Atrial Fibrillation, Atrial Flutter, Intracranial Hemorrhage, Hypertensive, Intracranial Hemorrhages, Intraventricular Hemorrhage, Microhaemorrhage, Small Vessel Cerebrovascular Disease, Subarachnoid Hemorrhage, Subdural Hematoma
Conditions
Keywords
Oral anticoagulant, Factor Xa inhibitors, Direct thrombin inhibitor, Vitamin K antagonist, Antiplatelet drug
Brief summary
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
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.
Interventions
DRUGApixaban
The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.
DRUGRivaroxaban
The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.
DRUGEdoxaban
The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.
DRUGDabigatran
The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.
DRUGAcenocoumarol
The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.
DRUGPhenindione
The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.
DRUGWarfarin
The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.
Sponsors
NHS Lothian
University of Edinburgh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Masking description
PROBE design
Intervention model description
1:1 allocation of intervention: comparator, using a minimisation algorithm
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient age ≥18 years 2. 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) 3. Atrial fibrillation/flutter (persistent or paroxysmal) with a CHA2DS2-VASc score ≥2 4. 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
1. Symptomatic intracranial haemorrhage within the last 24 hours (when the risk of haemorrhage expansion/growth is greatest) 2. Symptomatic intracranial haemorrhage is exclusively due to trauma or haemorrhagic transformation of ischaemic stroke 3. Prosthetic mechanical heart valve or severe (haemodynamically significant) native valve disease 4. Left atrial appendage occlusion for prevention of systemic embolism in AF done in the past, or intended to be performed 5. Intention to start antiplatelet drug(s) if randomised to start full dose OAC 6. Intention to start OAC or parenteral anticoagulation 7. Intention to implement the allocated treatment strategy for \<1 year 8. Patient or their doctor is certain about whether to start or avoid full dose OAC 9. Brain imaging that first diagnosed the intracranial haemorrhage is not available 10. Patient is not registered with a general practitioner 11. Patient is pregnant, breastfeeding, or of childbearing age and not taking contraception 12. Patient and carer unable to understand spoken or written English 13. Contraindications to any of the IMPs, other than recent intracranial haemorrhage 14. Contraindication to MRI (brain MRI sub-study) 15. Life expectancy less than one year 16. Previously randomised in SoSTART
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrent symptomatic spontaneous intracranial haemorrhage (in the safety phase of the trial) | 1 year after randomisation | \ 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. |
| The number of participants recruited per site per month (in the pilot phase of the trial) | 1 year after trial initiation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 1 year after randomisation | The acceptability of the trial protocol to investigators and patients. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Ratings of participant quality of life completed by participant, their carer or or nominated contact | Randomisation and 1 year after randomisation | • The 5-level EQ-5D version (EQ-5D-5L) of the EuroQol |
| The number of Individual symptomatic vascular events: (in the safety phase of the trial) | 1 year after randomisation | * Major haemorrhagic events (Bleeding Academic Research Consortium types 3-5) * Recurrent symptomatic spontaneous intracranial haemorrhage * Extracranial haemorrhage * Symptomatic ischaemic events * ischaemic stroke * myocardial infarction * peripheral arterial occlusion * mesenteric ischaemia * central retinal arterial occlusion * deep vein thrombosis * pulmonary embolism * cardiac death with symptoms suggestive of myocardial ischaemia (type 3),or evidence of arrhythmia * Revascularisation procedures (carotid, coronary, or peripheral arterial) * Symptomatic stroke of uncertain sub-type * Non-fatal stroke, with brain imaging performed too late to distinguish haemorrhage from infarction * Rapidly fatal stroke, but without radiographic or pathological confirmation |
| The number of Symptomatic serious vascular events: (in the safety phase of the trial) | 1 year after randomisation | • All symptomatic serious vascular events (i.e. major adverse cardiac or cerebrovascular events \[MACCE\]) including: non-fatal (i.e. not followed by death within 30 days of onset) myocardial infarction; stroke (i.e. ischaemic, haemorrhagic, unknown sub-type) or spontaneous subdural haemorrhage; or death from a vascular cause (i.e. haemorrhagic or ischaemic events followed by death within 30 days), sudden death, or death of an unknown cause. |
| Annual ratings of participant dependence completed by participant, their carer or nominated contact, or healthcare provider (e.g. general practitioner): | 1 year after randomisation | • Simplified modified Rankin Scale |
Countries
United Kingdom
Outcome results
None listed