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

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.

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.

Study Overview

• Status: Recruiting
• Conditions: Intracranial Hemorrhages; Atrial Flutter; Atrial Fibrillation (AF)
• Intervention / Treatment: Device: Percutaneous closure of the LAA (Watchman / Watchman FLX)

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 Type: Interventional
• Enrollment (Estimated): 530
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sven Möbius-Winkler, Prof. Dr.; Phone Number: +4936419324503; Email: Sven.Moebius-Winkler@med.uni-jena.de
• Study Contact Backup: Name: Marcus Winter; Phone Number: +4936419396648; Email: marcus.winter@med.uni-jena.de

Study Locations

• Germany
  • Baden-Wurttemberg
    • Mannheim, Baden-Wurttemberg, Germany, 68167
      • Recruiting
      • University Hospital Mannheim
      • Contact: Ibrahim Akin, Prof. Dr.; Phone Number: +496213835229; Email: ibrahim.akin@umm.de
  • Bavaria
    • Bad Neustadt an der Saale, Bavaria, Germany, 97616
      • Active, not recruiting
      • Rhön-Klinikum Campus Bad Neustadt
    • Burgau, Bavaria, Germany, 89331
      • Active, not recruiting
      • Therapiezentrum Burgau
    • Coburg, Bavaria, Germany, 96450
      • Recruiting
      • Regiomed Klinikum Coburg
      • Contact: Steffen Schnupp, Dr.; Phone Number: +4995612233201; Email: steffen.schnupp@regiomed-kliniken.de
    • Erlangen, Bavaria, Germany, 91054
      • Recruiting
      • Universitätsklinikum Erlangen
      • Contact: Bernd Kallmünzer, Prof. Dr.; Phone Number: +4991318534306; Email: bernd.kallmuenzer@uk-erlangen.de
    • Ingolstadt, Bavaria, Germany, 85049
      • Recruiting
      • Klinikum Ingolstadt
      • Contact: Blerim Luani, PD Dr.; Phone Number: +498418802101; Email: blerim.luani@klinikum-ingolstadt.de
    • Rosenheim, Bavaria, Germany, 83022
      • Active, not recruiting
      • RoMed Klinikum
  • City state of Hamburg
    • Hamburg, City state of Hamburg, Germany, 22041
      • Recruiting
      • Cardiologicum Hamburg
      • Contact: Martin Bergmann, Prof. Dr.; Phone Number: +49401818811221; Email: mar.bergmann@asklepios.com
    • Hamburg, City state of Hamburg, Germany, 22043
      • Recruiting
      • Asklepios Klinik Wandsbek
      • Contact: Tudor C Pörner, PD Dr.; Phone Number: +49401818831051; Email: t.poerner@asklepios.com
    • Hamburg, City state of Hamburg, Germany, 22417
      • Recruiting
      • Asklepios Klinik Nord Heidberg
      • Contact: Alexander Ghanem, Prof. Dr.; Phone Number: +49401818873286; Email: a.ghanem@asklepios.com
    • Hamburg, City state of Hamburg, Germany, 22763
      • Recruiting
      • Asklepios Klinik Altona
      • Contact: Felix Meincke, Dr.; Phone Number: +49401818818902; Email: f.meincke@asklepios.com
  • Hesse
    • Rotenburg an der Fulda, Hesse, Germany, 44137
      • Active, not recruiting
      • Herz-Kreislauf-Zentrum
  • North Rhine-Westphalia
    • Bielefeld, North Rhine-Westphalia, Germany, 33617
      • Recruiting
      • Evangelisches Klinikum Bethel
      • Contact: Wladimir Tschichow, Dr.; Phone Number: +4952177277672; Email: Wladimir.Tschishow@evkb.de
    • Dortmund, North Rhine-Westphalia, Germany, 44137
      • Active, not recruiting
      • Klinikum Dortmund
    • Dortmund, North Rhine-Westphalia, Germany, 44309
      • Recruiting
      • Knappschaft Kliniken
  • Rhineland-Palatinate
    • Kaiserslautern, Rhineland-Palatinate, Germany, 67655
      • Recruiting
      • Westpfalz-Klinikum
      • Contact: Burghard Schumacher, Prof. Dr.; Phone Number: +496312031255; Email: bschumacher@westpfalz-klinikum.de
    • Koblenz, Rhineland-Palatinate, Germany, 56073
      • Recruiting
      • Katholisches Klinikum Koblenz • Montabaur
      • Contact: Jiangtao Yu, PD Dr.; Phone Number: +492614963132; Email: j.yu@kk-km.de
  • Saxony
    • Chemnitz, Saxony, Germany, 09113
      • Recruiting
      • Klinikum Chemnitz
      • Contact: Karim Ibrahim, Prof. Dr.; Phone Number: +4937133342211; Email: karim.ibrahim@skc.de
    • Dresden, Saxony, Germany, 01307
      • Recruiting
      • Dresden Heart Center
      • Contact: Norman Mangner, Prof. Dr.; Phone Number: +493514501701; Email: norman.mangner@tu-dresden.de
    • Leipzig, Saxony, Germany, 04103
      • Recruiting
      • University Hospital Leipzig
      • Contact: Karsten Lenk, PD Dr.; Phone Number: +493419720956; Email: Karsten.Lenk@medizin.uni-leipzig.de
    • Leipzig, Saxony, Germany, 04289
      • Recruiting
      • Heart Center Leipzig
      • Contact: Marcus Sandri, PD Dr.; Phone Number: +49341865252035; Email: marcus.sandri@medizin.uni-leipzig.de
    • Leipzig, Saxony, Germany, 04129
      • Recruiting
      • Klinikum St. Georg
      • Contact: Norbert Klein, PD Dr.; Phone Number: +493419092300; Email: norbert.klein@sanktgeorg.de
    • Pirna, Saxony, Germany, 01796
      • Recruiting
      • Helios Klinikum Pirna
      • Contact: Steffen Schön, Prof. Dr.; Phone Number: +49350171185211; Email: Steffen.Schoen@helios-gesundheit.de
    • Zwickau, Saxony, Germany, 08060
      • Recruiting
      • Heinrich-Braun-Klinikum (HBK)
      • Contact: Holger H Sigusch, PD Dr.; Phone Number: +49375512219; Email: holger.sigusch@hbk-zwickau.de
  • Saxony-Anhalt
    • Magdeburg, Saxony-Anhalt, Germany, 68167
      • Recruiting
      • University Hospital Magdeburg
      • Contact: Rüdiger Braun-Dullaeus, Prof. Dr.; Phone Number: +493916713203; Email: r.braun-dullaeus@med.ovgu.de
  • Schleswig-Holstein
    • Lübeck, Schleswig-Holstein, Germany, 23538
      • Recruiting
      • Universitätsklinikum Schleswig-Holstein (UKSH)
      • Contact: Ingo Eitel, Prof. Dr.; Phone Number: +4945150044504; Email: Ingo.Eitel@uksh.de
  • State of Berlin
    • Berlin, State of Berlin, Germany, 12203
      • Recruiting
      • Charité - Universitätsmedizin Berlin (CBF)
      • Contact: Carsten Skurk, Prof. Dr.; Phone Number: +4930450513725; Email: carsten.skurk@charite.de
    • Berlin, State of Berlin, Germany, 13353
      • Active, not recruiting
      • Charité - Universitätsmedizin Berlin (CVK
  • Thuringia
    • Erfurt, Thuringia, Germany, 99089
      • Recruiting
      • HELIOS Klinikum Erfurt
      • Contact: Frank Steinborn, Dr.; Phone Number: +493617812481; Email: frank.steinborn@helios-gesundheit.de
    • Jena, Thuringia, Germany, 07747
      • Recruiting
      • University Hospital Jena
      • Contact: Sissy Grund; Email: sissy.grund@med.uni-jena.de
      • Contact: Sven Möbius-Winkler, Prof. Dr.; Phone Number: +4936419324503; Email: Sven.Moebius-Winkler@med.uni-jena.de
• Poland
  • Greater Poland Voivodeship
    • Poznan, Greater Poland Voivodeship, Poland, 61-848
      • Not yet recruiting
      • Uniwersytecki Szpital Kliniczny w Poznaniu
      • Contact: Marek Grygier, Prof. Dr.; Email: mgrygier@wp.pl
  • Silesian Voivodeship
    • Bielsko-Biala, Silesian Voivodeship, Poland, 43-316
      • Not yet recruiting
      • Polsko-Amerykanskie Kliniki Serca
      • Contact: Krzysztof Milewski, Prof. Dr.; Email: Krzysztof.Milewski@ahop.pl
    • Katowice, Silesian Voivodeship, Poland, 40-635
      • Recruiting
      • Górnośląskim Centrum Medycznym
      • Contact: Wojciech Wojakowski, Prof. Dr.; Phone Number: +48604188669; Email: w.wojakowski@sum.edu.pl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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 (Watchman or Watchman FLX) 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)

