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

Atrial Fibrillation (AF) Clinical Trial

— CLEARANCE  

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04298723
• Other study ID #: ZKSJ0123_Clearance
• Status: Recruiting
• Phase: N/A
• Start date: June 16, 2020
• Est. completion date: June 2027

Study information

• Verified date: March 2023
• Source: Jena University Hospital
• Contact: Sven Möbius-Winkler, Univ. Prof.
• Phone: +493641-9324503
• Email: sven.moebius-winkler[@]med.uni-jena.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 530
• Est. completion date: June 2027
• Est. primary completion date: June 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrial Fibrillation
• Atrial Fibrillation (AF)
• Hemorrhage
• Intracranial Bleed
• Intracranial Hemorrhages

Intervention

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.

Locations

Country	Name	City	State
Germany	Rhön Klinikum Bad Neustadt	Bad Neustadt an der Saale
Germany	Charité - Universitätsmedizin Berlin (CBF)	Berlin
Germany	Evangelisches Klinikum Bethel Bielefeld	Bielefeld
Germany	Knappschaftskrankenhaus Bottrop Gmbh	Bottrop	Nordrhein Westfahlen
Germany	Klinikum Chemnitz	Chemnitz	Sachsen
Germany	REGIOMED Klinikum Coburg	Coburg
Germany	Klinikum Westfalen GmbH Dortmund	Dortmund
Germany	Heart Center Dresden- Universityhospital	Dresden
Germany	Städtisches Klinikum Friedrichstadt Dresden	Dresden	Sachsen
Germany	Helios Klinikum Erfurt	Erfurt
Germany	Katholisches Krankenhaus "St. Johann Nepomuk"	Erfurt	Thüringen
Germany	Universitätsklinikum Erlangen	Erlangen
Germany	Elisabeth-Krankenhaus Essen - Contilia Herz- und Gefäßzentrum Essen	Essen
Germany	CardioVasculäres Centrum Frankfurt (CVC)	Frankfurt
Germany	Universitätsklinikum der J.W. Goethe-Universität Frankfurt	Frankfurt am main	Hessen
Germany	Universitätsherzzentrum Freiburg - Bad Krozingen	Freiburg	Baden Württemberg
Germany	Klinikum Friedrichshafen GmbH	Friedrichshafen	Baden-Wurttemberg
Germany	SRH Wald-Klinikum Gera GmbH	Gera	Thüringen
Germany	Asklepios Klinik Hamburg Altona	Hamburg
Germany	Asklepios Klinik Hamburg Wandsbek	Hamburg
Germany	Asklepios Klinikum St. Georg	Hamburg
Germany	Cardiologicum Hamburg	Hamburg
Germany	UKE Hamburg	Hamburg
Germany	Asklepios Klinik Nord- Heidberg	Hamburg-Nord
Germany	Universitätsklinikum Saarland	Homburg/Saar
Germany	Klinikum Ingolstadt GmbH	Ingolstadt
Germany	Universityhospital	Jena
Germany	Westpfalz-Klinikum Kaiserslautern	Kaiserslautern
Germany	Universitätsklinikum Schleswig-Holstein (UKSH) Kiel	Kiel
Germany	Heart Center Leipzig	Leipzig
Germany	Klinikum St. Georg gGmbH	Leipzig	Sachsen
Germany	Universityhospital Leipzig	Leipzig
Germany	Universitätsklinikum Schleswig-Holstein (UKSH) Lübeck	Lübeck
Germany	Universityhospital Magdeburg	Magdeburg
Germany	Universityhospital Mannheim	Mannheim
Germany	Johannes Wesling Klinikum Minden	Minden
Germany	Katholisches Klinikum Koblenz (•Montabaur)	Montabaur
Germany	Marienhaus Kliniken GmbH Neuwied	Neuwied
Germany	Helios Klinikum Pirna	Pirna
Germany	Klinikum Vest GmbH	Recklinghausen
Germany	Universitätsklinikum Rostock	Rostock
Germany	HBK Zwickau	Zwickau	Sachsen

Sponsors (1)

Lead Sponsor	Collaborator
Jena University Hospital

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	Combined endpoint: MACCE	Combined endpoint: MACCE (stroke/systemic embolism/cardiovascular death/myocardial infarction)	up to 3 years after randomization
Secondary	Mortality	Mortality (including all-cause death, cardiovascular death, non- cardiovascular	up to 3 years after randomization
Secondary	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	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
Secondary	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
Secondary	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
Secondary	Myocardial infarction	A detailed description of the criteria for myocardial infarction can be found in the study protocol.	up to 3 years after randomization
Secondary	Hospitalization for bleeding or cardiovascular event	Hospitalization for bleeding or cardiovascular event	up to 3 years after randomization
Secondary	Intracranial bleeding	Intracranial bleeding	up to 3 years after randomization