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

NCT03463317 | Completed Phase 4 DMC

• 1 other identifier: CLOSURE-AF-DZHK16
• Study Type: interventional
• Target: 912
• Locations: 1 country
• Sites: 42

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).

Conditions

Atrial Fibrillation

Keywords

Atrial Fibrillation; Anticoagulation; Left atrial appendage closure; Stroke

Outcome Measures

Primary Outcomes (1)

• Primary endpoint (net clinical benefit)

  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

  After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months.

Secondary Outcomes (13)

• Primary endpoint events per year

  After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months.

• Combined endpoint: MACCE

  After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months.

• Mortality

  After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months.

• Major bleeding

  After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months.

• Systemic embolism

  After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months.

Other Outcomes (5)

• Device-related complications

  Until day 7 or discharge and after 3, 6,12 and 24 months.

• Procedure related death

  Until day 7 or discharge and after 3, 6,12 and 24 months.

• Technical and procedural success of device implantation

  Until day 7 or discharge and after 3, 6,12 and 24 months.

Study Arms (2)

LAA closure group

EXPERIMENTAL

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; Drug: Acetylsalicylic acid; Drug: Clopidogrel

Best medical care group

ACTIVE COMPARATOR

No left atrial appendage closure. Treatment with best medical care (NOACs (dabigatran, rivaroxaban, apixaban, edoxaban) or VKA (phenprocoumon, warfarin)

Drug: Dabigatran; Drug: Rivaroxaban; Drug: Apixaban; Drug: Edoxaban; Drug: Phenprocoumon; Drug: Warfarin

Interventions

CE-mark approved LAA closure devices DEVICE

LAA closure with post procedure treatment

LAA closure group

Acetylsalicylic acid DRUG

post procedure treatment according to the physicians (recommendation are made in the protocol); oral anticoagulation is not prescribed in this group

Also known as: ASS

LAA closure group

Clopidogrel DRUG

post procedure treatment according to the physicians (recommendation are made in the protocol); oral anticoagulation is not prescribed in this group

LAA closure group

Dabigatran DRUG

Patients allocated to the best medical care group receive either NOAC therapy or VKA

Also known as: Pradaxa®

Best medical care group

Rivaroxaban DRUG

Patients allocated to the best medical care group receive either NOAC therapy or VKA

Also known as: Xarelto®

Best medical care group

Apixaban DRUG

Patients allocated to the best medical care group receive either NOAC therapy or VKA

Also known as: Eliquis®

Best medical care group

Edoxaban DRUG

Patients allocated to the best medical care group receive either NOAC therapy or VKA

Also known as: LIXIANA®

Best medical care group

Phenprocoumon DRUG

Patients allocated to the best medical care group receive either NOAC therapy or VKA

Also known as: Marcumar®

Best medical care group

Warfarin DRUG

Patients allocated to the best medical care group receive either NOAC therapy or VKA

Also known as: Coumadin®

Best medical care group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• HAS-BLED-Score ≥3
• Prior intracranial/intraspinal bleed, intraocular bleed compromising vision (BARC: type 3c)
• 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
• Chronic kidney disease with eGFR 15-29 ml/min/1.73 m2
• 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
• negative SARS-CoV-2 PCR test (no longer than 48 hours prior to randomization in outpatients or not older than 14 days in continuously hospitalized patients without signs of COVID-19 infection) or negative SARS- CoV-2 rapid antigen test (no longer than 24 hours prior to randomization)

You may not qualify if:

• 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 symptoms suggestive of COVID-19 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 or current requirement for dialysis defined as current, regular renal replacement therapy performed at least weekly including hemodialysis and peritoneal dialysis within the last 30 days)
• 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

Sponsors & Collaborators

• Charite University, Berlin, Germany: lead
• Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK): collaborator
• Atrial Fibrillation Network: collaborator
• Stiftung Institut fuer Herzinfarktforschung: collaborator

Study Sites (42)

Charité Universitätsmedizin Berlin, Klinik für Kardiologie, Angiologie und Intensivmedizin, Deutsches Herzzentrum der Charité, Campus Benjamin Franklin (CBF)

