Left Atrial Appendage Occlusion Versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation

Study Overview
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Brief Summary
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Atrial fibrillation (AF) is progressively common, and increases the risk of stroke five-fold. Oral anticoagulation is the mainstay therapy; however, it increases the risk of bleeding. Moreover, 30% with AF and at risk of stroke are not in relevant anticoagulation. The randomized PROTECT-AF trial has demonstrated the superiority of left atrial appendage occlusion (LAAO) as compared to warfarin for prevention of the combined endpoint of stroke, major bleeding and cardiovascular mortality. However, studies comparing LAAO to therapy with novel oral anticoagulants (NOAC) have not been carried out. This study aims to assess the effect of left atrial appendage occlusion (LAAO) to reduce the incidence of stroke, systemic embolism, major bleeding and all-cause mortality in patients with atrial fibrillation (AF) and a prior ischemic stroke or transient ischemic attack (TIA).

Detailed Description
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An investigator-initiated multicenter, randomized open-label non-inferiority trial with blinded outcome evaluation (PROBE design). The active comparison LAAO is tested against NOAC therapy in a 1:1 stratified randomization. Patients should have AF, and an ischemic stroke or TIA within 6 months prior to enrollment. In total 750 patients will be included. Follow-up will be based on in-office and telephone follow-up during the first 3 years after randomization, along with up to 10 years long-term follow-up through the National Patient Registries. The main study outcomes: The primary outcome is a composite of stroke (hemorrhagic or ischemic), systemic embolism, major bleeding or all-cause mortality assessed after at least two years follow-up for the last enrolled patient. Secondary outcomes will examine early and late safety outcome measures. The long-term outcome will be assessed up to 10-years after randomization through the National Patient Registries.

Official Title
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Left Atrial Appendage Occlusion Versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation. A Multicenter Randomized Clinical Trial. (Occlusion-AF)

Conditions
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Atrial Fibrillation, Stroke

Intervention / Treatment
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* Device: Left atrial appendage occlusion
* Drug: NOAC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years documented non-valvular atrial fibrillation (paroxysmal, persistent or permanent) Eligible for long-term Novel Oral Anticoagulation (NOAC) therapy Ischemic stroke within the recent 6 months verified by neuroimaging, or Transient ischemic attack within 6 months with proven cerebral ischemia based on cerebral magnetic resonance imaging (MRI) Exclusion Criteria: Modified rankin scale > 3 at time of enrollment Glomerular filtration rate (GFR) below 15 ml/min/1.73 m2 Contraindication towards long-term aspirin therapy Planned combined cardiovascular interventional procedures at the time of enrollment Terminal illness or cancer with life expectancy less than 2 years.

