Study Cohort

The Fushimi AF registry is a community-based prospective survey of patients with AF who visited the participating medical institutions in Fushimi-ku, Kyoto, Japan. The detailed study design, patient enrollment, definition of measurements, and baseline clinical characteristics of the patients have been previously described (UMIN Clinical Trials Registry: UMIN000005834). ^, The inclusion criteria for the registry were AF on a 12-lead electrocardiogram or Holter monitoring at any time. There were no exclusion criteria. A total of 81 institutions participated in the registry. Patient enrollment was started on March 2011. All of the participating institutions aimed to enroll consecutive patients with AF under regular outpatient care or hospital admission. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the ethics committees of the National Hospital Organization Kyoto Medical Center and Ijinkai Takeda General Hospital. Written informed consent was not obtained from the patients owing to the observational design of the study, which is in accordance with the ethical guidelines for epidemiological research issued by the Ministry of Education, Culture, Sports, Science, and Technology and Ministry of Health, Labor, and Welfare, Japan.

Definitions and Study Endpoint

AF type was defined in accordance with the 2019 AHA/ACC/HRS and 2020 ESC guidelines for the management of patients with AF ^, : PAF was defined as self-terminating AF within 7 days; persistent AF was defined as AF that lasted longer than 7 days, including episodes that were terminated by cardioversion, either with drugs or by direct current cardioversion, after 7 days or more; long-standing persistent AF was defined as AF that lasted longer than 12 months; and permanent AF was defined as AF that is accepted by the patients following consultation with a physician. Because distinguishing between persistent, long-standing persistent, and permanent types is often difficult in daily clinical practice, these three subtypes were combined as SAF, as described in our previous studies. ^,

We collected follow-up data of the enrolled patients annually, and patients were classified into either type of AF based on the decision of the attending physician. AF regression was defined as a change in AF type from SAF at baseline to PAF during the follow-up period. Among the patients who were diagnosed as PAF at baseline, those who progressed from PAF to SAF during the follow-up period were excluded, as our previous study reported that there was a significant difference in the prognostic impact between PAF patients with and without progression. Analyses were performed among patients who were categorized at baseline and during follow-up as: i) SAF with regression, ii) SAF without regression, and iii) PAF without progression during follow-up ( Figure 1 ). We divided the follow-up period of the patients with SAF with regression into three distinct periods as follows: pre-regression period that was defined as the period before the time of last SAF; peri-regression period that was defined as the 1-year period changing from SAF to PAF; and post-regression period that was defined as the period after the time of first PAF.

Patient Flow Diagram. PAF, paroxysmal atrial fibrillation; SAF, sustained atrial fibrillation; FU, follow-up.

We further collected data regarding the therapies and interventions put in practice before the regression (defined as either receiving catheter ablation procedure or starting/changing antiarrhythmic drugs (AAD) within the pre-, or peri-regression period), among the entire SAF patients with regression.

The primary endpoint of this study was the incidence of major adverse cardiovascular events (MACE); a composite of cardiac death, myocardial infarction (MI), ischemic stroke, SE, or hospitalization due to HF during the follow-up period. Causes of cardiac death, including cardiac death due to HF, acute coronary syndrome, or dysrhythmia, were adjudicated after considering all the available information as reported previously. Stroke was defined as the sudden onset of a focal neurologic deficit in a location consistent with the territory of a major cerebral artery. The diagnosis of ischemic or hemorrhagic stroke was confirmed using computed tomography or magnetic resonance imaging. SE was defined as an acute vascular occlusion of an extremity or organ. Hospitalization due to HF was determined by the attending physician based on the history, clinical presentation (symptoms and physical examination), response to HF therapy, chest radiography, echocardiography, cardiac catheterization findings, and in-hospital course. With regard to the comorbidities at the baseline, chronic kidney disease (CKD) was defined as persistent proteinuria or an estimated glomerular filtration rate < 60 mL/min/1.73 m ² ; organic heart disease was defined as having either valvular heart disease, previous MI, or cardiomyopathy; vascular disease was defined as having either a coronary artery disease, peripheral artery disease, or both; anemia was defined according to the World Health Organization criteria (hemoglobin < 13 g/dl in men, < 12 g/dl in women); and major bleeding was defined according to the criteria of the International Society on Thrombosis and Haemostasis. Oral anticoagulants (OAC) included warfarin and direct OACs (dabigatran, rivaroxaban, apixaban, and edoxaban). Antiplatelet drugs included aspirin, clopidogrel, prasugrel, ticlopidine, and cilostazol. AAD were categorized according to the Vaughan Williams classification: class 1a (disopyramide, procainamide, and cibenzoline), class 1b (aprindine and mexiletine), class 1c (flecainide, pilsicainide and propafenone), class 3 (amiodarone), and class 4 (bepridil). Other class 4 agents (verapamil and diltiazem), which are commonly used for rate-control therapy, were excluded. The value of left atrial (LA) diameter on echocardiography was collected at the time of enrollment.

Statistical Analysis

Continuous variables were expressed as mean ± standard deviation (SD) or median and interquartile range (IQR). Categorical variables were presented as numbers and percentages, and these variables were compared using the chi-squared test when appropriate; otherwise, Fisher’s exact test was used. Continuous variables were compared using Student’s t-test for normally distributed data or Mann–Whitney U test for non-normally distributed data. The Kaplan–Meier method was used to estimate the cumulative incidence rate of clinical outcomes. Univariable and multivariable logistic regression analyses were performed to identify the variables associated with the regression from SAF to PAF. Multivariable analysis using Cox proportional hazards model was performed to determine the association of the regression from SAF to PAF with the incidence of clinical outcomes. The covariates chosen to be included were age ≥ 75 years, female sex, low body weight (BW: < 50 kg), history of stroke or SE, pre-existing HF, hypertension, diabetes mellitus, vascular disease, organic heart disease, CKD, chronic obstructive pulmonary disease, history of major bleeding, anemia, prescription of OAC, prescription of β-blockers, and prescription of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker at baseline.

We used JMP version 13.2.0 (SAS Institute, Cary, NC, USA) to perform analyses. Two-sided P values < 0.05 were considered statistically significant.

Baseline Characteristics

Of the entire cohort of 4,496 patients with available follow-up data, 25 patients due to unavailable prescription data at baseline and 343 patients who progressed from PAF to SAF during the follow-up were excluded. We analyzed a total of 4,128 patients (1,867 patients with PAF; 2,261 patients with SAF) at baseline. During the median follow-up period of 5.8 years (interquartile range, 2.3 – 8.8 years), 214 patients (9.5% of overall SAF patients) regressed from SAF to PAF ( Figure 1 ).

The characteristics of the patients at baseline are shown in Table 1 . SAF patients with regression were more likely to have a shorter mean interval since their first detection of AF, smaller mean LA diameter, and higher proportion of prior catheter ablation than those without regression. Baseline CHADS ₂ and CHA ₂ DS ₂ -VASc scores were comparable; however, organic heart disease and history of major bleeding were significantly lower in SAF patients with regression compared with those without regression. Regarding the medication status, diuretics and digitalis prescriptions were significantly lower, whereas that of AAD was significantly higher in SAF patients with regression compared with those without regression. Other medication status, including OAC prescription, was similar between patients with SAF with and without regression.

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