Pulsed field ablation vs. thermal ablation for pulmonary vein isolation: a network meta-analysis of randomized controlled trials

Abstract

Aims

Pulsed field ablation (PFA) has recently emerged as a promising alternative to conventional energy sources (ES) for atrial fibrillation (AF) ablation. However, comparative data between PFA and other ES—such as radiofrequency (RFA), cryoballoon (CBA), and laser balloon ablation (LBA)—remain limited.

This network meta-analysis (CRD420251054760) aimed to compare outcomes of PFA vs. thermal ES for AF ablation.

Methods and results

A systematic network meta-analysis using PubMed, Cochrane, and EMBASE from inception to March 2026 was performed. Randomized controlled trials comparing different ES in first-attempt pulmonary vein isolation were included. Data extraction was performed according to PRISMA guidelines. The primary outcome was the recurrence of any sustained atrial tachyarrhythmia (ATA) at 12-month follow-up. Safety and efficiency outcomes were also compared among groups. We included 18 studies, encompassing 4162 patients. Compared to PFA, thermal ablation technologies showed a higher risk of ATA recurrence at 12-month follow-up (RFA: RR of 1.48 (95% CI 1.10–2.00); CBA: 1.43 (95% CI 1.07–1.92); LBA: RR 1.29 (CI 95% 0.84–1.98)). PFA exhibited the lowest procedural time among transcatheter ES, whereas RFA displayed a significantly lower fluoroscopy time. No significant differences were recorded for major periprocedural complications. A subgroup analysis restricted to studies involving only paroxysmal AF patients, as well as those employing contemporary technologies, yielded consistent findings.

Conclusion

The present data indicate that, in patients undergoing a first transcatheter AF ablation, PFA may be associated with favourable efficacy and procedural efficiency compared with traditional thermal technologies, while showing a broadly comparable safety profile.

Graphical Abstract

Graphical Abstract.

CBA, Cryoballoon Ablation; CI, Confidence Interval; ES, Energy Sources; LBA, Laser Balloon Ablation; PAF, Paroxysmal Atrial Fibrillation; PFA, Pulsed Field Ablation; PsAF, Persistent Atrial Fibrillation; PVI, Pulmonary Vein Isolation; RCT, Randomized Controlled Trials; RFA, Radiofrequency Ablation; RR, Risk Ratio.

Introduction

Atrial fibrillation (AF) is the most common arrhythmia in the adult population^1–4 and is associated with reduced quality of life,⁵ significant morbidity,⁶ and a non-negligible increase in mortality risk.^6,7 Randomized controlled trials (RCTs)⁸ have demonstrated the superiority of catheter ablation (CA) over antiarrhythmic drugs in reducing AF recurrence and improving clinical outcome, making pulmonary vein isolation (PVI) a cornerstone of rhythm control therapy.

Radiofrequency ablation (RFA), cryoballoon ablation (CBA), and laser balloon ablation (LBA) have traditionally been the energy sources (ES) used for CA. These ES rely on heating or freezing myocardial tissue to achieve electrical isolation of the pulmonary veins (PVs), reporting good efficacy and safety outcomes.⁹

In recent years, pulsed field ablation (PFA) has emerged as a promising alternative to established thermal ES.^10,11 PFA is a non-thermal ablation ES that uses high-voltage, microsecond-scale electric pulses to induce irreversible electroporation, selectively disrupting myocardial cell membranes while sparing surrounding non-cardiac tissues^12,13 reducing the risk of possible damage to the phrenic nerve and the oesophagus.^12,14 Early observational studies suggest that PFA is both safe and effective.¹⁵ Although the body of evidence is expanding, high-quality data from RCTs directly comparing PFA with other ES remain limited.^16,17 The paucity of head-to-head comparisons represents a key gap in the current literature,¹⁸ which may be addressed through the use of network meta-analysis (NMA). This statistical approach extends beyond traditional meta-analyses since it allows simultaneous comparison of multiple treatments by combining direct and indirect evidence to estimate comparative effects even in the absence of head-to-head trials. The aim of this NMA was to compare the efficacy, safety, and procedural efficiency of PFA vs. traditional thermal ES for AF ablation.

Methods

This NMA was conducted and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁹ The study’s protocol was registered in PROSPERO (registration number CRD420251054760) and followed throughout the study period.

Literature search, study selection, and data extraction

A systematic search was performed in PubMed, Cochrane, and EMBASE from inception to March 2026. The detailed Search Queries are reported in the Supplementary material. Additionally, bibliographies of included studies and prior meta-analyses on similar topics were screened (‘backward snowballing’), and congress programs from the last 10 years were reviewed, with particular focus on late-breaking trial sessions.

Studies were eligible if they met all the following inclusion criteria: (i) RCTs comparing different ES for AF ablation; (ii) trials reporting a PVI-only approach (studies including additional lesion sets were accepted if such lesions involved ≤5% of the total population with the exception of cavo-tricuspid isthmus ablation if concomitant typical atrial flutter was documented); and (iii) a minimum follow-up of 12 months. Trials reporting outcomes for paroxysmal (PAF) or persistent atrial fibrillation (PsAF) were included.

