Highlights
– In the multicentre randomized CRRF‑PeAF trial (n=499), cryoballoon pulmonary vein isolation (PVI) was non‑inferior to radiofrequency (RF) ablation for the composite endpoint of recurrent atrial tachyarrhythmia at 1 year (after a 90‑day blanking period): 22.5% vs 23.2% respectively (HR 0.99; 95% CI 0.69–1.43; P = .96).
– At 1 year, RF ablation produced a greater median reduction in left atrial volume index than cryoballoon ablation: −11 mL/m2 (IQR −19 to −4) vs −4 mL/m2 (IQR −13 to 3), P < .001, suggesting more pronounced reverse atrial remodelling after RF‑based strategies in this cohort.
Background and clinical context
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke, heart failure progression, hospital admissions and impaired quality of life. Catheter ablation with pulmonary vein isolation (PVI) is a guideline‑recommended rhythm control option for symptomatic AF and is increasingly used earlier in the disease course. Most randomized data comparing cryoballoon and radiofrequency ablation derive from patients with paroxysmal AF (notably the FIRE AND ICE trial), where cryoballoon PVI demonstrated non‑inferior clinical outcomes to point‑by‑point RF ablation.
However, persistent AF presents greater procedural challenges owing to more extensive substrate beyond the pulmonary veins, more advanced atrial remodelling, and typically higher arrhythmia recurrence after PVI alone. Whether the cryoballoon—designed primarily for circumferential PVI—delivers outcomes comparable to RF ablation in persistent AF, and how both strategies affect atrial reverse remodelling, has been less clear.
Study design (CRRF‑PeAF)
CRRF‑PeAF is a prospective, multicentre, randomized, non‑inferiority trial that compared cryoballoon to radiofrequency ablation in patients with persistent AF. The trial randomized 500 patients across 12 centres; 499 were included in the final analysis. Patients had persistent AF and were randomized 1:1 to cryoballoon (n=249) or radiofrequency ablation (n=250). The primary endpoint was the occurrence of atrial tachyarrhythmias (ATa) at 1 year, applying a 90‑day post‑ablation blanking period. The analysis reported is intention‑to‑treat.
Key results
Population: Median age in the cohort was 69 years (IQR 61–74). Baseline patient characteristics beyond age were not detailed in the summary provided here; the full report includes the complete baseline table and procedural details.
Primary efficacy—arrhythmia recurrence
At 1 year (after a 90‑day blanking period) the proportion of patients experiencing recurrent atrial tachyarrhythmia was similar between groups: 56/249 (22.5%) in the cryoballoon group versus 58/250 (23.2%) in the RF group. The hazard ratio was 0.99 (95% CI 0.69–1.43) with P = .96, satisfying the trial’s prespecified non‑inferiority threshold. In short, cryoballoon PVI provided equivalent clinical control of atrial tachyarrhythmias at 1 year compared with RF ablation in this persistent AF population.
Left atrial reverse remodelling
An important secondary outcome was change in left atrial volume index (LAVI) as a marker of structural reverse remodelling. At 1 year, RF ablation was associated with a greater median reduction in LAVI compared with cryoballoon: −11 mL/m2 (IQR −19 to −4) versus −4 mL/m2 (IQR −13 to 3), P < .001. This suggests that RF strategies in this trial led to more pronounced reductions in left atrial size over 12 months.
Safety
The summary provided here does not enumerate specific safety endpoints or event rates (periprocedural stroke, tamponade, phrenic nerve palsy, vascular complications, esophageal injury, or mortality). The paper’s full text includes detailed safety data; readers should consult the original publication for complete adverse‑event reporting. Historically, cryoballoon ablation carries a higher risk of transient phrenic nerve injury but similar overall major complication rates compared with RF in paroxysmal AF trials.
Other outcomes
Additional outcomes, such as quality of life, AF burden, need for repeat ablation, antiarrhythmic drug use, and subgroup analyses (for example by LA size, AF duration, or operator experience) should be referenced in the full report. The summary here focuses on the primary and the LAVI findings as key signals with immediate clinical relevance.
Interpreting the findings: mechanistic and practical considerations
The equivalence in 1‑year ATa recurrence between cryoballoon and RF ablation in persistent AF is an important expansion of prior evidence. FIRE AND ICE and other randomized studies established similar efficacy in paroxysmal AF; CRRF‑PeAF extends non‑inferiority to a persistent AF population under trial conditions.
Several mechanistic explanations might account for the discordant findings between rhythm outcome (similar) and remodelling (greater after RF):
- Lesion set and non‑pulmonary vein substrate: RF ablation is frequently used to deliver tailored lesion sets beyond the PVs (linear lesions, targeted substrate modification), depending on operator strategy. Even when PVI is the procedural core, RF energy allows point‑by‑point titration, targeted ablation of low‑voltage areas, and adjunctive lesions that could influence remodelling.
