- 1Department of Electrophysiology, Institut Jantung, Negara—National Heart Institute, Kuala Lumpur, Malaysia
- 2Department of Cardiology, Cardioangiologisches Centrum Bethanien, Frankfurt, Germany
- 3Internal Medicine and Cardiology, Sana Klinikum Lichtenberg, Berlin, Germany
- 4Department of Electrophysiology, Institituo Cardiovascular Buenos Aires (ICBA), Buenos Aires, Argentina
- 5Cardiac Ablation Solutions, Medtronic, Inc., Minneapolis, MN, United States
- 6Department of Cardiology and Intensive Care Medicine, Städtische Kliniken Bielefeld gem. GmbH—Klinikum Mitte, Bielefeld, Germany
- 7Department of Cardiology, Liverpool Heart and Chest Hospital, Liverpool, United Kingdom
- 8Department of Electrophysiology, Centralny Szpital Kliniczny Uniwersytetu Medycznego w Łodzi, Łódź, Poland
- 9Department of Electrophysiology, Gottsegen György Országos Kardiovaszkuláris Intézet, Budapest, Hungary
Introduction: Cryoballoon ablation (CBA) is a well-established treatment for atrial fibrillation (AF). However, evidence on the impact of sex on outcome is sparse. This real-world analysis aims to describe outcome after CBA in both sexes.
Methods: This registry is an ongoing, global evaluation of CBA procedures in standard-of-care practice. Females undergoing CBA were compared to males at baseline and 12-, and 24-months post-ablation. Serious procedure-related adverse event rate, rate of atrial arrhythmia (AA) recurrence, repeat ablation, hospitalization, cardioversion, and quality-of-life (QoL; EQ-5D-3l) were compared.
Results: Of 3,089 patients with 12-month follow-up, 1,136 (36.8%) were female; and a subset of 1,099 patients (400 female) were followed through 24 months. Females presented with different comorbidities at baseline. The complication rate was low overall in females (3.9%) and males (2.7%, p = 0.07). At 24-month follow-up, the rate of AA recurrence was 25.0% in females and 22.1% in males and female sex was a predictor of AA recurrence (HR adj = 1.21, p = 0.047) and rehospitalizations (HR adj = 1.25, p = 0.03) in a propensity score adjusted analysis. In addition, females stayed in the hospital longer compared to males during the index ablation procedure (47.9% with 2 or more days in hospital vs. 39.3% in males, p < 0.01), as well as during the first hospital stay post-ablation (78.2% with 2 or more days in hospital vs. 60.2% in males, p < 0.01). QoL improved from baseline to 12 months in females (0.85 ± 0.15–0.90 ± 0.13) and males (0.91 ± 0.13–0.94 ± 0.11) and remained high at 24 months.
Discussion: CBA performed according to standard-of-care practice was safe in both sexes. The efficacy of CBA is marginally lower in females, but 75% of females remained free from AA recurrence at 24-months and reported a meaningful improvement in QoL post ablation.
Systematic Review Registration: https://clinicaltrials.gov/ct2/show/NCT02752737, The Cryo Global Registry (NCT02752737)
Introduction
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, and its prevalence is increasing in adults worldwide (1, 2). The worldwide prevalence of AF ranges from equal to lower in females compared to males (3, 4) and increases over time in both sexes (1). If left untreated, AF poses an increased risk for morbidity and mortality, causing a significant burden for patients and healthcare institutions (5). Moreover, the relative risk of all-cause mortality, stroke, cardiovascular mortality, cardiac events, and heart failure in individuals with AF vs. those without AF is higher in females compared to males (6). Catheter ablation (CA) is a well-adopted evidence-based safe and efficacious treatment for managing AF and preventing recurrences of AF (2, 7). Despite the increased cardiovascular risks, females are less likely to be referred to a specialized outpatient arrhythmia clinic for management of AF, and females are less likely to undergo electrical cardioversion or catheter ablation (8). In addition, females are large underrepresented in large randomized controlled trials (9, 10). Several catheter ablation studies have shown sex-based differences in atrial arrhythmia recurrences (11–13). Differences in co-morbidity burden, as well as the underlying electrophysiological substrate may explain the lower arrhythmia-free survival in females. Studies have shown lower mean voltage, significant conduction slowing, more fractionated electrograms and more fibrosis across the atria of females with AF, as well as decreased left atrium (LA) strain and higher stiffness, compared to males (14–17). Literature on sex-specific cryoballoon ablation (CBA) outcomes is limited. Some studies have shown that females with AF may be more symptomatic and report a lower quality of life, although it is unclear whether this is related to sex differences (5). The recent 2024 expert consensus statement indicates that sex disparity in AF outcomes may be attributed to factors such as delayed catheter ablation referral, differences in anatomical features, and differences in burden of associated comorbidities (7). This sub-analysis of the Cryo Global Registry aims to evaluate the real-world experience of CBA in a large cohort of males and females, comparing their baseline characteristics, safety and efficacy outcomes, disease symptom burden, and health care utilization after propensity score matching. A better understanding of routine CBA in females with AF can lead to improved quality of care and tailored treatment in this underrepresented patient population.
