Start or STop Anticoagulants Randomised Trial (SoSTART)

Study Overview
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Brief Summary
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Primary research question: For adults surviving spontaneous (non-traumatic) symptomatic intracranial haemorrhage with persistent/paroxysmal atrial fibrillation/flutter (AF), does starting full treatment dose oral anticoagulation (OAC) result in a beneficial net reduction of all serious vascular events compared with not starting OAC? Trial design: Investigator-led, multicentre, randomised, open, assessor-masked, parallel group, clinical trial of investigational medicinal product (CTIMP) prescribing strategies. Investigators plan for a pilot phase, followed by a safety phase.

Detailed Description
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Bleeding within the skull, also known as brain haemorrhage, affects 3 million people in the world each year. One in five people who survive brain haemorrhage have an irregular heart rhythm called 'atrial fibrillation', which puts them at risk of stroke and other blood clots. Blood-thinning medicines, known as 'anticoagulant' drugs, are used in everyday clinical practice to protect people with atrial fibrillation from developing blood clots. However, these drugs also increase the risk of bleeding and are usually stopped when the brain haemorrhage occurs. But when patients recover from brain haemorrhage, they and their doctors are often uncertain about whether to start or stop these drugs to prevent further clots occurring, or whether to avoid them in case they increase the risk of brain haemorrhage happening again. Investigators want to find out whether starting or not starting an anticoagulant drugs is better for those patients. A network of hospital doctors, nurses, and other staff will identify people who survive brain haemorrhage and have atrial fibrillation. If a patient and their doctor are uncertain about whether to start an anticoagulant drug, they may invite the patient to participate. In the pilot phase, investigators aim to recruit at least 60 participants to determine the feasibility of recruiting the target sample size of at least 190 participants in the safety phase of the trial. Investigators will follow-up all participants for at least one year to determine whether prescribing an anticoagulant drug reduces the occurrence of all serious vascular events like heart attack, stroke compared with a policy of avoiding oral anticoagulant.

Official Title
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Start or STop Anticoagulants Randomised Trial (SoSTART) After Spontaneous Intracranial Haemorrhage

Conditions
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Subarachnoid Hemorrhage, Subdural Hematoma, Intraventricular Hemorrhage, Atrial Fibrillation, Atrial Flutter, Small Vessel Cerebrovascular Disease, Microhaemorrhage, Intracranial Hemorrhages, Intracranial Hemorrhage, Hypertensive

Intervention / Treatment
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* Drug: Apixaban
* Drug: Rivaroxaban
* Drug: Edoxaban
* Drug: Dabigatran
* Drug: Acenocoumarol
* Drug: Phenindione
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient age ≥18 years Symptomatic intracranial haemorrhage (i.e. intracerebral haemorrhage, non-aneurysmal subarachnoid haemorrhage,intraventricular haemorrhage, or subduralhaemorrhage) Not attributable to a known underlying intracranial aneurysm, arteriovenous malformation, cerebral cavernous malformation, dural arteriovenous fistula, intracranial venous thrombosis Not attributable to known head injury, based on: a history from the patient/witness of spontaneous symptom onset without preceding head trauma (head trauma occurring after symptom onset is permissible) brain imaging appearances consistent with spontaneous intracranial haemorrhage (which may be accompanied by the brain/bone/soft tissue appearances of trauma occurring subsequently) Atrial fibrillation/flutter (persistent or paroxysmal) with a CHA2DS2-VASc score ≥2 If included in the brain magnetic resonance imaging (MRI) sub-study, the scan must be done after symptomatic intracranial haemorrhage and before randomisation Exclusion Criteria: Symptomatic intracranial haemorrhage within the last 24 hours (when the risk of haemorrhage expansion/growth is greatest) Symptomatic intracranial haemorrhage is exclusively due to trauma or haemorrhagic transformation of ischaemic stroke Prosthetic mechanical heart valve or severe (haemodynamically significant) native valve disease Left atrial appendage occlusion for prevention of systemic embolism in AF done in the past, or intended to be performed Intention to start antiplatelet drug(s) if randomised to start full dose OAC Intention to start OAC or parenteral anticoagulation Intention to implement the allocated treatment strategy for <1 year Patient or their doctor is certain about whether to start or avoid full dose OAC Brain imaging that first diagnosed the intracranial haemorrhage is not available Patient is not registered with a general practitioner Patient is pregnant, breastfeeding, or of childbearing age and not taking contraception Patient and carer unable to understand spoken or written English Contraindications to any of the IMPs, other than recent intracranial haemorrhage Contraindication to MRI (brain MRI sub-study) Life expectancy less than one year Previously randomised in SoSTART

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 allocation of intervention: comparator, using a minimisation algorithm
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Start oral anticoagulant (OAC)<br>If the patient is randomized in this arm, an oral anticoagulant: Factor Xa inhibitors: Apixaban or Rivaroxaban or Edoxaban or Direct thrombin inhibitor: Dabigatran or Vitamin K antagonists: Acenocoumarol or Phenindione or Warfarin chosen by the patient's physician before the randomisation, will be prescribed long-term (≥1 year) to the patient. | Drug: Apixaban<br>* The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.<br>* Other names: Eliquis;Drug: Rivaroxaban<br>* The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.<br>* Other names: Xarelto;Drug: Edoxaban<br>* The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.<br>* Other names: Lixiana;Drug: Dabigatran<br>* The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.<br>* Other names: Pradaxa;Drug: Acenocoumarol<br>* The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.<br>* Other names: Sinthrome;Drug: Phenindione<br>* The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.<br>* Other names: Dindevan;Drug: Warfarin<br>* The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.<br>* Other names: Coumadin;|
| No Intervention: Do not start oral anticoagulant (OAC)<br>If the patient is randomized in this arm, anticoagulant drugs will not be prescribed to the patient during the entire study period. The standard clinical practice without OAC may include: antiplatelet drug(s) or no antithrombotic drugs. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of participants recruited per site per month (in the pilot phase of the trial) | The rate of recruiting up to 60 participants to determine the feasibility of recruiting the target sample size in the main phase of the trial in an acceptable timescale. | 1 year after trial initiation | 
| Recurrent symptomatic spontaneous intracranial haemorrhage (in the safety phase of the trial) |  60 hospital sites will recruit at least 190 participants to determine whether the risk of recurrent symptomatic intracranial haemorrhage is sufficiently low (non-inferior) to justify a definitive trial. | 1 year after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportions of all eligible patients recorded on screening logs who are recruited, unsuitable, or decline to participate (in the pilot phase of the trial) | The acceptability of the trial protocol to investigators and patients. | 1 year after randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oral anticoagulant, Factor Xa inhibitors, Direct thrombin inhibitor, Vitamin K antagonist, Antiplatelet drug