Prevention of Stroke by Left Atrial Appendage Closure in Atrial Fibrillation Patients After Intracerebral Hemorrhage

Study Description

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Brief Summary:

Intracerebral hemorrhage (ICH) in patients with non-valvular atrial fibrillation (NVAF) poses a particular dilemma for thromboprophylaxis. Left atrial appendage occlusion (LAAO) is a non-pharmacological approach to prevent cardiac embolism in NVAF. The risk-benefit ratio of LAAO in patients with NVAF after ICH is unknown. The aim of STROKECLOSE is to assess the effect of LAAO to reduce the incidence stroke, bleeding and cardiovascular mortality in patients with NVAF and prior ICH.

Condition or disease	Intervention/treatment	Phase
Atrial Fibrillation; Stroke; Intracerebral Hemorrhage	Device: LAAO; Drug: Medical Therapy	Not Applicable

Detailed Description:

Methods/design: A multicenter prospective randomized open-label clinical trial with blinded outcome evaluation (PROBE design) and blinded safety outcome assessment. The active comparison LAAO is tested against medical therapy in a 2:1 stratified randomization.

Study population: Patients should have had an ICH within 6 months prior to enrollment and have NVAF with increased risk of stroke or systemic embolism, as indicated by a CHA2DS2VASc score >2. In total 750 patients will be included. Active enrollment ensues over 3 years followed by 5 years follow-up and a long-term follow-up at 10 years.

Intervention and control: The intervention group will be treated by LAAO, using the Amplatzer Amulet device. Implantation requires a catheterization procedure using venous access and transseptal puncture and is guided by angiography, fluoroscopy and transesophageal echocardiography (TEE) or intracardiac echocardiography (ICE). Recommended post-implant antithrombotic therapy includes aspirin (ASA) therapy for at least 6 months, with or without clopidogrel for the first 45 days after implantation. The control group will receive medical therapy, delivered according to national standards and guidelines at the treating physicians' discretion. This may include oral anticoagulation (OAC) (vitamin-K antagonists, VKA), non-VKA OAC, antiplatelet therapy or no antithrombotic therapy at all.

Main study outcomes: The primary outcome is the composite endpoint of stroke (ischemic and hemorrhagic), systemic embolism, life-threatening or major bleeding and all-cause mortality, assessed over at least two years. Secondary outcome examines various early and late safety outcome parameters.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	750 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Single (Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Prevention of Stroke by Left Atrial Appendage Closure in Atrial Fibrillation Patients After Intracerebral Hemorrhage: A Multicenter Randomized Clinical Trial
Actual Study Start Date :	May 3, 2017
Estimated Primary Completion Date :	May 2022
Estimated Study Completion Date :	May 2030

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Left Atrial Appendage Occlusion (LAAO); The intervention is implantation of Amplatzer Amulet LAAO device within two months after randomization. Device implantation comprises a catheterization procedure using venous access and a transseptal puncture to obtain access to the left atrium (LA). Procedural imaging guidance is left to the physician's discretion and may include several techniques such as angiography/fluoroscopy, transesophageal echocardiography (TEE) and/or intracardiac echocardiography (ICE). Recommended post-implant antithrombotic therapy includes ASA therapy for at least 6 months, which may be combined with clopidogrel for the first 45 days after implantation.	Device: LAAO; The left atrial appendage is occluded with the AMPLATZER™ Amulet™ device, which offers a conformable disc and lobe designed for complete occlusion of the left atrial appendage.; Other Name: AMPLATZER™ Amulet™ (St. Jude Medical)
Active Comparator: Medical Therapy; The optimal medical therapy of stroke prevention in non-valvular atrial fibrillation (NVAF) after intracerebral hemorrhage (ICH) is not known. Therefore, it will be left to the discretion of the treating physician to decide if, when, and which pharmacological therapy will be prescribed. Available options include anticoagulation with oral anticoagulation (OAC) or novel oral anticoagulants (NOAC), antiplatelet therapy (including monotherapy and dual antiplatelet therapy) and no pharmacological antithrombotic therapy.	Drug: Medical Therapy; Available options included in Medical therapy are: anticoagulation with OAC or NOAC, antiplatelet therapy (including monotherapy and dual antiplatelet therapy) and no pharmacological antithrombotic therapy.

Outcome Measures

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Primary Outcome Measures :

1. Composite endpoint of stroke (ischemic or hemorrhagic), systemic embolism, life-threatening or major bleeding and all-cause mortality [ Time Frame: up to 5 years after randomization ]

   This endpoint will be assessed in patients with paroxysmal, persistent or long-standing NVAF and with ICH within 6 months prior to enrollment.

   The effect of LAAO will be compared to medical therapy at the treating physician's discretion as a control.

Secondary Outcome Measures :

1. Number of participants with a device-related complication [ Time Frame: up to 45 days after randomization ]

   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. Number of Participants with a device success [ Time Frame: up to 45 days after randomization ]
   Device deployed and implanted in correct position.
3. Number of Participants with a Technical success [ Time Frame: up to 45 days after randomization ]
   Exclusion of the left atrial appendage (LAA) achieved without device-related complications and no leak >5 mm on color Doppler TEE.
4. Number of Participants with a Procedural success [ Time Frame: up to 45 days after randomization ]
   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).
5. Number of Participants with Significant peridevice leak [ Time Frame: up to 45 days after randomization ]
   Consistent with the definition of technical success, a significant peridevice leak is defined as a leak shown as a jet >5 mm on color Doppler TEE.
6. Compare the functional status prior to and post treatment [ Time Frame: 24 months after randomization ]
   The Modified Rankin Scale (mRS) will be used for measuring the Functional status.
7. Compare the cognitive status prior to and post treatment [ Time Frame: 24 months after randomization ]
   The cognitive status will be assessed by using Montreal Cognitive Assessment (MOCA) and Mini-mental state examination (MMSE)
8. Compare the neurological status prior to and post treatment [ Time Frame: 24 months after randomization ]
   The National Institutes of Health Stroke Scale (NIHSS) is used to assess the neurological status
9. Compare the quality of life prior to and post treatment by using EuroQol [ Time Frame: 24 months after randomization ]
10. Late safety outcome parameters of LAAO and Medical therapy [ Time Frame: up to 10 years after randomization ]
    Stroke (ischemic or hemorrhagic), systemic embolism, bleeding, all-cause mortality, intracranial hemorrhage, cardiovascular mortality and unplanned hospitalization will be evaluated

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• A diagnosis of paroxysmal, persistent or long-standing NVAF with CHA2DS2VASc score >2.
• Clinical and CT/MRI evidence of ICH within 6 months but not less than 4 weeks prior to enrollment.
• Age > 18 years.
• Signed informed consent.

Exclusion Criteria:

• ICH secondary to vascular malformation or tumors
• Estimated life expectancy of less than 1 year at eligibility assessment
• mRS > 3 at enrollment
• Contraindications to LAAO known at the time of enrollment, such as LAA thrombus or systemic infection, prior surgical LAA excision
• Planned combined interventional procedures at the time of enrollment

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Berit Larsson	+46 72 580 29 12	berit.larsson@sll.se

Locations

Sweden
Sahlrenska University Hospital	Recruiting
Göteborg, Sweden
Contact: Jacob Odenstedt jacob.odenstedt@vgregion.se
Danderyd Hospital	Active, not recruiting
Stockholm, Sweden

Sponsors and Collaborators

Karolinska University Hospital

St. Jude Medical

Investigators

Principal Investigator:	Mårten Rosenqvist, MD	Karolinska Institutet

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Professor Mårten Rosenqvist, Professor, Karolinska University Hospital
ClinicalTrials.gov Identifier:	NCT02830152 History of Changes
Other Study ID Numbers:	STROKECLOSE
First Posted:	July 12, 2016
Last Update Posted:	May 18, 2017
Last Verified:	May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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

Keywords provided by Professor Mårten Rosenqvist, Karolinska University Hospital:

Stroke; intracerebral hemorrhage; left atrial appendage occlusion	atrial fibrillation; oral anticoagulation; preventive therapy

Additional relevant MeSH terms:

Stroke; Atrial Fibrillation; Hemorrhage; Cerebral Hemorrhage; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases	Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Heart Diseases; Pathologic Processes; Intracranial Hemorrhages