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary Safety Endpoints	Periprocedural complications within 7 days combined from: pericardial effusion, stroke, major bleeding, device embolization, intracranial bleeding, air embolism; Device related thrombus/fracture/erosion; Vascular access related complications requiring intervention; Procedure-related death; Technical and procedural success of device implantation (LAA closure); Post-procedure infection rate; Periprocedural outcomes at 7 and 45 calendar days after implantation; Bleeding requiring transfusion (BARC 2-5); Air embolism	As indicated within description.

Collaborators and Investigators

• Sponsor: Jena University Hospital
• Collaborators: KCRI
• Investigators: Principal Investigator: P. Christian Schulze, Prof. Dr., Department of Internal Medicine I, Jena University Hospital; Principal Investigator: Sven Möbius-Winkler, Prof. Dr., Department of Internal Medicine I, Jena University Hospital; Principal Investigator: Albrecht Günther, Dr., Department of Neurology, Jena University Hospital; Principal Investigator: Christian Senft, Prof. Dr., Department of Neurosurgery, Jena University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2020
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: March 1, 2020
• First Submitted That Met QC Criteria: March 5, 2020
• First Posted (Actual): March 6, 2020

Study Record Updates

• Last Update Posted (Estimated): September 2, 2025
• Last Update Submitted That Met QC Criteria: August 25, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Atrial Fibrillation; Anticoagulation; Intracranial Hemorrhage; LAA Occlusion; Intracranial Bleeding
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Hemorrhage; Pathological Conditions, Signs and Symptoms; Atrial Fibrillation; Atrial Flutter; Intracranial Hemorrhages
• Other Study ID Numbers: ZKSJ0123_Clearance

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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