Abstract
Background
Frailty is highly prevalent in patients with atrial fibrillation (AF) and is associated with adverse outcomes compared with non-frail individuals. This study aimed to explore whether the effects of ablation versus drug therapy on clinical outcomes and quality of life (QoL) differ according to frailty status in patients with AF.
Methods
This is a post hoc analysis of the Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial. The frailty index (FI) was calculated using 30 items, with an FI ≥ 0.21 defined as frailty. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. The secondary outcomes included all-cause death and heart failure (HF) hospitalization. QoL was assessed periodically over 60 months using the Mayo AF-Specific Symptom Inventory (MAFSI).
Results
In this study, a total of 2189 and 2070 patients were included in the intention-to-treat (ITT) and per-protocol (PP) populations, respectively. Over a median follow-up of 1440 (IQR, 900–2880) days, 184 patients experienced the primary endpoint, 122 died, and 174 experienced HF hospitalizations. Compared with drug therapy, catheter ablation did not significantly reduce the risk of clinical outcomes, with no significant difference observed across frailty strata. Regarding QoL, patients with AF and frailty in the ablation group experienced significant improvement compared with those in the drug group: a mean difference among all follow-ups of − 1.58 (− 2.11 to − 1.06; P < 0.001) in the MAFSI frequency score and − 1.26 (− 1.69 to − 0.84, P < 0.001) in the MAFSI severity score. However, patients with AF and without frailty in the ablation group showed no significant QoL improvement compared with those in the drug group.
Conclusions
There is no significant difference in the effectiveness of reducing clinical outcomes of catheter ablation according to frailty status in patients with AF compared with drug therapy, while patients with AF and frailty could derive a higher QoL improvements from catheter ablation therapy. These findings highlight the potential role of catheter ablation in improving QoL for patients with AF and frailty.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12916-026-04676-4.
Keywords: Atrial fibrillation, Catheter ablation, Drug therapy, Frailty
Background
The Global Burden of Disease 2019 study revealed that over 59 million people had atrial fibrillation (AF), with a significant increase from 33.5 million in 2010 [1]. Projections estimate that the prevalence of AF will reach 15.9 million in the USA by 2050 and 17.9 million in Europe by 2060 [2–4]. AF is more prevalent in aging populations [5], as old age is usually associated with comorbidities and functional changes, such as subclinical malnutrition, inactivity, and inflammation, which overlap with frailty [6]. Frailty, defined as an increased vulnerability to stressors and a decreased ability to maintain homeostasis [7, 8], is highly prevalent among patients with AF, with the highest prevalence of 75.4% [9, 10]. These patients with AF and frailty are more prone to an increased risk of adverse outcomes than their non-frail counterparts [11–13], with 5.56-, 1.59-, and 1.64-fold increased risks of all-cause death, stroke, and bleeding, respectively [10]. Although these values are not calculated consistently across different sources, they do demonstrate a substantial increase in risk of adverse outcomes for frail subjects. Managing patients with AF and frailty remains a critical clinical challenge.
Catheter ablation has emerged as a pivotal treatment for AF, and its efficacy varies among patient groups [14]. Regarding sex, men experience greater benefits from catheter ablation in reducing AF recurrence than women [15–17]. Similarly, age is a significant factor. Catheter ablation more effectively reduces the risk of composite of death, disabling stroke, severe bleeding, or cardiac arrest in individuals aged < 65 years than in older adults [16, 18]. In addition, region, race, and ethnicity influence the efficacy of catheter ablation, emphasizing that it is modulated by patient-specific factors [19, 20]. Given the high prevalence of frailty among patients with AF and the frailty status-induced varying effects of anticoagulation in these individuals [21–23], tailoring the AF treatment based on the patient’s frailty status is essential [7–9]. However, the comparative benefit of catheter ablation versus drug therapy across frail statuses remains largely unexplored. Therefore, elucidating the clinical utility and advantages of catheter ablation over drug treatment in frail and non-frail patients with AF is crucial.
Accordingly, using data obtained from the Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial, this post hoc analysis aimed to explore whether the effects of ablation versus drug therapy on clinical outcomes and quality of life (QoL) differ according to frailty status in patients with AF.
Methods
Data source, design, and population
The data for this study were sourced from the CABANA dataset, accessible via the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC) at https://biolincc.nhlbi.nih.gov/home. The study design of CABANA has been previously described [16, 24]. CABANA aimed to test the hypothesis that catheter ablation for AF is more effective than state-of-the-art drug therapy in many symptomatic and inadequately treated patients with AF. A total of 2204 eligible patients aged ≥ 65 or < 65 years with ≥ 1 risk factor for stroke were enrolled. Among them, 1108 patients were randomized to the catheter ablation group and 1096 to the medication therapy group. In the drug therapy arm, 941 patients received rhythm-control drugs, while 146 received rate-control agents. Each patient provided written informed consent, and all participating sites in the trial were approved by the institutional review board or ethics committee.
In this study, 15 patients without follow-up information were excluded from the analysis. The per-protocol (PP) and intention-to-treat (ITT) sets were used. In the PP set, the drug treatment arm comprised patients randomized to drug therapy without crossover to ablation. Patients in the drug arm who crossed over to catheter ablation were censored during the ablation. The ablation treatment arm comprised patients randomized to the ablation group who underwent the procedure within a 12-month window following randomization. A flowchart is shown in Fig. 1.
Fig. 1.
