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

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

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 Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Device: CE-mark approved LAA closure devices; Drug: Acetylsalicylic acid; Drug: Clopidogrel; Drug: Dabigatran; Drug: Rivaroxaban; Drug: Apixaban; Drug: Edoxaban; Drug: Phenprocoumon; Drug: Warfarin

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 Type: Interventional
• Enrollment (Anticipated): 1512
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Johannes J Hartung, MD; Phone Number: +49 30 450 513 706; Email: johannes-jakob.hartung@charite.de

Study Locations

• Germany
  • Berlin, Germany, 10967
    • Recruiting
    • Vivantes Klinik Am Urban, Kardiologie
  • Berlin, Germany, 12203
    • Recruiting
    • Charité Universitätsmedizin Berlin, CBF, Kardiologie
  • Berlin, Germany, 12351
    • Recruiting
    • Vivantes Klinikum Neukölln, Kardiologie
  • Berlin, Germany, 12559
    • Recruiting
    • DRK-Kliniken Berlin Köpenick, Klinik für Innere Medizin - Schwerpunkt Kardiologie und Angiologie
  • Berlin, Germany, 13353
    • Recruiting
    • Charité Universitätsmedizin Berlin, CVK, Kardiologie
  • Berlin, Germany, 13353
    • Recruiting
    • Deutsches Herzzentrum Berlin, Innere Medizin - Kardiologie
  • Brandenburg, Germany, 14770
    • Recruiting
    • Klinikum Brandenburg GmbH, Zentrum für Innere Medizin I
  • Bremen, Germany, 28277
    • Recruiting
    • Gesundheit Nord gGmbH, Klinikum Links der Weser, Klinik für Kardiologie und Angiologie
  • Detmold, Germany, 32756
    • Recruiting
    • Klinikum Lippe, Klinik für Kardiologie, Angiologie und Internistische Intensivmedizin
  • Erfurt, Germany, 99097
    • Recruiting
    • Katholisches Krankenhaus "St. Johann Nepomuk", Klinik für Innere Medizin II - Kardiologie
  • Erlangen, Germany, 91054
    • Recruiting
    • Universitätsklinikum Erlangen, Medizinische Klinik II - Kardiologie und Angiologie
  • Essen, Germany, 45131
    • Recruiting
    • Alfried Krupp Krankenhaus
  • Greifswald, Germany, 17475
    • Recruiting
    • Universität Greifswald, Klinik für Innere Medizin B - Kardiologie
  • Hamburg, Germany, 22291
    • Recruiting
    • Asklepios Klinik Barmbek, I. Med. Abteilung - Kardiologie
  • Herford, Germany, 32049
    • Recruiting
    • Klinikum Herford, Med. Klinik III/ Kardiologie
  • Kaiserslautern, Germany, 67655
    • Recruiting
    • Westpfalz-Klinikum GmbH, Klinik für Innere Medizin II - Kardiologie
  • Kiel, Germany, 24105
    • Recruiting
    • UKSH - Campus Kiel, Medizinische Klinik III - Kardiologie, Angiologie, Intensivmedizin
  • Lübeck, Germany, 23538
    • Recruiting
    • UKSH - Universitäres Herzzentrum Lübeck, Medizinische Klinik II - Kardiologie, Angiologie, Intensivmedizin
  • Mainz, Germany, 55131
    • Recruiting
    • Universitätsmedizin Mainz, Kardiologie I - Zentrum für Kardiologie
  • Mannheim, Germany, 68167
    • Recruiting
    • Universitätsmedizin Mannheim, I. Medizinische Klinik - Kardiologie, Angiologie, Intensivmedizin
  • München, Germany, 80636
    • Recruiting
    • Deutsches Herzzentrum München, Klinik an der TU München
  • München, Germany, 81377
    • Recruiting
    • LMU Universität München, Medizinische Klinik und Poliklinik I
  • München, Germany, 81379
    • Recruiting
    • Peter Osypka Herzzentrum Munchen
  • München, Germany, 81737
    • Recruiting
    • Städt. Klinikum München GmbH, Klinikum Neuperlach, Klinik für Kardiologie, Pneumologie, intern. Intensivmedizin
  • Ulm, Germany, 89081
    • Recruiting
    • Universitätsklinik Ulm, Klinik für Innere Medizin II - Kardiologie
  • Zwickau, Germany, 08060
    • Recruiting
    • Heinrich-Braun-Klinikum Zwickau, Klinik für Innere Medizin I - Kardiologie, Angiologie, Intern. Internsivmedizin

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

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.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	follow-up: 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary endpoint events per year	assessed by the number of primary endpoint events during the follow-up period.	follow-up: 24 months
Combined endpoint: MACCE	(stroke/systemic embolism/cardiovascular death/myocardial infarction)	follow-up: 24 months
Mortality	(including all-cause death, cardiovascular death, non- cardiovascular death, peri-procedural death)	follow-up: 24 months
Major bleeding	BARC type 3-5 (according to the BARC (Bleeding Academic Research Consortium) definition for bleeding).	follow-up: 24 months
Systemic embolism	assessed by the rate of systemic embolism during the follow-up period.	follow-up: 24 months
Ischemic/hemorrhagic stroke including transient ischemic attack	(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.	follow-up: 24 months
Myocardial infarction	Myocardial infarction will be assessed according to the third universal definition of myocardial infarction (Eur Heart J, 2012).	follow-up: 24 months
Hospitalization for bleeding or cardiovascular event	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.	follow-up: 24 months
Changes in cognitive function	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.	follow-up: 24 months
Changes in health-related quality of life	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.	follow-up: 24 months
Device-related thrombus	assessed by echocardiographic follow-up.	follow-up: 24 months

Collaborators and Investigators

• Sponsor: Charite University, Berlin, Germany
• Collaborators: Stiftung Institut fuer Herzinfarktforschung; Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK); Atrial Fibrillation Network
• Investigators: Study Chair: Ulf Landmesser, MD, Charite University, Berlin, Germany

Publications and helpful links

Helpful Links

• trial website

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2018
• Primary Completion (Anticipated): September 1, 2023
• Study Completion (Anticipated): March 1, 2025

Study Registration Dates

• First Submitted: February 16, 2018
• First Submitted That Met QC Criteria: March 10, 2018
• First Posted (Actual): March 13, 2018

Study Record Updates

• Last Update Posted (Actual): July 30, 2021
• Last Update Submitted That Met QC Criteria: July 29, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Stroke; Atrial Fibrillation; Anticoagulation; Left atrial appendage closure
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Clopidogrel; Rivaroxaban; Dabigatran; Apixaban; Edoxaban; Phenprocoumon; Warfarin
• Other Study ID Numbers: CLOSURE-AF-DZHK16

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No