Cryoballoon versus Radiofrequency for Pulmonary Vein Isolation

Cryoballoon versus Radiofrequency for Pulmonary Vein Isolation:

Clinical and Economic perspectives after Fire and Ice

Dr Ahran Arnold MBBS BSc MRCP

Academic Clinical Fellow in Cardiology, Imperial College London

Specialist Registrar in Cardiology, Imperial College Healthcare NHS Trust

Catheter Ablation of AF

Catheter ablation of paroxysmal atrial fibrillation (AF) for symptom reduction in drug-refractory paroxysmal AF is a class I level of evidence A recommendation in the most recent European Society of Cardiology (ESC) guidelines for the management of AF (Kirchhof et al., 2016). Most recently MANTRA-PAF 5 year follow up data shows that in a non-blinded randomized controlled trial (RCT), ablation as initial therapy is superior to anti-arrhythmic drugs (AAD) for maintenance of sinus rhythm (Nielsen et al., 2016). Freedom from AF was lower in ablation compared to AAD with a relative risk of 0.82 (Confidence Interval (CI): 0.73 – 0.93).

Radiofrequency Ablation

The tradition technique is the use of radiofrequency (RF) energy to isolate the pulmonary veins, where Haissaguerre et al (Haissaguerre et al., 1998) identified the ectopy that trigger AF in a significant proportion of patients. This is a time consuming procedure with high technical expertise requirements and a steep learning curve. Complex three-dimensional electro-anatomical mapping is required after trans-septal puncture to access the left atrium from the femoral vein. This mapping may permit limitation of fluoroscopy. The ablation itself requires point-by-point application of RF energy to isolate the pulmonary veins in, for example, a wide area circumferential ablation (WACA).

Cryoablation

A newer technology has been developed in an attempt to overcome some of these purported drawbacks of RF energy. The Cryoballoon (CB) ablation approach uses trans-septal puncture to access the left atrium but does not require electro-anatomical mapping. Instead a balloon is positioned in the pulmonary vein ostium under fluoroscopic guidance and a single shot of freezing energy is applied to the circumference of the inflated balloon to produce a circular lesion. The extra radiation is felt to be the cost of reduced procedure time and an easier technique. The more recent identification that pulmonary vein isolation (PVI) alone rather, than accompanied by linear substrate or complex-fractionated-atrial-electrogram (CFAE) ablation, seems to be the optimal first procedure lend credence to the Cryoballoon concept as a faster, easier but acceptable alternative.

Head-to-head comparisons

There are efficacy, safety and economic perspectives to the debate over the ideal technology. Even though we still await a properly sham controlled double-blinded RCT of ablation versus AAD for the efficacy of ablation to eliminate the obvious potential placebo effect of a highly invasive procedure, there have now been multiple observation and randomized head-head comparisons of RF ablation against Cryoballoon. The advantage of both procedures involving invasive ablation is that the need for blinding is mitigated, so we can draw conclusions from open label trials with greater confidence.

Fire And Ice

Kuck et al’s Fire and Ice trial (Kuck et al., 2016) is the largest and most recent randomized head-to-head comparison of cryo versus RF. An open label, multi-center, non-inferiority study, its primary end-point was time to recurrence of AF excluding the ninety-day blanking period (where early recurrence of AF is not deemed to be necessarily predictive of longer term treatment failure). With 376 in the RF arm and 274 in the CB arm the baseline characteristics were balanced and there was a 35% AF recurrence rate at one year and CB was non-inferior to RF (RR 0.96, CI 0.76 – 1.22, p<0.001 for non-inferiority). As the largest randomized trial there were notable secondary endpoint results. Procedure time was significantly longer with RF but standard deviations overlapped (RF 140.9 +/- 54.9 mins versus CB 124.4 +/-39.0 mins) and fluoroscopy time was longer with CB than RF (CB 21.7 +/- 13.9 mins versus RF 16.6+/- 17.8 mins) again with overlap of SD. There was a trend toward more non-AF atrial arrhythmia (atrial flutter and atrial tachycardia) with RF (p = 0.09) and a trend to more effusion including tamponade with RF (p = 0.22). RF ablation may leave ablation gaps that allow for re-entry arrhythmia and more extensive ablation predisposes to effusion, meanwhile electro-anatomical mapping allows less fluoroscopy at the cost of longer procedure time. Thus the intuitive result is borne out by trends in a 762 patient trial.

