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: Atrial Fibrillation (AF); Intracranial Bleed
• 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 (Anticipated): 530
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sven Möbius-Winkler, Univ. Prof.; Phone Number: +493641-9324503; Email: sven.moebius-winkler@med.uni-jena.de
• Study Contact Backup: Name: P. Christian Schulze, Prof. Dr.; Email: christian.schulze@med.uni-jena.de

Study Locations

• Germany
  • Bad Neustadt an der Saale, Germany
    • Not yet recruiting
    • Rhön Klinikum Bad Neustadt
    • Contact: Hassan Soda, Dr.; Email: Hassan.Soda@campus-nes.de
  • Berlin, Germany, 12203
    • Recruiting
    • Charité - Universitätsmedizin Berlin (CBF)
    • Contact: Carsten Skurk, Prof. Dr.; Email: carsten.skurk@charite.de
  • Bielefeld, Germany, 33617
    • Recruiting
    • Evangelisches Klinikum Bethel Bielefeld
    • Contact: Wladimir Tschichow, MD; Phone Number: 0049-521-77277672; Email: Wladimir.Tschishow@evkb.de
  • Coburg, Germany
    • Not yet recruiting
    • REGIOMED Klinikum Coburg
    • Contact: Steffen Schnupp, MD; Phone Number: +49 9561 22 7248; Email: steffen.schnuppl@klinikum-coburg.de
  • Dortmund, Germany, 44309
    • Recruiting
    • Klinikum Westfalen GmbH Dortmund
    • Contact: Ahmed Farah, Dr.; Email: Ahmed.Farah@klinikum-westfalen.de
  • Dresden, Germany
    • Recruiting
    • Heart Center Dresden- Universityhospital
    • Contact: Norman Mangner, MD; Phone Number: +49 351 450 25 297; Email: Norman.Mangner@mailbox.tu-dresden.de
  • Erfurt, Germany, 99089
    • Recruiting
    • Helios Klinikum Erfurt
    • Contact: Anja Schade, Dr.; Email: anja.schade@helios-gesundheit.de
  • Erlangen, Germany, 91054
    • Recruiting
    • Universitätsklinikum Erlangen
    • Contact: Joji Kuramatsu, PD Dr.; Email: Joji.Kuramatsu@uk-erlangen.de
  • Essen, Germany
    • Not yet recruiting
    • Elisabeth-Krankenhaus Essen - Contilia Herz- und Gefäßzentrum Essen
    • Contact: Thomas Schmitz, Dr.; Phone Number: +49 201 897 0; Email: t.schmitz@contilia.de
  • Frankfurt, Germany, 60389
    • Not yet recruiting
    • CardioVasculäres Centrum Frankfurt (CVC)
    • Contact: Horst Sievert, MD; Phone Number: 0049-69 46 03 13 40; Email: horstsievertmd@aol.com
  • Hamburg, Germany, 22041
    • Recruiting
    • Cardiologicum Hamburg
    • Contact: Martin Bergmann, MD; Phone Number: 0049-40 682806-74; Email: studie.bergmann@cardiologicum.net
  • Hamburg, Germany, 20099
    • Not yet recruiting
    • Asklepios Klinikum St. Georg
    • Contact: Stephan Willems, Prof. Dr.; Email: s.willems@asklepios.com
  • Hamburg, Germany, 20246
    • Not yet recruiting
    • UKE Hamburg
    • Contact: Götz Thomalla, Prof. Dr.; Email: thomalla@uke.de
  • Hamburg, Germany, 22043
    • Recruiting
    • Asklepios Klinik Hamburg Wandsbek
    • Contact: Tudor C. Pörner, PD Dr.; Email: t.poerner@asklepios.com
  • Hamburg, Germany, 22763
    • Recruiting
    • Asklepios Klinik Hamburg Altona
    • Contact: Felix Meincke, Dr.; Email: f.meincke@asklepios.com
  • Hamburg-Nord, Germany, 22417
    • Recruiting
    • Asklepios Klinik Nord- Heidberg
    • Contact: Alexander Ghanem, MD; Phone Number: 0049-40 181887-3286; Email: a.ghanem@asklepios.com
