Sex differences in atrial fibrillation ablation in‐hospital outcomes from the National Inpatient Sample database 2016–2019

Abstract Background Research has shown mixed results when comparing in‐hospital complications following atrial fibrillation ablation in women compared to men. Objectives To better quantify sex differences and in‐hospital outcomes in atrial fibrillation ablation procedures and identify factors associated with poorer outcomes. Methods We queried the NIS database from 2016 to 2019 for hospitalizations with a primary diagnosis of atrial fibrillation ablation and excluded patients with any other arrhythmias, ICD/pacemaker placement. We assessed demographics, in‐hospital mortality, and complications of women compared to men. Results Admissions for atrial fibrillation were more common in females than males (849 050 vs. 815 665; p < .001). However, females were less likely to receive ablation (1.65% vs. 2.71%, OR: 0.60; 95% confidence interval: 0.57–0.64, p < .001), which persisted after adjusting for cardiomyopathy (adjusted OR: 0.61; 95% confidence interval: 0.58–0.65, p < .001). The primary outcome of in‐hospital mortality was not statistically different in univariate analysis (0.39% vs. 0.36%, OR: 1.09, 95% CI: 0.44–2.72, p = .84), finding that did not change when adjusted for comorbidities (adjusted OR: 0.94, 95% CI: 0.36–2.49). The complication rate in hospitalized patients following ablation was 8.08%. The total unadjusted complication rate was higher for females than males (9.58% vs. 7.09%, p = .001); however, it was not significant when adjusted for risks (adjusted OR: 1.23, 95% CI: 0.99–1.53, p = .06). Conclusion Female sex is not associated with increased complications or death in a real‐world study of catheter ablation when results are adjusted for risks. However, females admitted with atrial fibrillation receive ablation less often than males during hospital admission.

To further evaluate this question, we queried a large US.inpatient database, the National Inpatient Sample (NIS), to analyze differences in demographics, comorbidities, and complications of atrial fibrillation ablation and their potential differences in incidence between women and men. Our research questions included: (A) How is the annual hospitalization utilization trend of atrial fibrillation ablation changing in women and men? (B) Are there differences in demographics and comorbidities between women and men undergoing catheter ablation that may be associated with in-hospital mortality rates? (C) Are there any identifiable confounding variables (age and comorbidities) that could explain differences in outcomes in women compared to men?  (Table S1). Furthermore, we excluded hospitalized patients undergoing atrioventricular node ablation with pacemaker/ICD implantation during that admission. Records for hospitalized patients undergoing open ablation were also excluded based on its ICD procedural code (Table S1). 24 We chose this strategy to identify only atrial fibrillation patients undergoing percutaneous catheter ablation in isolation. This methodology has been previously described in similar studies involving atrial fibrillation catheter ablation utilizing the NIS database. 9, 10 We identified records of an ablation procedure using procedural codes 02563ZZ, 02573ZZ, 02583ZZ, 025S3ZZ, and 025T3ZZ. We excluded records for patients aged <18 years and those with missing sex, age, or in-hospital mortality status. The study population was then divided into two comparative cohorts, women and men, based on NIS data elements. 23 We calculated the annual utilization rate of atrial fibrillation catheter ablation procedures in the overall hospitalized population and in our comparative cohorts (in males and females) from 2016 to 2019 ( Figure 2). We also collected demographic characteristics,  (Table S4). We did not analyze the data set for complications such as pulmonary vein stenosis that would have occurred long after the procedure and were unlikely to be related to the index procedure studied.

| Statistical analysis
Among included patients, we created two mutually exclusive groups of females and males and analyzed characteristics of patient demographic and in-hospital outcomes. Continuous variables were expressed as mean, and a 95% confidence interval was estimated.
Categorical variables were represented in the percentage of the total population. We used weights provided by HCUP and svyset;  Table S1 for Atrial Fibrillation ICD-10 code. @ See Table S1 for Other Arrhythmia ICD-10 code. # See Table S1 for Catheter Ablation ICD-10 code.
svy functions in STATA to generate a national estimate of hospitalized US population from the observed hospitalization-level data. 22 Differences between groups were tested for continuous and categorical variables using t-test and Chi-square tests. p-values of <.05 were considered statistically significant. We reported an unadjusted odds ratio for ablation rates between females and males and adjusted the odds ratio for cardiomyopathy in a bivariable logistic regression analysis. To estimate comorbidity burden, we We did not seek an Institutional Review Board (IRB) approval as the data set contains no personally identifiable information.

| RE SULTS
Out of the overall hospitalized patients weighted sample size of 0.58-0.65, p < .001). We found that the lower rates of atrial fibrillation ablation in females persisted even when stratified by age as seen in Table 3. We found that annual utilization of the ablation procedure did not significantly change through the years of our study (annual percent change of 1.68, p = .66) and did not change for either sex ( Figure 2 Figure 3).

| DISCUSS ION
This study identified that utilization of in-hospital catheter ablation in females with atrial fibrillation was lower than in males ( and gender-specific higher individual refusal rates. 32 Females in our study had higher CHA 2 DS 2− VASc scores (even when accounting for additional points for female sex) but also significantly higher CHADS 2 scores, similar to previous studies, 6,7,[11][12][13][17][18][19] indicating that they potentially had higher stroke risk and could possibly benefit more from the restoration of sinus rhythm. We saw no significant difference in insurance status that could explain differences in procedures and noted more federal insurance in females than males in our study.
Complication rates in all hospitalized patients following ablation were 8.08%, similar to the ranges reported in other trials (5.67%-8.85%). 11,13,15,18 The total unadjusted complication rate was higher for females than males (9.58% vs. 7.09%, p = .001); however, it was not significant when adjusted for risks (adjusted OR: 1.23, 95% CI: 0.99-1.53, p = .06). This was despite a lower overall comorbidity burden in females as determined by the Elixhauser comorbidity index, contrary to previous studies. [7][8][9]11 Other authors had identified that females had higher complications than males attributed to higher comorbidities and later stage presentation. 11,15 Studies have shown that female patients are more symptomatic at presentation for atrial fibrillation than males. 13 Moreover, anatomic differences, including smaller femoral size, vascular anatomy difference, 33 and smaller left atrial diameter/geometry, 34,35 were thought to increase the risk of hematoma, puncture, and pericardial effusion. This data set did not find an association between female sex and increased complications when controlled for risk factors. These findings align with the recently published CABANA trial. 18 Our observation was different from the previously observed study using a comparable NIS database, which can be partially explained by the fact that the ICD-9 code for catheter ablation used by those authors was nonspecific as it was common for both atrial and ventricular ablation. 9,10 Most importantly, our study showed a similar in-hospital mortality rate between men and women. Although two studies have shown higher mortality rates in women, 7,8 other studies have shown no significant differences. 9,10,[12][13][14]19,21 Our higher overall in-hospital mortality rate for both sexes of 0.37% (compared to 0.03% to 0.32% reported in clinical trials) 11,13,14,19 may reflect the real-world experience in actual patient populations that are not highly selected in clinical trials.
The strengths of our study are the size of the database used, national representation, and appropriateness of the database to study hospitalization outcomes. HCUP data is a large and validated database for which the differences observed are likely clinically relevant.
We acknowledge some limitations, most of which are inherent to the nature of administrative databases and reliance on billing codes. We, however, have done the due diligence of using validated ICD codes to identify hospitalizations and comorbidities, adjusted our analyses  if present. However, this study was large enough to detect overall complications. Therefore, we believe the complication rates unique to the actual procedure could be relied upon to assess real-world complication rates accurately.

| CON CLUS ION
Catheter ablation for atrial fibrillation is a safe and effective technique. Female sex is not associated with increased complications or death in real-world experience when controlled for risk factors.
However, there still seems to be a lower utilization rate than expected and a later age at presentation in females for ablation procedures. More study is needed regarding whether personal, physician or other factors contribute to later referral for females for catheter ablation.

ACK N OWLED G M ENTS
I am grateful to Shruti Shrestha, a master's student in Data Science at Georgia State University, who helped me with the Elixhauser F I G U R E 3 Unadjusted and adjusted odds ratios* for overall complication, in-hospital mortality, pericardial effusion, pericardial drain, post-operative shock, pseudoaneurysm, and post-procedure stroke in females compared to males. *Adjusted for age, BMI < 20, history of valvular disease, stroke, coronary artery disease, cardiomyopathy, cancer, autoimmune disease, Elixhauser comorbidity index and CHADS 2 score. Software analysis using SAS software. All authors contributed to the conception, study design, and manuscript writing. The manuscript has not been submitted elsewhere for publication.

FU N D I N G I N FO R M ATI O N
This project reports no source of funding.

CO N FLI C T O F I NTER E S T S TATEM ENT
The remaining authors have nothing to disclose.

E TH I C S S TATEM ENT
As the database contains no patient identifiable information, we did not get patient consent or ethical approval.

CLI N I C A L TR A I L R EG I S TR ATI O N
Retrospective study from large nationally available database hence we did not get any registration.