Excluded studies comprised cohort studies, case reports, case series, guidelines, letters, comments, non-English publications, and studies without available abstract and/or full text. Secondary analyses from RCTs were also excluded.

Two independent reviewers (A.C.L. and M.P.) screened all abstracts, followed by a full-text review of eligible articles.

Data extraction was independently performed by two investigators (M.P. and A.C.L.) at the study level, and included: (i) study characteristics (first author, publication year, journal, sponsor); (ii) sample size; (iii) patient demographics and clinical data (age, sex, ethnicity, CHA₂DS₂-VASc score, AF type, etc.); (iv) ablation technology used in intervention and control arms; (v) procedural details (procedure time, fluoroscopy time, follow-up duration, recurrence detection method); and (vi) efficacy and safety outcomes. When the number of events was not reported, risk ratio (RR) estimates and 95% confidence intervals (CIs) were extracted.

Competitive arms and risk of bias assessment

Different transcatheter ablation ES accounted for the competitive arms of the NMA and were categorized as follows: (i) PFA; (ii) RFA; (iii) CBA; (iv) LBA, with PFA being the reference arm.

According to PRISMA guidelines,¹⁹ risk of bias assessments were performed at the study level using the Cochrane risk-of-bias assessment tool (RoB2)²⁰ by two investigators (M.P. and A.C.L.) independently. Studies were classified as low risk if all domains were low risk; if up to 3 domains presented some concerns, studies were classified as intermediate risk; if more than 3 domains presented some concerns or one domain was high risk, studies were deemed at high risk for bias. Results were reported according to the Cochrane recommendation²¹ and the specific PRISMA statement.¹⁹

Study outcomes

The primary outcome consisted of recurrence of atrial tachyarrhythmias (ATAs) (defined as AF, atrial flutter, or atrial tachycardia lasting ≥ 30 s) at 12-month follow-up after a 2− to 3-month blanking period. Study designs and primary outcome definitions are detailed in Table 1. Safety outcome consisted of major periprocedural complications; a detailed list of major periprocedural complication definitions in each study is reported in Supplementary material online, Table S2. Procedural characteristics were also collected and compared (see Supplementary material online, Table S1).

Table 1.

Study design

	Bordignon et al.22	Luik et al.23	Kuch et al.	Schmidt et al.24	Buist et al.25	Davtyan et al.26
Publication year, journal	2013, JCE	2015, Circulation	2016, NEJM	2017, Circulation	2018, Clin Res in Cardiology	2018, BioMed Res International
Short title (if present)	The Laser vs. Cryo Study	FreezeAF Study	FIRE AND ICE Study	N/A	N/A	N/A
Country	Germany	Germany	European countries	European countries	Netherlands	Russia
General characteristics	Investigator-initiated, monocentric, open-label	Monocentric, open label	Investigator-initiated, multicentric, open label	Investigator-initiated, multicentric, open label	Investigator-initiated, monocentric, open-label	Investigator-initiated, monocentric, open-label
Patient population	PAF	PAF	PAF	PsAF	PAF or PsAF	PAF
No of patients	140	315	750	134	269	89
Comparison arms	CBA vs. LBA	CBA vs. RFA	CBA vs. RFA	LBA vs. RFA	CBA vs. RFA	CBA vs. RFA
Major inclusion criteria	1) Age 18–75; 2) No prior PVI; 3) Lad < 50 mm; 4) LVEF > 45%	1) Age 18–75; 2) ≥2 AF episodes during last three months	1) Age 18–75; 2) ≥2 AF episodes with ≥ 1 documented; 3) failure of ≥1 AAD	1) Age 18–80; 2) failure of ≥1 AAD	1) failure of ≥1 AAD	1) Age 18–79; 2) ≥2 PAF episodes; 3) failure of ≥1 AAD; 4) LAd > 50 mm; 5) LVEF > 50%
Major exclusion criteria	N/A	1) Previous AF ablation; 2) LAd >55 mm; 3) LA thrombus	1) Previous AF ablation; 2) LAd >55 mm; 3) LA thrombus	1) Previous AF ablation; 2) LAd >50 mm; 3) Long-standing PsAF; 4) LA thrombus; 5) LVEF <45%; 6) moderate or severe MVD	1) Long-standing PsAF	1) MI or cardiac surgery ≤ 3-months; 2) CVA ≤ 1 year; 3) thyroid dysfunction
Follow-up	393 (365–485) days	12 months	1.5 years	12 months	389 (219–599)	12 months
ATA-recurrence assessment	72-Hour Holter ECG	7− to 14-day Holter ECG	24-hour Holter ECG, weekly ECG	72-hour Holter ECG	24–72-hour Holter ECG	ILR
Blanking period	3 months	3 months	3 months	3 months	3 months	3 months
Primary endpoint	Efficacy outcome: documented AF recurrence (≥ 30 s) 90–365 days after ablation Safety outcome: incidence of periprocedural complications	Efficacy outcome: absence of atrial arrhythmias with absence of persistent complications at 6− and 12-month follow-up	Efficacy outcome: time to first documented clinical failure (AF/AFL/AT recurrence, AADs use or repeat ablation) Safety outcome: composite of death, CVA or serious related adverse events	Efficacy outcome: freedom from AF or any ATA >30 s 90–365 days after index procedure Safety outcome: incidence of periprocedural complications	Efficacy outcome: primary single procedure freedom from AF/AFL/AT recurrence	Efficacy outcome: freedom from AF > 30 s, AFL or AT at 12-months at ECG, Holter ECG and ILR Safety outcome: rate of adverse events
Secondary endpoints	Procedure time; fluoroscopy time; number of acutely isolated PV	Procedural data; total radiation exposure; total procedure duration; occurrence of adverse events	Death from any cause, arrhythmic death, procedure time, fluoroscopy time, first re-hospitalization for CV causes	N/A	N/A	Evaluation of post-ablation blanking period at ILR