Other randomized trials

FreezeAF (Luik et al., 2015) was a randomized non-inferiority head-to-head comparison in 315 patients that demonstrated non-inferiority with similar findings to Fire and Ice for fluoroscopy and procedure times. COR (Perez-Castellano et al., 2014) was a small randomized trial of fifty patients that found superiority of RF in the intention-to-treat analysis (p=0.05) and used reveal devices as a gold standard measure of AF recurrence. In the cryoballoon group residual gaps were not closed with further ablation so only cryoballoon application performed (this was the same as Kuck et al but Luik et al allowed touch ups with conventional cryocatheters). Cryo versus RF (Hunter et al., 2015) was a 152 patient randomized trial that found superiority of CB over RF (p = 0.015).

Meta-analyses: Efficacy

As observed earlier the randomized trials provide signals about secondary end-points that did not reach significant in individual trials. All RCTs and observational data have been summarized in a 2016 meta-analysis (Cardoso et al., 2016) that allows exploration of the significance of these trends. With moderate heterogeneity (I² = 30%) they found that for the outcome “freedom from atrial arrhythmia” there was no significant difference between groups in a summary of nineteen trials comprising 7411 patients. Exclusion of observational trials did not change this result. Notably atrial fibrillation and non-AF AT were included in the atrial arrhythmia outcome for this analysis. In reality, post AF ablation atrial tachycardia is a complication of ablation rather than a failure of treatment as such. It is therefore interesting to note that non-AF AT was significantly less likely to occur in the CB group (OR 0.46, CI 0.26 – 0.83) indicating that perhaps if these were excluded from atrial arrhythmia in the primary analysis, CB might be superior. The heterogeneity of outcome definitions across trials makes this difficult to assume without performing laborious individual patient level meta-analysis.

Meta-analyses: Safety

The suspected safety signals are revealed to be statistically significant in the meta-analysis by Cardoso et al. Effusions are less common in CB (OR 0.44, CI 0.28-0.69, p = 0.0004, I² = 0%) and tamponade follows the same pattern with significance (OR 0.31, CI 0.15 – 0.64, I² = 0%, p = 0002). Notably Phrenic Nerve Palsy (PNP) is significantly more frequent in CB (OR 7.4, CI 2.56 – 21.34, p = 0.0002, I² = 0%).

Economic perspectives

Cost-effectiveness analyses (CEA) have been undertaken comparing RF to AAD in multiple studies most recently using the MANTRA-PAF data set to guide Markov modelling (Aronsson et al., 2015; Neyt, Van Brabandt, & Devos, 2013; Reynolds et al., 2009). It was shown to have an incremental cost-effectiveness ratio (ICER) of €3434/QALY (quality adjusted life year) in patients under the age of 50. But €108,937/QALY in over 50s (Aronsson et al., 2015). This was highly sensitive to the cost of ablation and the readiness to offer crossover to ablation. No pre-specified willingness-to-pay (WTP) threshold was set but for under 50s the ICER will fall within any commonly used WTP threshold.

A single CEA has been performed for CB versus AAD (Reynolds et al., 2014) that found it to be cost-effective at £21,957/QALY with this meeting most WTP thresholds. The result was again sensitive to cost of ablation but also to time horizon and follow up costs of recurrence. There are no head-to-head economic evaluations of CB versus RF in the literature, indicating a future direction of research.

Conclusions

Cryoballoon ablation appears to be non-inferior to radiofrequency ablation for pulmonary vein isolation in paroxysmal atrial fibrillation. Cryoablation seems to offer lower procedure times, fewer non-AF atrial tachycardia and fewer pericardial effusions and tamponades at the cost of longer radiation exposure and significantly higher phrenic nerve palsies. Both procedure appear to be cost-effective when compared to anti-arrhythmic therapy in drug-refractory atrial fibrillation in a younger population but for both procedures this is contingent on the cost of ablation, which is largely determined by industry.

In the context of non-inferiority of efficacy and comparative trade-off in safety that may be in favour of cryoballoon (since phrenic nerve palsy is generally less dangerous and costly to manage than atrial tachycardia or tamponade), a head-to-head cost-effectiveness analysis is mandated here to determine the future expansion of atrial fibrillation ablation services to meet the challenges posed by the impending AF epidemic driven by an aging population and rising obesity (Kirchhof et al., 2016). 

Cryoballoon ablation may allow first time AF ablation to leave the tertiary EP centre and enter the milieu of procedures offered in the district general hospital by less specialized operators, with electro-anatomical mapping reserved for redo ablation and complications of atrial tachycardia.

References

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Haissaguerre, M., Jais, P., Shah, D. C., Takahashi, A., Hocini, M., Quiniou, G., . . . Clementy, J. (1998). Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med, 339(10), 659-666. doi:10.1056/nejm199809033391003

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