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STroke secondary prevention with catheter ABLation and EDoxaban for patients with non-valvular atrial fibrillation (STABLED study)

STroke secondary prevention with catheter ABLation and EDoxaban for patients with non-valvular atrial fibrillation (STABLED study)

251

In the ITT analysis population (249 patients: standard medical therapy group 124 patients, standard medical therapy plus catheter ablation group 125 patients),the mean age was 71.7 years overall (SD 7.5), 71.0 years in the standard medical therapy group (SD 7.5), and 72.3 years in the standard medical therapy plus catheter ablation group (SD 7.4). The median age was 72.0 years overall, 72.0 years in the standard medical therapy group and 73.0 years in the standard medical therapy plus catheter ablation group. By age group, 32.9% of the total were <70 years, 67.1% were >=70 years, 59.4% were <75 years, and 40.6% were >=75 years. The gender was 75.1% (187 patients) in males and 24.9% (62 patients) in females. There were 79.8% males and 20.2% females in the standard medical therapy group and 70.4% males and 29.6% females in the standard medical therapy plus catheter ablation group. Mean height was global 164.5cm (SD 8.0), 165.7cm in the standard medical therapy group (SD 7.2), and 163.2cm in the standard medical therapy plus catheter ablation group (SD 8.5). Mean weight was global 62.73kg (SD 10.82), 63.67kg in the standard medical therapy group (SD 10.87), and 61.801kg in the standard medical therapy plus catheter ablation group (SD 10.73). The mean BMI was 23.13 (SD 3.31) overall, 23.13 (SD 3.28) in the standard medical therapy group, and 23.14 (SD 3.35) in the standard medical therapy plus catheter ablation group. Subjects with a BMI of less than 22 accounted for 38.2% of the total and more than 22 accounted for 61.8%. The mean CHADS2 scoring was 3.3 (SD 0.9) overall, 3.2 (SD 0.9) in the standard medical therapy group, and 3.4 (SD 0.9) in the standard medical therapy plus catheter ablation group, with 78.3% of the total subjects having 3 or more and 42.2% having 4 or more. Regarding lesions, 22.4% of the total subjects scored below ASPECTS:DWI scored and 77.6% scored above 8. The mean CHA2DS2-VASc scoring was 4.5 overall, with 4.3 in the standard medical therapy group and 4.6 in the standard medical therapy plus catheter ablation group. Regarding medical history and complications, all subjects (249 patients) had some medical history, especially hypertension was reported in 64.7%, dyslipidemia in 55.4%, and diabetes mellitus in 19.3%. Regarding smoking habits, there were 17.7% of current smokers, 45.4% of former smokers, and 36.9% of never smokers. Regarding drinking habits, 60.6% of the patients had habits and 39.4% of the patients had no habits. As another classification item, I degree was 88.4% and II degree were 11.6% in NYHA classification, and III and IV degree did not exist. In terms of mRS scores, "no symptoms" or "no disability" were 67.4%, while "mild disability" or more were 32.6%.

This study started registration from April 2018, finished the registration in July 2021, and the observation period ended in March 2024, with the investigation of all patients completed in July 2024. In this study, patients were randomized into standard medical therapy group and standard medical therapy plus catheter ablation group. All of the 251 subjects who gave informed consent were enrolled, of whom 2 subjects withdrew consent, resulting in an analysis set of 249 subjects. There were 124 patients assigned to the standard medical therapy group and 125 patients assigned to the standard medical therapy plus catheter ablation group. In the standard medical therapy group, 124 patients received edoxaban, with 110 patients indicated for the package insert and 14 patients not indicated for the package insert. In addition, there were 16 patients in which catheter ablation was performed and 108 patients in which it was not performed. In the standard medical therapy plus catheter ablation group, 125 patients received edoxaban, with 112 patients indicated for package insert and 13 patients not indicated for package insert. In this group, there were 106 patients in which catheter ablation was performed and 19 patients in which it was not performed. In addition, no patients of significant ICH-GCP violations or missing data after randomization were identified in both groups, indicating that the study was conducted as specified. The analysis set consisted of 124 patients in the standard medical therapy group and 125 patients in the standard medical therapy plus catheter ablation group, and 0 patients in both groups were not included in the analysis.

