Ischemic Stroke, Atrial Fibrillation
Conditions
Keywords
Pulmonary vein isolation, Occluder implantation, PILOS, PILOS-AF, LAA ocludder implantation, ischemic stroke, atrial fibrillation
Brief summary
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.
Interventions
PROCEDUREPVI + LAAO, single stage
Treatment with a complex procedure of pulmonary vein isolation (PVI) and left atrial appendage occludder implantation (LAAO) via single transseptal puncture within 4 weeks from randomization. PVI will be performed only by means of radiofrequency (RF) ablation. Other types of PVI will not be allowed (cryoballoon or pulsed field ablation). LAAO implantation will comprise the use of either Amplatzer™ Amulet™ (Abbott) or WATCHMAN FLX™ (Boston Scientific) depending on local center's expertise. The procedure will be carried out within 4 weeks from randomization and will be performed during 3-day hospitalization in cardiology department. The procedure will be preceded by at least 4-week adequate anticoagulation with non-vitamin K antagonists (NOAC). The last dose of NOAC will be administered 12 h (apixaban or dabigatran) or 24 h prior to PVI+LAAO (rivaroxaban). NOAC will be continued for 3 months. Given the exlusion of PDL\>=5 mm or DRT at 3 months, NOAC will be switched to chronic aspirin.
PROCEDURELAAO
Left atrial appendage occluder implantation (LAAO) will be performed via transseptal puncture under fluoroscopic and TEE guidance. LAAO implantation will comprise the use of either Amplatzer™ Amulet™ (Abbott) or WATCHMAN FLX™ (Boston Scientific) depending on local center's expertise. The procedure will be carried out within 4 weeks from randomization and will be performed during 3-day hospitalization in cardiology department. The procedure will be preceded by at least 4-week adequate anticoagulation with non-vitamin K antagonists (NOAC). The last dose of NOAC will be administered 12 h (apixaban or dabigatran) or 24 h prior to PVI+LAAO (rivaroxaban). NOAC will be continued for 3 months. Given the exlusion of PDL\>=5 mm or DRT at 3 months, NOAC will be switched to chronic aspirin.
DRUGNOAC
Patients will be chronically treated with NOAC including apixaban (2x5 mg or 2x2.5 mg depending on the dose reduction regimen) or dabigatran (2x150 mg or 2x110 mg depending on the dose reduction regimen) or rivaroxaban (1x20 mg or 1x15 mg depending on the dose reduction regimen). The use vitamin K antagonists after the randomization is not allowed.
Sponsors
Medical University of Silesia
Medical University of Lodz
Silesian Centre for Heart Diseases
Pomeranian Medical University Szczecin
American Heart of Poland
Leszek Giec Upper-Silesian Medical Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. 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. 2. 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. 3. CHA2DS2-VA risk score ≥2 points 4. Left atrial anatomy (atrial septum, pulmonary vein orifices and left atrial appendage) suitable for 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: 1. patients with atrial fibrillation who have been adequately treated with anticoagulation (VKA/NOAC) and have had an ischemic stroke 2. patients without prior history of atrial fibrillation and without anticoagulation who have an ischemic stroke and the atrial fibrillation is clinically overt (de novo) 3. 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
Exclusion criteria
* 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: 1. history of mechanical valve implantation 2. history of mitral biological valve implantation within 3 months prior to randomization 3. history of deep vein thrombosis or pulmonary embolism within preceding 6 months or indication for chronic anticoagulation 4. genetically or immunologically confirmed thrombophilia * contraindications to NOAC treatment: 1. eGFR ≤15 ml/min/1.73 m2 2. mechanical valve prosthesis 3. moderate or severe mitral valve stenosis of rheumatic etiology 4. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The rate of cardiovascular deaths, ischemic stroke, transient ischemic attack (TIA), systemic embolism or major bleeding unrelated to the procedure, including intracranial bleeding. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 composite primary 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. |
| The rate of cardiovascular death | 3, 6, 12, 24, 36, 48 months | Evaluation of the rate of cardiovascular death |
| The rate of ischemic stroke and/or TIA and/or systemic embolism | 3, 6, 12, 24, 36, 48 months | Evaluation of the rate of ischemic stroke and/or TIA and/or systemic embolism |
| The rate of major non-procedural bleeding | 3, 6, 12, 24, 36, 48 months | Evaluation of the rate of major non-procedural bleeding defined by ISTH |
| The rate of all-cause death | 3, 6, 12, 24, 36, 48 months | Evaluation of the rate of all-cause death |
| The proportion of procedural feasibility | Immediately after intervention | Evaluation of the proportion of procedures completed according to prespecified allocation |
| AF burden on Holter ECG monitoring | 12 and 48 months | Proportion of time during 24, 7-day or 30-day monitoring with AF rhythm evaluated by prolonged surface ECG monitoring system. |
| Evaluation of the freedom from AF | 12 and 48 months | Lack of AF episodes on 24-hour, 7-day or 30 day ECG monitoring |
| Change of symptomatic class according to NYHA classification | 3, 6, 12, 24, 36 and 48 months | Evaluation of the change of symptomatic class according to NYHA classification |
| Change of symptomatic class according to EHRA classification | 3, 6, 12, 24, 36, 48 months | Evaluation of the change of symptomatic class according to EHRA classification |
| 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 left ventricular ejection fraction based on transthoracic echocardiography using biplane Simpson's method |
| Evaluation of the change of E/e' based on transthoracic echocardiography | 12, 48 months | Evaluation of the change of E/e' based on transthoracic echocardiography |
| Evaluation of the change of GLS LA strain based on transthoracic echocardiography | 12, 48 months | Evaluation of the change of GLS LA strain based on transthoracic echocardiography |
| Evaluation of the change of segmental LA strain based on transthoracic echocardiography | 12, 48 months | Evaluation of the change of segmental LA strain based on transthoracic echocardiography |
| Change of cardiac biomarker concentration using ELISA method | 3 and 12 months | Change of cardiac biomarker concentration using ELISA method: * NT-proBNP * ST-2 * galectin-3 |
| 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 EQ-5D questionnaire |
| 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 KCCQ questionnaire |
| Evaluation of the change of quality of life reflected by SF-36 questionnaire | 3, 12 and 48 months | Evaluation of the change of quality of life reflected by SF-36 questionnaire |
| Evaluation of the presence of PDL >=5 mm on transesophageal echocardiography at 3 months | 3 months | Evaluation of the presence of peri-device leak of \>=5 mm on transesophageal echocardiography at 3 months |
| Evaluation of the presence of device-related thrombus on transesophageal echocardiography at 3 months | 3 months | Evaluation of the presence of device-related thrombus on transesophageal echocardiography at 3 months |
Countries
Poland
Contacts
CONTACTMaciej T. Wybraniec, MD, PhD, Professor
CONTACTKrystian Wita, MD, PhD, Professor
PRINCIPAL_INVESTIGATORMaciej T. Wybraniec, MD, PhD, Professor
Medical University of Silesia
Outcome results
None listed