  • Homburg/Saar, Germany, 66421
    • Not yet recruiting
    • Universitätsklinikum Saarland
    • Contact: Christian Ukena, MD; Phone Number: 06841 1615922; Email: Christian.ukena@uks.eu
  • Ingolstadt, Germany, 85049
    • Recruiting
    • Klinikum Ingolstadt GmbH
    • Contact: Silke Gläser
  • Jena, Germany, 07747
    • Recruiting
    • Universityhospital
    • Contact: Sven Möbius-Winkler, MD; Phone Number: 0049-3641-9324503; Email: Sven.Moebius-Winkler@med.uni-jena.de
    • Contact: Sissy Grund; Email: sissy.grund@med.uni-jena.de
  • Kaiserslautern, Germany, 67655
    • Not yet recruiting
    • Westpfalz-Klinikum Kaiserslautern
    • Contact: Burghard Schumacher, Prof. Dr.; Email: bschumacher@westpfalz-klinikum.de
  • Kiel, Germany, 24105
    • Not yet recruiting
    • Universitätsklinikum Schleswig-Holstein (UKSH) Kiel
    • Contact: Mohammed Saad, PD Dr.; Email: mohammed.saad@uksh.de
  • Leipzig, Germany, 04289
    • Recruiting
    • Heart Center Leipzig
    • Contact: Marcus Sandri, MD; Phone Number: +49 341 865252035; Email: marcus.sandri@medizin.uni-leipzig.de
  • Leipzig, Germany
    • Recruiting
    • Universityhospital Leipzig
    • Contact: Karsten Lenk, MD; Phone Number: +49 341 9720956; Email: Karsten.Lenk@medizin.uni-leipzig.de
    • Contact: Dirk Lindner, MD; Phone Number: +49 341 9717943; Email: dirk.lindner@medizin.uni-leipzig.de
  • Lübeck, Germany, 23538
    • Recruiting
    • Universitätsklinikum Schleswig-Holstein (UKSH) Lübeck
    • Contact: Ingo Eitel, Prof. Dr.; Email: Ingo.Eitel@uksh.de
  • Magdeburg, Germany
    • Recruiting
    • Universityhospital Magdeburg
    • Contact: Rüdiger CC Braun-Dulleus, MD; Phone Number: +49-391-67-13203; Email: r.braun-dullaeus@med.ovgu.de
    • Contact: Jens Neumann, MD; Phone Number: +49 391 67 15001; Email: jens.neumann@med.ovgu.de
  • Mannheim, Germany
    • Recruiting
    • Universityhospital Mannheim
    • Contact: Ibrahim Akin, MD; Phone Number: +49 621383 1492; Email: ibrahim.akin@umm.de
  • Minden, Germany, 32429
    • Not yet recruiting
    • Johannes Wesling Klinikum Minden
    • Contact: Marcus Wiemer, Prof. Dr.; Email: marcus.wiemer@muehlenkreiskliniken.de
  • Montabaur, Germany
    • Recruiting
    • Katholisches Klinikum Koblenz (•Montabaur)
    • Contact: Jiangtao Yu, MD; Phone Number: +49 0261 4963132; Email: j.yu@kk-km.de
  • Neuwied, Germany, 56564
    • Not yet recruiting
    • Marienhaus Kliniken GmbH Neuwied
    • Contact: Burkhard Hügl, Dr.; Email: Burkhard.Huegl@marienhaus.de
  • Pirna, Germany, 01796
    • Recruiting
    • Helios Klinikum Pirna
    • Contact: Steffen Schön, MD; Phone Number: (03501) 71 18-52 11; Email: Steffen.Schoen@helios-gesundheit.de
  • Recklinghausen, Germany
    • Not yet recruiting
    • Klinikum Vest GmbH
    • Contact: Frank Weidemann, MD; Phone Number: 02361 56 3401; Email: frank.weidemann@klinikum-vest.de
  • Rostock, Germany, 18057
    • Not yet recruiting
    • Universitätsklinikum Rostock
    • Contact: Hüseyin Ince, Prof. Dr.; Email: Hueseyin.Ince@med.uni-rostock.de
  • Baden Württemberg
    • Freiburg, Baden Württemberg, Germany, 79106
      • Not yet recruiting
      • Universitätsherzzentrum Freiburg - Bad Krozingen
