Start or STop Anticoagulants Randomised Trial (SoSTART) (SoSTART)

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

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.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation; Intracranial Hemorrhages; Subarachnoid Hemorrhage; Intraventricular Hemorrhage; