ETM Experimental and Therapeutic Medicine 1792-0981 1792-1015 D.A. Spandidos ETM-30-4-12933 10.3892/etm.2025.12933 Articles Efficacy and safety of cryoballoon ablation in the elderly: A systematic review and meta-analysis of clinical trials ZhangQian 1 * YuLei 2 * GengJing 3 TianHong-Bo 3 LiXuexun 3 Department of Endocrinology, Jinan Third People's Hospital, Ji'nan, Shandong 250021, P.R. China Department of Cardiology, Jinan Third People's Hospital, Ji'nan, Shandong 250021, P.R. China Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Ji'nan, Shandong 250021, P.R. China Correspondence to: Dr Xuexun Li, Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Weiqi Road, Huaiyin, Ji'nan, Shandong 250021, P.R. China lixuexun2005@163.com

*Contributed equally

 102025 29072025 30 4 183 10 01 2024 09 08 2024 Copyright: © 2025 Zhang et al. 2025 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cryoballoon ablation has comparable efficacy with catheter ablation in atrial fibrillation (AF) treatment. However, there has been no systematic review or meta-analysis on this subject despite some studies on cryoballoon ablation in elderly patients with AF. The PubMed, Embase, Cochrane Library and Web of Science databases were comprehensively searched up to February 2023. The present study selected trials that compared the efficacy and safety of cryoballoon ablation in the elderly with the young that lasted for ≥12 months. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to conduct the present review. For quality assessment of included studies, the Newcastle-Ottawa scale was used. Two reviewers screened all articles independently according to the inclusion criteria. The main outcomes were procedural time, fluoroscopy time, success rate and transient phrenic nerve palsy (tPNP). A total of six articles were ultimately included. Data regarding procedural time, fluoroscopy time and success rate were available for five trials. The tPNP complication rate was reported in all trials. The differences in procedural time (mean difference, 0.29; 95% CI, -4.93 to 5.50; P=0.91), fluoroscopy time (mean difference, -0.59; 95% CI, -2.07 to 0.89; P=0.43), success rate (odds ratio, 0.981; 95% CI, 0.72 to 1.34; P=0.903) and tPNP rate (mean difference, 0.955; 95% CI, 0.452 to 2.020; P=0.904) between the elderly and young groups were all not significant. It was concluded that cryoballoon ablation was as safe and effective in elderly patients with AF as in young patients.

 cryoballoon ablation elderly atrial fibrillation meta-analysis Funding: The present study was supported by a grant from the Natural Science Foundation of Shandong Province (grant no. ZR2022MH253). Introduction

The most common arrhythmia is atrial fibrillation (AF), which can increase certain morbidities, such as heart failure and stroke, and also increase mortality rates, due to stroke and other cardiovascular diseases (1,2). The incidence and prevalence of AF in the elderly has increased significantly from 2004-2016. The prevalence of atrial fibrillation was 0.95%, and the incidence of AF ranges between 0.21 and 0.41 per 1,000 person/years in the elderly over 70 years or older (3,4). As common triggers of AF have been observed to be originated from pulmonary veins, and pulmonary vein (PV) isolation (PVI) with catheter ablation has been established as an effective treatment for AF and is recommended by current guidelines (1,3).

With the aging of the general population, more elderly people need to receive catheter ablation for AF. The elderly population are more likely to be diagnosed with coronary artery disease, type 2 diabetes, hypertension, stroke, a higher risk of thrombo-embolic events, renal insufficiency and other chronic diseases, which can greatly increase the incidence of intraoperative complications (4). Additionally, catheter ablation for AF and long operation and sedation time increases the incidence of intraoperative complications in the elderly (5). The relatively simple learning curve of cryoballoon ablation and short intraoperative operation time associated with this treatment, may be more suitable for the treatment of AF in the elderly.

Studies have confirmed that cryoballoon ablation had comparable efficacy compared with catheter ablation (4,5). The success rate of catheter ablation in elderly patients with AF has been revealed to be promising in several studies (6,7).