Materials and methods
Study design
The Cryo Global Registry (NCT02752737) is an ongoing, prospective, multicenter post- market registry to evaluate the outcomes of CBA procedures performed with the Arctic Front Advance Family of cryoablation catheters (Medtronic, Inc.) for the treatment of AF. A global steering committee of international physicians oversees data quality, statistical analyses, and publication milestones. Data collection was in alignment with the principles outlined in the Declaration of Helsinki (2013) and Good Clinical Practices. Patients provided written informed consent prior to any study specific procedures, and the study was approved by local institutional review boards and ethics committees at each participating center. All procedures performed in the registry were performed according to standard-of-care hospital protocols at the time of data collection. More details on the study design and the cryoballoon procedure have been previously described (18, 19).
Patient population
Patients ≥18 years old with a planned CBA procedure were eligible for inclusion in the registry and were not excluded based on pre-existing medical conditions nor baseline characteristics. This analysis included patients with a minimum of 12 months of follow-up post ablation. Patients with prior cardiac ablations and longstanding persistent AF patients (continuous AF >12 months) were excluded. Real-world experience of CBA between sexes was analyzed in patients enrolled between May 2016 and July 2020 at 96 international centers in 37 countries. Classification of AF was done in accordance with international guidelines; paroxysmal AF (PAF; AF that terminates spontaneously or with intervention within 7 days of onset) or persistent AF (PsAF; continuous AF that is sustained beyond 7 days and ≤12 months) (7).
Cryoballoon ablation procedure
The cryoballoon ablation procedure was conducted according to standard of care at each participating site. This procedure has been described in detail in previous publications (18, 20–22). The cryoballoon ablation procedure was conducted according to standard of care at each participating site. This procedure has been described in detail in previous publications (citations included in the manuscript). In brief, after patient sedation, the LA was accessed through a transseptal puncture. A 15-F OD steerable sheath was used to introduce a 23 or 28 mm cryoballoon ablation catheter (Medtronic, Inc) into the LA. The cryoballoon catheter and sheath were maneuvered to the targeted pulmonary vein (PV) with either a J-tip guidewire or a inner-lumen octopolar/decapolar circular mapping catheter (Medtronic, Inc). After antral occlusion of the targeted PV was achieved, the cryoapplication was triggered. The number and duration of cryoapplications per PV were determined by the operating physician. Sites were recommended to monitor phrenic nerve function during right-sided PVI by pacing with a diagnostic catheter. All cryoapplications were terminated upon detection of an attenuated diaphragmatic response. Application of additional lesions (other non-PVI ablation), adjunctive imaging (e.g., intracardiac echocardiography, three-dimensional electroanatomical mapping), intraprocedural esophageal temperature monitoring and use of ablation tools were determined by the operating physician for each patient. PVI was confirmed by demonstration of entrance and/or exit block following the ablation. Pre-procedure, intra-procedure, and post-procedure tools and techniques to guide, monitor and assess the CBA procedure were all applied at the discretion of the physician per patient. Physicians also determined appropriate peri-procedural anticoagulation, initiation or continuation of AADs, and followed local standard-of-care policies to discharge patients from the hospital.
Patient follow-up and endpoints
Patients were followed through 12 or 24 months according to the hospital's standard-of care. The study protocol required annual status visits; however, the method and frequency of rhythm monitoring was not dictated by the study protocol. Monitoring methods included, but were not limited to, 12-lead electrocardiogram, Holter monitor, trans-telephonic monitor, insertable cardiac monitor, pacemaker, and/or implantable cardioverter defibrillator.
Efficacy and safety after the index-CBA procedure throughout 24 months of follow-up were reported. Efficacy was assessed by freedom from ≥30 s recurrence and atrial arrhythmias [AA; defined as AF/atrial flutter (AFL)/atrial tachycardia (AT)] between a 90-day blanking period and 24-month follow-up. During the 90-day blanking period, recurrent atrial arrhythmias could be managed with cardioversion, repeat ablation, and medication per hospital standard of care practices. All reported adverse events from Cryo Global registry were assessed for seriousness/relatedness by the investigator and by safety team. Adverse events were classified by the treating physician by seriousness and relatedness to the procedure or CBA system. Serious adverse events included all events that led to a) death, or b) to a serious deterioration in health that resulted in either (1) a life-threatening illness or injury, (2) a permanent impairment in body structure or function, (3) in-patient or prolonged hospitalization, or (4) medical intervention to prevent life-threatening illness or injury.
Patient demographics and procedural characteristics were assessed. Predefined AF-related symptoms and quality-of-life (QoL, measured by EQ-5D-3l) were reported by the patient at baseline, 12, and 24 months. The EQ-5D-3l questionnaire measures five dimensions of health, including: (1) mobility, (2) selfcare, (3) physical activities, (4) pain and discomfort, and (5) anxiety and depression. Each question has three levels of response indicating no problem, some problem, or extreme problem. Rate of repeat ablations and cardioversions (in addition to all-cause non-procedure related hospitalizations post-index procedure) were reported throughout 24 months of follow-up.
