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Left Atrial Appendage Occlusion Versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation (Occlusion-AF)

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ClinicalTrials.gov Identifier: NCT03642509
Recruitment Status : Recruiting
First Posted : August 22, 2018
Last Update Posted : October 11, 2018
Sponsor:
Collaborators:
Aarhus University Hospital
Aalborg University Hospital
Odense University Hospital
Sahlgrenska University Hospital, Sweden
Karolinska University Hospital
Turku University Hospital
Information provided by (Responsible Party):
University of Aarhus

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).


Condition or disease Intervention/treatment Phase
Atrial Fibrillation Stroke Device: Left atrial appendage occlusion Drug: NOAC Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 750 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description: Open-label study with blinded outcome assessment by an independent clinical event committee
Primary Purpose: Prevention
Official Title: Left Atrial Appendage Occlusion Versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation. A Multicenter Randomized Clinical Trial. (Occlusion-AF)
Actual Study Start Date : October 1, 2018
Estimated Primary Completion Date : October 1, 2022
Estimated Study Completion Date : October 1, 2030

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: LAAO group
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
Interventional left atrial appendage occlusion with the Amulet or Watchman device
Other Name: Left atrial appendage closure

Experimental: NOAC group
Patients will be treated with one of the currently available NOAC drugs; Apixaban, Dabigatran, Edoxaban or Rivaroxaban.
Drug: NOAC
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.
Other Names:
  • Edoxaban
  • Apixaban
  • Rivaroxaban
  • Dabigatran




Primary Outcome Measures :
  1. Composite endpoint of stroke (ischemic and hemorrhagic), systemic embolism, major bleeding and all-cause mortality. [ Time Frame: Up to 5-years from randomization ]
    The primary endpoint is the combined rate of stroke, systemic embolism, major bleeding and all-cause mortality.


Secondary Outcome Measures :
  1. Incidence of ischemic stroke [ Time Frame: 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.

  2. Incidence of hemorrhagic stroke [ Time Frame: 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.

  3. Incidence of systemic embolism [ Time Frame: 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).

  4. Incidence of major or life-threatening bleeding [ Time Frame: 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.

  5. Incidence of all-cause mortality [ Time Frame: 2-, 3-, 5- and 10-years ]
    The occurrence of death from any cause

  6. Incidence of Transient ischemic attack (TIA) [ Time Frame: 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.

  7. Number of patients with a device-related complication [ Time Frame: 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

  8. Number of patients with a procedure-related complication [ Time Frame: 2 months ]
    All complications related to the LAAO-procedure will be assessed.

  9. Number of patients with a device success [ Time Frame: 2 months ]
    Device deployed and implanted in correct position

  10. Number of patients with technical success [ Time Frame: 2 Months ]
    Exclusion of the left atrial appendage (LAA) achieved without device-related complications and no leak >5 mm on color Doppler TEE.

  11. Number of patients with procedural success [ Time Frame: 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).

  12. Number of patients with peri-device leaks at follow-up imaging [ Time Frame: 2 months ]
    Detection of any peri-device flow/gap at follow-up cardiac CT/TEE.

  13. Changes in functional status based on Modified Rankin Scale [ Time Frame: 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).

  14. Changes in Quality of life [ Time Frame: 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.

  15. Compliance to NOAC [ Time Frame: 2-, 3-, 5-, and 10-years ]
    Adherence to assigned NOAC therapy will be assessed through the National Prescription Registries.

  16. Changes in neurological status based on National Institute of Health (NIH) Stroke scale score [ Time Frame: 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


Other Outcome Measures:
  1. Minor bleeding [ Time Frame: 24 months ]
    Any bleeding clinically mentionable that does not qualify as life-threatening, disabling or major.

  2. Comparison of the cost-effectiveness of LAAO and NOAC therapy [ Time Frame: 24 months ]
    All costs and cost-effectiveness will be evaluated and compared between the two diagnostic strategies.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03642509


Contacts
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Contact: Kasper Korsholm, MD 004578452254 kasperkorsholm@clin.au.dk

Locations
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Denmark
Aarhus University Hospital Recruiting
Aarhus, Central Denmark Region, Denmark, 8200
Contact: Kasper Korsholm, MD    004578452254    kasperkorsholm@clin.au.dk   
Contact: Jens Erik Nielsen-Kudsk, MD DMSc Prof    0078452024    jensnils@rm.dk   
Odense University Hospital Not yet recruiting
Odense, Region Of Southern Denmark, Denmark, 5000
Contact: Jacob Pontoppidan, MD, PhD         
Aalborg University Hospital Not yet recruiting
Aalborg, The North Denmark Region, Denmark, 9000
Contact: Boris Modrau, MD, PhD         
Finland
Turku University Hospital Not yet recruiting
Turku, Finland, 20521
Contact: Juha Lund, MD         
Sweden
Sahlgrenska University Hospital Not yet recruiting
Göteborg, Sweden, 41345
Contact: Jacob Odenstedt, MD, PhD         
Karolinska University Hospital Not yet recruiting
Stockholm, Sweden, 17176
Contact: Magnus Settergren, MD, PhD         
Sponsors and Collaborators
University of Aarhus
Aarhus University Hospital
Aalborg University Hospital
Odense University Hospital
Sahlgrenska University Hospital, Sweden
Karolinska University Hospital
Turku University Hospital
Investigators
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Study Chair: Kasper Korsholm, MD Aarhus University Hospital
Study Chair: Jens Erik Nielsen-Kudsk, MD DMSc Prof Aarhus University Hospital
Study Chair: Dorte Damgaard, MD PhD Aarhus University Hospital
Study Chair: Søren Paaske Johnsen, MD PhD Prof Aalborg University Hospital

Publications:

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Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT03642509     History of Changes
Other Study ID Numbers: Occlusion-AF-AUH250418-32
First Posted: August 22, 2018    Key Record Dates
Last Update Posted: October 11, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Aarhus:
Left atrial appendage occlusion
Novel oral anticoagulation

Additional relevant MeSH terms:
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Stroke
Atrial Fibrillation
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Arrhythmias, Cardiac
Heart Diseases
Pathologic Processes
Rivaroxaban
Apixaban
Edoxaban
Dabigatran
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants