Safety and acute efficacy of catheter ablation for atrial fibrillation with pulsed field ablation vs thermal energy ablation: A meta-analysis of single proportions

Background Pulsed field ablation (PFA) has emerged as a novel energy source for the ablation of atrial fibrillation (AF) using ultrarapid electrical pulses to induce cell death via electroporation. Objective The purpose of this study was to compare the safety and acute efficacy of ablation for AF with PFA vs thermal energy sources. Methods We performed an extensive literature search and systematic review of studies that evaluated the safety and efficacy of ablation for AF with PFA and compared them to landmark clinical trials for ablation of AF with thermal energy sources. Freeman-Tukey double arcsine transformation was used to establish variance of raw proportions followed by the inverse with the random-effects model to combine the transformed proportions and generate the pooled prevalence and 95% confidence interval (CI). Results We included 24 studies for a total of 5203 patients who underwent AF ablation. Among these patients, 54.6% (n = 2842) underwent PFA and 45.4% (n = 2361) underwent thermal ablation. There were significantly fewer periprocedural complications in the PFA group (2.05%; 95% CI 0.94–3.46) compared to the thermal ablation group (7.75%; 95% CI 5.40–10.47) (P = .001). When comparing AF recurrence up to 1 year, there was a statistically insignificant trend toward a lower prevalence of recurrence in the PFA group (14.24%; 95% CI 6.97–23.35) compared to the thermal ablation group (25.98%; 95% CI 15.75–37.68) (P = .132). Conclusion Based on the results of this meta-analysis, PFA was associated with lower rates of periprocedural complications and similar rates of acute procedural success and recurrent AF with up to 1 year of follow-up compared to ablation with thermal energy sources.


Introduction
Atrial fibrillation (AF) is the most common arrhythmia and is associated with significant morbidity and mortality. 1Catheter ablation has been included in guidelines as a viable therapy in rhythm control treatment of AF, especially in symptomatic patients with significant AF burden refractory to antiarrhythmic drugs (AADs). 2,3Thermal energy using either ra-diofrequency or cryoballoon catheters is delivered to atrial cardiomyocytes to isolate the pulmonary veins as the mainstay of rhythm control therapy.However, thermal energy is not selective to cardiomyocytes and thus can lead to complications such as pulmonary vein stenosis, phrenic nerve palsy, and the extremely morbid atrioesophageal fistula. 46][7] In contrast to thermal ablation, different noncardiac tissues have characteristic thresholds of vulnerability to pulsed field energy.][10][11] The purpose of our current study was to perform a systematic review of the literature and meta-analysis evaluating the safety and efficacy of PFA in comparison to thermal ablation.

Methods
Electronic databases were searched from inception up to March 2023 using the keywords "atrial fibrillation" and "pulsed field ablation" or "electroporation."No language restriction was applied.The PRISMA statement for reporting systemic reviews and meta-analyses was applied to the methods for this study. 12The studies were required to fulfill the following criteria to be considered in the analysis: (1)  include at least 10 patients undergoing PFA; (2) report the rates of periprocedural complications or recurrent AF; and (3) have been published in a peer-reviewed scientific journal.][15][16][17][18][19] We aimed to compare the safety and efficacy of ablation for AF with PFA vs thermal energy sources.Two authors (OMA, AMA) independently performed the literature search and extracted data from eligible studies.Outcomes were extracted from original manuscripts and supplementary data.Information was gathered using standardized protocol and reporting forms.Disagreements were resolved by consensus.Two reviewers (OMA, AMA) independently assessed the quality items and discrepancies were resolved by consensus or involvement of a third reviewer (JCH), if necessary.
Two authors (OMA, CL) independently assessed the risk of bias of the included trials using standard criteria defined in the Cochrane Handbook for Systematic Reviews of Interventions.Discrepancies were resolved by discussion or adjudication by a third author (JCH).

Statistical analysis
Statistical analyses for studies including both PFA and thermal ablation arms were performed by the Review Manager (RevMan Version 5.3, The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, The Netherlands).Data were summarized across treatment arms using the inverse variance mean difference (MD), where MD ,0 favored the PFA group.Heterogeneity of effects was evaluated using the Higgins I 2 statistic.Randomeffects models for analyses were used with high heterogeneity (defined as I 2 .25%);otherwise fixed effects models of DerSimonian and Laird were used.Statistical analyses involving the meta-analysis of single proportions were performed using Stata 11 (StataCorp LLC, College Station, TX) statistical software.We used the Freeman-Tukey double arcsine method to establish variance of raw proportions.The DerSimonian and Laird method with a random-effects model was used to generate a pooled estimate based on the transformed values and their variances.Finally, we backtransformed the pooled estimates and plotted the data on forest plots.Data was summarized as prevalence (%) with 95% confidence interval (CI).Heterogeneity of effects was evaluated using the Higgins I 2 statistic.We used meta-regression to establish residual heterogeneity and test for subgroup differences between the PFA and thermal ablation groups, where P ,.05 was considered significant.Descriptive statistics are presented as mean 6 SD for continuous variables or number of cases (n) and percentage (%) for dichotomous and categorical variables.

KEY FINDINGS
-The results of this meta-analysis show that there are significantly fewer complications with pulsed field ablation (PFA) compared to thermal ablation.
-There is no statistically significant difference in the rate of recurrent atrial arrhythmias between PFA and thermal ablation when looking at studies with followup out to 1 year, although follow-up data with PFA are limited.
-Among the studies with both PFA and thermal ablation arms, there were no differences in fluoroscopy or procedure times.However, among studies that reported left atrial dwell times, the time was ,1 hour in the PFA group.