	Andrade et al.27	Üçer et al.28	Chun et al.29	Baimbetov et al.30	Shi et al.31	Theis et al.32
Publication year, journal	2019, Circulation	2020, Circulation Journal	2021, Circulation Arrhythmia	2022, AJC	2022, Europace	2022, JCE
Short title (if present)	CIRCA-DOSE Study	N/A	N/A	N/A	NO-PERSAF Study	N/A
Country	Canada	Germany	Germany	Kazakhstan	Norway	Germany
General characteristics	Investigator-initiated, multicentric, single-blinded	Investigator-initiated, monocentric, open-label	Investigator-initiated, monocentric, open-label	Investigator-initiated, monocentric, open-label	Investigator-initiated, multicentre, open-label	Investigator-initiated, monocentric, open-label
Patient population	PAF	PAF	PAF and PsAF	PsAF	PsAF	PAF
N of patients	346	50	200	100	101	150
Comparison arms	CBA vs. RFA	LBA vs. RFA	CBA vs. LBA	CBA vs. RFA	CBA vs. RFA	CBA vs. RFA
Major inclusion criteria	1) Age ≥ 18; 2) failure of ≥ 1 AAD; 3) ≥PAF documented ≤ 2-years	1) failure of ≥ 1 AAD	1) 18–80 years; 2) failure of ≥ 1 AAD	1) failure of ≥ 2 AADs	1) Age 18–75 years; 2) failure of ≥ 1 AAD; 3) ≥1 previous CVE	1) ≥ 1 documented PAF
Major exclusion criteria	1) Previous AF ablation; 2) LAd >55 mm	1) Previous PVI; 2) LAd > 55 mm	1) Previous PVI; 2) Long-standing PsAF; 3) LAd > 45 mm; LVEF < 45%; 4) ≥ moderate MVD	1) Previous PVI; 2) LAd > 50 mm; 3) LVEF < 40%	1) Previous PVI; 2) LAd > 60 mm; 3) AF lasting > 36 months	N/A
Follow-up	12 months	12 months	12 months	36 months	12 months	12 ± 4.5 months
ATA recurrence assessment	ILR	72-hour Holter ECG	72-hour Holter ECG	ILR	7-day Holter ECG	48-hour Holter ECG
Blanking period	3 months	3 months	3 months	3 months	3 months	3 months
Primary endpoint	Efficacy outcome: time to 1st documented recurrence AF, AFL or AT at 91–365 days after ablation or a repeat ablation at 0–365 days	Efficacy outcome: recurrence of any ATA of >30 s at 12 months	Efficacy outcome: single-procedure freedom from ATA at 90–365 days	Efficacy outcome: freedom from any ATA, AAD use, or any intervention for AF	Efficacy outcome: documented recurrent ATA of > 30 s	Efficacy outcome: freedom from ATA at 12 months
Secondary endpoints	Freedom from symptomatic arrhythmia; AF burden; rate of re-ablation; 4) serious periprocedural complications	N/A	Procedural parameters; periprocedural complications	N/A	Procedure-related complications; procedure time; ablation time; fluoroscopy time	Procedural complications; PV recovery during redo procedures.

	Mililis et al.33	Reddy et al.34	Rechlin et al.	Sultan et al.35	Soo cho et al.	Jais et al.36
Publication year, journal	2023, JCE	2023, NEJM	2025, NEJM	2025, Europace	2025, JACC EP	2026, EHJ
Short title (if present)	N/A	ADVENT Study	SINGLE SHOT CHAMPION Study	HIPAF trial	EXCAPE-AF trial	BEAT PAROX AF trial
country	Greece	USA	Switzerland	Germany	South Korea	Europe
General characteristics	Investigator-initiated, monocentric, open-label	Sponsor-initiated, multicentric, single-blinded	Investigator-initiated, multicentric, open-label	Investigator-initiated, single centre	Investigator-initiated, multicentric	Investigator-initiated, multicentric, open-label
Patient population	PsAF	PAF	PAF	PAF	PeAF	PAF
No. of patients	199	607	210	170	288	289
Comparison arms	CBA vs. RFA	PFA vs. CBA vs. RFA	PFA vs. CBA	RFA vs. CBA	RFA vs. CBA	PFA vs. RFA
Major inclusion criteria	1) Age > 18 years	1) Age 18–75 years; 2) failure of ≥ 1 AAD	1) Age > 18 years; 2) ≥ 1 documented PAF within 24 months	1) Age > 18 years; 2) documented PAF	1) Age > 18 years; 2) PsAF refractory to class I/III AADs	1) Age 18–80 years; 2) PAF resistant to at leat 1 AAD; 3) OAC > 3 weeks
Major exclusion criteria	1) Previous PVI; 2) more than moderate VHD	1) Previous PVI; 2) LAd > 55 mm; 3) LVEF < 40%	1) Previous PVI; 2) LVEF < 35%; 3) severe MR; NYHA ≥ III	1) previous AF ablation; 2) PeAF; 3) severe obesity; 4) significant valvular heart disease	1) PAF; 2) LA diameter ≥50 mm; 3) atrial septal defect closure device; 4) prior AF ablation	1) PsAF; 2) LA diameter ≥ 5.5 cm; 3) priora trial ablation; 4) PV anomaly
Follow-up	12 months	12 months	12 months	12 months	12 months	12 months
ATA recurrence assessment	24-hours Holter ECG	72-hour Holter ECG	ILR	24-hour Holter ECG	24-hour Holter ECg, 2-week patch ECG	24-hour Holter ECG
Blanking period	3 months	3 months	3 months	3 months	3 months	2 months
Primary endpoint	Efficacy outcome: arrhythmia relapse in the early postprocedural period (first 3 months) and in the middle term follow-up (3–12 months)	Efficacy outcome: freedom from a composite of initial procedural failure, documented ATA, AADs, ECV, or repeat ablation Safety outcome: acute and chronic device- and procedure-related serious adverse events	Efficacy outcome: first recurrence of an ATA Safety outcome: composite of procedure-related complications	Efficacy outcome: freedom from a composite of any ATA, new AAD onset or reablation at 12 months	Efficacy outcome: 12-month freedom from ATA without AADs	Efficacy outcome: 12-month freedom from ATA recurrence, cardioversion, class I/III drug resumption or repeat ablation
Secondary endpoints	Procedure time; fluoroscopy time, procedural complications	Change in the aggregate pulmonary vein cross-sectional area at 3 months; primary efficacy outcome but assessed for superiority	1st recurrence of ATA at 1− 90 days; atrial arrhythmia burden; QOL; death; stroke; TIA; unplanned hospitalization; CVE; repeat ablation; reinitiation of AADs	Procedural parameters; procedure associated complications; necessity of rehospitalization; electrical cardioversion	Freedom from ATA irrespective of AAD use; freedom from ATA after 1 or 2 procedures; procedural characteristics; periprocedural complications, QOL, AF burde.	12-month multiple procedure success; 6− and 12-month QOL; adverse events at 12-months; 7-day device and procedure-related adverse events

AADs, antiarrhythmic drugs; AF, atrial fibrillation; AFL; atrial flutter; ATA, atrial tachyarrhythmia; CBA, cryoballoon ablation; CV, cardiovascular; CVA; cardiovascular accident; ECV, electric cardioversion; ILR, implantable loop recorder; LAd, left atrial diameter; LBA, laser balloon ablation; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; MVD, mitral valve disease; NYHA, New York Heart Association; PAF, paroxysmal atrial fibrillation; PFA, pulsed field ablation; PsAF, persistent atrial fibrillation; PV, pulmonary vein; PVI, pulmonary vein isolation; QOL, quality of life; RFA, radiofrequency ablation; TIA, transient ischaemic attack.

Statistical analysis

Pooled estimates of baseline characteristics of study populations were calculated by meta-analysis of mean values for continuous variables and proportions for categorical variables with the corresponding 95% CI, using a generic random-effect inverse variance model. Follow-up duration was summarized as median values between the studies with the corresponding interquartile range (IQR). In the case of a binary endpoint, we used RR as the effect estimate, while mean difference (MD) was used as the summary measure in the case of a continuous outcome. For each endpoint, RR, its standard error, and the corresponding 95% CI were calculated. NMA was performed in a frequentist framework, using a random-effect model accounting for correlations induced by multi-arm trials.

