Avoiding Anticoagulation After IntraCerebral Haemorrhage

Study Overview
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Brief Summary
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Randomised controlled trials (RCTs) demonstrate a substantial benefit from oral anticoagulant drugs for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation (AF). However, these RCTs excluded patients with prior intracerebral haemorrhage (ICH). Therefore, guidelines are unable to recommend whether oral anticoagulant drugs, in particular non-vitamin K antagonist (called direct OAC) - can be used for patients with AF after an intracerebral haemorrhage. Roughly 30% of adults with ICH have AF but in 2017 it remains unclear whether they should start oral anticoagulant drugs, be treated with left atrial appendage closure (LAAC) or avoid anticoagulation and LAAC.

Detailed Description
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Open label randomised controlled multicentre clinical trial with masked outcome assessment (PROBE design) comparing 3 strategies (1:1:1): anticoagulation with a Direct OAC (Apixaban 5mgx2/day) vs avoid anticoagulation with left atrial appendage closure (LAAC) compared to usual care (avoid anticoagulation). Primary outcome: the net clinical benefit (composite outcome of major ischaemic and haemorrhagic events) during a follow-up of 24 months (adjudication committee masked to the randomisation arm The results of A3ICH will help the clinician to decide which strategy is the most effective in terms of benefit/risk ratio to prevent the risk of stroke or systemic embolism in patients with a history of ICH and AF. A3ICH will address this increasingly common dilemma and could affect clinical practice. Data from A3ICH will contribute to an international individual patient data meta-analysis.

Official Title
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Avoiding Anticoagulation After IntraCerebral Haemorrhage

Conditions
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Intracerebral Hemorrhage, Atrial Fibrillation, Microhaemorrhage

Intervention / Treatment
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* Drug: Apixaban 5 MG
* Device: left atrial appendage closure


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Adult (older than 18 years old, no upper age limit) with a history of paroxysmal, persistent or long-standing non-valvular atrial fibrillation (documented on an electrocardiogram) and a CHA2DS2VASc score of 2 or more who have an indication for long-term anticoagulation who suffered from a spontaneous intracerebral haemorrhage (while being treated with oral anticoagulants or not) documented with brain CT or MRI more than 14 days before randomization (no upper delay limit) for whom there is a clinical equipoise regarding the choice of the best preventive strategy to avoid future vascular events. Exclusion criteria for all treatment groups Pre-randomisation modified Rankin score of 4 or 5 Conditions other than atrial fibrillation for which the patient requires long term anticoagulation (for example prosthetic mechanical heart valve) Serious bleeding events within the 6 months before randomisation (except for intracerebral haemorrhage) Life expectancy of less than 1 year Pregnancy or breastfeeding Exclusion criteria related to the LAAC only Contraindications due to local, anatomical reasons (such as thrombus in the left atrial appendage, infection with a risk of endocarditis) Patients older than 85 years CHA2DS2VASc score of 2 or 3 Patient or attending physician are unwilling to undergo/perform intervention for LAAC Exclusion criteria related to the Direct OAC only Chronic renal insufficiency (clearance of creatinine by Cockcroft method < 30ml/min) Body weight lower than 50 kg Allergy to apixaban Coexisting conditions predisposing to head trauma (e.g. gait disturbances, uncontrolled seizures disorders) Patient or attending physician are unwilling to use of Direct OAC

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
Interventional Model Description: 1:1:1
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Direct Oral Anticoagulant (DOAC)<br>Apixaban 5MG twice daily | Drug: Apixaban 5 MG<br>* Apixaban 5mg x 2 during 24 months<br>* Other names: ELIQUIS 5mg;|
| Experimental: Left Atrial Appendage Closure (LAAC)<br>Devices will be chosen by local teams. | Device: left atrial appendage closure<br>* left atrial appendage closure<br>|
| No Intervention: Control<br>avoiding anticoagulation and LAAC during the entire study period The standard clinical practice without OAC may include: antiplatelet drug (in case of comorbidities such as coronary heart disease) or no antithrombotic drug | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite of all fatal or non-fatal major cardiovascular/cerebrovascular ischaemic or haemorrhagic intracranial/extracranial events | The composite endpoint will enable to evaluate the net clinical benefit of the different therapeutic strategies. Definition of fatal event: when death is occurring within 30 days after the events. | within 24 months after randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Each individual component of the composite outcome (fatal or non-fatal major cardiovascular/cerebrovascular ischaemic or haemorrhagic intracranial/extracranial events). | fatal or non-fatal major cardiovascular/cerebrovascular ischaemic or haemorrhagic intracranial/extracranial events). | at 12 and 24 months after randomization | 
| Death of any cause | death | at 12 and 24 months after randomization | 
| Modified Rankin Scale | functional dependence | at 12 and 24 months after randomization | 
| EQ-5D (EuroQoL) Score | health-related quality of life | at 12 and 24 months after randomization | 
| neuroradiological biomarkers | on brain MRI | Baseline | 
| Complications of endovascular treatment | including device related complications | up to 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intracerebral hemorrhage, atrial fibrillation, microhemorrhage, oral anticoagulation, left atrial appendage closure