Flowchart of the study. Abbreviations: CABANA, catheter ablation vs antiarrhythmic drug therapy for atrial fibrillation; ITT, intention to treat; PP, per protocol
Measurement of frailty
In this analysis, frailty was assessed using the Rockwood cumulative deficit approach [25–30]. Referring to a previous study, a 30-item frailty index (FI) was created based on medical history, vital signs, laboratory data, and the Euro-QoL five dimensions questionnaire (EQ5D) (Additional file 1: Table S1). The EQ5D scale is a 5-item questionnaire for assessing health status across five dimensions, namely mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has three levels: no problems, some problems, and extreme problems. The responses were added to produce a total severity score ranging from 0 (worst imaginable health) to 100 (perfect health). Each non-missing item was assigned a score, and the FI score was calculated as the sum of these scores divided by the total number of non-missing items. Higher scores indicated greater frailty. Participants were categorized as frail using a cutoff of FI ≥ 0.21, a threshold previously validated and employed in studies of similar patient populations [25, 30, 31].
Outcomes
The primary endpoint was a composite of all-cause mortality, disabling stroke, serious bleeding, or cardiac arrest. The secondary endpoints included all-cause mortality and heart failure (HF)-related hospitalizations. The definitions of primary and secondary endpoints have been defined previously [24].
Two QoL instruments were used: the Mayo AF-Specific Symptom Inventory (MAFSI). QoL data were collected through structured interviews at baseline, 3 and 12 months, and annually thereafter, as previously described [24].
MAFSI used in the CABANA study comprises a 10-item checklist for assessing the frequency and severity of AF symptoms. In the questionnaire, the participants were asked to indicate the frequency of their symptoms over the past month on a scale of 0 (never), 1 (rarely), 2 (sometimes), 3 (often), or 4 (always). The total frequency score ranged from 0 (no AF symptoms) to 40 (most severe AF symptoms). Regarding severity, the participants rated symptoms as 1 (mild), 2 (moderate), or 3 (extreme), with the total severity score ranging from 0 (no AF symptoms) to 30 (most severe AF symptoms). For each patient, a clinically meaningful change in the MAFSI score was considered to be 1.6 points for frequency and 1.3 points for severity [32].
Statistical analysis
All statistical analyses were performed using the PP and ITT sets. Data are presented as mean (standard deviation), median [interquartile range (IQR)], or number (percentage), as appropriate. To compare demographic and laboratory characteristics, Student’s t-tests were performed for continuous variables and chi-square tests for categorical variables. Ordinal variables were analyzed using rank-based nonparametric tests. Cox regression models were applied to determine hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the associations between the intervention and the clinical outcomes.
A mixed model for repeated measures was used to analyze the QoL endpoints following the methods mentioned in the primary CABANA QoL report [33]. Baseline and follow-up scores at 3, 12, 24, 36, 48, and 60 months were included as dependent variables. The model incorporates time, treatment, and time by treatment as fixed effects. The parameters were estimated using restricted maximum likelihood with an unstructured covariance matrix and the Kenward–Roger degrees of freedom approximation. In addition, we conducted comprehensive sensitivity analyses to validate the robustness of our findings. First, we performed stratified analyses according to AF type (paroxysmal AF vs. persistent AF), and the interaction between treatment and AF type was examined (interaction P-value = 0.34). Second, to test the robustness of our results, we conducted a sensitivity analysis using a more stringent cutoff (FI > 0.29) to define a severe frailty subgroup [34, 35].
All statistical tests were two-sided, and statistical significance was set at P < 0.05. All statistical analyses were conducted using the R software, version 4.0.1 (R Core Team, Vienna, Austria).
Results
Baseline characteristics
In the final analysis, 2189 and 2070 patients were enrolled in the ITT and PP sets, respectively (Fig. 1).
In the ITT set, 1452 patients were classified as frail and 737 as non-frail. Patients with AF and frailty were older, had a higher body mass index, and exhibited worse AF severity and New York Heart Association class than patients without frailty. These patients also had a higher prevalence of hypertension, diabetes mellitus, and a history of HF (all P < 0.05). A small but statistically significant difference was observed in baseline FI between treatment groups among frail subjects (P < 0.001), though other characteristics were balanced (Table 1). The ITT set showed a similar distribution of baseline characteristics (Additional file 1: Table S2). No significant differences were observed between the catheter ablation and drug therapy groups in the baseline MAFSI frequency score, MAFSI severity score, and EQ5D score among the different frail subgroups based on the ITT (Table 1) and PP (Additional file 1: Table S2) sets.
Table 1.
Baseline characteristics by frailty status and treatment subgroups (intention to treat)
| Frail | Non-frail | P3 | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Overall | Catheter ablation | Drug therapy | P1 | Overall | Catheter ablation | Drug therapy | P2 | ||
| (N = 1452) | (N = 738) | (N = 714) | (N = 737) | (N = 364) | (N = 373) | ||||
| Sex, N (%) | 0.574 | 0.574 | 0.167 | ||||||
| Female | 526 (36.2) | 273 (37.0) | 253 (35.4) | 290 (39.3) | 139 (38.2) | 151 (40.5) | |||
| Male | 926 (63.8) | 465 (63.0) | 461 (64.6) | 447 (60.7) | 225 (61.8) | 222 (59.5) | |||