Cochran’s Q statistics and I² statistics were used to evaluate heterogeneity/inconsistency across the network. In particular, the Q statistic was decomposed into a within-design Q statistic (representing heterogeneity in studies comparing the same treatment arms) and a between-design Q statistic (which incorporates the concept of design inconsistency). To assess the inconsistency in a random effect model, the between-design Q statistic was calculated based on a full design-by-treatment interaction random-effects model, as proposed by Higgins.³⁷ Publication bias was assessed by comparison-adjusted funnel plot³⁸ and Egger’s test.³⁹ The Grading of Recommendations, Assessment, Development and Evaluation (GRADE)⁴⁰ method was used to evaluate the certainty of the NMA evidence.

Treatment ranking was assessed by p-scores, the frequentist analogues of Surface Under the Cumulative RAnking curve (SUCRA)⁴¹ values in the Bayesian framework, which measure the extent of certainty that a treatment is better than another, averaged over all competing treatments.

Additionally, sensitivity analyses were conducted to assess the robustness of our findings. This involved excluding studies that were identified as having a high risk of bias based on the ROB2 assessment tool. Furthermore, we performed supplementary sensitivity analyses focusing on specific subsets of studies. These included: (i) studies that enrolled only patients with PAF, (ii) studies that used the most advanced ES available. These analyses aimed to evaluate whether the main results remained consistent between different study populations, methodologies, and diagnostic techniques.

Finally, a leave-one-out sensitivity analysis was performed by iteratively excluding each trial from the network and recalculating the effect estimates to determine whether the overall results were disproportionately driven by any single study.

Analyses were performed using the R version 4.0.0 and R package netmeta (version 1.2).

Results

A total of 2904 records were identified through electronic database searches from inception to March 2026. After removing duplicates, 1470 studies were screened, of which 1423 were excluded based on title and abstract. Among the remaining 47 studies, 18 fulfilled the inclusion criteria and were included in the final analysis. The complete study selection process is illustrated in the PRISMA flowchart (see Supplementary material online, Figure S1).

The included trials^{17,22–36,42,43} enrolled a total of 4162 patients and were published between 2013 and 2026. The median follow-up duration was 365 days (IQR 365–389). A summary of study characteristics is provided in Table 1. All trials evaluated primary PVI procedures in accordance with the protocol eligibility criteria. Eleven studies enrolled patients with only PAF, five studies enrolled patients with only PsAF, and two studies enrolled a mixed population. Among PsAF studies, long-standing PsAF was consistently an exclusion criterion, except in Shi et al.³¹ which allowed AF duration up to 36 months.

Thirteen of the 18 studies were conducted in Europe, two in North America,^27,34 and three in non-Western countries.^26,30,43 Only one study³⁴ reported patient ethnicity (91.9% White); however, most studies likely enrolled predominantly Caucasian participants.

Baseline characteristics

The pooled mean age was 61.5 years (95% CI: 59.0–65.0), with a male predominance (63.4%, 95% CI: 57.3–71.0). Hypertension was the most common comorbidity (61.4%, 95% CI: 54.6–69.4), and the mean CHA₂DS₂-VASc score was 1.6 (95% CI: 1.3–2.0). A history of thromboembolic events was present in 5.2% of patients (95% CI: 3.9–7.6). Mean LVEF was 59.2% (95% CI: 56.3–60.9) and mean left atrial diameter was 40 mm (95% CI: 39.4–43.1), consistent with inclusion of patients without significant structural remodelling. Most patients were on direct oral anticoagulants (99.7%, 95% CI: 93.4–100), while beta-blocker use was reported in 65.2% (95% CI: 61.8–69.3), and Class I/III antiarrhythmic drugs in 50.8% (95% CI: 29.0–99.5), with high inter-study variability. Full baseline data and procedural characteristics are presented in Table 2 and Supplementary material online, Table S1, respectively.

Table 2.

Patients’ characteristics

Baseline characteristics	Pooled mean/proportion (95% CI)
Age (years)	61.5 (59.6–65.0)
Males (%)	63.4 (57.3–71)
BMI (kg/m2)	28.2 (27.4–29.2)
Hypertension (%)	61.4 (54.6–69.4)
Diabetes (%)	10.2 (8.8–11.4)
Coronary artery disease (%)	11.2 (8.4–16.5)
Previous thromboembolic events (%)	5.2 (3.9–7.6)
Beta-blockers (%)	65.2 (61.8–69.3)
AADs use (%)	50.8 (29.0–99.5)
Class 1c (%)	11 (5–24.9)
Class III (%)	25.4 (11.4–71.3)
OAC use (%)	99.7 (93.4–100)
DOAC use (%)	87.1 (53.9–95.3)
CHA2DS2-VASc	1.6 (1.3–2.0)
LVEF (%)	59.2 (56.3–60.9)
LAd (mm)	40 (39.4–43.1)

AADs, antiarrhythmic drugs; BMI, body mass index; DOAC, direct oral anticoagulant; LAd, left atrial diameter; LVEF, left ventricular ejection fraction; OAC, oral anticoagulant.

Primary outcome

All included studies reported arrhythmia recurrence at ≥12-month follow-up, consistently applying a three-month blanking period⁴⁴ with the only exception of Jais and colleagues.³⁶ Four ES were assessed across 18 pairwise comparisons; one study³⁴ was multi-armed. The network of treatment comparisons is displayed in Supplementary material online, Figure S3, with RFA vs. CBA being the most frequent direct comparison (12 studies).

Compared with PFA (Figure 1), both RFA and CBA were associated with a significantly higher risk of arrhythmia recurrence (RFA: RR 1.48, 95% CI: 1.10–2.00; CBA: RR 1.43, 95% CI: 1.07–1.92). The comparison with LBA showed a non-significant trend favouring PFA (RR 1.29, 95% CI: 0.84–1.98).

Figure 1.

Forest plot for primary outcome analysis. CI, confidence Interval; CBA, cryoballoon ablation; LBA, laser balloon ablation; PFA, pulsed field ablation; RFA, radiofrequency ablation; RR, risk ratio.

The network league table (Table 3) displays all pairwise comparisons with corresponding effect estimates. PFA showed significantly lower recurrence rates than RFA (RR 0.68, 95% CI: 0.50–0.91) and CBA (RR 0.70, 95% CI: 0.52–0.94). Direct estimates also favoured PFA over RFA (RR 0.75, 95% CI: 0.51–1.11) and over CBA (RR 0.59. 95% CI 0.42–0.84), while the risk of recurrence was similar with PFA and LBA (RR 0.78, 95% CI: 0.51–1.19). No significant differences were observed among the thermal techniques (RFA, CBA, LBA) (see also Supplementary material online, Figure S4).

Table 3.

League table for the pairwise comparison of the primary outcome according to the network meta-analysis

	PFA	RFA	CBA	LBA
PFA	PFA	0.75 (0.51–1.11) High	0.59 (0.42–0.84) Moderate	NA
RFA	0.68 (0.50–0.91) Moderate	RFA	1.05 (0.89–1.25) Moderate	1.15 (0.74–1.78) Low
CBA	0.70 (0.52–0.94) Moderate	1.03 (0.88–1.22) Moderate	CBA	1.11 (0.70–1.76) Moderate
LBA	0.78 (0.51–1.19) Moderate	1.15 (0.83–1.59) Low	1.11 (0.80–1.54) Moderate	LBA

For each pairwise comparison, GRADE evaluation is reported under the relative risk estimate.

Above the diagonal are direct comparisons, whereas below are network estimates incorporating both direct and indirect evidence. CBA, cryoballoon ablation; LBA, laser balloon ablation; PFA, pulsed field ablation; RFA, radiofrequency ablation.

Based on P-scores (Figure 2), PFA ranked as the most effective treatment (P-score 0.95), followed by LBA (0.55), CBA (0.31), and RFA (0.18).

Figure 2.

Treatment ranking for primary outcome analysis, showing that PFA ranked as the most effective treatment (P-score 0.95), followed by LBA (P-score 0.55), CBA (P-score 0.31) and RFA (P-score 0.18). CBA, cryoballoon ablation; LBA, laser balloon ablation; PFA, pulsed field ablation; RFA, radiofrequency ablation.

Six studies were judged at high risk of bias, primarily due to missing outcome data, and in some cases, deviations from the intended intervention. The complete risk of bias assessment is shown in Supplementary material online, Figure S2. No evidence of publication bias was identified (see Supplementary material online, Figure S5). Egger’s test indicated the absence of publication bias and small study effect (P = 0.4981). Total heterogeneity was moderate (Q = 31.67, df = 16, P = 0.011; I² = 49.5%, 95% CI: 11.6–71.1%). Within-design heterogeneity was significant (Q = 21.61, P = 0.042), while between-design inconsistency was limited but statistically significant (Q = 10.06, P = 0.039). The main source of heterogeneity was the RFA vs. CBA comparison (Q = 17.46, P = 0.065).

No individual design disproportionately influenced network consistency. A full design-by-treatment interaction model confirmed global consistency (Q = 4.78, P = 0.311). Node-splitting analysis showed agreement between direct and indirect estimates for most comparisons, although moderate-to-high heterogeneity was noted for CBA vs. PFA (I² = 72.6%), RFA vs. PFA (I² = 75.9%), and LBA vs. RFA (I² = 68.1%), both based on limited data.

Primary outcome subanalyses

Sensitivity analysis excluding the six high-risk-of-bias studies yielded consistent findings: PFA remained associated with significantly lower recurrence compared to RFA and CBA, while a non-significant trend favouring PFA over LBA was observed (see Supplementary material online, Figures S14–S17; Supplementary material online, Table S5).

In the PAF-only subgroup, PFA remained superior to RFA (RR 1.41, 95% CI: 1.05–1.88) and CBA (RR 1.49, 95% CI: 1.13–1.98), with a non-significant trend compared to LBA (RR 1.21, 95% CI: 0.80–1.85) (see Supplementary material online, Figures S10–S13; Supplementary material online, Table S4).

In another subanalysis including only studies using second-generation catheters (e.g. cryoballoons and contact-force RFA), PFA maintained a lower recurrence risk compared with RFA (RR 1.50, 95% CI: 1.13–2.00), CBA (RR 1.42, 95% CI: 1.08–1.88), while similar risk of recurrence was observed with LBA (RR 1.39, 95% CI: 0.92–2.09) (see Supplementary material online, Figures S18–S21; Supplementary material online, Table S6).

When performing the leave-one-out sensitivity analysis, after excluding Reichlin et al.¹⁷ PFA was no longer statistically superior to CBA [RR 1.44 (0.97–2.14)], but a clear trend in favour of PFA was maintained. Importantly, PFA remained significantly more effective than RFA [RR 1.49 (1.02–2.18)], supporting the robustness of the present findings (see Supplementary material online, Table S9).

Secondary outcomes

All included trials reported on procedural complications, procedure time, and fluoroscopy duration.

No significant differences in major complications were observed between ES in either direct or network comparisons. Based on P-scores, PFA had the highest likelihood of being the safest option (P-score 0.86), followed by RFA (0.53) (see Supplementary material online, Figures S6–S9; Supplementary material online, Table S3).

PFA was associated with significantly shorter procedure time compared to RFA (MD −36.63 min, 95% CI: −54.01 to −19.24) and LBA (MD −37.33 min, 95% CI: −62.01 to −12.64), but not vs. CBA (MD −9.17, 95% CI: −26.54 to 8.21). PFA ranked highest for procedural efficiency (P-score 0.95), while RFA and LBA ranked lowest (P-scores 0.18 and 0.16, respectively). However, heterogeneity was high in CBA vs. RFA (I² = 95.0%) and CBA vs. LBA (I² = 97.3%) comparisons (see Supplementary material online, Figures S22–S25; Supplementary material online, Table S7).

For what concerns fluoroscopy time, RFA showed a significantly shorter duration as compared to PFA (MD −5.89 min; 95% CI: −10.70 to −1.09), whereas no statistically significant differences were recorded among other ES. This trend was confirmed by treatment ranking (P-score 0.98) (see Supplementary material online, Figures S26–S29; Supplementary material online, Table S8).

Discussion

The principal findings of the present study can be summarized as follows: (i) among transcatheter technologies for PVI, PFA reported the highest ATA freedom at 12-month follow-up; (ii) PFA was associated with the highest procedural efficiency, having lower procedural time compared to established thermal ES; (iii) RFA displayed a significantly lower fluoroscopy time compared to single-shot ablation strategies; (iv) safety profiles were comparable between studied technologies.

The added value of network meta-analysis

In recent years, PFA has emerged as a promising alternative to conventional thermal ES. Initial studies were designed to validate firstly procedural safety⁴⁵ and, in a second time, non-inferiority in acute PVI as well as recurrence-free survival at short and mid-term follow-up.¹⁵ The recently published SINGLE SHOT CHAMPION trial,¹⁷ which randomized patients to PFA or CBA, was the first trial to prove superiority for ATA recurrence after PVI. Given the relative scarcity of RCTs comparing the different ES, several meta-analyses have been conducted in recent years, typically comparing only two sources. Three meta-analyses^46–48 performed before the SINGLE SHOT CHAMPION trial reported that PFA was associated with significant improvement in acute endpoints and shorter procedure times compared with CBA; one of them also demonstrated lower arrhythmia recurrence and a reduced risk of periprocedural complications.⁴⁸ PFA was likewise associated with shorter procedure times when compared with thermal ES,⁴⁹ even in studies including high-power short-duration ablations.⁵⁰ However, these meta-analyses mainly included non-randomized studies. The present meta-analysis is the first comparing all major existing ablation ES in the treatment of AF with data derived from RCTs only. By integrating both direct and indirect evidence, this approach not only enabled simultaneous comparison of multiple ablation modalities but also provided estimates for comparisons that have not yet been evaluated in head-to-head trials.

Primary outcome: arrhythmia-free survival

The present meta-analysis suggested a higher arrhythmia-free survival with PFA than with other ES. To date, only one RCT has demonstrated a benefit of PFA on arrhythmia-free survival. To ensure that our findings were not driven solely by this study, we performed a leave-one-out sensitivity analysis excluding it; a clear trend favouring PFA persisted, supporting the robustness of the results (see Supplementary material online, Table S9).

