not significantly different in the three groups (Table 1).

There were no major complications (defined as requiring an extended inpatient stay, causing long-term sequelae or requiring an interventional procedure). There were the same three minor complications in both the combined group and the cryoablation alone group: two phrenic nerve palsies that recovered by 3 months and one groin haematoma. There was one minor complication in the RFA group: a grounding plate burn. There were no PV stenoses identified in any of the groups. At the time of discharge all patients were in sinus rhythm.

Follow-up

Follow-up ranged from 0.6 to 4.4 years, with a median per group ranging from 1.0 to 2.2 years. Figure 1 shows the AF free survival in each group, with only one recurrence of arrhythmia occurring later than year. Although there was no difference in the proportion of patients free from AF/AT in the cryoablation alone or RFA alone groups (56% vs. 52%, P = 0.995), there were a greater proportion free from AF/AT in the combined group (80%, P = 0.037 compared with RFA alone group, or P = 0.048 compared with cryoablation group). The number needed to treat with the combined approach to prevent one recurrence of AF was 2.9 compared with the cryoablation alone group, or 3.2 compared with the RFA alone group.

Figure 1

Atrial fibrillation free survival. Kaplan–Meier curves showing freedom from atrial fibrillation and other atrial tachyarrhythmia in each of the three drugs. Curves were compared using the log-rank test.

Procedural cost

The procedural cost for each group is shown in Table 2. Catheter ablation was cheapest in the RFA group, the cryoablation group was £800 more than the RFA group, and the combined group was £2100 more expensive than the RFA group. Using the number needed to treat of 3.2 to prevent one recurrence of AF/AT for the combined approach compared with the RFA alone group, the cost of preventing one recurrence was £6720.

Table 2

Costs for consumables which vary between groups in Pounds Sterling

	CARTO	Cryo sheath	Cryoballoon	RFA catheter	Mullin's sheath	Total
RFA alone	400	0	0	800	200	1400
Cryo alone	0	300	1800	0	100	2200
RFA and Cryo	400	300	1800	800	200	3500

Costs in pounds sterling for consumables in each of the three groups. Costs that are equal between groups (the coronary sinus catheter, the pulmonary vein mapping catheter, the transoesophageal echocardiogram, the cost of a hospital bed and time in the catheter laboratory) have been excluded. RFA, radiofrequency ablation; Cryo, cryoablation.

Discussion

The main finding of this study is that a combined approach of WACA using RFA followed by ostial ablation with a cryoballoon was safe and led to a significant increase in the proportion of patients achieving freedom from AF after a single procedure compared with RFA or cryoablation alone. There was no difference in efficacy between the RFA alone or cryoablation alone strategies. There was a trend towards longer procedure and fluoroscopy times with the combined approach, although this was by a small margin and did not reach statistical significance in this small cohort. The increased procedural cost with the combined approach may remain cost-effective by reducing the need for repeat procedures.

Wide area circumferential ablation and segmental ostial isolation as approaches to pulmonary vein isolation

There are theoretical advantages to PV isolation by either WACA or SOI. Proponents of WACA point out that it encloses proximal/ostial PV triggers that SOI might miss, that it reduces the remaining surface area of the left atrium available to fibrillate, it may encircle more ganglionic plexi^12,13 and that it may interrupt ostial and posterior wall complex fractionated electrograms.¹⁴

Advocates of SOI suggest that it may be easier to perform without necessarily requiring use of 3D-mapping systems. The strategy of creating long WACA lines by placing contiguous point lesions is also vulnerable to gaps where tissue has recovered, which is associated with PV reconnection and recurrence of AF and may also be proarrhythmic in itself creating the substrate for atrial tachycardias.⁴ Evidence is still conflicting as to which technique is most effective.^7,8 However, many groups have moved towards WACA rather than SOI, as although efficacy may be comparable, there is an increased risk of PV stenosis with SOI.⁶

One small case series examined the feasibility of performing both lesion sets together during the same procedure using RFA.¹⁵ The technique appeared successful without excessive procedure times or complications, although the authors published nothing further using this technique.

The results that we obtain for RFA only are similar to what other centres have shown. For example, Wilber et al.¹⁶ report freedom from AF or any other ATs at 9 months in 63%, and 13% of patients underwent repeat procedures during an initial blanking period to achieve this. Our results report freedom from AF after a single procedure over a longer follow-up, and it is well recognized there is a gradual attrition in success rates over time. It can be seen from our Kaplan–Meier curve that freedom from AF/AT after a single procedure at 9 months is 60%. This is very comparable to the 63% success reported by Wilber et al. after repeat procedures, which would presumably be exactly 50% if the 13% requiring repeat procedures were not counted as successes. Similar success rates were also recently reported by the Bordeaux group.¹⁷