Although there have been some studies on cryoballoon ablation in elderly patients with AF, most studies lacked controlled studies with young people and the number of included cases was small (8,9), to the best of the authors' knowledge, there has been no systematic review or meta-analysis on this subject. Therefore, it was decided to perform a systematic review and meta-analysis on this important subject.

 Materials and methods <sec> <title>Protocol

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used in conducting the review (10).

 Data sources and literature search

A total of four databases (PubMed https://pubmed.ncbi.nlm.nih.gov/, Embase https://www.embase.com/, Cochrane Library https://www.cochranelibrary.com/ and Web of Science https://www.webofscience.com/) were searched until February 2023. A comprehensive search was performed to identify published articles or studies on the efficacy and safety of cryoballoon ablation in elderly patients with AF (such as procedure time, fluoroscopy time, success rate and complications). Medical Subject Heading terms were used in PubMed, EMTREE terms in Embase, and keyword search terms for cryoballoon ablation, elderly and atrial fibrillation were used in all four databases with the use of following search terms as single or complex terms in titles, abstracts and keywords: (aged OR elderly OR aged 80 and over OR oldest old OR centenarian OR supercentenarian OR semi-supercentenarians OR octogenarian OR nonagenarian) AND (cryoablation OR cryoballoon OR cryosurgery) AND (atrial fibrillation OR auricular fibrillation OR persistent Atrial Fibrillation OR familial Atrial Fibrillation OR paroxysmal Atrial Fibrillation). No language limitations were applied.

 Study selection and inclusion criteria

All articles were screened independently by two reviewers according to the following inclusion criteria: i) Full-text and relevant data could be acquired; ii) controlled clinical trials involving cryoballoon ablation; iii) comparing efficacy and safety of cryoballoon ablation in the elderly and the young population; iv) minimum follow-up time of 12 months.

Articles such as reviews, abstracts or summaries presented in meetings were excluded. Disagreements between reviewers were resolved by discussion.

 Quality assessment and data extraction

Data of study characteristics such as sample size, follow-up period, age and sex were independently extracted by the two reviewers according to the predefined protocol. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS) for observational studies (7). Studies were scored according to selection of study groups (four points), comparability of groups (two points), and ascertainment of exposure and outcomes (three points) for case-control and cohort studies.

 Statistical analysis

Stata (version 14.0; StataCorp LLC) was used to perform the primary statistical analyses. Data are presented as the mean difference and were pooled using the inverse variance for continuous outcome measures. For dichotomous outcomes, data are presented as the odds ratio (OR) and were pooled using the Mantel-Haenszel random effects model. The 95% CI was used to express procedural and long-term outcomes of the two groups, respectively. Heterogeneity was quantified using I2.

Random effect models were applied to assess the studies regardless of the heterogeneity (I2). P<0.05 was considered to indicate a statistically significant difference.

 Results <sec> <title>Search results

Based on the search strategy, 1,099 studies were identified in the Cochrane library, Embase, PubMed and Web of Science databases. Finally, six studies (8-13) that met the inclusion criteria were identified (Fig. 1).

 Characteristics of the included studies and quality assessment

The characteristics of the included studies are shown in Table I. Studies were performed in Germany (n=3), Italy (n=1), China (n=1), Belgium (n=1) and Japan (n=1). Most trials were single-center studies (n=4) and all the included trials (n=6) were of high quality (NOS score of 8-9). Of the six studies, five (12-16) included elderly patients ≥75 years old, but one (17) included elderly patients ≥80 years old. The follow-up time was 12 months for five studies and 11.8±5.4 months for one study. Two studies included patients with paroxysmal AF only (Table I).

A total of 1,652 patients (936 male patients; 56.66%) were enrolled in the studies (428 patients in the elderly group and 1,224 patients in the control group), with a mean age of 66.61 years. The mean left ventricular ejection fraction was 60.4% (Table II). The left atrial size was not significantly different between the two groups (42 mm in the elderly group compared with 41 mm in the young group; P=0.58).