Statistical analysis
Baseline characteristics and clinical data were summarized using the appropriate summary statistics; continuous variables are summarized as mean and standard deviation, and categorical variables are summarized as counts and percentages. Differences in baseline characteristics between the male and female cohorts were tested with a two-sample t-test for continuous variables and Fisher's exact test for categorical variables. Similarly, differences in procedural characteristics were tested with a two-sample t-test for continuous variables and Fisher's exact test for categorical variables. For skewed continuous data, Wilcoxon rank-sum test was utilized. Kaplan–Meier methods were used to estimate the 24-month freedom from arrhythmia recurrence, repeat ablations, cardioversions and hospitalizations. Standard error was approximated with Greenwood's formula. Unadjusted and adjusted hazard ratios were calculated with Cox regression. Unadjusted models included only group cohort (female vs. male) as a covariate in the model. Adjusted models accounted for differences in baseline characteristics between the female and male cohorts utilizing propensity score methods, specifically propensity score covariate adjustment method. In the adjusted Cox model, group cohort (female vs. male) and propensity score were included as covariates with propensity score calculated as follows. Logistic regression was used to calculate propensity score for each subject where group cohort (female vs. male) was the dependent variable, and baseline variables from Table 1 including age, body mass index, type of AF (paroxysmal vs. persistent), years diagnosed with AF, history of atrial flutter, history of atrial tachycardia, left atrial diameter, left ventricular ejection fraction, number of prior failed AADs, hypertension, baseline NYHA, prior myocardial infarction, prior stroke/TIA, coronary artery disease, diabetes and sleep apnea were included as covariates. CHA2DS2-VASc score was excluded as it is a composite of other variables in the model (heart failure, hypertension, age, diabetes, prior stroke/transient ischemic attack).
Multiple imputation methods were utilized in the propensity score modeling, imputing baseline data for patients missing data. Multivariate imputation by fully conditional specification methods were utilized with logistic regression method specified for classification variables and regression methods utilized for continuous variables (23). Differences in safety event rates between male and female patients were assessed with a Fisher's exact test. Differences in first hospitalization post-ablation length of stay was assessed with Wilcoxon rank-sum test. Changes in symptoms and QoL from baseline to 24-months were assessed with a t-test. Values of P < 0.05 were considered significant. Statistical analyses were conducted using SAS software version 9.4 (SAS Institute, Cary, North Carolina).
Results
Patient demographics and follow-up
A total of 3,089 patients (36.8% female) that were enrolled and treated in the Cryo Global Registry had 12-month follow-up data available, and a subset of 1,099 patients had 24-month data available. Attrition was low with 301 (9.7%) of patients exiting early, including: 53 withdrawn by the investigator early, 188 lost to follow-up, 49 patients requested withdrawal, and 11 for “other” reasons. On average, patients had a follow-up visit 2.3 ± 1.6 times during the first 12 months post CBA, and 1.2 ± 0.9 times in the second year of follow-up, per the hospital's standard-of-care. There was no difference in the mean number of follow-up visits in females and males through 12 months (2.3 ± 1.6 vs. 2.3 ± 1.6, p = 0.47), nor during the 12-to-24-month follow-up period (1.2 ± 0.8 vs. 1.2 ± 0.9, p = 0.73). In total, 23 (0.7%) deaths were reported during the follow-up period, of which three occurred within 30 days of the procedure. Of the three deaths, one was confirmed to be related to the procedure (cerebrovascular accident), and the other two deaths were due to infective exacerbation of chronic obstructive airways disease and acute myocardial infarction, respectively.
Baseline characteristics are presented in Table 1. Females were on average older (64 ± 10 vs. 59 ± 12, p < 0.01) than male study patients and presented more often with PAF (84.4% vs. 80.0%, p < 0.01). In addition, females had a significantly higher CHA2DS2−VASc score (2.9 ± 1.4 vs. 1.4 ± 1.3, p < 0.01) as well as a higher CHA2DS2−VA score (excluding the female sex component; 1.9 ± 1.4 vs. 1.4 ± 1.3; p < 0.01). Furthermore, females presented more often with hypertension (60.3% vs. 51.5%, p < 0.01), but they less often presented with prior myocardial infarction (1.7% vs. 3.3%, p < 0.01) and history of coronary artery disease (7.7% vs. 12.3%, p < 0.01) compared to males. Females had a significantly higher left ventricular ejection fraction (61 ± 9 vs. 59 ± 9, p < 0.01). In addition, the left atrial (LA) diameter (40 ± 7 vs. 41 ± 7, p < 0.01) and LA diameter corrected for BMI (1.50 ± 0.32 vs. 1.54 ± 0.28, p < 0.01) were smaller in females compared to males, respectively. There was no difference in the number failed antiarrhythmic drugs (AADs) at baseline.
Procedural characteristics
Procedure times, presented in Table 2, were not statistically different between sexes. A trend was observed towards more additional ablations other than pulmonary vein isolation (PVI) and cavotricuspid isthmus ablation (CTI) in females vs. males (6.7% vs. 5.0%, p = 0.06). Length of hospital stay during the index procedure was longer for females (2.24 ± 6.02 days vs. 2.17 ± 12.95 days in males, p < 0.01). More females reported length of stay of 2 or more days (47.9% vs. 39.3% of males, p < 0.01). At discharge, 580 (51.1%) females and 1,013 males (51.9%) males were on AADs. At 12 months, 274 (26.2%) females and 432 (24.7%) males were on AADs. At 24 months, 118 (31.8%) females and 198 (31.4%) males were on AADs.