| Age, N (%) | 0.581 | 0.95 | 0.026 | ||||||
| < 65 | 518 (35.7) | 254 (34.4) | 264 (37.0) | 243 (33.0) | 118 (32.4) | 125 (33.5) | |||
| 65–74 | 717 (49.4) | 373 (50.5) | 344 (48.2) | 406 (55.1) | 202 (55.5) | 204 (54.7) | |||
| ≥ 75 | 217 (14.9) | 111 (15.0) | 106 (14.8) | 88 (11.9) | 44 (12.1) | 44 (11.8) | |||
| Race, N (%) | 0.931 | 0.937 | < 0.001 | ||||||
| Black | 67 (4.6) | 33 (4.5) | 34 (4.8) | 13 (1.8) | 7 (1.9) | 6 (1.6) | |||
| Other | 30 (2.1) | 16 (2.2) | 14 (2.0) | 60 (8.1) | 29 (8.0) | 31 (8.3) | |||
| White | 1355 (93.3) | 689 (93.4) | 666 (93.3) | 664 (90.1) | 328 (90.1) | 336 (90.1) | |||
| BMI, kg/m2 | 32.2 (6.1) | 32.0 (6.0) | 32.3 (6.2) | 0.245 | 28.6 (5.6) | 28.5 (5.3) | 28.7 (5.8) | 0.719 | < 0.001 |
| AF severity, N (%) | 0.132 | 0.159 | < 0.001 | ||||||
| 0 | 129 (8.9) | 64 (8.7) | 65 (9.1) | 92 (12.5) | 40 (11.0) | 52 (14.0) | < 0.001 | ||
| 1 | 212 (14.7) | 93 (12.7) | 119 (16.7) | 126 (17.1) | 73 (20.1) | 53 (14.2) | |||
| 2 | 448 (31.0) | 223 (30.4) | 225 (31.6) | 251 (34.1) | 127 (35.0) | 124 (33.3) | |||
| 3 | 546 (37.8) | 293 (39.9) | 253 (35.6) | 233 (31.7) | 106 (29.2) | 127 (34.1) | |||
| 4 | 110 (7.6) | 61 (8.3) | 49 (6.9) | 33 (4.5) | 17 (4.7) | 16 (4.3) | |||
| NYHA class, N (%) | 0.296 | 0.257 | 0.029 | ||||||
| I | 174 (24.4) | 93 (26.3) | 81 (22.6) | 104 (31.0) | 59 (34.1) | 45 (27.8) | |||
| II/III | 538 (75.6) | 261 (73.7) | 277 (77.4) | 231 (69.0) | 114 (65.9) | 117 (72.2) | |||
| Medical history, N (%) | |||||||||
| Hypertension | 1304 (89.8) | 656 (88.9) | 648 (90.8) | 0.276 | 461 (62.6) | 216 (59.3) | 245 (65.7) | 0.089 | < 0.001 |
| Diabetes mellitus | 494 (34.0) | 252 (34.1) | 242 (33.9) | 0.963 | 60 (8.1) | 25 (6.9) | 35 (9.4) | 0.265 | < 0.001 |
| CVA | 93 (6.4) | 46 (6.2) | 47 (6.6) | 0.869 | 33 (4.5) | 22 (6.0) | 11 (2.9) | 0.064 | 0.083 |
| TIA | 103 (7.1) | 50 (6.8) | 53 (7.4) | 0.705 | 21 (2.8) | 13 (3.6) | 8 (2.1) | 0.346 | < 0.001 |
| Heart failure | 268 (18.5) | 140 (19.0) | 128 (17.9) | 0.657 | 67 (9.1) | 33 (9.1) | 34 (9.1) | 1 | < 0.001 |
| Frail index | 0.3 [0.2, 0.3] | 0.3 [0.2, 0.3] | 0.3 [0.2, 0.3] | 0.03 | 0.2 [0.1, 0.2] | 0.2 [0.1, 0.2] | 0.2 [0.1, 0.2] | 0.609 | < 0.001 |
| CHA2DS2-VASc | 3.0 [2.0, 3.0] | 3.0 [2.0, 3.0] | 3.0 [2.0, 3.0] | 0.659 | 2.0 [1.0, 3.0] | 2.0 [1.0, 3.0] | 2.0 [1.0, 3.0] | 0.125 | < 0.001 |
| Type of AF | 0.944 | 0.3 | 0.027 | ||||||
| Long-standing persistent | 148 (10.2) | 75 (10.2) | 73 (10.2) | 63 (8.5) | 37 (10.2) | 26 (7.0) | |||
| Paroxysmal | 596 (41.0) | 300 (40.7) | 296 (41.5) | 346 (46.9) | 168 (46.2) | 178 (47.7) | |||
| Persistent | 708 (48.8) | 363 (49.2) | 345 (48.3) | 328 (44.5) | 159 (43.7) | 169 (45.3) | |||
| QoL measurement | |||||||||
| MAFSI frequency | 12.5 (6.4) | 12.4 (6.2) | 12.6 (6.5) | 0.453 | 10.3 (5.7) | 10.3 (5.8) | 10.4 (5.7) | 0.880 | < 0.001 |
| MAFSI severity | 9.9 (5.1) | 9.9 (5.0) | 9.9 (5.2) | 0.781 | 8.3 (4.7) | 8.3 (4.7) | 8.2 (4.7) | 0.890 | < 0.001 |
| EQ-5D | 67.7 (17.5) | 68.2 (17.9) | 67.1 (17.1) | 0.207 | 73.5 (15.9) | 73.1 (16.4) | 73.9 (15.4) | 0.488 | < 0.001 |
Data are presented as mean (standard derivation), median [interquartile range], or number (percentage). P1 indicate differences between catheter ablation and drug therapy within frail patients. P2 indicates differences between catheter ablation and drug therapy within non-frail patients. P3 indicates differences between frail and non-frail patients
Abbreviations: NYHA New York Heart Association, CVA cerebral vascular accident, TIA transient ischemic attack, AF atrial fibrillation, QoL quality of life, BMI body mass index, MAFSI Mayo AF-Specific Symptom Inventory, EQ5D EuroQoL five dimensions questionnaire
Data are presented as mean (standard derivation), median [interquartile range], or number (percentage). P1 indicate differences between catheter ablation and drug therapy within frail patients. P2 indicates differences between catheter ablation and drug therapy within non-frail patients. P3 indicates differences between frail and non-frail strata
Abbreviations: NYHA New York Heart Association, CVA cerebral vascular accident, TIA transient ischemic attack, AF atrial fibrillation, QoL quality of life, BMI body mass index, MAFSI Mayo AF-Specific Symptom Inventory, EQ5D Euro-QoL five dimensions questionnaire, HF heart failure
Clinical outcomes
Among the ITT population, 184 patients (149 frail and 35 non-frail) experienced primary endpoint events over a median follow-up of 1440 days (IQR 900–2880). No significant difference was observed in the risk of the primary endpoint between ablation and drug therapy in the overall cohort (HR 0.85, 95% CI 0.64–1.14, P = 0.275). Similarly, no significant association was found in either patients with frailty (HR 0.77, 95% CI 0.56–1.06, P = 0.108) or patients without frailty (HR 1.14, 95% CI 0.58–2.24, P = 0.698). Regarding the secondary endpoint of all-cause death, 122 patients died (100 frail, 22 non-frail). Again, ablation did not significantly differ from drug therapy in the overall population (HR 0.86, 95% CI 0.60–1.22, P = 0.397), nor in patients with frailty (HR 0.86, 95% CI 0.58–1.27, P = 0.450) or patients without frailty (HR 0.65, 95% CI 0.27–1.56, P = 0.335). Additionally, 174 patients (148 frail, 26 non-frail) were hospitalized for heart failure (HF) during follow-up. Compared with drug treatment, ablation did not reduce the risk of HF hospitalization in the overall cohort or within either frailty subgroup. No significant interaction by frailty status was detected for the primary endpoint, all-cause death, or HF hospitalization (P for interaction = 0.385, 0.592, and 0.551, respectively). These results are summarized in Fig. 2. There were no significant differences in the cumulative probability of primary endpoint in all patients or among the different frail subgroups (Fig. 3).
