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

Study Overview
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Brief Summary
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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).

Detailed Description
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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).

Official Title
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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

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Device: CE-mark approved LAA closure devices
* Drug: Acetylsalicylic acid
* Drug: Clopidogrel
* Drug: Dabigatran
* Drug: Rivaroxaban
* Drug: Apixaban
* Drug: Edoxaban
* Drug: Phenprocoumon
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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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): 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 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.)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Event-driven group-sequential design, non-inferiority test, if significant followed by superiority test
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LAA closure group<br>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<br>* LAA closure with post procedure treatment<br>Drug: Acetylsalicylic acid<br>* post procedure treatment according to the physicians (recommendation are made in the protocol); oral anticoagulation is not prescribed in this group<br>* Other names: ASS;Drug: Clopidogrel<br>* post procedure treatment according to the physicians (recommendation are made in the protocol); oral anticoagulation is not prescribed in this group<br>|
| Active Comparator: Best medical care group<br>No left atrial appendage closure. Treatment with best medical care (NOACs (dabigatran, rivaroxaban, apixaban, edoxaban) or VKA (phenprocoumon, warfarin) | Drug: Dabigatran<br>* Patients allocated to the best medical care group receive either NOAC therapy or VKA<br>* Other names: Pradaxa®;Drug: Rivaroxaban<br>* Patients allocated to the best medical care group receive either NOAC therapy or VKA<br>* Other names: Xarelto®;Drug: Apixaban<br>* Patients allocated to the best medical care group receive either NOAC therapy or VKA<br>* Other names: Eliquis®;Drug: Edoxaban<br>* Patients allocated to the best medical care group receive either NOAC therapy or VKA<br>* Other names: LIXIANA®;Drug: Phenprocoumon<br>* Patients allocated to the best medical care group receive either NOAC therapy or VKA<br>* Other names: Marcumar®;Drug: Warfarin<br>* Patients allocated to the best medical care group receive either NOAC therapy or VKA<br>* Other names: Coumadin®;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Stroke, Anticoagulation, Left atrial appendage closure, Atrial Fibrillation