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

Atrial Fibrillation Clinical Trial

— CLOSURE-AF  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03463317
• Other study ID #: CLOSURE-AF-DZHK16
• Status: Recruiting
• Phase: Phase 4
• Start date: February 28, 2018
• Est. completion date: March 1, 2025

Study information

• Verified date: July 2021
• Source: Charite University, Berlin, Germany
• Contact: Johannes J Hartung, MD
• Phone: +49 30 450 513 706
• Email: johannes-jakob.hartung[@]charite.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1512
• Est. completion date: March 1, 2025
• Est. primary completion date: September 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.)

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

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
• Clopidogrel
post procedure treatment according to the physicians (recommendation are made in the protocol); oral anticoagulation is not prescribed in this group
• Dabigatran
Patients allocated to the best medical care group receive either NOAC therapy or VKA
• Rivaroxaban
Patients allocated to the best medical care group receive either NOAC therapy or VKA
• Apixaban
Patients allocated to the best medical care group receive either NOAC therapy or VKA
• Edoxaban
Patients allocated to the best medical care group receive either NOAC therapy or VKA
• Phenprocoumon
Patients allocated to the best medical care group receive either NOAC therapy or VKA
• Warfarin
Patients allocated to the best medical care group receive either NOAC therapy or VKA

Locations

Country	Name	City	State
Germany	Charité Universitätsmedizin Berlin, CBF, Kardiologie	Berlin
Germany	Charité Universitätsmedizin Berlin, CVK, Kardiologie	Berlin
Germany	Deutsches Herzzentrum Berlin, Innere Medizin - Kardiologie	Berlin
Germany	DRK-Kliniken Berlin Köpenick, Klinik für Innere Medizin - Schwerpunkt Kardiologie und Angiologie	Berlin
Germany	Vivantes Klinik Am Urban, Kardiologie	Berlin
Germany	Vivantes Klinikum Neukölln, Kardiologie	Berlin
Germany	Klinikum Brandenburg GmbH, Zentrum für Innere Medizin I	Brandenburg
Germany	Gesundheit Nord gGmbH, Klinikum Links der Weser, Klinik für Kardiologie und Angiologie	Bremen
Germany	Klinikum Lippe, Klinik für Kardiologie, Angiologie und Internistische Intensivmedizin	Detmold
Germany	Katholisches Krankenhaus "St. Johann Nepomuk", Klinik für Innere Medizin II - Kardiologie	Erfurt
Germany	Universitätsklinikum Erlangen, Medizinische Klinik II - Kardiologie und Angiologie	Erlangen
Germany	Alfried Krupp Krankenhaus	Essen
Germany	Universität Greifswald, Klinik für Innere Medizin B - Kardiologie	Greifswald
Germany	Asklepios Klinik Barmbek, I. Med. Abteilung - Kardiologie	Hamburg
Germany	Klinikum Herford, Med. Klinik III/ Kardiologie	Herford
Germany	Westpfalz-Klinikum GmbH, Klinik für Innere Medizin II - Kardiologie	Kaiserslautern
Germany	UKSH - Campus Kiel, Medizinische Klinik III - Kardiologie, Angiologie, Intensivmedizin	Kiel
Germany	UKSH - Universitäres Herzzentrum Lübeck, Medizinische Klinik II - Kardiologie, Angiologie, Intensivmedizin	Lübeck
Germany	Universitätsmedizin Mainz, Kardiologie I - Zentrum für Kardiologie	Mainz
Germany	Universitätsmedizin Mannheim, I. Medizinische Klinik - Kardiologie, Angiologie, Intensivmedizin	Mannheim
Germany	Deutsches Herzzentrum München, Klinik an der TU München	München
Germany	LMU Universität München, Medizinische Klinik und Poliklinik I	München
Germany	Peter Osypka Herzzentrum München	München
Germany	Städt. Klinikum München GmbH, Klinikum Neuperlach, Klinik für Kardiologie, Pneumologie, intern. Intensivmedizin	München
Germany	Universitätsklinik Ulm, Klinik für Innere Medizin II - Kardiologie	Ulm
Germany	Heinrich-Braun-Klinikum Zwickau, Klinik für Innere Medizin I - Kardiologie, Angiologie, Intern. Internsivmedizin	Zwickau

Sponsors (4)

Lead Sponsor	Collaborator
Charite University, Berlin, Germany	Atrial Fibrillation Network, Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Stiftung Institut fuer Herzinfarktforschung

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Primary endpoint events per year	assessed by the number of primary endpoint events during the follow-up period.	follow-up: 24 months
Secondary	Combined endpoint: MACCE	(stroke/systemic embolism/cardiovascular death/myocardial infarction)	follow-up: 24 months
Secondary	Mortality	(including all-cause death, cardiovascular death, non- cardiovascular death, peri-procedural death)	follow-up: 24 months
Secondary	Major bleeding	BARC type 3-5 (according to the BARC (Bleeding Academic Research Consortium) definition for bleeding).	follow-up: 24 months
Secondary	Systemic embolism	assessed by the rate of systemic embolism during the follow-up period.	follow-up: 24 months
Secondary	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
Secondary	Myocardial infarction	Myocardial infarction will be assessed according to the third universal definition of myocardial infarction (Eur Heart J, 2012).	follow-up: 24 months
Secondary	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
Secondary	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
Secondary	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
Secondary	Device-related thrombus	assessed by echocardiographic follow-up.	follow-up: 24 months

External Links

•   trial website