Berlin, 12203, Germany

Location

DRK-Kliniken Berlin Köpenick, Klinik für Innere Medizin - Schwerpunkt Kardiologie und Angiologie

Berlin, 12559, Germany

Location

Deutsches Herzzentrum der Charité, Klinik für Kardiologie, Angiologie und Intensivmedizin, Campus Virchow-Klinikum

Berlin, 13353, Germany

Location

Klinik für Kardiologie, Angiologie und Intensivmedizin, Deutsches Herzzentrum der Charité, Campus Virchow-Klinikum (CVK)

Berlin, 13353, Germany

Location

Charité Universitätsmedizin Berlin, Campus Charité Mitte, Med. Klinik für Kardiologie und Angiologie

Berlin, Germany

Location

Klinikum Brandenburg GmbH, Zentrum für Innere Medizin I

Brandenburg, 14770, Germany

Location

Gesundheit Nord gGmbH, Klinikum Links der Weser, Klinik für Kardiologie und Angiologie

Bremen, 28277, Germany

Location

Klinikum Coburg GmbH II. Med. Klinik für Innere Medizin und Kardiologie

Coburg, Germany

Location

Amper Kliniken AG, Helios Amper-Klinikum Dachau, Innere Medizin I - Kardiologie & Pneumologie

Dachau, Germany

Location

Städtisches Klinikum Dresden, II. Medizinische Klinik

Dresden, Germany

Location

Technische Universität Dresden, Herzzentrum Dresden, Universitätsklinik, Medizinische Klinik Kardiologie

Dresden, Germany

Location

Katholisches Krankenhaus "St. Johann Nepomuk", Klinik für Innere Medizin II - Kardiologie

Erfurt, 99097, Germany

Location

HELIOS Klinikum Erfurt GmbH, 3. Medizinische Klinik

Erfurt, Germany

Location

Universitätsklinikum Frankfurt, Medizinische Klinik III/ Kardiologie

Frankfurt, Germany

Location

UHZ Freiburg Bad Krozingen Klinik für Kardiologie und Angiologie II

Freiburg im Breisgau, Germany

Location

Universitätsmedizin Göttingen, Klinik für Kardiologie und Pneumologie

Göttingen, Germany

Location

Universität Greifswald, Klinik für Innere Medizin B - Kardiologie

Greifswald, 17475, Germany

Location

Universitätsklinikum Halle (Saale), Universitätsklinik und Poliklinik für Innere Medizin III

Halle, Germany

Location

Asklepios Klinik Barmbek, I. Med. Abteilung - Kardiologie

Hamburg, 22291, Germany

Location

Asklepios Klinik St. Georg Hamburg, Abteilung für Kardiologie

Hamburg, Germany

Location

Cardiologicum Hamburg

Hamburg, Germany

Location

Universitätsklinikum Hamburg-Eppendorf, Universitäres Herzzentrum, Klinik für Allgemeine und Interventionelle Kardiologie

Hamburg, Germany

Location

Westküstenklinikum Heide Medizinische Klinik 2 - Kardiologie

Heide, Germany

Location

Universitätsklinikum Heidelberg, Medizinische Klinik für Kardiologie, Angiologie und Pneumologie

Heidelberg, Germany

Location

Oberhavel Kliniken, Klinik Hennigsdorf, Innere Medizin

Hennigsdorf, Germany

Location

Universitätsklinikum Jena, Klinik für Innere Medizin I - Kardiologie

Jena, Germany

Location

UKSH - Campus Kiel, Medizinische Klinik III - Kardiologie, Angiologie, Intensivmedizin

Kiel, 24105, Germany

Location

Herzzentrum Leipzig, Universitätsklinik für Kardiologie

Leipzig, Germany

Location

Universitätsklinikum Leipzig, Klinik und Poliklinik für Kardiologie

Leipzig, Germany

Location

UKSH - Universitäres Herzzentrum Lübeck, Medizinische Klinik II - Kardiologie, Angiologie, Intensivmedizin

