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

Sponsor

Jena University Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT04298723

Collaborator

(none)

550

Enrollment

Locations

Arms

59.5

Anticipated Duration (Months)

19.6

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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)	N/A

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.

Study Design

Study Type:

Interventional

Anticipated 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 designmulticenter, 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 :

Jun 16, 2020

Anticipated Primary Completion Date :

Jun 1, 2025

Anticipated Study Completion Date :

Jun 1, 2025

Arms and Interventions

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)

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)

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Cardiovascular or unexplained death per year; Stroke per year; Systemic embolism per year; Bleeding per Year [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;
Combined endpoint: MACCE [up to 2 years after randomization]
Combined endpoint: MACCE (stroke/systemic embolism/cardiovascular death/myocardial infarction)
Mortality [up to 2 years after randomization]
Mortality (including all-cause death, cardiovascular death, non- cardiovascular
Bleeding (BARC type 2-5) [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 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)
Systemic embolism [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.
Ischemic stroke [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.
Hemorrhagic stroke [up to 2 years after randomization]
An acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, intraventricular, or subarachnoid hemorrhage
Myocardial infarction [up to 2 years after randomization]
A detailed description of the criteria for myocardial infarction can be found in the study protocol.
Hospitalization for bleeding or cardiovascular event [up to 2 years after randomization]
Hospitalization for bleeding or cardiovascular event
Intracranial bleeding [up to 2 years after randomization]
Intracranial bleeding

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universitätsherzzentrum Freiburg - Bad Krozingen	Freiburg	Baden Württemberg	Germany	79106
2	Klinikum Friedrichshafen GmbH	Friedrichshafen	Baden-Wurttemberg	Germany	88048
3	Universitätsklinikum der J.W. Goethe-Universität Frankfurt	Frankfurt am main	Hessen	Germany	60590
4	Knappschaftskrankenhaus Bottrop Gmbh	Bottrop	Nordrhein Westfahlen	Germany	46242
5	Herzzentrum Harz - Quedlinburg	Quedlinburg	Sachsen-Anhalt	Germany	06484
6	Klinikum Chemnitz	Chemnitz	Sachsen	Germany	09116
7	Städtisches Klinikum Friedrichstadt Dresden	Dresden	Sachsen	Germany	01067
8	Klinikum St. Georg gGmbH	Leipzig	Sachsen	Germany	04129
9	HBK Zwickau	Zwickau	Sachsen	Germany	08060
10	Katholisches Krankenhaus "St. Johann Nepomuk"	Erfurt	Thüringen	Germany	99097
11	SRH Wald-Klinikum Gera GmbH	Gera	Thüringen	Germany	07548
12	Rhön Klinikum Bad Neustadt	Bad Neustadt An Der Saale		Germany
13	Evangelisches Klinikum Bethel Bielefeld	Bielefeld		Germany	33617
14	REGIOMED Klinikum Coburg	Coburg		Germany
15	Heart Center Dresden- Universityhospital	Dresden		Germany
16	Elisabeth-Krankenhaus Essen - Contilia Herz- und Gefäßzentrum Essen	Essen		Germany
17	CardioVasculäres Centrum Frankfurt (CVC)	Frankfurt		Germany	60389
18	Asklepios Klinik Nord- Heidberg	Hamburg-Nord		Germany	22417
19	Cardiologicum and Asklepios Klinik Altona	Hamburg		Germany	22041
20	Universitätsklinikum Saarland	Homburg/Saar		Germany	66421
21	Universityhospital	Jena		Germany	07747
22	Heat Center Leipzig	Leipzig		Germany	04289
23	Universityhospital Leipzig	Leipzig		Germany
24	Universityhospital Magdeburg	Magdeburg		Germany
25	Universityhospital Mannheim	Mannheim		Germany
26	Katholisches Klinikum Koblenz (•Montabaur)	Montabaur		Germany
27	Helios Klinikum Pirna	Pirna		Germany	01796
28	Klinikum Vest GmbH	Recklinghausen		Germany

Sponsors and Collaborators

Jena University Hospital

Investigators

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