Fig. 2.
Effects of catheter ablation compared with drug therapy (intention-to-treat) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status. Abbreviations: HR, hazard ratio; CI, confidence interval; HF, heart failure
Fig. 3.
Kaplan–Meier curves of the incidence of the primary endpoint comparison between catheter ablation and therapy (intention to treat) among all (A), frail (B), and non-frail strata (C)
In the PP analysis set, 158 patients (127 frail and 31 non-frail) experienced primary endpoint events over a median follow-up period of 1260 (IQR, 720–2880) days. Ablation therapy resulted in a 29% reduction in the risk of the primary endpoint (HR 0.71, 95% CI, 0.52–0.97; P = 0.030) compared with medication therapy in all patients. This association remained significant in patients with frailty (HR, 0.66; 95% CI, 0.46–0.94; P = 0.020); however, it was not significant in non-frail patients (HR, 0.78; 95% CI, 0.38–1.60; P = 0.497), with no significant interactions by frailty status (P for interaction = 0.776). Regarding the secondary endpoint of all-cause death, 108 patients (87 frail and 21 non-frail) died. Ablation therapy reduced the risk of all-cause death by 33% (HR, 0.67; 95% CI, 0.46–0.97; P = 0.036) in all patients; however, this association was not significant when stratified by frailty status. In addition, 149 patients (128 frail and 21 non-frail) had HF hospitalization during follow-up. Ablation did not reduce the risk of HF hospitalization in all patients or within the different frailty subgroups compared with drug treatment. There were also no significant interactions by frailty status for all-cause death and HF hospitalization (P for interaction was 0.585 and 0.434, respectively) (Additional file 1: Fig. S1). Catheter ablation was associated with a lower cumulative probability of the primary endpoint in all cohort and in patients with frailty, but not in non-frail patients (Additional file 1: Fig. S2).
QoL outcome
The QoL values based on ITT analysis at baseline and different follow-up points across frailty strata by treatment groups are presented in Fig. 4 and Additional file 1: Tables S3 and S4. In patients with AF and frailty, at all follow-up periods, the mean MAFSI frequency and MAFSI severity scores were 1.58 (95% CI, − 2.11 to − 1.06, P < 0.001) and 1.26 (95% CI, − 1.69 to − 0.84; P < 0.001) points lower in the catheter ablation group than in the drug therapy group (Figs. 5 and 6). All QoL measurements showed greater improvements in the catheter ablation group than in the drug therapy group at different follow-up points among patients with AF and frailty. Among patients with non-frailty, no significant differences were observed in QoL scores during follow-ups between the catheter ablation and drug therapy groups.
Fig. 4.
Mean MAFSI frequency (A, B) and MAFSI severity (C, D) scores among frail (upper panel) and non-frail strata (lower panel) according to treatment subgroups (intention to treat). Abbreviations: MAFSI, Mayo AF-Specific Symptom Inventory
Fig. 5.
Effects of catheter ablation versus drug therapy (intention to treat) on the MAFSI frequency score differences according to frailty status. Abbreviation: CI, confidential interval
Fig. 6.
Effects of catheter ablation versus drug therapy (intention to treat) on the MAFSI severity score differences according to the frailty status. Abbreviation: CI, confidential interval
The QoL values based on PP analysis at baseline and at different follow-up points, across frailty strata and by treatment group, are presented in Additional file 1: Tables S5 and S6. In patients with AF and frailty, the mean differences at all follow-up points were − 1.62 (− 2.15 to − 1.08, P < 0.001) for the MAFSI frequency score and − 1.28 (− 1.71 to − 0.84, P < 0.001) for the MAFSI severity score (Additional file 1: Figs. S3 and S4). All three QoL measurements showed greater improvement in the catheter ablation group than in the drug therapy group (all P < 0.05). Patients with frailty consistently experienced benefits from catheter ablation at different follow-up points. Among patients without frailty, no significant differences were observed in MAFSI frequency or MAFSI severity scores during follow-up between the catheter ablation and drug therapy groups (Additional file 1: Figs. S3 and S4).
Sensitivity analyses
The results demonstrated similar treatment effects across different AF subgroups and frailty definitions (see Additional file 1: Tables S8, S9, S10, S11, S12 for details), indicating that our primary findings remain robust to clinically relevant variations in population characteristics and frailty classifications.
