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Left Atrial Appendage CLOSURE in Patients With Atrial Fibrillation Compared to Medical Therapy (CLOSURE-AF)

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ClinicalTrials.gov Identifier: NCT03463317
Recruitment Status : Recruiting
First Posted : March 13, 2018
Last Update Posted : March 13, 2018
Sponsor:
Collaborators:
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Atrial Fibrillation Network
Stiftung Institut fuer Herzinfarktforschung
Information provided by (Responsible Party):
Ulf Landmesser, Charite University, Berlin, Germany

Brief Summary:
The study goal is to determine the clinical benefit of percutaneous catheter‐based left atrial appendage (LAA) closure in patients with non-valvular atrial fibrillation (NVAF) at high risk of stroke (CHA2DS2‐VASc Score ≥2) as well as high risk of bleeding as compared to best medical care (including a [non-vitamin K] oral anticoagulant [(N)OAC] when eligible).

Condition or disease Intervention/treatment Phase
Atrial Fibrillation Device: CE-mark approved LAA closure devices Drug: Acetylsalicylic acid Drug: Clopidogrel Drug: Dabigatran Drug: Rivaroxaban Drug: Apixaban Drug: Edoxaban Drug: Phenprocoumon Drug: Warfarin Phase 4

Detailed Description:

The individualized therapy with oral anticoagulants is considered to be an essential preventive therapy in patients with atrial fibrillation. The risk of stroke can be reduced by approximately 65%. However, long-term anticoagulation therapy also increases the risk of major bleeding.

A significant proportion of patients at high risk of stroke do not tolerate long-term anticoagulation due to various relative or absolute contraindications. As demonstrated in previous studies with non-vitamin K antagonist anticoagulants (NOAK), 20-25% of patients were unable to tolerate long-term anticoagulation therapy.

For this reason, additional therapeutic approaches for stroke prevention in patients with atrial fibrillation have been developed.

A promising approach is catheter-based closure of the left atrial appendage, because more than 90% of cardiac thrombi in patients with non-valvular atrial fibrillation are detected in the left atrial appendage. Recent registry studies show that the safety of LAA occluder implantation is promising. However, further scientific studies are required, in order to explore more benefits of the underlying method and eligible patients for implantation.

Study objectives:

The study goal is to determine the clinical benefit of percutaneous catheter‐based left atrial appendage (LAA) closure in patients with non-valvular atrial fibrillation (NVAF) at high risk of stroke (CHA2DS2‐VASc Score ≥2) as well as high risk of bleeding as compared to best medical care (including a [non-vitamin K] oral anticoagulant [(N)OAC] when eligible).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1512 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Event-driven group-sequential design, non-inferiority test, if significant followed by superiority test
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Left Atrial Appendage CLOSURE in Patients With Atrial Fibrillation at High Risk of Stroke and Bleeding Compared to Medical Therapy: a Prospective Randomized Clinical Trial
Actual Study Start Date : February 28, 2018
Estimated Primary Completion Date : February 28, 2021
Estimated Study Completion Date : February 28, 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: LAA closure group
Left atrial appendage closure by use of CE-mark approved LAA closure devices followed by post procedure treatment (antiplatelet therapy e.g. acetylsalicylic acid, clopidogrel)
Device: CE-mark approved LAA closure devices
LAA closure with post procedure treatment

Drug: Acetylsalicylic acid
post procedure treatment according to the physicians (recommendation are made in the protocol); oral anticoagulations are not prescribed in this group
Other Name: ASS

Drug: Clopidogrel
post procedure treatment according to the physicians (recommendation are made in the protocol); oral anticoagulations are not prescribed in this group

Active Comparator: Best medical care group
No left atrial appendage closure. Treatment with best medical care (NOACs (dabigatran, rivaroxaban, apixaban, edoxaban) or VKA (phenprocoumon, warfarin)
Drug: Dabigatran
Patients allocated to the best medical care group receive either NOAC therapy or VKA
Other Name: Pradaxa

Drug: Rivaroxaban
Patients allocated to the best medical care group receive either NOAC therapy or VKA
Other Name: Xarelto

Drug: Apixaban
Patients allocated to the best medical care group receive either NOAC therapy or VKA
Other Name: Eliquis

Drug: Edoxaban
Patients allocated to the best medical care group receive either NOAC therapy or VKA
Other Name: Lixiana

Drug: Phenprocoumon
Patients allocated to the best medical care group receive either NOAC therapy or VKA
Other Name: Marcumar

Drug: Warfarin
Patients allocated to the best medical care group receive either NOAC therapy or VKA
Other Name: Coumadin




Primary Outcome Measures :
  1. Primary endpoint (net clinical benefit) [ Time Frame: follow-up: 24 months ]

    Survival time free of the composite of:

    • Stroke (including ischemic or hemorrhagic stroke)
    • Systemic embolism
    • Major bleeding (BARC type 3‐5)
    • Cardiovascular or unexplained death


Secondary Outcome Measures :
  1. Primary endpoint events per year [ Time Frame: follow-up: 24 months ]
    Assessed by the number of primary endpoint events during the follow-up period.