Radiofrequency ablation and cryoablation alone for pulmonary vein isolation

Cryothermal energy has been used for surgical ablation of arrhythmias for a number of years and has been reported from animal experiments to produce less endothelial disruption and overlying thrombus formation compared with RFA energy.¹⁸ Furthermore, cryothermy may be associated with a lower risk of PV stenosis^19–21 and has been shown to be feasible and safe in the treatment of AF in humans^18,22 with a similar success rate as RFA in achieving PV isolation. The published single procedure success rates vary widely for both RFA and cryotherapy, ranging from 60 to 86% at one year for WACA by RFA, and from 49 to 86% using cryoablation.^1,23–25 This non-randomized comparison showed equivalent efficacy of these two techniques in the treatment of AF. However, there is no randomized evidence yet to compare these modalities. Cryoablation has raised a great deal of interest as it is relatively simple and quick to perform, and although the position of the lesion is comparable to SOI, it appears not to carry the same risk of PV stenosis.^21–23 However, it is worth bearing in mind that 24% of patients in the cryoablation alone group required point lesions to isolate the PVs, and it is uncertain if the results would have been equal between the cryoablation alone and RFA alone groups if the cryobaloon was used as a stand alone technique. This may have implications for non-electrophysiologists who might be considering this strategy for PV isolation.

Potential benefits of the combined approach

The reliance of WACA on continuity between point lesions to create lasting PV isolation is its greatest drawback.⁴ Tissue injury and oedema may cause temporary conduction block between lesions which subsequently recovers without forming scar. The use of these two modalities in combination may therefore offer synergy by creating two rings of scar to insulate the pulmonary veins. This may draw on the advantages of each strategy, but limiting the risk of pulmonary vein stenosis by using the cryoballoon for SOI. The creation of continuous circular lesions using the cryoballoon is also particularly desirable in this context, since it is difficult to verify a second line of block (as the PVs are electrically silent after WACA). The combined approach produced a 28 and 24% absolute increase in freedom from AF compared with RFA or cryoablation alone, respectively.

An argument can be made for doing either line first, but our decision on RFA followed by cryoablation was based on the hypothesis that tissue oedema following RFA can prevent successful lesion creation. This leads to acute success because of electrical stunning of tissue, but reconnection occurs when this recovers. Theoretically cryoablation in oedematous tissue is advantageous since greater water content results in more ice crystal formation, greater tissue destruction and elimination of the stunned tissue.²⁶ Cryotherapy therefore works synergistically with RFA.

Safety of the combined approach

Possible safety concerns using this burn and freeze approach included the risk of perforation and tamponade when applying cryotherapy to a region of the left atrium which had already received RFA. Exchange of long sheaths over a wire also carries a small risk of air embolus. However, neither of these problems arose in the study. Indeed, this approach was safe and well tolerated. In both the cryoablation alone and the combined groups, there was an 8% rate of transient phrenic nerve palsy, although all recovered.

Economic feasibility of the combined approach

With a number needed to treat of 3.2 to prevent one recurrence of AF with the combined approach, the cost of preventing one recurrence was £6720 compared with the RFA alone group. If one ignores for a moment the benefit to the patient and reduced risk from repeat procedures in the combined group and considers only the procedural cost, the cost of preventing one recurrence using the combined approach is likely to be less than that of a repeat procedure in most centres. However, the proportion of patients with recurrent AF that will undergo a repeat procedure is uncertain, and therefore a fuller economic analysis from larger studies is desirable.

Limitations

This small non-randomized study was intended as a feasibility study, aiming to demonstrate the safety and efficacy of this new technique. Although Holter monitoring was performed at 6 months, longer term assessment was based on symptoms. This could miss asymptomatic recurrences and should be addressed in future studies. Although central adjudication is essential for reporting of complex data such as echocardiograms or other imaging, it is extremely rare for single centre registries to have central adjudication of routine clinical follow-up (and uncommon for anything but large multicenter RCTs to have adjudication of endpoints. We therefore thought it reasonable for this feasibility study. A properly powered randomized controlled study is underway to determine whether the burn and freeze strategy is superior to either treatment alone in the catheter ablation of paroxysmal AF.

Conclusion

Although catheter ablation is successful in eliminating paroxysmal AF, the need for repeat procedures remains its Achilles’ heel. This study demonstrates the safety and feasibility of an approach combining WACA using RFA and ostial ablation using a cryoballoon. This combined approach was associated with an increased single procedure success rate which likely reflects more effective and lasting PV isolation.

Author contributions

Concept/design was done by R.J.S. and M.H.T.; data collection by M.H.T., V.B., E.D. and A.C.; data analysis/interpretation was conducted by M.H.T., R.J.S. and R.H.; M.H.T. drafted the article; critical revision of article was done by R.J.S., M.J.E., S.S. and R.J.H.; statistics were done by R.J.H. and M.H.T.

Conflict of interest: none declared.