Discussion
This study provides several crucial findings. First, based on the PP set, catheter ablation reduced the risk of the primary endpoint compared with drug therapy in patients with AF and frailty, whereas this treatment effect was not significant in patients with non-frailty. However, in the ITT analysis, ablation did not reduce the risk of the primary endpoint, all-cause death, or HF hospitalization in all patients or among the different frail subgroups. Second, catheter ablation resulted in significant QoL improvements over drug therapy at different follow-up points in patients with AF and frailty, whereas the benefit was not observed in patients with non-frailty. This finding remained consistent whether analyzed on an ITT or PP basis. These results suggest that patients with AF and frailty could benefit from catheter ablation, particularly an improved QoL. This study provides valuable insights into treatment strategy decision-making in patients with AF and frailty.
Evidence on whether the benefits of catheter ablation versus drug therapy vary according to the frailty status is limited. A Korean study evaluated the effect of catheter ablation on outcomes in patients with AF based on different frailty strata [36]. The study included 1818 frail patients (ablation: N = 119) and 1907 non-frail patients (ablation: N = 230). The study revealed that catheter ablation was not associated with improved clinical outcomes in frail patients but was associated with a lower risk of adverse clinical outcomes in non-frail patients. In our study, frail patients with AF benefited more from catheter ablation than non-frail patients, which is inconsistent with the findings of the Korean study. There are several possible explanations for this discrepancy. First, the patients enrolled in the Korean study were older (mean age ≥ 75 years) than those enrolled in the CABANA study. Second, only 6.5% of patients in the Korean study underwent catheter ablation, whereas approximately 50% of patients in the CABANA study underwent catheter ablation. Furthermore, the follow-up period was longer in the CABANA study than in the Korean study. Our study implies that there is heterogeneity in the efficacy of catheter ablation based on the frailty status in patients with AF.
Heterogeneity in the therapeutic response based on the frailty status of patients with AF has been demonstrated under oral anticoagulant (OAC) treatment. The TREAT-AF study from the Veterans Health Administration revealed that OAC use was associated with a lower risk of 1-year mortality in patients with AF across frailty strata [37]. However, OAC use was associated with an increased risk of major bleeding only in patients with AF and frailty. Regarding non-vitamin K antagonist OACs (NOACs), large randomized trials and post-marketing surveillance studies including patients with non-frailty demonstrated that NOACs were at least non-inferior in preventing ischemic stroke, with an overall better safety profile than warfarin [21, 22, 38]. Nevertheless, the advantages of NOACs over warfarin are controversial in patients with AF and frailty. Søgaard et al. observed a similar thromboembolism risk between NOACs and warfarin in patients with AF and frailty, with a significantly lower major bleeding risk with NOACs than with warfarin [39]. Conversely, the Frail Atrial Fibrillation trial in older patients with AF and frailty showed that switching from warfarin to NOACs was associated with more bleeding complications than continuing warfarin, without a corresponding reduction in thromboembolic complications [23]. Regarding specific NOAC, dabigatran and rivaroxaban were associated with a lower rate of the composite endpoint than warfarin for the non-frail subgroup but not for the pre-frail or frail subgroup. These studies suggest that frailty acts as an effect modifier of therapeutic benefits, highlighting the significance of considering the frailty status when tailoring treatment for patients with AF.
Frailty status-induced heterogeneity in therapeutic responses has also been investigated in other diseases. In a post hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT) of patients with hypertension, intensive blood pressure control was associated with a 70% lower risk of cardiovascular death in patients with non-frailty, whereas the association was not significant in those with frailty [40]. In the Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial, frailty was classified into three levels, namely, non-frail, more frail, and most frail [25]. The study revealed that compared with placebo, dapagliflozin reduced the risk of worsening HF or cardiovascular death by 26% in patients with the most frailty. However, the treatment effect was not significant in patients with non-frailty or more frailty. Additionally, improvements in health-related QoL with dapagliflozin occurred early and were greater in patients with the most frailty. Liu et al. found that frailty is independently associated with the platelet responses to clopidogrel and aspirin in patients with coronary artery disease undergoing percutaneous coronary intervention [41]. These studies reveal differential outcomes in cardiovascular treatments based on frailty status, highlighting its significance in tailoring treatment approaches based on frailty status.
In our study, patients with AF and frailty experienced greater improvements in QoL from catheter ablation than non-frail patients, and several factors may contribute to this. Patients with AF and frailty usually present with many comorbidities [42] and receive multiple medications [43]. These conditions may influence therapeutic choices owing to the high risk of drug-drug and drug-disease interactions [43]. Patients with frailty have a lower tolerance for the side effects of medication. Catheter ablation reduces the need for long-term medications, minimizing drug-related adverse effects. Regarding QoL, patients without frailty have a better ability to adapt to AF-induced physiological stress and might already maintain a relatively good QoL with medication, making the additional benefits of ablation less noticeable. In contrast, patients with frailty struggle with the negative effects of AF, making the physiological stability provided by catheter ablation particularly significant.
This study aimed to address a critical gap in AF management by focusing on the impact of frailty, a common and significant factor influencing patient outcomes. These findings demonstrate that patients with AF and frailty substantially benefit more from catheter ablation than from drug therapy in terms of QoL improvements. The significance of this study lies in its potential to inform clinical decision-making regarding the use of catheter ablation in patients with AF and frailty. The study results can alleviate physicians’ concerns about whether patients with AF and frailty should undergo more aggressive catheter ablation treatments, potentially improving therapeutic inertia. By highlighting the differential effects of ablation on drug therapy based on the frailty status, this study advocates a more personalized approach to AF treatment, emphasizing the significance of assessing frailty in managing AF and tailoring treatment strategies accordingly. Despite the observed efficacy, catheter ablation in patients with AF and frailty warrants careful consideration due to a heightened risk profile. This population is particularly vulnerable to periprocedural complications, such as bleeding, vascular injury, or acute kidney injury, compounded by their reduced physiological reserve and multimorbidity. Therefore, the decision to pursue ablation must be individualized, balancing these potential risks against the anticipated benefits in symptom relief and quality of life.
The main strengths of this study include its large sample size, enhanced statistical power, and the generalizability of the findings. Second, we assessed clinical outcomes (composite of death, disabling stroke, critical bleeding, and cardiac arrest) and QoL using validated instruments (MAFSI and EQ5D), offering a well-rounded evaluation of interventions. Moreover, with a follow-up period of 60 months, this study provided long-term data on the effects of catheter ablation versus drug therapy. However, this study has some limitations. First, as a post hoc analysis of the CABANA trial, the study may have been subject to biases inherent in retrospective analyses, including confounding factors that were not controlled for in the original trial design. Second, in this analysis, frailty was assessed using the Rockwood cumulative deficit approach, which is standardized; however, we recognize that the heterogeneity in frailty definitions across studies may limit the generalizability of our findings. Third, while our study evaluated “hard” clinical outcomes, the lack of AF recurrence data in the available dataset precludes analysis of whether frailty results in sinus rhythm more often or not. This represents a key mechanistic gap that future studies should address, particularly as the relationship between AF burden and clinical outcomes may differ by frailty status. In addition, the CABANA study enrolled patients with at least one stroke risk factor, generally frailer than those in other landmark trials, even though patients with true “frailty” are often not enrolled in a long-term randomized control trial, which significantly impacts the external validity and generalizability of the results, and future studies specifically targeting patients with AF and frailty would be valuable in addressing this knowledge gap. Despite these limitations, our analysis provides valuable real-world evidence regarding ablation outcomes across frailty strata in a rigorously conducted trial population.
Conclusions
In this post hoc analysis of the CABANA trial, regardless of whether the ITT or PP analyses were applied, catheter ablation consistently improved QoL in patients with AF and frailty. However, there is no significant difference in the effectiveness of catheter ablation in reducing adverse clinical outcomes in patients with AF across frailty strata compared with drug therapy. These findings suggest that catheter ablation is a viable treatment option for patients with AF and frailty, emphasizing the significance of assessing frailty in managing AF and tailoring treatment strategies accordingly. However, further validation is required.
Supplementary Information
Additional file 1: Table S1. Component of the Frailty index. Table S2. Baseline characteristics by frailty status and treatment subgroups (per-protocol). Table S3. Quality of Life Measures among patients with frailty according to treatment subgroups (intention-to-treat). Table S4. Quality of Life Measures among patients with non-frailty according to treatment subgroups (intention-to-treat). Table S5. Quality of Life Measures among patients with frailty according to treatment subgroups (per-protocol). Table S6. Quality of Life Measures among patients with non-frail according to treatment subgroups (per-protocol). Table S7. Effects of catheter ablation compared with drug therapy (per-protocol) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with paroxysmal AF. Table S8. Effects of catheter ablation compared with drug therapy (per-protocol) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with persistent AF. Table S9. Effects of catheter ablation compared with drug therapy (intention-to-treat) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with paroxysmal AF. Table S10. Effects of catheter ablation compared with drug therapy (intention-to-treat) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with persistent AF. Table S11. Effects of catheter ablation compared with drug therapy (per-protocol) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with persistent AF. (*Frail was defined as FI > 0.25, non-frail was defined as FI ≤ 0.25). Table S12. Effects of catheter ablation compared with drug therapy (intention-to-treat) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with paroxysmal AF. (*Frail was defined as FI ≥ 0.25, non-frail was defined as FI < 0.25). Figure S1. Effects of catheter ablation compared with drug therapy (per-protocol) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status. Figure S2. Kaplan–Meier Curves of the incidence of the primary endpoint comparison between catheter ablation and therapy (per-protocol) among all (A), frail (B) and non-frail patients (C). Figure S3. Effects of catheter ablation compared with drug therapy (per-protocol) on MAFSI Frequency score difference according to frailty status. Figure S4. Effects of catheter ablation compared with drug therapy (per-protocol) on MAFSI Severity score difference according to frailty status.
Acknowledgements
We thank all the investigators, staff, and participants of the CABANA study for their valuable contributions. This manuscript was prepared using the CABANA Research Materials obtained from the NHLBI.
Abbreviations
- AF
Atrial fibrillation
- QoL
Quality of life
- FI
Frailty index
- HF
Heart failure
- CI
Confidence interval
- MAFSI
Mayo AF-Specific Symptom Inventory
- CABANA
Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation
- PP
Per protocol
- ITT
Intention to treat
- OACs
Oral anticoagulants
Authors’ contributions
Concept and design: LW, YL, QX and YW; Acquisition, analysis, or interpretation of data: LW, YL, QL, XL, SW, YY, QW, YL, ZH, HG, RX, ZL, TZ, XQ and YW; Drafting and revising the article: LW, YL, QL, XL, SW, YY, QW, YL, ZH, HG, RX, ZL, TZ, and ZL; Final approval of the version to be published: LW, YL, QL, XL, SW, YY, QW, YL, ZH, HG, RX, ZL, TZ, XQ and YW; All authors read and approved the final manuscript.
Funding
This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project (Nos. 2024ZD0521500 and 2024ZD0521504).
Data availability
The data for this study were sourced from the CABANA dataset, accessible via the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC).
Declarations
Ethics approval and consent to participate
This study is based on a secondary analysis of publicly available data. The original data were collected in compliance with ethical standards and are anonymized, with no identifiable personal information included. Since the data are publicly accessible and do not involve direct interaction with human subjects or the collection of new data, additional ethics approval and consent to participate were waived.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Lili Wang and Yanguang Li contributed equally as co-first authors for this article.
Yunlong Wang and Xin Quan are co-corresponding authors and share corresponding responsibility.
Contributor Information
Xin Quan, Email: xquan@hotmail.com.
Yunlong Wang, Email: yunlong76818@126.com.