Efficacy and safety
Long-term efficacy is depicted in Figure 1A. The rate of AA recurrence was 25.0% in females and 22.1% in males at 24-months follow-up. Female sex was a predictor of AF/AFL/AT recurrence rate (HR adj = 1.21, p = 0.047) in a propensity score adjusted analysis (Table 3). Although not statistically significant, repeat ablations and cardioversion were also higher in females with a 15% increase in repeat ablation risk (HR adj = 1.15, p = 0.35) and 28% increase in cardioversion risk (HR adj = 1.28, p = 0.21). Arrhythmia monitoring was conducted per standard of care at study centers. ECG and Holter monitoring rates were similar between male and female. In the first 12-months, female patients received 1.6 ± 1.7 12-lead ECGs on average and 1.6 ± 1.7 for males (p = 0.65). Holter rates in the first 12-months were 0.8 ± 1.1 in female and 0.8 ± 1.1 in male patients (p = 0.78). In the 12–24 month time period, ECG and Holter rates were also similar (ECG: 0.7 ± 1.0 in females, 0.7 ± 1.0 in males, p = 0.45; Holter: 0.3 ± 0.6 in females, 0.3 ± 0.5 in males, p = 0.15). Intracardiac loop recording was available in 2.1% of patients (2.3% female, 1.9% male).

Figure 1. Rate of atrial arrhythmia recurrence and All-cause rehospitalizations over 24-months. Kaplan–Meier graphs of (A) the rate of a ≥30 s recurrence of atrial fibrillation (AF)/atrial flutter (AFL)/atrial tachycardia (AT) after the blanking period through 24 months of follow-up and (B) all-cause rehospitalizations through 24 months of follow-up. Females are represented in red lines, males in blue lines.

Table 3. Cox regression analysis of efficacy, repeat ablation, cardioversion and all-cause hospitalization.
The rate of serious procedure-related adverse events was low overall in females (3.9%) and males (2.7%, p = 0.07). A detailed list of adverse events per sex is provided in Table 4. Of particular note, the number of phrenic nerve injuries classified as serious by the investigators was low and similar in both cohorts (0.8% in females vs. 0.3% in males, p = 0.10). Also, similar rates of cardiac tamponade, cardiac perforation, or pericardial effusion were reported, with 7 (0.6%) reports in females and 5 (0.3%, p = 0.14) in males.
Rehospitalizations
Females had a 25% increase in the risk for rehospitalization post ablation (HR adj = 1.25, p = 0.03) after a propensity adjusted analysis (Figure 1B). In addition, females stayed in the hospital longer (Table 3) compared to males (5.7 ± 7.7 days vs. 3.5 ± 5.6, respectively; p < 0.01) and 78.2% of females stayed in the hospital ≥2 days vs. 60.2% of males, p < 0.01. The majority of patients was not rehospitalized (83.0% of females and 87.2% of males) in the 24 months post ablation. However, if hospitalized, this happened more often in females than males (4.1% females with ≥ 2 hospitalizations vs. 2.7% males, p < 0.01). The most common reason for the first report of an all-cause rehospitalization was AA recurrence in 124 (10.9%) female and 174 (8.9%) male patients. No other reason for the first report of an all-cause rehospitalization was prominent in either cohort.
Symptom burden and quality-of-life
The percentage of patients reporting each AF-related symptom per sex can be found in Figure 2. Females had more AF-related symptoms at baseline than males (1.9 ± 1.2 vs. 1.6 ± 1.1, p < 0.01). Females reported a similar reduction of symptoms [−1.38 (95% CI:−1.46, −1.29) symptoms] from baseline to 12 months compared to males [−1.30 (95% CI: −1.36, −1.25) symptoms, p = 0.13].

Figure 2. AF-related symptom burden over 24-months. Proportion of (A) female and (B) male patients with predefined symptoms (dizziness, palpitations, rapid heartbeat, dyspnea, fatigue, syncope) related to AF at baseline, 12-month, and 24-month follow-up.
QoL as measured by the EQ-5D-3l summary score and VAS analog scale are summarized in Table 5. Females had a significantly lower QoL score at baseline compared to males (EQ-5D: 0.85 ± 0.15 vs. 0.91 ± 0.13, respectively, p < 0.01; VAS analog scale: 70.3 ± 17.0 vs. 75.3 ± 16.2, respectively, p < 0.01). Both sexes experienced a statistically significant improvement in QoL from baseline to 12-months (p < 0.01 for both sexes) that remained high at 24-months. The absolute improvement in EQ-5D summary score from baseline to 12-months was higher in females compared to males (0.05 vs. 0.03 points, respectively, p < 0.01). The VAS analog scale also improved significantly more in females compared to males (8.1 vs. 6.6 points, respectively, p = 0.03).
Discussion
Primary findings
In this real-world observation, females made up 37% of the total cohort. Females undergoing CBA for AF had significant differences in baseline characteristics compared to males. There were no differences in procedure times, but females stayed in the hospital longer following index-CBA. In addition, there was no significant difference between females and males in complication rate, repeat ablations, and cardioversions. However, female sex was an independent predictor of AA recurrences and rehospitalizations at 24 months of follow-up. Females had a higher symptom burden and lower QoL compared to males at baseline. Both sexes reported a significant improvement in symptoms and QoL at 12-months that remained high at 24-months, and the absolute improvement in QoL after 12-months was higher in females.
Patient population
The percentage of females enrolled in previous CBA studies ranged from 25% to 32%. (12, 24, 25) Importantly, the percentage of females in this registry is higher (37%); however, this percentage of female participation is still lower than the reported median percentage of females with AF in the total population (45.3%, IQ 40.6%-47.2%) (10). These data indicate that a “rhythm control treatment gap” may still exist for females with AF. It has been suggested that the presence of symptoms atypical to AF in females may delay diagnosis and therapy (3). A recent single-center study has shown that females were not more reluctant to accept CA when offered (26), and reasons for this disparity warrant further investigation.