  2. Combined endpoint: MACCE [ Time Frame: follow-up: 24 months ]
    (stroke/systemic embolism/cardiovascular death/myocardial infarction)

  3. Mortality [ Time Frame: follow-up: 24 months ]
    (including all-cause death, cardiovascular death, non‐ cardiovascular death, peri‐procedural death)

  4. Major bleeding [ Time Frame: follow-up: 24 months ]
    BARC type 3‐5 (according to the BARC (Bleeding Academic Research Consortium) definition for bleeding).

  5. Systemic embolism [ Time Frame: follow-up: 24 months ]
    Assessed by the rate of systemic embolism during the follow-up period.

  6. Ischemic/hemorrhagic stroke including transient ischemic attack [ Time Frame: follow-up: 24 months ]
    (TIA: defined as neurological deficit of vascular origin lasting ≤24 hours without corresponding brain lesion). Stroke and TIA will be assessed according to 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/AmericanHeart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). J Am Coll Cardiol, 2015.

  7. Myocardial infarction [ Time Frame: follow-up: 24 months ]
    Myocardial infarction will be assessed according to the third universal definition of myocardial infarction (Eur Heart J, 2012).

  8. Hospitalization for bleeding or cardiovascular event [ Time Frame: follow-up: 24 months ]
    Hospitalization for bleeding or cardiovascular event will be assessesd according to 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/AmericanHeart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). J Am Coll Cardiol, 2015.

  9. Changes in cognitive function [ Time Frame: follow-up: 24 months ]
    assessed by MoCA (= Montreal Cognitive Assessment). The MoCA will be used to assess the cognition of patients. Minimum score: 0 points, maximum score: 30 points.

  10. Changes in health-related quality of life [ Time Frame: follow-up: 24 months ]
    assessed by EQ-5D-5L (German Version 1.0). The EQ-5D-5L consists of a 5-question multi-attribute questionnaire and a visual analogue self-rating scale. Minimum score: 0, maximum score: 100.

  11. Device-related complications [ Time Frame: follow-up: 24 months ]
    The device-associated complications will be assesd by device thrombus, device embolization, device fracture/erosion, clinically significant device interference with surrounding structure, device infection/endocarditis/pericarditis, device allergy (according to the percutaneous left atrial appendage occlusion: the Munich Consensus document on definitions, endpoints, and data collection requirements for clinical studies. Europace, 2016)

  12. Peri-procedural outcomes [ Time Frame: 7 and 30 calendar days ]
    The peri-procedural outcomes will be assessed at 7 and 30 calendar days after implantation. The following will be evaluated: technical and procedural success of device implantation, vascular access related complications requiring intervention, procedure related death and post-procedure infection rate, pericardial tamponade/effusion, major bleeding requiring transfusion (BARC 3-5), pulmonary embolism, air embolism, procedure-related stroke/TIA, device embolization (according to the percutaneous left atrial appendage occlusion: the Munich consensus document on definitions, endpoints, and data collection requirements for clinical studies. Europace, 2016).



Information from the National Library of Medicine

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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

Key Inclusion Criteria:

  • Age ≥18 years
  • Documented atrial fibrillation (paroxysmal, persistent, long-standing persistent or permanent)
  • CHA2DS2VASc-Score ≥2
  • High risk of bleeding under oral anticoagulation or contraindication for (N)OAC therapy, in particular patients with at least one of the following conditions:

    1. HAS-BLED-Score ≥3
    2. Prior intracranial/intraspinal bleed (BARC: type 3c)
    3. Hemorrhagic/bleeding complication fulfilling BARC type 3a or 3b: gastrointestinal tract, genitourinary tract or respiratory tract bleeding, where the patient is considered to be at a persistently increased risk of bleeding, e.g. the cause of bleeding cannot be successfully eliminated
    4. Chronic kidney disease with eGFR <30 ml/min/1.73m2
  • Subject eligible for an LAA occluder device

Key Exclusion Criteria:

  • Absolute contraindication to acetylsalicylic acid (ASA)
  • Comorbidities other than AF requiring chronic (N)OAC therapy, e.g. mechanical heart valve prosthesis
  • Symptomatic carotid disease (if not treated)
  • Complex aortic atheroma with mobile plaque (Kronzon classification grade V)
  • Heart transplant
  • Active infection or active endocarditis or other infections producing bacteremia
  • Cardiac Tumor
  • Severe liver failure (Child-Pugh class C or liver failure with coagulopathy)
  • Severe renal failure (GFR <15 ml/min/1.73m2)
  • Known terminal disease with life expectancy <1 year (including those with end-stage heart failure)

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): NCT03463317


Contacts
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Contact: Johannes J Hartung, MD +49 30 450 513 706 johannes-jakob.hartung@charite.de