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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LAAO group<br>Patients will be treated with transcatheter left atrial appendage occlusion. The LAAO may be performed with the Amulet or Watchman device. | Device: Left atrial appendage occlusion<br>* Interventional left atrial appendage occlusion with the Amulet or Watchman device<br>* Other names: Left atrial appendage closure;|
| Experimental: NOAC group<br>Patients will be treated with one of the currently available NOAC drugs; Apixaban, Dabigatran, Edoxaban or Rivaroxaban. | Drug: NOAC<br>* Medical treatment arm. Patients will be treated with one of the available NOAC drugs; Apixaban, Dabigatran, Edoxaban or Rivaroxaban. The specific drug and dose is at the discretion of the treating physician.<br>* Other names: Dabigatran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite endpoint of stroke (ischemic and hemorrhagic), systemic embolism, major bleeding and all-cause mortality. | The primary endpoint is the combined rate of stroke, systemic embolism, major bleeding and all-cause mortality. | Up to 5-years from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of ischemic stroke | The occurrence of an acute onset of a focal neurological deficit of presumed vascular origin lasting for ≥ 24 hours or resulting in death. Stroke is categorized as ischemic based on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain or autopsy. | 2-, 3-, 5- and 10-years | 
| Incidence of hemorrhagic stroke | The occurrence of an acute onset of a focal neurological deficit of presumed vascular origin lasting for ≥ 24 hours or resulting in death. Stroke is categorized as hemorrhagic based on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain or autopsy. | 2-, 3-, 5- and 10-years | 
| Incidence of systemic embolism | The occurrence of an acute vascular insufficiency or occlusion of the extremities or any non-CNS organ associated with clinical, imaging, surgical or autopsy evidence of arterial occlusion in the absence of other likely mechanism (e.g. trauma, atherosclerosis, or instrumentation). | 2-, 3-, 5- and 10-years | 
| Incidence of major or life-threatening bleeding | The occurrence of an overt bleeding associated with one or more of the following: decrease in hemoglobin of at least 3.0 g/dL, transfusion of 2 or more units of blood, causing hospitalization, requiring surgery, causing discontinuation of all antithrombotic therapy or pericardial bleeding with/without tamponade or occurring during the index LAAO procedure or during hospitalization for the index procedure (major bleeding). Life-threatening bleeding is defined as fatal bleeding, causing hypovolaemic shock or severe hypotension requiring vasopressor therapy or intervention, symptomatic bleeding in a critical organ (intracranial, intraspinal, intraocular, intramuscular with compartment syndrome, pericardial bleeding after hospitalization for the index LAAO) or overt bleeding with decrease in hemoglobin ≥ 5 g/dL or requiring transfusion of ≥ 4 units of blood. | 2-, 3-, 5- and 10-years | 
| Incidence of all-cause mortality | The occurrence of death from any cause | 2-, 3-, 5- and 10-years | 
| Incidence of Transient ischemic attack (TIA) | an episode of neurological dysfunction caused by focal brain, spinal cord or retinal ischemia leading to symptoms lasting less than 24 hours, without acute infarction based on neuroimaging. | 2-, 3-, 5- and 10-years | 
| Number of patients with a device-related complication | A complication related to the presence of the device. Device-related complications include: Device embolization Device erosion Clinically significant device interference with surrounding structures. This includes structures at the implant location (circumflex coronary artery, mitral valve, pulmonary artery, pulmonary vein) or cardiovascular structures in the vicinity of the location to which the device migrated (if applicable). Device thrombus Device fracture Device infection/endocarditis/pericarditis Device perforation/laceration Device allergy | 2 months | 
| Number of patients with a procedure-related complication | All complications related to the LAAO-procedure will be assessed. | 2 months | 
| Number of patients with a device success | Device deployed and implanted in correct position | 2 months | 
| Number of patients with technical success | Exclusion of the left atrial appendage (LAA) achieved without device-related complications and no leak >5 mm on color Doppler TEE. | 2 Months | 
| Number of patients with procedural success | Technical success and no procedure-related complications, except uncomplicated device embolization (i.e. device embolization resolved by percutaneous retrieval during the procedure without surgical intervention or damage to surrounding cardiovascular structures). | 2 months | 
| Number of patients with peri-device leaks at follow-up imaging | Detection of any peri-device flow/gap at follow-up cardiac CT/TEE. | 2 months | 
| Changes in functional status based on Modified Rankin Scale | The Modified Rankin scale is used to measure the degree of disability or dependence in daily activities caused by a stroke. The scale runs from 0-6, from no symptoms (0) to death (6). | 24 months | 
| Changes in Quality of life | Based on patient self-reported EuroQol-5D questionnaires. The EuroQol-5D is a standardized instrument to measure health-related quality of life. It includes five self-rated dimensions of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The questionnaire have 3 levels of severity for each of the five dimensions. It also includes a visual scale from 0 (worst thinkable health condition) to 100 (best thinkable health condition) to report an overall measure. | 12 months | 
| Compliance to NOAC | Adherence to assigned NOAC therapy will be assessed through the National Prescription Registries. | 2-, 3-, 5-, and 10-years | 
| Changes in neurological status based on National Institute of Health (NIH) Stroke scale score | Assessed by the NIH stroke scale at baseline and 12 month follow-up. A scale to quantify the neurological impairment caused by a stroke. It includes 11 items, each of which scores a specific ability between 0 to 4. For each item, a score of 0 typically indicates normal function in that specific ability, while a higher score is indicative of some level of impairment. The individual scores are summed to calculate the total NIH Stroke Scale score, that can range from 0 to 42, with 0 being no symptoms. Score 0: No stroke symptoms Score 1-4: Minor stroke Score 5-15: Moderate stroke Score 16-20: Moderate to severe stroke Score 21-42: Severe stroke | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Left atrial appendage occlusion, Novel oral anticoagulation