Clinical outcomes
Several studies and meta-analyses have compared outcomes in females and males after index CA, with contradictory results (8, 11–13, 24, 25, 27–36). However, only a limited number of observational studies have investigated the impact of sex on differences in outcome following a CBA procedure, specifically (12, 24, 25). Two observational studies showed higher rates of adverse events in females undergoing CBA (12, 24, 25). Ricciardi, et al. reported similar complication rates between sexes (12). Common complications in females were phrenic nerve injury, cardiac tamponade, cardiac perforation, and pericardial effusion (12, 24, 25). In the current analysis, overall serious procedure-related adverse event rate was similarly low in both sexes and there was no difference in the rate of phrenic nerve injury, and cardiac tamponade, cardiac perforation, and pericardial effusion. The low adverse event rate found here is in alignment with other contemporary CBA trials (22, 37).
Previous CBA publications have reported differences in efficacy results between sexes. A recent publication from Ekrami et al. (25) showed no statistical difference in the rate of AA recurrences between sexes at 12 months. Looking at longer follow-up durations, Hermida et al. (12) showed that females with PAF undergoing cryo-PVI had a higher risk of AA recurrence after 24 and 36 months of follow-up. In the 1-STOP Italian registry (24), the 24-month freedom from AF was not found to be statistically different between sexes, but a trend was observed for a lower AF-free survival in females. In the current large real-world analysis, females also had an increased risk of AA recurrences after 24 months of follow-up, after correcting for differences in baseline characteristics. The majority of females still benefited from CA as 75% of females remained free from AA recurrence at 24-months. Literature suggests that females often present with more advanced structural remodeling at the time of ablation and a lower incidence of rotational activity outside the pulmonary veins (14, 15). These mechanistic findings may potentially account for the post-ablation differences and higher AA recurrences in females (15).
In the present analysis, females also had a significantly longer hospital stay at index-CBA and first rehospitalization, as well as more rehospitalizations post-ablation compared to males. AA recurrence was the main reason for rehospitalization, but it did not explain all of the difference in rehospitalization rate between sexes. Although minimal, some other causes of rehospitalizations include sinus node dysfunction [5(0.4%) females, 3(0.2%) males], diverticulitis [3(0.3%) females, none in male], pneumonia [2(0.2%) females, 3(0.2%) males], and hypertension [2(0.2%) females, 1(0.1%) male]. Index-hospital stay is known to be longer for females (13, 32), and physician precaution (for an anticipated increased risk for cardiovascular complications in females undergoing CA) may be one potential reason for this observation (32). Although females in this study reported more symptoms and had an increased risk of recurrences; they did not undergo more additional treatment for AAs (meaning repeat ablations or cardioversions) than males within 24 months of follow-up. Female sex was also reported to be associated with a 36% increased risk of cardiovascular rehospitalization compared to males in a retrospective analysis of the FIRE and ICE randomized controlled trial (13). A predefined sub-analysis of the EAST-AFNET4 trial showed that early rhythm intervention led to improved cardiovascular outcome and hospitalization for heart failure or acute coronary syndrome in both sexes (despite females having higher CHA2DS2-VASc) compared to usual care, which underlines the importance of early treatment in females with AF (38). Further studies are needed to better understand the differences in hospitalization between sexes.
The current findings on sex differences in QoL and symptoms confirm earlier results in literature; females report a lower QoL (26, 32, 39) and higher symptom burden (12, 24, 26, 39) at baseline compared to males, regardless of the QoL questionnaire or symptoms score used, and CA results in an absolute improvement of QoL and symptoms in females with PAF and PsAF that is similar (32–34) or better (26) compared to males. The absolute improvement in QoL in the current analysis (females: 0.05, males: 0.03) was within the range of the minimally clinically important difference (MCID: 0.03–0.52) (40) reported in literature for the EQ-5D QoL instrument.
In summary, this study should encourage physicians to evaluate females for non-traditional AF disease symptoms and consider earlier rhythm management treatment from the time of diagnosis in line with current AF guidelines (2, 5). Also, female patients should not delay general cardiac care management, and they should proactively seek out specialized cardiac care, including electrophysiological intervention. These results may also apply to emerging Pulsed Field Ablation (PFA) technologies. Regardless of the energy type, PVI remains the cornerstone of AF ablation (2, 5, 7). Real-world sex-based outcomes of PFA are being collected in large registries (e.g., MANIFEST, 1-STOP Italian Registry) that will provide insights in the near term.
Limitations
It is acknowledged that there are several limitations because of the observational study design. The analysis describes real-world usage and outcomes of CBA. Patients were not excluded based on pre-existing baseline characteristics, and females enrolled in the Cryo Global Registry had more comorbidities than males. Statistical methods were utilized to account for these differences but are limited by the data collected in this study. However, there may be other confounders (e.g., lifestyle factors, socioeconomic status and center-specific procedural protocols, and medication usage) that could not be accounted for. Furthermore, the follow-up was conducted per the hospital's standard-of-care, and consequently, only a subset of patients with 12-month follow-up data were followed up for 24 months. Lastly, site-specific arrhythmia monitoring methods were not uniform across centers. Hence, it is possible that asymptomatic arrhythmias could have been under reported.