Locations
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Germany
Vivantes Klinik Am Urban, Kardiologie Not yet recruiting
Berlin, Germany, 10967
Charité Universitätsmedizin Berlin, CBF, Kardiologie Recruiting
Berlin, Germany, 12203
Vivantes Klinikum Neukölln, Kardiologie Not yet recruiting
Berlin, Germany, 12351
DRK-Kliniken Berlin Köpenick, Klinik für Innere Medizin - Schwerpunkt Kardiologie und Angiologie Not yet recruiting
Berlin, Germany, 12559
Charité Universitätsmedizin Berlin, CVK, Kardiologie Recruiting
Berlin, Germany, 13353
Deutsches Herzzentrum Berlin, Innere Medizin - Kardiologie Not yet recruiting
Berlin, Germany, 13353
Klinikum Brandenburg GmbH, Zentrum für Innere Medizin I Not yet recruiting
Brandenburg, Germany, 14770
Gesundheit Nord gGmbH, Klinikum Links der Weser, Klinik für Kardiologie und Angiologie Not yet recruiting
Bremen, Germany, 28277
Medizinisches Versorgungszentrum am Küchenwald GmbH Not yet recruiting
Chemnitz, Germany, 09113
Klinikum Lippe, Klinik für Kardiologie, Angiologie und Internistische Intensivmedizin Not yet recruiting
Detmold, Germany, 32756
Katholisches Krankenhaus "St. Johann Nepomuk", Klinik für Innere Medizin II - Kardiologie Not yet recruiting
Erfurt, Germany, 99097
Universitätsklinikum Erlangen, Medizinische Klinik II - Kardiologie und Angiologie Not yet recruiting
Erlangen, Germany, 91054
Alfried Krupp Krankenhaus Not yet recruiting
Essen, Germany, 45131
Universität Greifswald, Klinik für Innere Medizin B - Kardiologie Not yet recruiting
Greifswald, Germany, 17475
Asklepios Klinik St. Georg Hamburg, Kardiologie Not yet recruiting
Hamburg, Germany, 20099
Asklepios Klinik Barmbek, I. Med. Abteilung - Kardiologie Not yet recruiting
Hamburg, Germany, 22291
Klinikum Herford, Med. Klinik III/ Kardiologie Recruiting
Herford, Germany, 32049
Westpfalz-Klinikum GmbH, Klinik für Innere Medizin II - Kardiologie Not yet recruiting
Kaiserslautern, Germany, 67655
UKSH - Campus Kiel, Medizinische Klinik III - Kardiologie, Angiologie, Intensivmedizin Not yet recruiting
Kiel, Germany, 24105
UKSH - Universitäres Herzzentrum Lübeck, Medizinische Klinik II - Kardiologie, Angiologie, Intensivmedizin Not yet recruiting
Lübeck, Germany, 23538
Städt. Klinikum Lüneburg gGmbH, Klinik für Kardiologie und Internistische Intensivmedizin Not yet recruiting
Lüneburg, Germany, 21339
Universitätsmedizin Mainz, Kardiologie I - Zentrum für Kardiologie Not yet recruiting
Mainz, Germany, 55131
Universitätsmedizin Mannheim, I. Medizinische Klinik - Kardiologie, Angiologie, Intensivmedizin Not yet recruiting
Mannheim, Germany, 68167
Deutsches Herzzentrum München, Klinik an der TU München Not yet recruiting
München, Germany, 80636
LMU Universität München, Medizinische Klinik und Poliklinik I Not yet recruiting
München, Germany, 81377
Peter Osypka Herzzentrum München Not yet recruiting
München, Germany, 81379
Städt. Klinikum München GmbH, Klinikum Neuperlach, Klinik für Kardiologie, Pneumologie, intern. Intensivmedizin Not yet recruiting
München, Germany, 81737
Robert-Bosch-Krankenhaus, Abteilung für Kardiologie Not yet recruiting
Stuttgart, Germany, 70376
Universitätsklinik Ulm, Klinik für Innere Medizin II - Kardiologie Not yet recruiting
Ulm, Germany, 89081
Heinrich-Braun-Klinikum Zwickau, Klinik für Innere Medizin I - Kardiologie, Angiologie, Intern. Internsivmedizin Not yet recruiting
Zwickau, Germany, 08060
Sponsors and Collaborators
Charite University, Berlin, Germany
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Atrial Fibrillation Network
Stiftung Institut fuer Herzinfarktforschung
Investigators
Layout table for investigator information
Study Chair: Ulf Landmesser, MD Charite University, Berlin, Germany

Additional Information:
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Responsible Party: Ulf Landmesser, Prof. Dr., Charite University, Berlin, Germany
ClinicalTrials.gov Identifier: NCT03463317     History of Changes
Other Study ID Numbers: CLOSURE-AF-DZHK16
First Posted: March 13, 2018    Key Record Dates
Last Update Posted: March 13, 2018
Last Verified: March 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ulf Landmesser, Charite University, Berlin, Germany:
Atrial Fibrillation
Anticoagulation
Left atrial appendage closure
Stroke
Additional relevant MeSH terms:
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Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Aspirin
Warfarin
Rivaroxaban
Dabigatran
Apixaban
Edoxaban
Phenprocoumon
Clopidogrel
Platelet Aggregation Inhibitors
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anticoagulants
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics