Association of Permanent Atrial Fibrillation With Mortality and Heart Failure Progression in Low Thromboembolic Risk Patients

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide, and its prevalence is expected to double in the coming decades due to an aging population, increasing chronic disease burden, and improved detection methods [1,2]. AF is associated with adverse outcomes, including stroke, heart failure (HF), and increased mortality, with mortality rates up to 3 times higher than in the general population [1,2]. AF promotes structural and electrical remodeling of the atria and ventricles, reinforcing its self-perpetuating nature and limiting the effectiveness of rhythm control therapies [2]. Compared to paroxysmal AF, permanent AF is linked with larger left atrial volumes and more impaired atrial function [2,3]. AF imposes a growing burden on healthcare systems, driven by its progressive course – from paroxysmal, self-limiting episodes to persistent and permanent forms – and the associated need for hospitalizations and interventions. The 10-year progression rate to permanent AF reaches 26.1% [4]. As a result, early rhythm control strategies, particularly catheter ablation (CA), are gaining prominence. Randomized trials have shown that early CA reduces AF progression. In the EARLY-AF trial, only 1.9% of patients undergoing cryoballoon ablation progressed to persistent AF at 3 years, versus 7.4% in the antiarrhythmic drug (AAD) group (HR 0.25) [5]. Similarly, radiofrequency ablation significantly reduced progression rates compared to AAD (2.4% vs 17.5%; HR 0.107; P=0.0009) [6]. CA has also been shown to alleviate symptoms and improve quality of life [7,8]. Core components of AF management include risk factor control, anticoagulation, and symptom relief via rate or rhythm control [2,9]. Early rhythm control, particularly with CA, is now viewed as a disease-modifying approach that can prevent progression.

The diagnosis of permanent AF is based on a shared decision between patient and physician [2]. Although stroke risk scores like CHA2DS2-VASc guide anticoagulation, they may underestimate overall clinical risk in some subgroups – especially those with permanent AF. Of note, the 2024 ESC guidelines updated the score by removing female sex as an independent risk factor. However, our analysis is based on the previous version of the score, widely used during the CRAFT registry period.

In this study, we examined 418 patients with low thromboembolic risk (CHA2DS2-VASc ≤2 for women and ≤1 for men), including 63 with permanent AF. The aim of this study was to assess the long-term clinical outcomes of patients with low CHA2DS2-VASc (≤2 for women and ≤1 for men) score, comparing those with permanent and non-permanent AF, and to test the hypothesis that permanent AF is independently associated with higher mortality and adverse events even in this low-risk population.

Material and Methods

STATISTICAL ANALYSIS:

All continuous variables were assessed for normality using Shapiro-Wilk test. For every continuous variable, at least in one subgroup the distribution was non-normal. Variables were as median with interquartile range. Categorical variables were summarized as absolute numbers and corresponding percentages. Comparisons between categorical variables were conducted using the Fisher’s exact test. For continuous variables, Mann-Whitney U test was applied. Kaplan-Meier survival analysis was used to estimate event-free survival over time. Differences between groups were assessed using log-rank test. A P value of <0.05 was considered statistically significant. The statistical analysis was performed using Statistical Analysis Software (Cary, NC, USA), version 9.4.

Results

PATIENTS’ CHARACTERISTICS:

This analysis included 418 patients with AF, CHA₂DS₂-VASc ≤2 for women and ≤1 for men. The median age was 61 years (IQR 54–66), and 99 patients (23.9%) were women. Among the cohort, 63 patients (15%) had permanent AF, 69 (19.4%) had persistent AF, and 286 (68.4%) had paroxysmal AF.

Patients with permanent AF were older (median age 64 vs 60 years; P<0.0001) and less likely to be women (6.4% vs 26.8%; P<0.0001). They more frequently had chronic heart failure (48.4% vs 15.5%; P<0.0001), lower left ventricular ejection fraction (LVEF: 43.5% [IQR 24.5–54] vs 55% [IQR 45–60]; P=0.0005), and reduced glomerular filtration rate (GFR: 66.97 vs 72.82 ml/min/1.73 m²; P=0.0114).

Device implantation was more common in the permanent AF group, including pacemakers (36.2% vs 8.4%; P<0.0001) and ICDs (21.3% vs 5.6%; P=0.0008). Use of ACE inhibitors or ARBs (80.9% vs 59.9%; P=0.0024) and beta-blockers (87.2% vs 76.0%; P=0.0346) was also more frequent in this group.

CLINICAL OUTCOMES:

During follow-up, all-cause mortality occurred in 56 patients (13.4%), with significantly higher rates in the permanent AF group compared to the non-permanent group (39.7% vs 8.7%; P<0.0001). Detailed data are presented in Tables 1 and 2. Kaplan-Meier analysis demonstrated significantly lower survival probability in patients with permanent AF (P<0.0001; Figure 1). Ischemic events were also more frequent in this group (P=0.047; Figure 2), while no significant difference was observed in bleeding event-free survival (P=0.61; Figure 3). A composite endpoint of all-cause mortality, ischemic events, and bleeding occurred significantly more often and earlier in the permanent AF group (P<0.0001). The Kaplan-Meier curves showed early and sustained divergence, indicating a consistently worse prognosis in this population (Figure 4).

Discussion

LIMITATIONS:

This study has several limitations. First, its retrospective observational design precludes establishing causal relationships. Second, despite careful data collection, unmeasured confounding factors cannot be excluded. Third, the analysis was based on hospitalized patients enrolled in the CRAFT registry, which may limit the generalizability of results to the broader AF population. Fourth, the number of patients with permanent AF was relatively small, which may reduce the statistical power to detect differences in secondary endpoints.

Conclusions

Our findings show the prognostic relevance of AF type, even in patients classified as low risk based on CHA2DS2-VASc score. Permanent AF was associated with significantly higher all-cause mortality and more frequent adverse events, including ischemic episodes. These results suggest that current risk stratification tools underestimate the true risk in patients with sustained AF, and that AF type should be considered an independent prognostic factor.

Our study calls for a reassessment of what constitutes “low risk” in AF and supports incorporating AF type into future risk models. The data also reinforce the rationale for earlier rhythm control strategies aimed at preventing AF progression and atrial remodeling. Prospective studies are needed to better characterize the risk profile of patients with non-paroxysmal AF and low CHA2DS2-VASc score.

Data Availability Statement

The data that support the findings of this study are derived from the Polish National Health Fund (NFZ) and hospital records. Due to legal and ethical restrictions, they are not publicly available.