Conclusion
CBA performed according to standard-of-care practice was safe in both sexes. Although the benefit of CA was marginally lower in females compared to males, the majority of females remained free from AA recurrence at 24-months and reported a meaningful improvement in QoL and symptom burden at 24 months post ablation. This report may help to close the “rhythm control treatment gap” and improve access to CBA therapy for females suffering from AF.
Data availability statement
The datasets presented in this article are not readily available because of patient privacy and informed consents, including the potential for release of protected health information and adherence to global country standards on privacy. Requests to access the datasets should be directed to Medtronic,a2VsbHkudmFuLmJyYWd0QG1lZHRyb25pYy5jb20=.
Ethics statement
The studies involving humans were approved by each hospitals' individual institutional review board. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.
Author contributions
SK: Conceptualization, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing. KC: Investigation, Writing – review & editing. CD: Investigation, Writing – review & editing. FS: Investigation, Writing – review & editing. FK: Formal analysis, Validation, Writing – review & editing, Methodology. KB: Methodology, Supervision, Writing – original draft, Writing – review & editing. TL: Investigation, Writing – review & editing. DT: Investigation, Writing – review & editing. PP: Investigation, Writing – review & editing. CF: Investigation, Writing – review & editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This study was sponsored by Medtronic.
Acknowledgments
The data in this manuscript were previously presented at scientific meetings: Surinder Kaur Khelae. Real-world sex differences in health care utilization after cryoballoon ablation: 2- year outcomes from the Cryo Global Registry. Oral presentation at APHRS, Nov 18th, 2022. Surinder Kaur Khelae. Differences in Atrial Fibrillation Cryoballoon Ablation by Gender: 24-month Outcomes from the Cryo AF Global Registry. Moderated poster at HRS, April 30th, 2022. The authors sincerely thank the Cryo Global Registry sites and staff for their commitment and contributions to the study. The authors also thank Neha Sawhney, Ryan Radtke, Jada Selma, Rachelle Kaplon, and Hae Lim from Medtronic for their support of the trial and generation of this manuscript.
Conflict of interest
KC reports a relationship with Medtronic Inc that includes: funding grants and speaking and lecture fees. DT reports a relationship with Medtronic Ltd that includes: speaking and lecture fees. PP reports a relationship with Medtronic Inc that includes: consulting or advisory. CF reports a relationship with Medtronic Inc that includes: speaking and lecture fees. KB reports a relationship with Medtronic Inc that includes: employment. FK reports a relationship with Medtronic Inc that includes: employment.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
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References
1. Schnabel RB, Yin X, Gona P, Larson MG, Beiser AS, McManus DD, et al. 50 Year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the framingham heart study: a cohort study. Lancet. (2015) 386(9989):154–62. doi: 10.1016/S0140-6736(14)61774-8
2. Joglar JA, Chung MK, Armbruster AL, Benjamin EJ, Chyou JY, Cronin EM, et al. 2023 ACC/AHA/ACCP/HRS guideline for the diagnosis and management of atrial fibrillation: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation. (2024) 149(1):e1–e156. doi: 10.1161/CIR.0000000000001193
3. Odening KE, Deiss S, Dilling-Boer D, Didenko M, Eriksson U, Nedios S, et al. Mechanisms of sex differences in atrial fibrillation: role of hormones and differences in electrophysiology, structure, function, and remodelling. Europace. (2019) 21(3):366–76. doi: 10.1093/europace/euy215
4. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation. (2020) 141(9):e139–596. doi: 10.1161/CIR.0000000000000757
5. Van Gelder IC, Rienstra M, Bunting KV, Casado-Arroyo R, Caso V, Crijns H, et al. ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. (2024) 45(36):3314–414. doi: 10.1093/eurheartj/ehae176
6. Emdin CA, Wong CX, Hsiao AJ, Altman DG, Peters SA, Woodward M, et al. Atrial fibrillation as risk factor for cardiovascular disease and death in women compared with men: systematic review and meta-analysis of cohort studies. Br Med J. (2016) 532:h7013. doi: 10.1136/bmj.h7013
7. Tzeis S, Gerstenfeld EP, Kalman J, Saad EB, Shamloo AS, Andrade JG, et al. European Heart rhythm association/heart rhythm society/Asia Pacific heart rhythm society/Latin American heart rhythm society expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. (2024) 21(9):e31–e149. doi: 10.1016/j.hrthm.2024.03.017