Lübeck, 23538, Germany

Location

Universitätsmedizin Mainz, Kardiologie I - Zentrum für Kardiologie

Mainz, 55131, Germany

Location

Universitätsmedizin Mannheim, I. Medizinische Klinik - Kardiologie, Angiologie, Intensivmedizin

Mannheim, 68167, Germany

Location

Deutsches Herzzentrum München, Klinik an der TU München

München, 80636, Germany

Location

LMU Universität München, Medizinische Klinik und Poliklinik I

München, 81377, Germany

Location

Peter Osypka Herzzentrum München

München, 81379, Germany

Location

Städt. Klinikum München GmbH, Klinikum Neuperlach, Klinik für Kardiologie, Pneumologie, intern. Intensivmedizin

München, 81737, Germany

Location

Klinikum rechts der Isar, TU München, Klinik und Poliklinik für Innere Medizin I - Kardiologie

München, Germany

Location

Universitätsmedizin Rostock, Herzzentrum, Zentrum Innere Medizin - Abteilung für Kardiologie

Rostock, Germany

Location

Universitätsklinikum Tübingen, Medizinische Klinik, Abteilung III Kardiologie und Kreislauferkrankungen

Tübingen, Germany

Location

Universitätsklinik Ulm, Klinik für Innere Medizin II - Kardiologie

Ulm, 89081, Germany

Location

Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik I

Würzburg, Germany

Location

Heinrich-Braun-Klinikum Zwickau, Klinik für Innere Medizin I - Kardiologie, Angiologie, Intern. Internsivmedizin

Zwickau, 08060, Germany

Location

Related Publications (2)

• Landmesser U, Skurk C, Kirchhof P, Lewalter T, Hartung J, Rroku A, Pieske B, Brachmann J, Akin I, Jacobshagen C, Meder B, Zeiher A, Anker SD, Thiele H, Blankenberg S, Massberg S, Schunkert H, Frey N, Joost A, Bergmann M, von Bardeleben RS, Friede T, Placzek M, Suling A, Haeusler KG, Endres M, Wegscheider K, Boldt LH, Eitel I; CLOSURE-AF Trial Investigators. Left Atrial Appendage Closure or Medical Therapy in Atrial Fibrillation. N Engl J Med. 2026 Mar 18. doi: 10.1056/NEJMoa2513310. Online ahead of print.

  PMID: 41849741 DERIVED

• Landmesser U, Skurk C, Kirchhof P, Lewalter T, Hartung J, Rroku A, Pieske B, Brachmann J, Akin I, Jacobshagen C, Meder B, Zeiher A, Anker SD, Thiele H, Blankenberg S, Massberg S, Schunkert H, Frey N, Joost A, Bergmann M, Haeusler KG, Endres M, Wegscheider K, Boldt LH, Eitel I. Catheter-based left atrial appendage CLOSURE in patients with atrial fibrillation at high risk of stroke and bleeding as compared to best medical therapy: Rationale and design of the prospective randomized CLOSURE-AF trial. Am Heart J. 2026 Feb;292:107273. doi: 10.1016/j.ahj.2025.09.005. Epub 2025 Sep 12.

  PMID: 40946883 DERIVED

Related Links

• trial website

MeSH Terms

Conditions

Atrial Fibrillation; Stroke

Interventions

Aspirin; Clopidogrel; Dabigatran; Rivaroxaban; apixaban; edoxaban; Phenprocoumon; Warfarin

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases

Intervention Hierarchy (Ancestors)

Salicylates; Hydroxybenzoates; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzimidazoles; Morpholines; Oxazines; 4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans

Study Officials

• Ulf Landmesser, MD

  Charite University, Berlin, Germany

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr.

Model Details: Prospective, multicenter, event-driven, randomized controlled trial (Following 2nd blinded interim analysis: no longer event-driven).

Study Record Dates

• First Submitted: February 16, 2018
• First Posted: March 13, 2018
• Study Start: February 28, 2018
• Primary Completion: November 30, 2024
• Study Completion: November 30, 2024
• Last Updated: December 12, 2025

Record last verified: 2025-11

Locations

DE (42)