Comparison of LAA-Closure vs Oral Anticoagulation in Patients With NVAF and Status Post Intracranial Bleeding.

Study Overview
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Brief Summary
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Atrial fibrillation is the most common cardiac arrhythmia. In atrial fibrillation, there is a risk that clots can form in the heart, especially in the left atrium. If these clots come loose, there is a risk of stroke. To prevent strokes, patients with atrial fibrillation and status post ICB can be treated with anticoagulants. This medication therapy prevents blood clots from forming in the heart, but can also cause bleeding. Another therapy option is the occlusion of the left atrium. After closure of the left atrium, only a short anticoagulation therapy is necessary until the occluder has healed. The aim of the study is to compare these two treatment approaches. In this study only already approved drugs and occlusion systems will be used.

Detailed Description
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Within the current trial, two novel strategies are tested in a randomized fashion in patients with atrial fibrillation and status post intracranial bleeding. Patients with ICH were usually excluded from the large NOAC trials and were also not representatively included in the large Watchman device trials. On the other hand, registries show that there is a significant proportion of patients with status post ICH that were implanted with a LAA closure device in clinical routine, and also there are those patients treated with NOAC due to their high stroke risk, despite the risk of recurrent ICH. Both therapies, NOAC and LAA closure are effective in preventing stroke in patients with AF at high risk for stroke. Also, for both therapies there is evidence for prevention of bleedings, especially intracranial bleeding events. Patients within the LAA closure group will have the chance after successful closure of the LAA to quit oral anticoagulation medication and therefore reduce their lifetime risk for bleeding and recurrent bleeding. Patients in the NOAC group are provided with an excellent protection against stroke and a significant reduced bleeding risk compared to Vitamin K antagonist therapy. The trial will help to develop data and hopefully guidelines for management of patients with AF and status post intracranial bleedings. It may help to give physicians data to therapy patients post ICH adequately and help to reduce mortality rates in those patients.

Official Title
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Randomized Comparison of Interventional Closure of the Left Atrial Appendage Using a LAA Closure Device Versus Oral Anticoagulation Therapy in Patients With Non-valvular Atrial Fibrillation and Status Post Intracranial Bleeding.

Conditions
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Atrial Fibrillation (AF), Intracranial Bleed

Intervention / Treatment
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* Device: Percutaneous closure of the LAA (Watchman / Watchman FLX)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent Documented atrial fibrillation (paroxysmal, persistent, long-standing persistent or permanent) CHA2DS2VASc-Score ≥2 Status post intracranial bleeding >6 weeks Favorable LAA anatomy Subject eligible for a LAA occluder device Age ≥18 years Exclusion Criteria: Comorbidities other than AF requiring chronic (N)OAC therapy, e.g. mechanical heart valve prosthesis, hereditary thrombophilia requiring livelong OAC - recurrent thrombosis Symptomatic carotid disease (if not treated) Thrombus in the left atrium or left atrial appendage Active infection or active endocarditis or other infections resulting in bacteremia Functional Impairment (modified ranking scale ≥4 ) Severe liver failure (Child-Pugh class C or liver failure with coagulopathy) Pregnancy or breastfeeding Subject with participation in another interventional clinical trial during this study or within 30 days before entry into this trial. Known terminating disease with life expectancy <1 year (including those with end-stage heart failure) Subjects, who are committed to an institution due to binding official or court order Subjects with planned cardiac or non-cardiac surgery or intervention. (These subjects can be included 30 days after intervention / surgery