Adverse events occurred in 85 patients (69.1%) in the standard medical therapy group (123 patients) and in 78 patients (63.4%) in the standard medical therapy plus catheter ablation group (123 patients). Adverse events that occurred in at least 3 patients in the standard medical therapy group included cerebral infarction in 19 patients (15.4%), atrial fibrillation and COVID-19 in 13 patients (10.6%), cardiac failure in 12 patients (9.8%), congestive cardiac failure, large intestine polyp, pneumonia and contusion in 5 patients (4.1%), fall and hypertension in 4 patients (3.3%), and constipation, death, dizziness, embolic stroke, insomnia, haematuria and renal impairment in 3 patients (2.4%), respectively. In the catheter ablation add-on group, cerebral infarction occurred in 17 patients (13.8%), atrial fibrillation in 13 patients (10.6%), COVID-19 in 6 patients (4.9%), anaemia, cardiac failure, large intestine polyp and hypertension in 5 patients (4.1%), death, pneumonia and haematuria in 4 patients (3.3%), and cataract, diverticulum intestinal, haematochezia, pneumonia aspiration, humerus fracture, colon cancer and epistaxis in 3 patients (2.4%), respectively. Serious adverse events occurred in 48 patients (39.0%) in the standard medical therapy group and in 54 patients(43.9%) in the standard medical therapy plus catheter ablation group. Serious adverse events that occurred in 3 or more patients were cerebral infarction in 12 patients (9.8%), cardiac failure in 5 patients (4.1%), congestive cardiac failure, pneumonia, and COVID-19 in 4 patients (3.3%), and large intestine polyp, death, and embolic stroke in 3 patients (2.4%), respectively, in the standard medical therapy group. In the standard medical therapy plus catheter ablation group, there were 10 patients (8.1%) of cerebral infarction, 6 patients (4.9%) of atrial fibrillation, 4 patients (3.3%) of cardiac failure, COVID-19, and death, respectively, and 3 patients (2.4%) of pneumonia aspiration and colonic carcinoma, respectively. Adverse events related to edoxaban included adverse drug reactions in 13 patients (10.6%) in the standard medical therapy group, 17 patients (13.8%) in the standard medical therapy plus catheter ablation group, and only 3 patients (2.4%) in the standard medical therapy plus catheter ablation group experienced haematuria in more than 3 patients. Serious adverse reactions occurred in 3 patients (2.4%) in the standard medical therapy group, 9 patients (7.3%) in the standard medical therapy plus catheter ablation group, and no serious adverse reactions occurred in 3 or more patients. In the standard medical therapy plus catheter ablation group, adverse events related to catheter ablation included adverse reactions in 7 patients (5.7%), serious adverse reactions in 2 patients (1.6%), and important adverse events related to the procedure in 2 patients (1.6%). Adverse reactions that occurred in more than one patient were cerebral infarction in 3 patients (2.4%), and serious adverse reacotins were cerebral infarction in 2 patients (1.6%). Significant procedural adverse events included cardiac tamponade and cerebral infarction in one patient each (0.8%).

[Primary endpoint]. Composite of events during the observation period (recurrence of ischemic stroke, systemic embolism, all-cause death, and hospitalization for heart failure) The incidence was 22 in both groups (18.0% in the standard medical therapy group and 18.0% in the standard medical therapy plus catheter ablation group). The number of index events per total observed patient-years was 4.9/100 patient-years in the standard medical therapy group and 5.6/100 patient-years in the standard medical therapy plus catheter ablation group. The hazard proportions were estimated to be 1.11(95% CI: 0.62-2.01, p=0.719). The p-value of the log-rank test was 0.702. [Secondary endpoints]. (1) Onset of stroke The incidence was 14 (11.5%) in the standard medical therapy group and 13 (10.7%) in the standard medical therapy plus catheter ablation group. The incidence rate per total patient-years of observation was 3.1 /100 patient-years in the standard medical therapy group and 3.2 patients/100 patient-years in the standard medical therapy plus catheter ablation group. The hazard ratio of the standard medical therapy plus catheter ablation group to the standard medical therapy group was 0.99(95% CI: 0.46-2.11, p=0.979). The p-value of the log-rank test was 0.940. (2) Recurrence of ischemic stroke The incidence was 14 (11.5%) in the standard medical therapy group and 10 (8.2%) in the standard medical therapy plus catheter ablation group. The event rate per total observed patient-years was 3.1 patients/100 patient-years in the standard medical therapy group and 2.5 patients/100 patient-years in the standard medical therapy plus catheter ablation group. The hazard ratio was 0.75(95% CI: 0.33-1.70, p=0.494). The p-value of the log-rank test was 0.562. (3) Onset of haemorrhagic stroke The incidence rate was no expression in the standard medical therapy group, 3 patients (2.5%) in the standard medical therapy plus catheter ablation group, and 0.7 patients per total patient-years of observation. The hazard ratio was not calculated, and the p-value of the log-rank test was 0.067. (4) Systemic embolism There was no incidence of systemic embolism in both groups. (5) All-cause death The incidence was 5 (4.1%) in the standard medical therapy group and 12 (9.8%) in the standard medical therapy plus catheter ablation group. The event rate per total observed patient-years was 1.0 patients/100 patient-years in the standard medical therapy group and 2.8 patients/100 patient-years in the standard medical therapy plus catheter ablation group. The hazard ratio was 2.79(95% CI:0.98-7.92, p=0.054). The p-value of the log-rank test was 0.047. (6) Cardiovascular death The incidence rate was 2 (1.6%) in the standard medical therapy group and 6 (4.9%) in the standard medical therapy plus catheter ablation group, and the event rate per total observed patient-years was 0.4 patients/100 patient-years in the standard medical therapy group and 1.4 patients/100 patient-years in the standard medical therapy plus catheter ablation group. The hazard ratio was 3.47(95%CI:0.70-17.20, p=0.128). The p-value of the log-rank test was 0.105. (7) Hospitalization for heart failure The incidence of hospitalization for heart failure was 7 (5.7%) in the standard medical therapy group and 4 (3.3%) in the standard medical therapy plus catheter ablation group; the incidence rate per total observed patient-years was 1.5 patients/100 patient-years in the standard medical therapy group and 1.0 patients/100 patient-years in the standard medical therapy plus catheter ablation group. The hazard ratio was 0.66(95%CI:0.19-2.27, p=0.513). The p-value of the log-rank test was 0.492. (8) All haemorrhagic adverse events (major bleeding and minor bleeding, major bleeding, minor bleeding) 1) All bleeding adverse events (major bleeding and minor bleeding) The incidence rate was 21 (17.2%) in the standard medical therapy group and 23 (18.9%) in the standard medical therapy plus catheter ablation group; the incidence rate per total observed patient-years was 4.8 patients/100 patient-years in the standard medical therapy group and 6.0 patients/100 patient-years in the standard medical therapy plus catheter ablation group. The hazard ratio was 1.21(95%CI:0.67-2.19, p=0.524). The p-value of the log-rank test was 0.519. 2) Major bleeding The incidence rate was 3 (2.5%) in the standard medical therapy group and 8 (6.6%) in the standard medical therapy plus catheter ablation group, with an incidence rate of 0.6 patients/100 patient-years and 1.9 patients/100 patient-years per total observed patient-years, respectively. The hazard ratio was 2.99(95%CI:0.79-11.28, p=0.106). The p-value of the log-rank test was 0.09. 3) Minor bleeding The incidence rate was 19 (15.6%) in the standard medical therapy group and 18 (14.8%) in the standard medical therapy plus catheter ablation group, with an incidence rate of 4.3 patients per 100 patient-years and 4.6 patients per 100 patient-years, respectively, per total observed patient-years. The hazard ratio was 1.05(95%CI:0.55-2.00, p=0.889). The p-value of the log-rank test was 0.889. (9) Onset of intracranial hemorrhage The incidence rate was 2 (1.6%) in the standard medical therapy group and 4 (3.3%) in the standard medical therapy plus catheter ablation group, with an incidence rate of 0.4 patients per 100 patient-years and 0.9 patients per 100 patient-years, respectively, per total observed patient-years. The hazard ratio was 2.26(95%CI:0.41-12.35, p=0.347). The p-value of the log-rank test was 0.327. (10) Gastrointestinal hemorrhage The incidence rate was 13 (10.7%) in the standard medical therapy group and 10 (8.2%) in the standard medical therapy plus catheter ablation group, and the incidence rate per total observed patient-years was 2.9 patients/100 patient-years and 2.4 patients/100 patient-years, respectively. The hazard ratio was 0.82(95%CI:0.36-1.88, p=0.646). The p-value of the log-rank test was 0.627. (11) Composite events of all-cause death, onset of stroke, onset of systemic embolism, hospitalization for heart failure, and serious adverse events related to catheter ablation procedures. The incidence rate was 22 (18.0%) in the standard medical therapy group and 23 (18.9%) in the standard medical therapy plus catheter ablation group, with an incidence rate of 4.9 patients/100 patient-years and 5.9 patients/100 patient-years per total observed patient-years, respectively. The hazard ratio was 1.18(95%CI:0.66-2.11, p=0.587). The p-value of the log-rank test was 0.575.