      • Contact: Sebastian Grundmann, MD; Phone Number: 0761 270-34010; Email: sebastian.grundmann@universitaetsherzzentrum.de
  • Baden-Wurttemberg
    • Friedrichshafen, Baden-Wurttemberg, Germany, 88048
      • Recruiting
      • Klinikum Friedrichshafen GmbH
      • Contact: Jochen Wöhrle, MD; Phone Number: 07541 96 251; Email: j.woehrle@klinikum-fn.de
      • Sub-Investigator: Julia Seeger, MD
  • Hessen
    • Frankfurt am main, Hessen, Germany, 60590
      • Not yet recruiting
      • Universitätsklinikum der J.W. Goethe-Universität Frankfurt
      • Contact: Mariuca Vasa-Nicotera, MD; Phone Number: 069v630180440; Email: mariuca.vasa-nicotera@kgu.de
  • Nordrhein Westfahlen
    • Bottrop, Nordrhein Westfahlen, Germany, 46242
      • Not yet recruiting
      • Knappschaftskrankenhaus Bottrop GmbH
      • Contact: Martin Christ, MD; Phone Number: 02041 15-1051; Email: martin.christ@kk-Bottrop.de
  • Sachsen
    • Chemnitz, Sachsen, Germany, 09116
      • Not yet recruiting
      • Klinikum Chemnitz
      • Contact: Karim Ibrahim, MD; Phone Number: 0371 333 422 11; Email: karim-ibrahim@skc.de
    • Dresden, Sachsen, Germany, 01067
      • Not yet recruiting
      • Städtisches Klinikum Friedrichstadt Dresden
      • Contact: Sebastian Schellong, Prof. Dr.; Email: Sebastian.Schellong@klinikum-dresden.de
    • Leipzig, Sachsen, Germany, 04129
      • Recruiting
      • Klinikum St. Georg gGmbH
      • Contact: Norbert Klein, MD; Phone Number: 0341/909 2300; Email: norbert.klein@sanktgeorg.de
    • Zwickau, Sachsen, Germany, 08060
      • Recruiting
      • HBK Zwickau
      • Contact: Holger H. Sigusch, MD; Phone Number: 0375 512219; Email: holger.sigusch@hbk-zwickau.de
  • Thüringen
    • Erfurt, Thüringen, Germany, 99097
      • Not yet recruiting
      • Katholisches Krankenhaus "St. Johann Nepomuk"
      • Contact: Henning Ebelt, MD; Phone Number: 0361 6541111; Email: hebelt@kkh-erfurt.de
    • Gera, Thüringen, Germany, 07548
      • Not yet recruiting
      • SRH Wald-Klinikum Gera GmbH
      • Contact: Martin Winterhalter, MD; Phone Number: 0 365 828 1731; Email: winterhalter.studienzentrum@wkg.srh.de

Participation Criteria

Eligibility Criteria

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

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 (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)

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

Collaborators and Investigators

• Sponsor: Jena University Hospital
• Investigators: 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; Principal Investigator: Sven Möbius-Winkler, Univ. Prof., Department of Internal Medicine I, Jena University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2020
• Primary Completion (Anticipated): June 1, 2027
• Study Completion (Anticipated): June 1, 2027

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 (Actual): March 17, 2023
• Last Update Submitted That Met QC Criteria: March 15, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Atrial Fibrillation; Anticoagulation; LAA occlusion; Intracranial bleeding
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Hemorrhage; 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