Atrial Fibrillation
Conditions
Keywords
Atrial Fibrillation, Anticoagulation, Left atrial appendage closure, Stroke
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).
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).
Interventions
DEVICECE-mark approved LAA closure devices
LAA closure with post procedure treatment
DRUGAcetylsalicylic acid
post procedure treatment according to the physicians (recommendation are made in the protocol); oral anticoagulation is not prescribed in this group
DRUGClopidogrel
post procedure treatment according to the physicians (recommendation are made in the protocol); oral anticoagulation is not prescribed in this group
DRUGDabigatran
Patients allocated to the best medical care group receive either NOAC therapy or VKA
DRUGRivaroxaban
Patients allocated to the best medical care group receive either NOAC therapy or VKA
DRUGApixaban
Patients allocated to the best medical care group receive either NOAC therapy or VKA
DRUGEdoxaban
Patients allocated to the best medical care group receive either NOAC therapy or VKA
DRUGPhenprocoumon
Patients allocated to the best medical care group receive either NOAC therapy or VKA
DRUGWarfarin
Patients allocated to the best medical care group receive either NOAC therapy or VKA
Sponsors
Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK)
Atrial Fibrillation Network
Stiftung Institut fuer Herzinfarktforschung
Charite University, Berlin, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Prospective, multicenter, event-driven, randomized controlled trial (Following 2nd blinded interim analysis: no longer event-driven).
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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: * 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)
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 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 * Persons who are not proficient in the German language * Unstable/not fully recompensated acute heart failure corresponding to NYHA class III and/or IV * Subjects with known antiphospholipid syndrome * Subjects with planned cardiac or non-cardiac surgery or intervention. (These subject can be included 30 days after such intervention / surgery.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary endpoint (net clinical benefit) | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 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
| Measure | Time frame | Description |
|---|---|---|
| Systemic embolism | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months. | assessed by the rate of systemic embolism during the follow-up period. |
| Myocardial infarction | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months. | Myocardial infarction will be assessed according to the third universal definition of myocardial infarction (Eur Heart J, 2012). |
| Hospitalization for bleeding or cardiovascular event | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 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. |
| Changes in cognitive function | At day 0 and after 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. |
| Changes in health-related quality of life | At day 0 and after 6, and 12 months, twice a year until 24 months and once a year after 24 months of follow-up. | 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. |
| Changes in modified Ranking Scale (mRS) | At day 0, 1 day after implantation (device group only) and after 3, 12 and 24 months. | — |
| Primary endpoint events per year | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months. | assessed by the number of primary endpoint events during the follow-up period. |
| Combined endpoint: MACCE | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months. | (stroke/systemic embolism/cardiovascular death/myocardial infarction) |
| Mortality | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months. | (including all-cause death, cardiovascular death, non- cardiovascular death, peri-procedural death) |
| Major bleeding | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months. | BARC type 3-5 (according to the BARC (Bleeding Academic Research Consortium) definition for bleeding). |
| Ischemic stroke | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months. | Stroke 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. |
| Hemorrhagic stroke | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months. | Stroke 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. |
| Transient ischemic attack | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months. | Defined as neurological deficit of vascular origin lasting ≤24 hours without corresponding brain lesion. 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Technical and procedural success of device implantation | Until day 7 or discharge and after 3, 6,12 and 24 months. | — |
| Peri-procedural outcomes | At 7 days or discharge, 30 calendar days after implantation and after 3, 6,12 and 24 months. | — |
| Additionally, the total number of SAEs will be analyzed. | After 3, 6, and 12 months. Twice a year until 24 months and once a year after 24 months. | — |
| Device-related complications | Until day 7 or discharge and after 3, 6,12 and 24 months. | Device thrombus/fracture/erosion/infection/embolization, Pericardial effusion. |
| Procedure related death | Until day 7 or discharge and after 3, 6,12 and 24 months. | — |
Countries
Germany
Outcome results
None listed