- Lesion durability and transmurality: Cryoballoon delivers circumferential antral PVI with contiguous large lesions. In persistent AF there may be greater need for transmural, heterogeneous substrate modification; differences in lesion geometry and collateral tissue effect could influence atrial reverse remodelling.
- Remodelling kinetics: Structural reverse remodelling is influenced by multiple factors including restoration of sinus rhythm, control of atrial rate, and underlying comorbidities (hypertension, sleep apnea, valvular disease). Similar 1‑year arrhythmia freedom does not guarantee identical remodelling, particularly if residual atrial scarring patterns differ.
Clinical implications
For clinicians, CRRF‑PeAF provides randomized evidence that cryoballoon PVI is a valid, efficacious strategy in persistent AF with similar 1‑year arrhythmia outcomes to RF ablation. That supports using cryoballoon as an initial PVI strategy in appropriate patients, especially in centres with cryoballoon expertise or where workflow efficiency favors a single‑shot device.
However, the larger reduction in LA volume following RF ablation raises the question of whether RF‑based approaches (or adjunctive lesion strategies delivered with RF) may confer additional structural benefit that could translate to longer‑term outcomes beyond 1 year. Whether the observed difference in LAVI will affect late recurrence, heart failure progression, stroke risk, or symptom trajectories requires longer follow‑up and mechanistic study.
Strengths and limitations of the trial
Strengths
- Prospective, randomized design with near‑complete follow‑up (499/500 patients analysed) across multiple centres enhances internal validity.
- Intention‑to‑treat analysis and a clinically relevant primary endpoint increase applicability.
- Objective imaging endpoint (LAVI change) provides structural data in addition to rhythm outcomes.
Limitations
- The summary provided here does not include detailed safety data, ablation lesion sets, operator experience, or rhythm‑monitoring strategies; these factors materially influence outcomes and generalizability.
- Non‑inferiority margin and statistical assumptions that defined the primary analysis are not included in this summary; readers should consult the full paper to judge the robustness of the non‑inferiority claim.
- Follow‑up is limited to 1 year. Persistent AF is a chronic disease with recurrence risk that may diverge beyond 12 months; longer follow‑up is needed to assess durability and clinical consequences of differential remodelling.
- Subgroup signals (for example very enlarged LA or longstanding persistent AF) that might favour one energy source over another require prespecified or exploratory analyses before changing practice in special populations.
Where does this fit with existing evidence and guidelines?
Expert consensus and guideline documents (for example the 2020 ESC AF Guidelines) emphasize that PVI is the cornerstone of catheter ablation for both paroxysmal and persistent AF, while acknowledging that outcomes are generally worse in persistent AF and that additional lesion strategies have not reliably improved outcomes in randomized comparisons. The FIRE AND ICE randomized trial demonstrated non‑inferiority of cryoballoon vs RF in paroxysmal AF; CRRF‑PeAF now extends comparable efficacy to a persistent AF cohort at 1 year. These data support choosing ablation modality based on operator expertise, centre resources, and patient preferences, rather than an a priori superiority claim for either technology in persistent AF.
Conclusions and practical takeaways
CRRF‑PeAF shows that cryoballoon PVI is non‑inferior to RF ablation for preventing atrial tachyarrhythmias at 1 year in patients with persistent AF. However, RF ablation produced a greater reduction in left atrial volume over 12 months, raising questions about differential effects on structural remodelling. Clinicians should integrate these findings with individual patient anatomy, AF duration, comorbidities, and local expertise. Further research should report long‑term recurrence rates, detailed safety outcomes, and whether remodelling differences translate into late clinical divergence.
Funding and trial registration
Funding and clinical trial registration details are provided in the original publication. Readers should consult Miyamoto et al., Eur Heart J 2025 for trial funding sources, site list, and registration identifiers.
Selected references
1. Miyamoto K, Kanaoka K, Yodogawa K, et al. Cryoballoon vs radiofrequency ablation in persistent atrial fibrillation: the CRRF‑PeAF trial. Eur Heart J. 2025 Nov 7;46(42):4426‑4437. doi: 10.1093/eurheartj/ehaf451. PMID: 40704730.
2. Kuck KH, Brugada J, Fürnkranz A, et al. Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation. N Engl J Med. 2016;374(23):2235‑2245. doi:10.1056/NEJMoa1510098.
3. Kirchhof P, Benussi S, Kotecha D, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio‑Thoracic Surgery (EACTS). Eur Heart J. 2020;42(5):373‑498. doi:10.1093/eurheartj/ehaa612.
Author note
This article summarizes key findings from the CRRF‑PeAF randomized trial and places them in clinical context. For procedural details, safety event rates, subgroup analyses, and trial registration/funding, please review the full manuscript by Miyamoto et al. (Eur Heart J 2025).
