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

Sponsor
Charite University, Berlin, Germany (Other)
Overall Status
Recruiting
CT.gov ID
NCT03463317
Collaborator
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK) (Other), Atrial Fibrillation Network (Other), Stiftung Institut fuer Herzinfarktforschung (Other)
1,512
Enrollment
26
Locations
2
Arms
84
Anticipated Duration (Months)
58.2
Patients Per Site
0.7
Patients Per Site Per Month

Study Details

Study Description

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
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).

Study Design

Study Type:
Interventional
Anticipated 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 testEvent-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 :
Feb 28, 2018
Anticipated Primary Completion Date :
Sep 1, 2023
Anticipated Study Completion Date :
Mar 1, 2025

Arms and Interventions

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 anticoagulation is not prescribed in this group
Other Names:
  • ASS

    • Drug: Clopidogrel
    post procedure treatment according to the physicians (recommendation are made in the protocol); oral anticoagulation is 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 Names:
  • Pradaxa®

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

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

    • Drug: Edoxaban
    Patients allocated to the best medical care group receive either NOAC therapy or VKA
    Other Names:
  • LIXIANA®

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

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

    		•

    Outcome Measures

    Primary Outcome Measures

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

      assessed by the number of primary endpoint events during the follow-up period.

    2. Combined endpoint: MACCE [follow-up: 24 months]

      (stroke/systemic embolism/cardiovascular death/myocardial infarction)

    3. Mortality [follow-up: 24 months]

      (including all-cause death, cardiovascular death, non- cardiovascular death, peri-procedural death)

    4. Major bleeding [follow-up: 24 months]

      BARC type 3-5 (according to the BARC (Bleeding Academic Research Consortium) definition for bleeding).

    5. Systemic embolism [follow-up: 24 months]

      assessed by the rate of systemic embolism during the follow-up period.

    6. Ischemic/hemorrhagic stroke including transient ischemic attack [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 [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 [follow-up: 24 months]

      Hospitalization for bleeding or cardiovascular event 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.

    9. Changes in cognitive function [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 [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 thrombus [follow-up: 24 months]

      assessed by echocardiographic follow-up.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Key Inclusion Criteria:

    • Signed written informed consent

    • 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 (a-e):

    1. HAS-BLED-Score ≥ 3

    2. Prior intracranial/intraspinal bleed, intraocular bleed compromising vision (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 15-29 ml/min/1.73 m2

    5. Any recurrent bleeding making chronic anticoagulation not feasible

    • Subject eligible for an LAA occluder device

    • Age ≥18 years

    • Willing and capable of providing informed consent, participating in all associated study activities

    Key Exclusion Criteria:

    • Absolute contraindication to acetylsalicylic acid

    • 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 resulting in bacteremia

    • Cardiac tumor

    • Severe liver failure (Child-Pugh class C or liver failure with coagulopathy)

    • Severe renal failure (GFR <15 ml/min/1.73m2)

    • Pregnancy or breastfeeding

    • For female patients of reproductive potential: Unwilling to agree to use a highly effective method of contraception (Pearl index <1) throughout the study period

    • 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

    • Subject who is dependent on the Site, the Site Investigator, any sub- investigator, his/her representative and/or the sponsor

    • Persons who are not proficient in the German language

    • Acute heart failure within the last 30 days

    • Cardiac intervention within the last 30 days

    • Subjects with planned cardiac or non-cardiac surgery or intervention. (These subject can be included 30 days after such intervention / surgery.)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Vivantes Klinik Am Urban, Kardiologie Berlin Germany 10967
    2 Charité Universitätsmedizin Berlin, CBF, Kardiologie Berlin Germany 12203
    3 Vivantes Klinikum Neukölln, Kardiologie Berlin Germany 12351
    4 DRK-Kliniken Berlin Köpenick, Klinik für Innere Medizin - Schwerpunkt Kardiologie und Angiologie Berlin Germany 12559
    5 Charité Universitätsmedizin Berlin, CVK, Kardiologie Berlin Germany 13353
    6 Deutsches Herzzentrum Berlin, Innere Medizin - Kardiologie Berlin Germany 13353
    7 Klinikum Brandenburg GmbH, Zentrum für Innere Medizin I Brandenburg Germany 14770
    8 Gesundheit Nord gGmbH, Klinikum Links der Weser, Klinik für Kardiologie und Angiologie Bremen Germany 28277
    9 Klinikum Lippe, Klinik für Kardiologie, Angiologie und Internistische Intensivmedizin Detmold Germany 32756
    10 Katholisches Krankenhaus "St. Johann Nepomuk", Klinik für Innere Medizin II - Kardiologie Erfurt Germany 99097
    11 Universitätsklinikum Erlangen, Medizinische Klinik II - Kardiologie und Angiologie Erlangen Germany 91054
    12 Alfried Krupp Krankenhaus Essen Germany 45131
    13 Universität Greifswald, Klinik für Innere Medizin B - Kardiologie Greifswald Germany 17475
    14 Asklepios Klinik Barmbek, I. Med. Abteilung - Kardiologie Hamburg Germany 22291
    15 Klinikum Herford, Med. Klinik III/ Kardiologie Herford Germany 32049
    16 Westpfalz-Klinikum GmbH, Klinik für Innere Medizin II - Kardiologie Kaiserslautern Germany 67655
    17 UKSH - Campus Kiel, Medizinische Klinik III - Kardiologie, Angiologie, Intensivmedizin Kiel Germany 24105
    18 UKSH - Universitäres Herzzentrum Lübeck, Medizinische Klinik II - Kardiologie, Angiologie, Intensivmedizin Lübeck Germany 23538
    19 Universitätsmedizin Mainz, Kardiologie I - Zentrum für Kardiologie Mainz Germany 55131
    20 Universitätsmedizin Mannheim, I. Medizinische Klinik - Kardiologie, Angiologie, Intensivmedizin Mannheim Germany 68167
    21 Deutsches Herzzentrum München, Klinik an der TU München München Germany 80636
    22 LMU Universität München, Medizinische Klinik und Poliklinik I München Germany 81377
    23 Peter Osypka Herzzentrum München München Germany 81379
    24 Städt. Klinikum München GmbH, Klinikum Neuperlach, Klinik für Kardiologie, Pneumologie, intern. Intensivmedizin München Germany 81737
    25 Universitätsklinik Ulm, Klinik für Innere Medizin II - Kardiologie Ulm Germany 89081
    26 Heinrich-Braun-Klinikum Zwickau, Klinik für Innere Medizin I - Kardiologie, Angiologie, Intern. Internsivmedizin 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

    • Study Chair: Ulf Landmesser, MD, Charite University, Berlin, Germany

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Ulf Landmesser, Prof. Dr., Charite University, Berlin, Germany
    ClinicalTrials.gov Identifier:
    NCT03463317
    Other Study ID Numbers:
    • CLOSURE-AF-DZHK16
    First Posted:
    Mar 13, 2018
    Last Update Posted:
    Jul 30, 2021
    Last Verified:
    Jul 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Ulf Landmesser, Prof. Dr., Charite University, Berlin, Germany
    Atrial Fibrillation
    Anticoagulation
    Left atrial appendage closure
    Stroke
    Additional relevant MeSH terms:
    Atrial Fibrillation
    Aspirin
    Warfarin
    Rivaroxaban
    Dabigatran
    Apixaban
    Edoxaban
    Phenprocoumon
    Clopidogrel

    Study Results

    No Results Posted as of Jul 30, 2021