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: multicenter, prospective, randomized, controlled, non-blinded clinical trial with a two-arm parallel group design
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Left Atrial Appendage Occlusion<br>Percutaneous closure of the LAA by use of CE-mark approved LAA occlusion device Watchman / Watchman FLX | Device: Percutaneous closure of the LAA (Watchman / Watchman FLX)<br>* LAA closure procedure will be done by experienced operators according to the local SOP. LAA closure will be performed under fluoroscopic and TEE guidance within conscious sedation or general anesthesia. Antibiotic single-shot prophylaxis should be administered peri-procedurally (i.e., cefazolin 2 g). The specific anatomy of the LAA is evaluated and an appropriately sized CE-marked device (WatchmanTM or Watchman FLXTM) is deployed. LAA angiography and TEE imaging is performed to identify optimal positioning of the device and to exclude a relevant leak. Following device deployment, patients will receive a therapy according to the manufacturers IFU, currently Aspirin and clopidogrel for 3 months followed by single Aspirin up to 12 months. Alternatively, 3 months of NOAC followed by Aspirin monotherapy up to 12 months are possible.<br>|
| No Intervention: Best medical therapy for anticoagulation<br>Standard of care (according to current guidelines) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival of the composite of Cardiovascular or unexplained death, Stroke (including ischemic or hemorrhagic stroke), Systemic embolism, Bleeding (BARC type 2-5) | Cardiovascular or unexplained death - Cardiovascular mortality: Death due to proximate cardiac cause e.g. myocardial infarction, cardiac tamponade, worsening heart failure, or endocarditis Death caused by non-coronary, non-CNS vascular conditions such as: pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm or other vascular disease Death from vascular CNS causes from hemorrhagic and ischemic stroke All procedure-related deaths including those related to a complication of the procedure or treatment for a complication of the procedure Sudden or unwitnessed death defined as non-traumatic, unexpected fatal event occurring within one hour of the onset of symptoms in an apparently healthy subject. If death is not witness, the definition applies when the victim was in good health 24 hours before the event Death of unknown cause | up to 3 years after randomization | 
| Event free survival of the composite of Cardiovascular or unexplained death, Stroke (including ischemic or hemorrhagic stroke), Systemic embolism, Bleeding (BARC type 2-5) | Stroke (including ischemic or hemorrhagic stroke) - A stroke is an acute episode (lasting >24 hours) of focal neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of hemorrhage or infarction. Strokes are characterized as follows: Ischemic stroke: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of the central nervous system tissue. Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an ischemic stroke with hemorrhagic transformation and not a hemorrhagic stroke. Hemorrhagic stroke: an acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage | up to 3 years after randomization | 
| Event free survival of the composite of Cardiovascular or unexplained death, Stroke (including ischemic or hemorrhagic stroke), Systemic embolism, Bleeding (BARC type 2-5) | Systemic embolism - Non-CNS systemic embolism is defined as abrupt vascular insufficiency of an extremity or organ associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms, (e.g., trauma, atherosclerosis, instrumentation). In the presence of atherosclerotic peripheral vascular disease, diagnosis of embolism to the lower extremities should be made with caution and requires angiographic demonstration of abrupt arterial occlusion. | up to 3 years after randomization | 
| Event free survival of the composite of Cardiovascular or unexplained death, Stroke (including ischemic or hemorrhagic stroke), Systemic embolism, Bleeding (BARC type 2-5) | Bleeding (BARC type 2-5) - Type 2 Any clinically overt sign of hemorrhage that is actionable and requires diagnostic studies, hospitalization, or treatment by a health care professional Type 3 Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL (provided hemoglobin drop is related to bleed); transfusion with overt bleeding Overt bleeding plus hemoglobin drop < 5 g/dL (provided hemoglobin drop is related to bleed); cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring IV vasoactive agents Intracranial hemorrhage confirmed by autopsy, imaging, or lumbar puncture; intraocular bleed compromising vision Type 4 CABG-related bleeding within 48 hours Type 5 Probable fatal bleeding Definite fatal bleeding (overt or autopsy or imaging confirmation) | up to 3 years after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovascular or unexplained death per year; Stroke per year; Systemic embolism per year; Bleeding per Year | Primary endpoint events per year: Cardiovascular or unexplained death per year; Stroke per year; Systemic embolism per year; Bleeding per Year; The study participants or, if consent has been obtained, relatives are questioned during the visits, if necessary, diagnostic results are obtained; | up to 3 years after randomization | 
| Combined endpoint: MACCE | Combined endpoint: MACCE (stroke/systemic embolism/cardiovascular death/myocardial infarction) | up to 3 years after randomization | 
| Mortality | Mortality (including all-cause death, cardiovascular death, non- cardiovascular | up to 3 years after randomization | 
| Bleeding (BARC type 2-5) | Type 2 Any clinically overt sign of hemorrhage that is actionable and requires diagnostic studies, hospitalization, or treatment by a health care professional Type 3 Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL (provided hemoglobin drop is related to bleed); transfusion with overt bleeding Overt bleeding plus hemoglobin drop < 5 g/dL (provided hemoglobin drop is related to bleed); cardiac tamponade; bleeding requiring surgical intervention for control; bleeding requiring IV vasoactive agents Intracranial hemorrhage confirmed by autopsy, imaging, or lumbar puncture; intraocular bleed compromising vision Type 4 CABG-related bleeding within 48 hours Type 5 Probable fatal bleeding Definite fatal bleeding (overt or autopsy or imaging confirmation) | up to 3 years after randomization | 
| Systemic embolism | Non-CNS systemic embolism is defined as abrupt vascular insufficiency of an extremity or organ associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms, (e.g., trauma, atherosclerosis, instrumentation). In the presence of atherosclerotic peripheral vascular disease, diagnosis of embolism to the lower extremities should be made with caution and requires angiographic demonstration of abrupt arterial occlusion. | up to 3 years after randomization | 
| Ischemic stroke | An acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of the central nervous system tissue. Hemorrhage may be a consequence of ischemic stroke. In this situation, the stroke is an ischemic stroke with hemorrhagic transformation and not a hemorrhagic stroke. | up to 3 years after randomization | 
| Hemorrhagic stroke | An acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage | up to 3 years after randomization | 
| Myocardial infarction | A detailed description of the criteria for myocardial infarction can be found in the study protocol. | up to 3 years after randomization | 
| Hospitalization for bleeding or cardiovascular event | Hospitalization for bleeding or cardiovascular event | up to 3 years after randomization | 
| Intracranial bleeding | Intracranial bleeding | up to 3 years after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial Fibrillation, Intracranial bleeding, LAA occlusion, Anticoagulation