Differences in energy delivery and lesion formation may account for these findings. In the SINGLE SHOT CHAMPION trial,¹⁷ Reichlin et al. suggested that lower recurrence rates might result from wider lesions with PFA vs. CBA; however, Cardiac Magnetic Resonance (CMR) at 3 months showed similarly wide lesions in both groups.⁴⁶

An alternative explanation is that, unlike thermal energy sources, PFA uses short, high-energy electrical pulses to induce irreversible electroporation,⁴⁷ leading to apoptosis rather than coagulative necrosis.⁴⁸ This mechanism may reduce inflammation and vascular injury, thereby potentially limiting the proarrhythmic effects of post-ablation oedema and patchy ischemic injury.⁴⁸

Preclinical studies show that PFA produces more homogeneous fibrosis than thermal ES,⁵¹ Whether these tissue-specific effects explain greater PVI durability and improved arrhythmia outcomes remains unproven, but they provide a plausible mechanistic pathway.

Safety and efficiency

No significant differences in major periprocedural complications were found among the ablation technologies evaluated. Some of the most severe events, such as atrio-oesophageal fistula (estimated prevalence 0.1–0.25%),⁵² are so infrequent that detecting a true difference would require a much larger study population. Consequently, the anticipated and desirable safety advantage of PFA over thermal ablation—largely hypothesized based on its nonthermal mechanism—has not yet been demonstrated in RCTs.

A significantly longer fluoroscopy time was observed with single-shot systems compared with RFA, most likely reflecting the near-universal use of non-fluoroscopic electroanatomical mapping with RFA procedures. The integration of adjunctive imaging and navigation tools, such as electroanatomical mapping or intracardiac echocardiography, into PFA workflows in the near future may help to reduce radiation exposure. Interestingly, no significant difference in procedural time was observed between PFA and CBA, in contrast with prior meta-analyses of predominantly non-RCTs. However, available evidence does not allow determination of whether this finding is driven by longer preparation times or by the operator learning curve with PFA; this question should be addressed in future randomized comparisons between the two ES.

Limitations

This NMA has several limitations that should be noted.

First and foremost, the observed superiority of PFA in achieving arrhythmia-free survival is largely driven by a single trial,¹⁷ which reported better outcomes with PFA compared with CBA. However, sensitivity analyses excluding this study continued to show significantly greater efficacy of PFA compared with RFA, along with a consistent trend towards superiority over CBA, although statistical significance was attenuated. These findings support the directional robustness of the overall results.

Secondly, the included RCTs span more than a decade of AF ablation, during which substantial advances in catheter technology (e.g. contact-force sensing), mapping systems, and procedural standardization have occurred, potentially contributing to the observed heterogeneity in the RFA vs. CBA comparison and to PFA superiority as well. However, subgroup analyses restricted to studies using contemporary technologies yielded consistent efficacy results, supporting the robustness of our findings despite this heterogeneity. Thirdly, the operator learning curve must be considered. While in the ADVENT trial,³⁴ where centres had no prior clinical experience with the PFA system, PFA demonstrated non-inferior efficacy compared to thermal ES, in the SINGLE SHOT CHAMPION trial,¹⁷ where all operators had at least six months of experience with PFA, it achieved superiority over CBA in arrhythmia-free survival.

Fourthly, since data were obtained by RCTs only, which were performed in high-volume tertiary-level hospitals, the generalizability of the results, both in terms of efficacy and safety, may be limited.

Fifthly, the assessment of ATA recurrence exhibited heterogeneity in monitoring duration across the included studies, with intermittent Holter ECG monitoring, as compared to implantable loop recorders (ILRs), potentially influencing the observed differences in recurrence rates.

Conclusions

In this NMA, PFA suggested a potential for superior outcomes compared with traditional thermal ablation-based approaches (RFA, CBA, and LBA) in terms of arrhythmia-free survival and procedural efficiency. All evaluated transcatheter technologies showed comparable safety profiles. These results should be interpreted cautiously, as they remain exploratory and require future confirmations. Future RCTs should adopt standardized and widely used ablation protocols to allow a more accurate comparison of each technology at its optimal performance level, thereby contributing robust evidence to this important area of electrophysiology.

Supplementary material

Supplementary material is available at Europace online.

Authors’ contribution

A.C.L.: concept/design, data collection, data analysis/interpretation, drafting article, critical revision of article, approval of article. M.P.: concept/design, data collection, data analysis/interpretation, drafting article, critical revision of article, approval of article. A.S.: data analysis/interpretation, critical revision of article, approval of article. F.L.: critical revision of article, approval of article. M.C.: data analysis/interpretation, critical revision of article, approval of article. A.V.: data analysis/interpretation, critical revision of article, approval of article. G.F.: data analysis/interpretation, critical revision of article, approval of article. S.C.: critical revision of article, approval of article. S.V.: critical revision of article, approval of the article. C.V.: critical revision of article, approval of article. F.A.: critical revision of article, approval of article. A.S.: critical revision of article, approval of article. C.P.: critical revision of article, approval of article. S.F.: critical revision of article, approval of article. M.V.T.: critical revision of article, approval of article. G.C.: critical revision of article, approval of article. D.P.: concept/design, critical revision of article, approval of article.

Funding

The publication fee for this work was covered by the Italian Ministry of Health’s ‘Ricerca Corrente’ funding to the IRCCS Humanitas Research Hospital.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.