8. Volgman AS, Benjamin EJ, Curtis AB, Fang MC, Lindley KJ, Naccarelli GV, et al. Women and atrial fibrillation. J Cardiovasc Electrophysiol. (2021) 32(10):2793–807. doi: 10.1111/jce.14838
9. Khaing E, Aroudaky A, Dircks D, Almerstani M, Alziadin N, Frankel S, et al. Representation of women in atrial fibrillation ablation randomized controlled trials: Systematic Review. J Am Heart Assoc. (2025) 14(2):e035181. doi: 10.1161/JAHA.124.035181
10. Noubiap JJ, Thomas G, Nyaga UF, Fitzgerald JL, Gallagher C, Middeldorp ME, et al. Sex disparities in enrollment and reporting of outcomes by sex in contemporary clinical trials of atrial fibrillation. J Cardiovasc Electrophysiol. (2022) 33(5):845–54. doi: 10.1111/jce.15421
11. Cheng X, Hu Q, Gao L, Liu J, Qin S, Zhang D. Sex-related differences in catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Europace. (2019) 21(10):1509–18. doi: 10.1093/europace/euz179
12. Hermida A, Burtin J, Kubala M, Fay F, Lallemand PM, Buiciuc O, et al. Sex differences in the outcomes of cryoablation for atrial fibrillation. Front Cardiovasc Med. (2022) 9:893553. doi: 10.3389/fcvm.2022.893553
13. Kuck KH, Brugada J, Furnkranz A, Chun KRJ, Metzner A, Ouyang F, et al. Impact of female sex on clinical outcomes in the FIRE AND ICE trial of catheter ablation for atrial fibrillation. Circ Arrhythm Electrophysiol. (2018) 11(5):e006204. doi: 10.1161/CIRCEP.118.006204
14. Wong GR, Nalliah CJ, Lee G, Voskoboinik A, Chieng D, Prabhu S, et al. Sex-Related differences in atrial remodeling in patients with atrial fibrillation: relationship to ablation outcomes. Circ Arrhythm Electrophysiol. (2022) 15(1):e009925. doi: 10.1161/CIRCEP.121.009925
15. Rios-Munoz GR, Soto N, Avila P, Carta A, Atienza F, Datino T, et al. Structural remodeling and rotational activity in persistent/long-lasting atrial fibrillation: gender-effect differences and impact on post-ablation outcome. Front Cardiovasc Med. (2022) 9:819429. doi: 10.3389/fcvm.2022.819429
16. Cochet H, Mouries A, Nivet H, Sacher F, Derval N, Denis A, et al. Age, atrial fibrillation, and structural heart disease are the main determinants of left atrial fibrosis detected by delayed-enhanced magnetic resonance imaging in a general cardiology population. J Cardiovasc Electrophysiol. (2015) 26(5):484–92. doi: 10.1111/jce.12651
17. Duarte F, Silva-Teixeira R, Aguiar-Neves I, Almeida JG, Fonseca P, Monteiro AV, et al. Sex differences in atrial remodeling and atrial fibrillation recurrence after catheter ablation. Heart Rhythm. (2025) 6:S1547-5271(25)00116-X. doi: 10.1016/j.hrthm.2025.02.003
18. Chun KRJ, Okumura K, Scazzuso F, On K, Kueffer Y, Braegelmann FJ, et al. Safety and efficacy of cryoballoon ablation for the treatment of paroxysmal and persistent AF in a real-world global setting: results from the Cryo AF global registry. J Arrhythm. (2021) 37(2):356–67. doi: 10.1002/joa3.12504
19. Foldesi C, Misikova S, Ptaszynski P, Todd D, Herzet JM, Braegelmann KM, et al. Safety of cryoballoon ablation for the treatment of atrial fibrillation: first European results from the cryo AF global registry. Pacing Clin Electrophysiol. (2021) 44(5):883–94. doi: 10.1111/pace.14237
20. Packer DL, Kowal RC, Wheelan KR, Irwin JM, Champagne J, Guerra PG, et al. Cryoballoon ablation of pulmonary veins for paroxysmal atrial fibrillation: first results of the North American Arctic front (STOP AF) pivotal trial. J Am Coll Cardiol. (2013) 61(16):1713–23. doi: 10.1016/j.jacc.2012.11.064
21. Kuck KH, Brugada J, Furnkranz A, Metzner A, Ouyang F, Chun KR, et al. Cryoballoon or radiofrequency ablation for paroxysmal atrial fibrillation. N Engl J Med. (2016) 374(23):2235–45. doi: 10.1056/NEJMoa1602014
22. Su WW, Reddy VY, Bhasin K, Champagne J, Sangrigoli RM, Braegelmann KM, et al. Cryoballoon ablation of pulmonary veins for persistent atrial fibrillation: results from the multicenter STOP persistent AF trial. Heart Rhythm. (2020) 17(11):1841–7. doi: 10.1016/j.hrthm.2020.06.020
23. van Buuren S. Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res. (2007) 16(3):219–42. doi: 10.1177/0962280206074463
24. Ricciardi D, Arena G, Verlato R, Iacopino S, Pieragnoli P, Molon G, et al. Sex effect on efficacy of pulmonary vein cryoablation in patients with atrial fibrillation: data from the multicenter real-world 1STOP project. J Interv Card Electrophysiol. (2019) 56(1):9–18. doi: 10.1007/s10840-019-00601-3
25. Ekrami NK, Magni FT, Dayalani V, van Gelder IC, Groenveld HF, Tieleman RG, et al. Assessment of sex-related differences and outcome in patients who underwent cryoballoon pulmonary vein isolation for atrial fibrillation: an observational cohort study. BMJ Open. (2022) 12(11):e063359. doi: 10.1136/bmjopen-2022-063359