References
- 1.Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al. Global burden of cardiovascular diseases and risk factors, 1990–2019: update from the GBD 2019 study. J Am Coll Cardiol. 2020;76(25):2982–3021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: a global burden of disease 2010 Study. Circulation. 2014;129(8):837–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114(2):119–25. [DOI] [PubMed] [Google Scholar]
- 4.Krijthe BP, Kunst A, Benjamin EJ, Lip GY, Franco OH, Hofman A, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J. 2013;34(35):2746–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, 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): the task force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373–498. [DOI] [PubMed] [Google Scholar]
- 6.Liberale L, Montecucco F, Tardif JC, Libby P, Camici GG. Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease. Eur Heart J. 2020;41(31):2974–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Walker DM, Gale CP, Lip G, Martin-Sanchez FJ, McIntyre HF, Mueller C, et al. Editor’s choice - frailty and the management of patients with acute cardiovascular disease: a position paper from the Acute Cardiovascular Care Association. Eur Heart J Acute Cardiovasc Care. 2018;7(2):176–93. [DOI] [PubMed] [Google Scholar]
- 8.Fumagalli S, Potpara TS, Bjerregaard Larsen T, Haugaa KH, Dobreanu D, Proclemer A, et al. Frailty syndrome: an emerging clinical problem in the everyday management of clinical arrhythmias. The results of the European Heart Rhythm Association survey. Europace. 2017;19(11):1896–902. [DOI] [PubMed] [Google Scholar]
- 9.Villani ER, Tummolo AM, Palmer K, Gravina EM, Vetrano DL, Bernabei R, et al. Frailty and atrial fibrillation: a systematic review. Eur J Intern Med. 2018;56:33–8. [DOI] [PubMed] [Google Scholar]
- 10.Proietti M, Romiti GF, Raparelli V, Diemberger I, Boriani G, DallaVecchia LA, et al. Frailty prevalence and impact on outcomes in patients with atrial fibrillation: a systematic review and meta-analysis of 1,187,000 patients. Ageing Res Rev. 2022;79:101652. [DOI] [PubMed] [Google Scholar]
- 11.He L, He R, Huang J, Zou C, Fan Y. Impact of frailty on all-cause mortality and major bleeding in patients with atrial fibrillation: a meta-analysis. Ageing Res Rev. 2022;73:101527. [DOI] [PubMed] [Google Scholar]
- 12.Gugganig R, Aeschbacher S, Leong DP, Meyre P, Blum S, Coslovsky M, et al. Frailty to predict unplanned hospitalization, stroke, bleeding, and death in atrial fibrillation. Eur Heart J Qual Care Clin Outcomes. 2021;7(1):42–51. [DOI] [PubMed] [Google Scholar]
- 13.Wilkinson C, Wu J, Searle SD, Todd O, Hall M, Kunadian V, et al. Clinical outcomes in patients with atrial fibrillation and frailty: insights from the ENGAGE AF-TIMI 48 trial. BMC Med. 2020;18(1):401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Hindricks G, Packer DL. Catheter ablation of atrial fibrillation: recent advances and future challenges. Europace. 2022;24(Suppl 2):ii1–2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Kaiser DW, Fan J, Schmitt S, Than CT, Ullal AJ, Piccini JP, et al. Gender differences in clinical outcomes after catheter ablation of atrial fibrillation. JACC Clin Electrophysiol. 2016;2(6):703–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, et al. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: the CABANA randomized clinical trial. JAMA. 2019;321(13):1261–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Russo AM, Zeitler EP, Giczewska A, Silverstein AP, Al-Khalidi HR, 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] [PMC free article] [PubMed] [Google Scholar]
- 18.Bahnson TD, Giczewska A, Mark DB, Russo AM, Monahan KH, Al-Khalidi HR, et al. Association between age and outcomes of catheter ablation versus medical therapy for atrial fibrillation: results from the CABANA trial. Circulation. 2022;145(11):796–804. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Cappato R, Mark DB, Silverstein AP, Noseworthy PA, Bonitta G, Poole JE, et al. Regional differences in outcomes with ablation versus drug therapy for atrial fibrillation: results from the CABANA trial. Am Heart J. 2024;270:103–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Thomas KL, Al-Khalidi HR, Silverstein AP, Monahan KH, Bahnson TD, Poole JE, et al. Ablation versus drug therapy for atrial fibrillation in racial and ethnic minorities. J Am Coll Cardiol. 2021;78(2):126–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. [DOI] [PubMed] [Google Scholar]
- 22.Romanelli RJ, Nolting L, Dolginsky M, Kym E, Orrico KB. Dabigatran versus warfarin for atrial fibrillation in real-world clinical practice: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2016;9(2):126–34. [DOI] [PubMed] [Google Scholar]
- 23.Joosten LPT, van Doorn S, van de Ven PM, Köhlen BTG, Nierman MC, Koek HL, et al. Safety of switching from a vitamin K antagonist to a non-vitamin K antagonist oral anticoagulant in frail older patients with atrial fibrillation: results of the FRAIL-AF randomized controlled trial. Circulation. 2024;149(4):279–89. [DOI] [PubMed] [Google Scholar]
- 24.Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Moretz K, et al. Catheter ablation versus antiarrhythmic drug therapy for atrial fibrillation (CABANA) trial: study rationale and design. Am Heart J. 2018;199:192–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Butt JH, Jhund PS, Belohlávek J, de Boer RA, Chiang CE, Desai AS, et al. Efficacy and safety of dapagliflozin according to frailty in patients with heart failure: a prespecified analysis of the DELIVER trial. Circulation. 2022;146(16):1210–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Sanders NA, Supiano MA, Lewis EF, Liu J, Claggett B, Pfeffer MA, et al. The frailty syndrome and outcomes in the TOPCAT trial. Eur J Heart Fail. 2018;20(11):1570–7. [DOI] [PubMed] [Google Scholar]
- 27.Dewan P, Jackson A, Jhund PS, Shen L, Ferreira JP, Petrie MC, et al. The prevalence and importance of frailty in heart failure with reduced ejection fraction-an analysis of PARADIGM-HF and ATMOSPHERE. Eur J Heart Fail. 2020;22(11):2123–33. [DOI] [PubMed] [Google Scholar]