 Procedural time

The procedural time was reported in five studies. The heterogeneity was moderate (I2=34.5%). The difference in procedural time between the two groups was not significant (mean difference, 0.29; 95% CI, -4.93 to 5.50; P=0.91; Fig. 2A).

 Fluoroscopy time

The fluoroscopy time was systematically reported in five studies. There was moderate heterogeneity among these trials (I2=26.4%). The fluoroscopy time in the elderly group was not significantly different compared with the younger group (mean difference, -0.59; 95% CI, -2.07 to 0.89; P=0.43; Fig. 2B).

 Freeze times in PVs

Data for freeze times in four PVs were available for four studies (12,15-17). The I2 index for left superior PVs (LSPVs), left inferior PVs (LIPVs), right superior PVs (RSPVs) and right inferior PVs (RIPVs) was 0.0, 64.0, 0.0 and 35.8%, respectively. There was no significant difference between the elderly and control group in terms of freeze times of LSPVs (mean difference, -0.051; 95% CI, -0.148 to 0.046; P=0.303), LIPVs (mean difference, -0.03; 95% CI, -0.17 to 0.11; P=0.36), RSPVs (mean difference, 0.079; 95% CI, -0.012 to 0.169; P=0.088) and RIPVs (mean difference, -0.033; 95% CI, -0.14 to 0.07; P=0.55; Fig. 3). When a sensitivity test was performed, the removal of any individual study did not affect the point estimate or confidence interval of the results (data not shown).

 Minimum temperature in PVs

A total of five trials reported the minimum temperature in PVs during the procedure. Cryoballoon freezing was associated with a significantly lower temperature in the elderly compared with the control group during the ablation of LSPVs (mean difference, -0.84; 95% CI, -1.60 to -0.08; P=0.03) and LIPVs (mean difference, -0.78; 95% CI, -1.46 to -0.09; P=0.03). In addition, there was no heterogeneity (I2=0.0%).

There was no significant difference between the two groups during the cryoablation process of the RSPVs (mean difference, -0.30; 95% CI, -1.14 to 0.55; P=0.49) and RIPVs (mean difference, -0.35; 95% CI, -1.33 to 0.64; P=0.49). In addition, there was no heterogeneity for RSPVs (I2=0.0%) and low heterogeneity for RIPVs (I2=22.6%) (Fig. 4).

 PV freeze duration

Data on PV freeze duration were available for three studies. There were no significant differences in freeze durations of LSPVs, RSPVs and RIPVs between the two groups. However, LIPV of the elderly group was characterized by longer freeze duration (mean difference, -18.14; 95% CI, -30.95 to -5.33; P=0.006). There was no heterogeneity between the two groups (I2=0.0%; Fig. 5).

 Success rate

All the included studies systematically reported the success rate. The heterogeneity in both groups was low (I2=2.1%). There was no difference in the success rate between the elderly and younger individuals (OR, 0.981; 95% CI, 0.72 to 1.34; P=0.903; Fig. S1).

In addition, three trials reported the PV reconduction in the redo procedure. There was no significant heterogeneity (I2=0.0%). The difference in PV reconduction between the elderly and control group was not significant (OR, 0.34; 95% CI, 0.10 to 1.16; P=0.08; Fig. 6).

 Transient phrenic nerve palsy (tPNP)

The results of tPNP were reported in all included studies. However, one study (17) reported tPNP in all patients, and was not included in the analysis. The heterogeneity was low (I2=0.0%). There was no difference in the rate of tPNP between the two groups (mean difference, 0.96; 95% CI, 0.45 to 2.02; P=0.90; Fig. S2). Other complications of the procedure are shown in Table III. There was no significant difference between the two groups.

