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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04298723
Recruitment Status : Recruiting
First Posted : March 6, 2020
Last Update Posted : June 29, 2020
Sponsor:
Information provided by (Responsible Party):
Sven Möbius-Winkler, Jena University Hospital

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Atrial Fibrillation (AF) Intracranial Bleed Device: Percutaneous closure of the LAA (Watchman / Watchman FLX) Not Applicable

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 550 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: multicenter, prospective, randomized, controlled, non-blinded clinical trial with a two-arm parallel group design
Masking: Single (Outcomes Assessor)
Masking Description: CEC blinded DSMB blinded
Primary Purpose: Prevention
Official Title: 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.
Actual Study Start Date : June 16, 2020
Estimated Primary Completion Date : June 2025
Estimated Study Completion Date : June 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Left Atrial Appendage Occlusion
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)
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.

No Intervention: Best medical therapy for anticoagulation
Standard of care (according to current guidelines)



Primary Outcome Measures :
  1. Event free survival of the composite of Cardiovascular or unexplained death, Stroke (including ischemic or hemorrhagic stroke), Systemic embolism, Bleeding (BARC type 2-5) [ Time Frame: up to 2 years after randomization ]

    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

  2. Event free survival of the composite of Cardiovascular or unexplained death, Stroke (including ischemic or hemorrhagic stroke), Systemic embolism, Bleeding (BARC type 2-5) [ Time Frame: up to 2 years after randomization ]

    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

  3. Event free survival of the composite of Cardiovascular or unexplained death, Stroke (including ischemic or hemorrhagic stroke), Systemic embolism, Bleeding (BARC type 2-5) [ Time Frame: up to 2 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.

  4. Event free survival of the composite of Cardiovascular or unexplained death, Stroke (including ischemic or hemorrhagic stroke), Systemic embolism, Bleeding (BARC type 2-5) [ Time Frame: up to 2 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

    1. Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL (provided hemoglobin drop is related to bleed); transfusion with overt bleeding
    2. 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
    3. Intracranial hemorrhage confirmed by autopsy, imaging, or lumbar puncture; intraocular bleed compromising vision

    Type 4

    CABG-related bleeding within 48 hours

    Type 5

    1. Probable fatal bleeding
    2. Definite fatal bleeding (overt or autopsy or imaging confirmation)


Secondary Outcome Measures :
  1. Cardiovascular or unexplained death per year; Stroke per year; Systemic embolism per year; Bleeding per Year [ Time Frame: up to 2 years after randomization ]
    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;

  2. Combined endpoint: MACCE [ Time Frame: up to 2 years after randomization ]
    Combined endpoint: MACCE (stroke/systemic embolism/cardiovascular death/myocardial infarction)

  3. Mortality [ Time Frame: up to 2 years after randomization ]
    Mortality (including all-cause death, cardiovascular death, non- cardiovascular

  4. Bleeding (BARC type 2-5) [ Time Frame: up to 2 years after randomization ]

    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

    1. Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL (provided hemoglobin drop is related to bleed); transfusion with overt bleeding
    2. 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
    3. Intracranial hemorrhage confirmed by autopsy, imaging, or lumbar puncture; intraocular bleed compromising vision

    Type 4

    CABG-related bleeding within 48 hours

    Type 5

    1. Probable fatal bleeding
    2. Definite fatal bleeding (overt or autopsy or imaging confirmation)

  5. Systemic embolism [ Time Frame: up to 2 years after randomization ]
    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.

  6. Ischemic stroke [ Time Frame: up to 2 years after randomization ]
    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.

  7. Hemorrhagic stroke [ Time Frame: up to 2 years after randomization ]
    An acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage

  8. Myocardial infarction [ Time Frame: up to 2 years after randomization ]
    A detailed description of the criteria for myocardial infarction can be found in the study protocol.

  9. Hospitalization for bleeding or cardiovascular event [ Time Frame: up to 2 years after randomization ]
    Hospitalization for bleeding or cardiovascular event

  10. Intracranial bleeding [ Time Frame: up to 2 years after randomization ]
    Intracranial bleeding



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  • Subjects eligible for NOAC therapy
  • 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)
  • Severe renal failure (GFR <15 ml/min/1.73m2)
  • Absolute contraindication for long-term NOAC therapy except index ICH
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04298723


Contacts
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Contact: Sven Möbius-Winkler, PD Dr. med. +493641-9324503 sven.moebius-winkler@med.uni-jena.de
Contact: P. Christian Schulze, Prof. Dr. christian.schulze@med.uni-jena.de

Locations
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Germany
Universityhospital Recruiting
Jena, Germany, 07747
Contact: Sven Möbius-Winkler, MD    0049-3641-9324503    Sven.Moebius-Winkler@med.uni-jena.de   
Contact: Sissy Grund       sissy.grund@med.uni-jena.de   
Sponsors and Collaborators
Jena University Hospital
Investigators
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Principal Investigator: Sven Möbius- Winkler, PD Dr. med. Department of Internal Medicine I, Jena University Hospital
Principal Investigator: Albrecht Günther, Dr. med. Department of Neurology, Jena University Hospital
Principal Investigator: Albrecht Waschke, PD Dr. med. Department of Neurosurgery, RHÖN-KLINIKUM Campus Bad Neustadt
Principal Investigator: P. Christian Schulze, Prof. Dr. Department of Internal Medicine I, Jena University Hospital
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Responsible Party: Sven Möbius-Winkler, Principal Investigator, Debuty director cardiology departement, Jena University Hospital
ClinicalTrials.gov Identifier: NCT04298723    
Other Study ID Numbers: ZKSJ0123_Clearance
First Posted: March 6, 2020    Key Record Dates
Last Update Posted: June 29, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Sven Möbius-Winkler, Jena University Hospital:
Atrial Fibrillation
Intracranial bleeding
LAA occlusion
Anticoagulation
Additional relevant MeSH terms:
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Atrial Fibrillation
Intracranial Hemorrhages
Hemorrhage
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases