Atrial Fibrillation, Stroke
Conditions
Keywords
Left atrial appendage occlusion, Novel oral anticoagulation
Brief summary
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
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.
Interventions
DEVICELeft atrial appendage occlusion
Interventional left atrial appendage occlusion with the Amulet or Watchman device
DRUGNOAC
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.
Sponsors
Aarhus University Hospital
Aalborg University Hospital
Odense University Hospital
Sahlgrenska University Hospital
Karolinska University Hospital
Haukeland University Hospital
Helsinki University Central Hospital
Gødstrup Hospital
Lund University Hospital
Oslo University Hospital
Trondheim University Hospital
Rigshospitalet, Denmark
Jena University Hospital
University of Aarhus
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Masking description
Open-label study with blinded outcome assessment by an independent clinical event committee
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite endpoint of stroke (ischemic and hemorrhagic), systemic embolism, major bleeding and all-cause mortality. | Up to 5-years from randomization | The primary endpoint is the combined rate of stroke, systemic embolism, major bleeding and all-cause mortality. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of hemorrhagic stroke | 2-, 3-, 5- and 10-years | 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. |
| Incidence of systemic embolism | 2-, 3-, 5- and 10-years | 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). |
| Incidence of major or life-threatening bleeding | 2-, 3-, 5- and 10-years | 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. |
| Incidence of all-cause mortality | 2-, 3-, 5- and 10-years | The occurrence of death from any cause |
| Incidence of Transient ischemic attack (TIA) | 2-, 3-, 5- and 10-years | 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. |
| Number of patients with a device-related complication | 2 months | 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 |
| Number of patients with a procedure-related complication | 2 months | All complications related to the LAAO-procedure will be assessed. |
| Number of patients with peri-device leaks at follow-up imaging | 2 months | Detection of any peri-device flow/gap at follow-up cardiac CT/TEE. |
| Incidence of ischemic stroke | 2-, 3-, 5- and 10-years | 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. |
| Number of patients with technical success | 2 Months | Exclusion of the left atrial appendage (LAA) achieved without device-related complications and no leak \>5 mm on color Doppler TEE. |
| Number of patients with procedural success | 2 months | 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). |
| Changes in functional status based on Modified Rankin Scale | 24 months | 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). |
| Changes in Quality of life | 12 months | 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. |
| Compliance to NOAC | 2-, 3-, 5-, and 10-years | Adherence to assigned NOAC therapy will be assessed through the National Prescription Registries. |
| Changes in neurological status based on National Institute of Health (NIH) Stroke scale score | 12 months | 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 |
| Number of patients with a device success | 2 months | Device deployed and implanted in correct position |
Other
| Measure | Time frame | Description |
|---|---|---|
| Comparison of the cost-effectiveness of LAAO and NOAC therapy | 24 months | All costs and cost-effectiveness will be evaluated and compared between the two diagnostic strategies. |
| Minor bleeding | 24 months | Any bleeding clinically mentionable that does not qualify as life-threatening, disabling or major. |
Countries
Denmark, Finland, Germany, Norway, Sweden
Contacts
Primary ContactKasper Korsholm, MD
Outcome results
None listed