 Risk of bias and sensitivity analysis

All trials included were nonrandomized controlled studies. A funnel plot of studies including procedural time was highly symmetrical, six dots were contained in the large triangle and no evidence of publication bias was identified (Fig. 7). A sensitive analysis showed that the direction and magnitude of combined estimates of fluoroscopy time did not vary markedly with the removal of any study, indicating that the meta-analysis had good reliability and the results were not overly influenced by each individual study (Fig. 8). However, it should be noted that the elderly patients were >80 years old in the study by Kanda et al (17), while the patients were >75 years old in the other five studies, which might be a source of bias.

 Discussion

To the best of our knowledge, the present study was the first meta-analysis to systematically evaluate the efficacy and safety of the cryoballoon ablation procedure in elderly patients with AF. The main finding of the present study was that the cryoballoon ablation procedure was as effective and safe in the elderly as in the younger patients with AF. Cryoballoon freezing was associated with a significantly lower temperature in the elderly compared with the control group during the ablation of LSPVs.

Since the study by Haïssaguerre et al (18) reported that triggers from the PVs initiated AF, PVI has been recommended as the cornerstone of ablation approaches for the treatment of AF (19). The efficacy and safety have been uniformly demonstrated in multiple trials (20,21). At present, it has been shown that cryoablation can have a similar effect to radiofrequency ablation (4,5). A number of studies have established that the prognosis of AF is worse in patients aged ≥75 years, and the rates of mortality and major adverse cardiac events are higher (22-25). As the remodeling and fibrosis of the atrium increase with aging, the success rate of PVI is supposed to be lower in the elderly population (15). Therefore, a number of clinical trials, such as the STOP-AF and RAAFT-2 trials, did not include elderly patients (26,27). However, some non-randomized clinical trials have reported that the results of catheter ablation in elderly patients with AF are promising (28,29). Furthermore, the risk of surgery is higher due to the poor physical conditions and more complications in the elderly. Compared with radiofrequency ablation, cryoablation has a shorter left atrial operation time, which seems to be more suitable for elderly patients (4,5).

The present meta-analysis focused on a comparison of cryoablation between older and young adults. The results were consistent with the observations from the aforementioned studies (12-17). In the present study, the procedural data and success rate for the efficacy analysis were pooled. No significant difference was observed between the procedural time (mean difference, 0.29; 95% CI, -4.93 to 5.50; P=0.91; Fig. 2A) and fluoroscopy time (mean difference, -0.59; 95% CI, -2.07 to 0.89; P=0.43; Fig. 2B). No significant difference was observed for the success rate (OR, 0.981; 95% CI, 0.72 to 1.34; P=0.903; Fig. S1).

Generally, it has been assumed that the elderly cannot endure long operations as can the young, which may affect the efficacy of the procedure (8,9). However, there was no difference between the two groups in the efficacy of the procedure. The cryoballoon ablation procedure takes a short time, which might be a possible explanation. Freeze times of PVs could be performed safely in the elderly as with the young. However, it should be noted that freezing energy could produce a lower temperature on LSPV and LIPV in the elderly compared with the control group in the present study. Nevertheless, in the present study, there was no significant difference between the left pulmonary veins and right pulmonary veins, although the mechanism is unclear. In addition, the LIPV freezing time was longer in the elderly. Therefore, it also suggested that doctors should be more careful in the process of LPV freezing in the elderly. The complication rates of the catheter ablation procedure in elderly patients with AF reported in some trials are inconsistent (30,31). A number of studies have indicated that the rate of complication of catheter ablation was higher in elderly patients with AF compared with the young population (32,33). Compared with catheter ablation, some studies have reported that there were fewer serious complications for the cryoballoon ablation procedure (34,35).

In addition to complications such as pericardial effusions or tamponades, PV stenosis may occur in rare instances (36). Phrenic nerve palsy is the most common complication for the cryoballoon procedure, and can be prevented by phrenic nerve pacing in the procedure (35). tPNP results were reported by all the included trials and it was identified that there was no significant difference in the rate of tPNP between the two groups (mean difference, 0.96; 95% CI, 0.45 to 2.02; P=0.90) and the heterogeneity was low. There was no significant difference for other complications such as atrio-esophageal fistula, tamponade and mortality (Table III).

Therefore, the incidence of complications of the cryoballoon procedure in the elderly was similar to that in the young. The data of some recurrent cases were also analyzed in the present study. It was found that there was no significant difference in PV reconduction between the two groups, which further verified that the effect of cryoablation in the elderly was not inferior to that in the young.

The trials included in the present meta-analysis were non-randomized trials, which might cause bias and yield limited meaningful results. Additionally, more high-quality randomized controlled trials are required to analyze the efficacy and safety of cryoballoon ablation in the elderly. Patients aged >80 years old were included in the Tscholl et al (12) trial, while patients were >75 years old in other trials. This could be a source of heterogeneity. The heterogeneity was low or moderate in the present study.

In conclusion, cryoballoon ablation was as safe and effective in elderly patients with AF as in young patients. The cryoballoon operation of the left pulmonary veins in the elderly requires more attention.

 Supplementary Material Success rate. Transient phrenic nerve palsy. Acknowledgements

Not applicable.

 Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

 Authors' contributions

XL and QZ conceived and designed the study. LY, JG and HBT performed the statistical analysis of the data. XL and JG drafted and wrote the paper. All authors reviewed and edited the manuscript. Data authentication is not applicable. All authors read and approved the final manuscript.

 Ethics approval and consent to participate

Not applicable.

 Patient consent for publication

Not applicable.

 Competing interests

The authors declare that they have no competing interests.

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Flow diagram of study selection for meta-analysis.

Pooled data for the analysis of efficacy and safety. (A) Procedural time. (B) Fluoroscopy time. WMD, weighted mean difference.

Freeze times in PVs. (A) LSPV, (B) LIPV, (C) RSPV and (D) RIPV. PVs, pulmonary veins; LSPV, left superior PV; LIPV, left inferior PV; RSPV, right superior PV; RIPV, right inferior PV; WMD, weighted mean difference.

Minimum temperature in PVs. (A) LSPV, (B) LIPV, (C) RSPV and (D) RIPV. PVs, pulmonary veins; LSPV, left superior PV; LIPV, left inferior PV; RSPV, right superior PV; RIPV, right inferior PV; WMD, weighted mean difference.

Pulmonary vein freeze duration. (A) LSPV, (B) LIPV, (C) RSPV and (D) RIPV. LSPV, left superior pulmonary vein; LIPV, left inferior pulmonary vein; RSPV, right superior pulmonary vein; RIPV, right inferior pulmonary vein.

Pulmonary vein reconduction in the redo procedure. OR, odds ratio.

Funnel plot. Comparison of procedure time between the elderly and young patients. WMD, weighted mean difference.

Sensitive analysis. Comparison of fluoroscopy time between the elderly and young patients.

Characteristics of trials included in the meta-analysis.

  Sample size  
First author/s, year Country Type Age of elderly group, years Elderly group, n Control group, n Follow-up, months PAF, n (%) NOS score (Refs.)
Abdin et al, 2019 Germany Single-center, controlled ≥75 55 183 11.8±5.4 91 (38.2) 8 (16)
Abugattas et al, 2017 Belgium and Italy Two-center, controlled ≥75 53 106 12 159(100) 8 (15)
Heeger et al, 2019 Germany Multi-center, controlled ≥75 104 104 12 119 (57.2) 9 (14)
Kanda et al, 2019 Japan Single-center, controlled ≥80 49 241 12 290(100) 8 (17)
Tscholl et al, 2018 Germany Single-center, controlled ≥75 40 40 12 37 (46.25) 9 (12)
Zhang et al, 2019 China Single-center, controlled ≥75 127 550 12 603 (89.1) 8 (14)

Data are presented as the mean ± SD. PAF, paroxysmal atrial fibrillation; NOS, Newcastle-Ottawa scale.

Baseline characteristics of the included studies.

  Age, years P-value Male patients, n P-value LVEF, % P-value CHA2DS2-vasc P-value HASBLED P-value LA diameter, mm P-value  
First author/s, year Elderly Control <0.01 Elderly Control <0.01 Elderly Control 0<0.01 Elderly Control 0<0.01 Elderly Control <0.01 Elderly Control 0.58 (Refs.)
Abdin et al, 2019 78± 2.8 60.8± 9.5 <0.01 25 120 <0.01 51.6± 8.3 52.5± 8.0 0.47 4.0± 1.3 2.0± 1.3 <0.01 2.2± 0.89 1.2± 0.97 <0.01 40.9± 5.5 40.8± 6.6 0.92 (16)
Abugattas et al, 2017 78.19± 2.7 58.97± 8.5 <0.01 24 62 0.12 59.2± 5.2 59.9± 6.4 0.49 NA NA NA NA NA NA 41.4± 7.2 40.9± 6.6 0.66 (15)
Heeger et al, 2019 77.5± 3.7 63± 13.3 <0.01 52 54 0.78 NA NA NA 3.8± 1.1 2.1± 1.3 <0.01 NA NA NA 44.5± 5.6 44.5± 5.6 >0.99 (14)
Kanda et al, 2019 84±3 66±10 <0.01 24 145 0.15 66±10 65±10 0.52 3.8±0.9 2.2±1.4 <0.01 NA NA NA 40±6 38±6 0.03 (17)
Tscholl et al, 2018 77.0± 2.2 65.5± 9.4 <0.01 20 26 0.17 63±4.4 65±7.4 0.15 4±0.74 2±1.48 <0.01 2±0.74 2±1.48 >0.99 NA NA   (12)
Zhang et al, 2019 79.2± 3.1 63.8± 7.6 <0.01 57 327 <0.01 58.7± 9.0 61.5± 6.5 0 4.8±1.6 2.6± 1.7 <0.01 2.0±0.8 1.8±0.8 0.01 41.0± 5.3 41.3± 5.6 0.58 (13)

Data are presented as the mean ± SD. NA, not available; LVEF, left ventricular ejection fraction; CHA2DS2-vasc, [congestive heart failure (C, 1 point), hypertension (H, 1 point), age ≥75 (A, 2 point), diabetes mellitus (D, 1 point), prior stroke or transient ischemic attack (S, 2 point), vascular disease (v, 1 point), age 65-74 (a, 1 point), female (sc, 1 point)]; HASBLED [hypertension (H, 1 point), abnormal liver/renal function (A, 1 point each), stroke (S, 1 point), bleeding history or predisposition (B, 1 point), labile international normalized ratio (L, 1 point), elderly (E, 1 point), and drugs/alcohol concomitantly (D, 1 point each)]; LA, left atrium.

Complications in the included studies.

  Persistent PNP, n Atrio-esophageal fistula, n Groin complications, n Tamponade, n Mortality, n MI, n Stroke/TIA, n Pericardial effusion, n  
First author/s, year Elderly Control Elderly Control Elderly Control Elderly Control Elderly Control Elderly Control Elderly Control Elderly Control (Refs.)
Abdin et al, 2019 0 0 0 0 2 4 1 1 0 0 0 0 0 0 0 0 (16)
Abugattas et al, 2017 0 1 0 0 1 1 0 0 0 0 0 0 0 0 NA NA (15)
Heeger et al, 2019 0 0 0 0 4 4 0 1 1 0 1 0 0 1 0 0 (14)
Kanda et al, 2019 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (17)
Tscholl et al, 2018 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 (12)
Zhang et al, 2019 0 0 0 0 NA NA 0 1 0 2 0 2 1 5 1 3 (13)

PNP, phrenic nerve palsy; MI, myocardial infarction; TIA, transient ischemic attack; NA, not available.