Study selection
The initial search resulted in 285 studies, of which 65 were duplications and 199 were excluded as outlined in Figure 1.Of the remaining 21 full-text articles, 4 were excluded because they did not meet eligibility criteria or did not have an outcome of interest.[15][16][17][18][19]

Study characteristics
Baseline demographics of patients included in the 17 PFA studies and 7 thermal energy AF ablation trials are summarized in Table 1.Study characteristics and average followup are listed in Table 2.Among the PFA studies, 14 were single-arm studies and 7 were single-center studies.

Quality assessment
The quality of observational studies was evaluated using the Newcastle-Ottawa Quality Assessment Scale.This scale assesses study selection, comparability, and outcomes/exposure.A good-quality study will have 3-4 stars in the selection domain, 1-2 in the comparability domain, and 2-3 in the outcomes/exposure domain.A fair-quality study will have 2 stars in the selection domain, 1-2 in the comparability domain, and 2-3 in the outcomes/exposure domain. 37

Study endpoints
There were no statistically significant differences in fluoroscopy time (MD 2.12; 95% CI -2.
Although it has been hypothesized that PFA could result in fewer complications after ablation of AF due to its superior cardiac tissue selectivity relative to thermal ablation, concerns have been raised about whether this is outweighed by complications more common with PFA, such as coronary vasospasm.This is especially a concern when ablating beyond the pulmonary veins and closer to the coronary arteries.However, coronary vasospasm has been shown to be subclinical in the majority of cases and is effectively treated prophylactically or post hoc with nitroglycerin. 44Despite including coronary vasospasm in the composite safety outcome, there were still significantly fewer periprocedural complications in the PFA group compared to the thermal ablation group.Furthermore, fluoroscopy time, procedure time, and complications with PFA are only expected to decrease as operators become more familiar with this new technology.Although many studies have examined the effects of different catheters, power settings, ablation durations, and lesion sets with radiofrequency and cryoablation, PFA still is in its nascent stage, so the optimal ablation strategy using this energy is to be determined.   R 1 (1.0) 1 (1.0) 0 (0.0) NR 2 (1.9) 2 (1.9) 0 (0.0) NR 0 (0.0) 0 (0.0) EARLY-AF (2021) 19 2 (1.3) 0 (0.0) NR 0 (0.0) NR 0 (0.0) 3 (1.9)NR 0 (0.0) NR 0 (0.0)

A B
Values are given as n (%).AEF 5 atrioesophageal fistula; TIA 5 transient ischemic attack; other abbreviations as in Table 2.
With regard to recurrent atrial arrhythmias, it is not surprising that PFA had similar acute procedural success as thermal ablation, with its rate of acute pulmonary vein isolation in both paroxysmal and persistent AF shown to be similar to that of thermal ablation. 16,36,45However, the physiology underlying this finding likely is more nuanced.It has been postulated that ganglionated plexuses, which are situated in the fat pads close to pulmonary vein ostia, may interact with the sympathetic and parasympathetic nervous systems in the development of AF. 46 It is possible that PFA may result in more transmural lesions with less incidence of pulmonary vein reconnection but does not adequately ablate the ganglionated plexuses because of its attenuated effect on nervous tissue, resulting in a net atrial arrhythmia recurrence similar to that of thermal ablation.However, this remains to be tested, as 3 of the PFA studies included in this meta-analysis had followup ,1 year and none .1 year. 25,30,34Thus, the durability of lesions created by PFA needs to be studied further.
However, it should be highlighted that the PFA group comprised a very heterogeneous population with multiple different catheters and waveforms used.Although this makes it difficult to know which catheter or waveform is optimal, it enhances the generalizability of the studied outcomes.Similarly, radiofrequency and cryoablation were evaluated as a conglomerate comparator arm to represent contemporary practice for AF ablation.

Study limitations
The current systematic review and meta-analysis has several important limitations that should be acknowledged.First, this was a meta-analysis of single proportions comparing proportions of events occurring between different populations and thus is subject to biases from uncontrolled confounders.Second, there were different study protocols, with single-arm studies making up the majority of the PFA studies and randomized controlled trials making up the thermal ablation studies.Third, some patients may have been counted in more than 1 study, as some of the included studies were at the same center or national surveys.Fourth, multiple different PFA catheters were used in the included studies, and what effect the heterogeneity of different catheter designs and PFA waveforms could have on the results studied is unknown.Fifth, there was not a standardized protocol for the detection of recurrent atrial arrhythmias, and follow-up was highly variable, with shorter follow-up on average in the PFA group.

Conclusion
Based on the results of this meta-analysis, PFA was associated with lower rates of periprocedural complications and similar rates of recurrent AF with up to 1 year of followup compared to ablation with thermal energy sources, but there was relatively shorter follow-up and higher use of AADs in the PFA group.Randomized controlled trials with longer follow-up comparing PFA to thermal ablation are needed.

Figure 1
Figure 1 Selection of studies.

Figure 2
Figure 2 Forest plots comparing the prevalence of periprocedural complications (A) and recurrent atrial arrhythmias up to 1 year postablation (B).Prevalence is expressed as a percentage with corresponding 95% confidence intervals.*Complications include access site complications, cardiac effusion/tamponade, major bleeding, transient ischemic attack or stroke, coronary vasospasm, myocardial infarction, phrenic nerve palsy, esophageal injury, atrioesophageal fistula, and death.

Table 1
Patient demographics and characteristics

Table 2
Descriptions of studies included in meta-analysis