26. Carnlof C, Iwarzon M, Jensen-Urstad M, Gadler F, Insulander P. Women with atrial fibrillation undergoing pulmonary vein isolation are more symptomatic but improve more in health-related quality of life and symptom burden than men. Scand Cardiovasc J. (2022) 56(1):316–24. doi: 10.1080/14017431.2022.2107235
27. Tanaka N, Inoue K, Kobori A, Kaitani K, Morimoto T, Kurotobi T, et al. Sex differences in atrial fibrillation ablation outcomes: insights from a large-scale multicentre registry. Europace. (2020) 22(9):1345–57. doi: 10.1093/europace/euaa104
28. Zylla MM, Brachmann J, Lewalter T, Hoffmann E, Kuck KH, Andresen D, et al. Sex-related outcome of atrial fibrillation ablation: insights from the German ablation registry. Heart Rhythm. (2016) 13(9):1837–44. doi: 10.1016/j.hrthm.2016.06.005
29. Stabile G, Bertaglia E, Pappone C, Themistoclakis S, Tondo C, Zorzi A, et al. Influence of age and gender on complications of catheter ablation for atrial fibrillation. J Atr Fibrillation. (2015) 7(6):1197.27957160
30. Shah RU, Freeman JV, Shilane D, Wang PJ, Go AS, Hlatky MA. Procedural complications, rehospitalizations, and repeat procedures after catheter ablation for atrial fibrillation. J Am Coll Cardiol. (2012) 59(2):143–9. doi: 10.1016/j.jacc.2011.08.068
31. Grecu M, Blomstrom-Lundqvist C, Kautzner J, Laroche C, Van Gelder IC, Jordaens L, et al. In-hospital and 12-month follow-up outcome from the ESC-EORP EHRA atrial fibrillation ablation long-term registry: sex differences. Europace. (2020) 22(1):66–73. doi: 10.1093/europace/euz225
32. Kloosterman M, Chua W, Fabritz L, HR A-K, Schotten U, Nielsen JC, et al. Sex differences in catheter ablation of atrial fibrillation: results from AXAFA-AFNET 5. Europace. (2020) 22(7):1026–35. doi: 10.1093/europace/euaa015
33. Forleo GB, Tondo C, De Luca L, Dello Russo A, Casella M, De Sanctis V, et al. Gender-related differences in catheter ablation of atrial fibrillation. Europace. (2007) 9(8):613–20. doi: 10.1093/europace/eum144
34. Singh SM, 'Avila D, Aryana A, Kim A, Mangrum YH, Michaud JM, et al. Persistent atrial fibrillation ablation in females: insight from the MAGIC-AF trial. J Cardiovasc Electrophysiol. (2016) 27(11):1259–63. doi: 10.1111/jce.13051
35. Deng H, Shantsila A, Guo P, Potpara TS, Zhan X, Fang X, et al. Sex-related risks of recurrence of atrial fibrillation after ablation: insights from the Guangzhou atrial fibrillation ablation registry. Arch Cardiovasc Dis. (2019) 112(3):171–9. doi: 10.1016/j.acvd.2018.10.006
36. Russo AM, Zeitler EP, Giczewska A, Silverstein AP, HR A-K, Cha YM, et al. Association between sex and treatment outcomes of atrial fibrillation ablation versus drug therapy: results from the CABANA trial. Circulation. (2021) 143(7):661–72. doi: 10.1161/CIRCULATIONAHA.120.051558
37. Wazni OM, Dandamudi G, Sood N, Hoyt R, Tyler J, Durrani S, et al. Cryoballoon ablation as initial therapy for atrial fibrillation. N Engl J Med. (2021) 384(4):316–24. doi: 10.1056/NEJMoa2029554
38. Van Gelder IC, Ekrami NK, Borof K, Fetsch T, Magnussen C, Mulder BA, et al. Sex differences in early rhythm control of atrial fibrillation in the EAST-AFNET 4 trial. J Am Coll Cardiol. (2023) 81(8):845–7. doi: 10.1016/j.jacc.2022.12.011
39. Piccini JP, Simon DN, Steinberg BA, Thomas L, Allen LA, Fonarow GC, et al. Differences in clinical and functional outcomes of atrial fibrillation in women and men: two-year results from the ORBIT-AF registry. JAMA Cardiol. (2016) 1(3):282–91. doi: 10.1001/jamacardio.2016.0529
Keywords: atrial fibrillation, catheter ablation, cryoballoon, sex, female, registry
Citation: Khelae SK, Chun KRJ, Drephal C, Scazzuso F, Kueffer FJ, van Bragt KA, Lawrenz T, Todd D, Ptaszyński P and Földesi C (2025) Real-world sex differences in healthcare utilization after cryoballoon ablation: 2-year outcomes from the Cryo Global Registry. Front. Cardiovasc. Med. 12:1549002. doi: 10.3389/fcvm.2025.1549002
Received: 20 December 2024; Accepted: 14 May 2025;
Published: 3 June 2025.
Edited by:
Richard Gary Trohman, Rush University, United StatesReviewed by:
Gonzalo Ricardo Ríos-Muñoz, Universidad Carlos III de Madrid, SpainXiao Dong Peng, Capital Medical University, China
Copyright: © 2025 Khelae, Chun, Drephal, Scazzuso, Kueffer, van Bragt, Lawrenz, Todd, Ptaszyński and Földesi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Surinder Kaur Khelae, c3VyaW5kZXJAaWpuLmNvbS5teQ==
†ORCID:
Surinder Kaur Khelae
orcid.org/0000-0002-7865-7323
Kyoung Ryul Julian Chun
orcid.org/0000-0002-2355-6015
Christian Drephal
orcid.org/0009-0005-4054-6715
Fernando Scazzuso
orcid.org/0000-0002-1623-0535
Fred J. Kueffer
orcid.org/0009-0004-1447-8811
Kelly A. van Bragt
orcid.org/0000-0003-4118-4291
Thorsten Lawrenz
orcid.org/0000-0002-2930-8493
Derick Todd
orcid.org/0000-0003-2290-2235
Paweł Ptaszyński
orcid.org/0000-0001-6084-7324
Csaba Földesi
orcid.org//0000-0002-5033-117X