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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 6-12 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-VASc score ≥2 pts in men; ≥3 pts in women) 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 treated with combined single-stage PVI + LAAO implantation during 3-day hospitalization and to control group subject to LAAO implantation or control group subject to chronic therapy with NOAC.
The duration of active enrollment phase will be 18 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 7-day Holter electrocardiography.
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. In addition, patients in study group and control group treated with LAAO will attend additional outpatient visit at 6 weeks in order to perform transesophageal echocardiography so as to confirm procedural success and allow for termination of chronic anticoagulation therapy. 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.
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Inclusion criteria
1 Status post ischemic stroke within 6-12 weeks of randomization with or without reperfusion therapy, confirmed by imaging studies (CT or MRI) that led to mild to moderate psychomotor dysfunction (mRS 1-3; NIHSS <16 points) and was treated with early neurological rehabilitation. An obligatory criterion is persistence of symptoms for >24 h.
Diagnosis of paroxysmal or persistent atrial fibrillation made on the basis of 12-lead ECG recording, ECG Holter monitoring, event-recorder or loop recorder at any time, but before the screening visit.
CHA2DS-VASc stroke and embolic complications risk scale ≥2 points in men and ≥3 points in women 4. left atrial anatomy (atrial septum, pulmonary vein orifices and left atrial appendage) to allow intervention (PVI + LAAO or LAAO) 5. ≥ 4 weeks of adequate anticoagulant treatment in the preceding period 6. no anatomical or functional contraindications and patient consent for transesophageal echocardiography (TEE)
Based on the aforementioned inclusion criteria, patients who can be classified into 3. groups will be enrolled in the study:
Exclusion criteria
current participation in another clinical trial
Lack of informed written consent to participate in the study
age <18 or ≥75 years
indication for chronic anticoagulant treatment independent of AF:
Contraindications to NOAC treatment:
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
persistent AF
persistent, prolonged (> 1 year) AF
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 ischemic stroke preceding the current episode
status after PVI or LAAO implantation
status after surgical closure of left atrial appendage
status after percutaneous or surgical ASD/PFO
symptoms of acute or chronic pericarditis
symptoms of 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
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240 participants in 3 patient groups
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Data sourced from clinicaltrials.gov
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