- 28.Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits as a proxy measure of aging. Sci World J. 2001;1:323–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Rockwood K, Mitnitski A. Frailty in relation to the accumulation of deficits. J Gerontol A Biol Sci Med Sci. 2007;62(7):722–7. [DOI] [PubMed] [Google Scholar]
- 30.Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A standard procedure for creating a frailty index. BMC Geriatr. 2008;8:24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Pajewski NM, Williamson JD, Applegate WB, Berlowitz DR, Bolin LP, Chertow GM, et al. Characterizing frailty status in the systolic blood pressure intervention trial. J Gerontol A Biol Sci Med Sci. 2016;71(5):649–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Mark DB. Assessing quality-of-life outcomes in cardiovascular clinical research. Nat Rev Cardiol. 2016;13(5):286–308. [DOI] [PubMed] [Google Scholar]
- 33.Mark DB, Anstrom KJ, Sheng S, Piccini JP, Baloch KN, Monahan KH, et al. Effect of catheter ablation vs medical therapy on quality of life among patients with atrial fibrillation: the CABANA Randomized Clinical Trial. JAMA. 2019;321(13):1275–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Song X, Mitnitski A, Rockwood K. Prevalence and 10-year outcomes of frailty in older adults in relation to deficit accumulation. J Am Geriatr Soc. 2010;58(4):681–7. [DOI] [PubMed] [Google Scholar]
- 35.Kim DH, Pawar A, Gagne JJ, Bessette LG, Lee H, Glynn RJ, et al. Frailty and clinical outcomes of direct oral anticoagulants versus warfarin in older adults with atrial fibrillation : a cohort study. Ann Intern Med. 2021;174(9):1214–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Yang PS, Sung JH, Kim D, Jang E, Yu HT, Kim TH, et al. Frailty and the effect of catheter ablation in the elderly population with atrial fibrillation- a real-world analysis. Circ J. 2021;85(8):1305–13. [DOI] [PubMed] [Google Scholar]
- 37.Pundi K, Perino AC, Fan J, Din N, Szummer K, Heidenreich P, et al. Association of CHA(2)DS(2)-VASc and HAS-BLED to frailty and frail outcomes: from the TREAT-AF study. Am Heart J. 2023;261:85–94. [DOI] [PubMed] [Google Scholar]
- 38.Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51. [DOI] [PubMed] [Google Scholar]
- 39.Søgaard M, Ording AG, Skjøth F, Larsen TB, Nielsen PB. Effectiveness and safety of direct oral anticoagulation vs. warfarin in frail patients with atrial fibrillation. Eur Heart J Cardiovasc Pharmacother. 2024;10(2):137–46. [DOI] [PubMed] [Google Scholar]
- 40.Wang Z, Du X, Hua C, Li W, Zhang H, Liu X, et al. The effect of frailty on the efficacy and safety of intensive blood pressure control: a post hoc analysis of the SPRINT trial. Circulation. 2023;148(7):565–74. [DOI] [PubMed] [Google Scholar]
- 41.Liu Y, Liu S, Wang K, Liu H. Association of frailty with antiplatelet response among elderly Chinese patients with coronary artery disease undergoing percutaneous coronary intervention. Clin Appl Thromb Hemost. 2020;26:1076029620915994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. Epidemiology and natural history of atrial fibrillation: clinical implications. J Am Coll Cardiol. 2001;37(2):371–8. [DOI] [PubMed] [Google Scholar]
- 43.Marcucci M, Iorio A, Nobili A, Tettamanti M, Pasina L, Marengoni A, et al. Factors affecting adherence to guidelines for antithrombotic therapy in elderly patients with atrial fibrillation admitted to internal medicine wards. Eur J Intern Med. 2010;21(6):516–23. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Additional file 1: Table S1. Component of the Frailty index. Table S2. Baseline characteristics by frailty status and treatment subgroups (per-protocol). Table S3. Quality of Life Measures among patients with frailty according to treatment subgroups (intention-to-treat). Table S4. Quality of Life Measures among patients with non-frailty according to treatment subgroups (intention-to-treat). Table S5. Quality of Life Measures among patients with frailty according to treatment subgroups (per-protocol). Table S6. Quality of Life Measures among patients with non-frail according to treatment subgroups (per-protocol). Table S7. Effects of catheter ablation compared with drug therapy (per-protocol) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with paroxysmal AF. Table S8. Effects of catheter ablation compared with drug therapy (per-protocol) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with persistent AF. Table S9. Effects of catheter ablation compared with drug therapy (intention-to-treat) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with paroxysmal AF. Table S10. Effects of catheter ablation compared with drug therapy (intention-to-treat) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with persistent AF. Table S11. Effects of catheter ablation compared with drug therapy (per-protocol) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with persistent AF. (*Frail was defined as FI > 0.25, non-frail was defined as FI ≤ 0.25). Table S12. Effects of catheter ablation compared with drug therapy (intention-to-treat) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status among patients with paroxysmal AF. (*Frail was defined as FI ≥ 0.25, non-frail was defined as FI < 0.25). Figure S1. Effects of catheter ablation compared with drug therapy (per-protocol) on the primary endpoint, all-cause death, and HF hospitalization according to frailty status. Figure S2. Kaplan–Meier Curves of the incidence of the primary endpoint comparison between catheter ablation and therapy (per-protocol) among all (A), frail (B) and non-frail patients (C). Figure S3. Effects of catheter ablation compared with drug therapy (per-protocol) on MAFSI Frequency score difference according to frailty status. Figure S4. Effects of catheter ablation compared with drug therapy (per-protocol) on MAFSI Severity score difference according to frailty status.
Data Availability Statement
The data for this study were sourced from the CABANA dataset, accessible via the Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC).