Single-stage Pulmonary Vein Isolation Combined With Percutaneous Left Atrial Appendage Occluder Implantation in Patients With Recent Onset Ischemic Stroke and Atrial Fibrillation (PILOS-AF)
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 240
- 试验地点
- 2
- 主要终点
- Evaluating the efficacy and safety of LAAO procedure
研究概览
简要总结
The project is a multicenter, open-label, randomized medical experiment, which was designed to evaluate the efficacy and safety of single-stage pulmonary vein isolation (PVI) and implantation of left atrial appendage occluder (LAAO) in comparison with either isolated LAAO implantation or chronic therapy with non-vitamin K antagonists anticoagulants (NOAC) in patients with recent-onset ischemic stroke and atrial fibrillation (AF). Based on former randomized controlled trials, percutaneous implantation of LAAO was shown to be non-inferior to vitamin K antagonists (VKA), but according to guidelines the use of LAAO is recommended only in patients with absolute contraindication to chronic anticoagulation therapy. PVI constitutes an acknowledged rhythm control management strategy in patients with paroxysmal and persistent AF, which leads to symptomatic relief in about 60% of treated patients, however, its beneficial effect on long-term outcome was demonstrated only in patients with heart failure with reduced ejection fraction. The feasibility and compatibility of both interventions performed as a combined single-stage procedure are warranted by common vascular access via transseptal puncture, which may lead to reduction of procedural cost and shortened overall duration of both interventions. Taking into consideration the preliminary registry data, the combined single-stage PVI and LAAO implantation are thought to be a safe procedure in patients with a high risk of recurrent ischemic stroke and cardiovascular death.
The study will comprise 240 patients who were diagnosed with ischemic stroke within preceding 2-12 weeks, with confirmed paroxysmal or persistent AF and low-to-moderate psychomotor dysfunction in the course of cerebral incident, who completed early neurological rehabilitation and are characterized by high risk of ischemic stroke recurrence (CHA2DS2-VA score ≥2 pts) and who received adequate oral anticoagulation therapy (NOAC/VKA) for ≥4 weeks. After exclusion of thrombus and potential anatomical contraindications to the procedure on transesophageal echocardiography, patients will be randomized in 1:1:1 ratio to study group A treated with combined single-stage PVI + LAAO implantation during 3-day hospitalization or to group B treated with LAAO implantation or control group subject to chronic therapy with NOAC.
Patients in Group A and B will be treated with NOAC until 3 months after procedure. At 3-month visit patients in Group A and B will undergo transesophageal echocardiography so as to confirm procedural success and allow for termination of chronic anticoagulation therapy. If device-related thrombus is excluded and not peri-device leak >=5 mm is present, the patients will be switched from NOAC to aspirin 1x75 mg daily until the end of the trial.
The duration of active enrollment phase will be 12 months. Subsequent follow-up phase will include scheduled outpatient visits (at 3, 12, 48 months) and phone call interview (at 6, 18, 24, 36 months) in order to evaluate the occurrence of clinical and safety endpoints, medical symptoms and signs, quality of life reflected by structured questionnaire, the presence of AF on 24, 7-day or 30-day ECG monitoring (at 12 and 48 months).
Follow-up visits will also include blood laboratory tests analysis, including biomarkers of heart failure and left atrial wall stress, as well as transthoracic echocardiography with tissue Doppler imaging and strain imaging.
Co-primary composite endpoint will comprise cardiovascular death, ischemic stroke, transient ischemic attack, systemic arterial embolism and major non-procedural bleeding, including intracranial bleeding (non-inferiority).
The current project was based on the preliminary results of nonrandomized studies, which delivered evidence for feasibility of combined single-stage PVI and percutaneous left atrial appendage closure and laid ground for future randomized controlled trials. It is expected that the proposed intervention will be non-inferior in terms of composite cerebrovascular events and superior in terms of major nonprocedural bleeding in comparison to chronic NOAC therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ischemic stroke within 2-12 weeks after randomization with or without reperfusion therapy, confirmed by imaging studies (CT or MRI) that led to mild to moderate psychomotor dysfunction (mRS 0-3; NIHSS <16 points) and was treated with early neurological rehabilitation or was exempt from neurological rehabilitation on account of excellent psychomotor function. An obligatory criterion is persistence of symptoms for >24 h.
- •Diagnosis of paroxysmal or persistent atrial fibrillation on the basis of 12-lead ECG recording, ECG Holter monitoring, event-recorder or loop recorder at any time, but before the screening visit.
- •CHA2DS2-VA risk score ≥2 points
- •Left atrial anatomy (atrial septum, pulmonary vein orifices and left atrial appendage) suitable for intervention (PVI + LAAO or LAAO)
- •≥ 4 weeks of adequate anticoagulant treatment in the preceding period
- •no anatomical or functional contraindications and patient consent for transesophageal echocardiography (TEE)
- •Based on the aforementioned inclusion criteria, patients who can be classified into
- •groups will be enrolled in the study:
- •patients with atrial fibrillation who have been adequately treated with anticoagulation (VKA/NOAC) and have had an ischemic stroke
- •patients without prior history of atrial fibrillation and without anticoagulation who have an ischemic stroke and the atrial fibrillation is clinically overt (de novo)
- •patients without a prior history of atrial fibrillation, with an initial diagnosis of so-called cryptogenic stroke, in whom further initial ECG monitoring allowed for the detection of clinically silent atrial fibrillation
排除标准
- •current participation in another clinical trial
- •lack of informed written consent to participate in the study
- •age <18 or >80 years
- •indication for chronic anticoagulant treatment independent of AF:
- •history of mechanical valve implantation
- •history of mitral biological valve implantation within 3 months prior to randomization
- •history of deep vein thrombosis or pulmonary embolism within preceding 6 months or indication for chronic anticoagulation
- •genetically or immunologically confirmed thrombophilia
- •contraindications to NOAC treatment:
- •eGFR ≤15 ml/min/1.73 m2
- •mechanical valve prosthesis
- •moderate or severe mitral valve stenosis of rheumatic etiology
- •life-threatening bleeding during NOAC therapy
- •Ischemic stroke of etiology other than AF, including cryptogenic stroke without evidence of AF etiology
- •valvular AF: presence of moderate to severe aortic stenosis of rheumatic etiology
- •permanent AF
- •persistent long-standing AF (>1 year)
- •presence of a thrombus in the left atrial appendage on TEE examination
- •significant psychomotor dysfunction defined as a modified Rankin Scale (mRS) score of 4-6 or NIHSS score ≥16
- •major bleeding as defined by ISTH within 14 days prior to randomization or intracranial bleeding ever
- •active hyperthyroidism
- •history of myocardial infarction with or without intervention within 90 days prior to randomization
- •history of PVI or LAAO implantation
- •history of surgical closure of left atrial appendage
- •history of percutaneous or surgical ASD/PFO closure
- •acute or chronic pericarditis
- •cardiac tamponade
- •lack of vascular access for PVI and LAAO implantation
- •chronic heart failure in NYHA functional class IV
- •left ventricular ejection fraction (LVEF) <30%
- •chronic kidney disease stage IV-V (eGFR <30 ml/min/1.73 m2)
- •Child-Pugh class B or C chronic liver failure
- •severe valvular heart defect
- •body mass index (BMI, body mass index) ≥40 kg/m2
- •woman in her childbearing years planning a pregnancy
- •pregnancy or lactation period
- •documented life expectancy < 4 years
- •active cancer < 5 years after remission
- •active infection, defined as CRP >30 mg/dL with symptoms of respiratory, urinary or gastrointestinal tract infection
研究组 & 干预措施
PVI+LAAO
80 patients
干预措施: PVI + LAAO, single stage (Procedure)
LAAO
80 patients
干预措施: LAAO (Procedure)
NOAC
80 patients
干预措施: NOAC (Drug)
结局指标
主要结局
Evaluating the efficacy and safety of LAAO procedure
时间窗: 48 months
Evaluating the efficacy and safety of implantation of left atrial appendage occluder (LAAO) (group B) through the number of cardiovascular deaths occurring, ischemic stroke, transient ischemic attack (TIA), systemic embolism or major bleeding unrelated to the procedure, including intracranial bleeding vs. standard-of-care
Evaluating the efficacy and safety of PVI and LAAO procedures
时间窗: 48 months
Evaluating the efficacy and safety of single-stage pulmonary vein isolation (PVI) and implantation of left atrial appendage occluder (LAAO) (group A) through the number of cardiovascular deaths occurring, ischemic stroke, transient ischemic attack (TIA), systemic embolism or major bleeding unrelated to the procedure, including intracranial bleeding vs. standard-of-care
The rate of cardiovascular deaths, ischemic stroke, transient ischemic attack (TIA), systemic embolism or major bleeding unrelated to the procedure, including intracranial bleeding.
时间窗: 12 months
The primary composite endpoint comprises the rate of cardiovascular deaths, ischemic stroke, transient ischemic attack (TIA), systemic embolism or major bleeding unrelated to the procedure, including intracranial bleeding.
次要结局
- The rate of cardiovascular deaths, ischemic stroke, transient ischemic attack (TIA), systemic embolism or major bleeding unrelated to the procedure, including intracranial bleeding.(3, 24 and 48 months)
- The rate of cardiovascular death(3, 6, 12, 24, 36, 48 months)
- The rate of ischemic stroke and/or TIA and/or systemic embolism(3, 6, 12, 24, 36, 48 months)
- The rate of major non-procedural bleeding(3, 6, 12, 24, 36, 48 months)
- The rate of all-cause death(3, 6, 12, 24, 36, 48 months)
- The proportion of procedural feasibility(Immediately after intervention)
- AF burden on Holter ECG monitoring(12 and 48 months)
- Evaluation of the freedom from AF(12 and 48 months)
- Change of symptomatic class according to NYHA classification(3, 6, 12, 24, 36 and 48 months)
- Change of symptomatic class according to EHRA classification(3, 6, 12, 24, 36, 48 months)
- Evaluation of the change of left ventricular ejection fraction based on transthoracic echocardiography using biplane Simpson's method(12, 48 months)
- Evaluation of the change of E/e' based on transthoracic echocardiography(12, 48 months)
- Evaluation of the change of GLS LA strain based on transthoracic echocardiography(12, 48 months)
- Evaluation of the change of segmental LA strain based on transthoracic echocardiography(12, 48 months)
- Change of cardiac biomarker concentration using ELISA method(3 and 12 months)
- Evaluation of the change of quality of life reflected by EQ-5D questionnaire(3, 12 and 48 months)
- Evaluation of the change of quality of life reflected by KCCQ questionnaire(3, 12 and 48 months)
- Evaluation of the change of quality of life reflected by SF-36 questionnaire(3, 12 and 48 months)
- Evaluation of the presence of PDL >=5 mm on transesophageal echocardiography at 3 months(3 months)
- Evaluation of the presence of device-related thrombus on transesophageal echocardiography at 3 months(3 months)