A total of 249 patients were randomized in this study, including 124 patients in the standard medical therapy group and 125 patients in the standard medical therapy plus catheter ablation group (CA group). Median follow-up was 3.69 years in the standard-drug arm and 3.59 years in CA arm. The primary endpoint occurred in 4.9 cases per 100 person-years in the standard medical therapy group and in 5.6 cases in CA group, which showed no significant differences between the groups. (log-rank test p = 0.70)

Mar. 31, 2026

Yes

Data sets retrieved and analyzed in this study will be disclosed by the responsible author or sponsor if warranted It is.

https://jrct.mhlw.go.jp/latest-detail/jRCTs031180249

Iwasaki Yu-ki

Nippon Medical School Hospital

1-1-5, Sendagi, Bunkyo-ku, Tokyo, Japan

iwasaki@nms.ac.jp

Iwasaki Yu-ki

Nippon Medical School Hospital

1-1-5, Sendagi, Bunkyo-ku, Tokyo, Japan

+81-3-3822-2131

iwasaki@nms.ac.jp

Complete

Mar. 01, 2018

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1)Age >=20 and =<85 years at time of giving informed consent
2)Nonvalvular atrial fibrillation
3)History of ischemic stroke in previous 6 months
4)Current or planned treatment with edoxaban
5)Modified Rankin Scale (mRS) =<3

1)Symptomatic paroxysmal atrial fibrillation resistant to anti-arrhythmic drugs
2)Presence of left atrial thrombus and/or left atrial appendage on transthoracic echocardiography, computed tomography or magnetic resonance imaging
3)Unable to take anticoagulation therapy for any reason, including tendency to bleed or considered at high risk for bleeding from anticoagulation therapy
4)Presence of severe renal disorder(estimated creatinine clearance <30 mL/min by Cockroft-Gault equation)
5)Previous catheter ablation or surgical intervention for atrial fibrillation
6)History of treatment with a left atrial appendage closure device
7)Left atrial diameter >=55 mm on transthoracic echocardiography
8)Ejection fraction =<35% on transthoracic echocardiography
9)Persistent Sustained AF for >=10 years
10)Atrial septal defect (ASD)
11)Pregnant or possibility of pregnancy
12)Unlikely to complete the study, such as due to progressive malignant tumor
13)Participating or planning to participate in another interventional clinical trial
14)Unwilling to participate
15)Judged as incompatible for the study by the investigators

Both

Non-valvular atrial fibrillation

Standard medication group:
The preferred anticoagulant is edoxaban. Antiarrhythmic drugs are administered as needed for the patient by well-trained cardiologists.

Catheter ablation additional group:
Catheter ablation should be performed from the onset of ischemic stroke. Catheter ablation is based on pulmonary vein isolation, with atrial ablation as required.

The following composite events during observation period
1) Recurrence of ischemic stroke
2) Systemic embolism
3) All-cause death
4) Hospitalization for heart failure

<<Secondary Endpoints>>
1)Onset of stroke
2)Recurrence of ischemic stroke
3)Hemorrhagic stroke
4)Systemic embolism
5) All-cause death
6)Cardiovascular death
7)Hospitalization for heart failure
8)Any bleeding(Major and minor bleeding, Major bleeding, Minor bleeding)
9)Onset of intracranial hemorrhage
10) Gastrointestinal bleeding
11)Composite events (all-cause death, onset of stroke, systemic embolism, hospitalization for heart failure, and serious adverse event caused by catheter ablation)

<<Other Endpoints>>
1)Modified Rankin scale score and NYHA classification at the end of observation period
2)Maintenance rate of sinus rhythm
3)Changes in Mini-Mental State Examination (MMSE) scores during observation period
4)The continuation rate of edoxaban
5)Recurrence rate of stroke according to whether or not Edoxaban discontinue
6)Factors which contribute to discontinue edoxaban

<<Safety outcomes>>
1)Serious adverse events related to catheter ablation maneuver
2)All adverse events not related to catheter ablation maneuver
3)Drug reaction to edoxaban

+81-3-3822-2131

Dec. 25, 2018

none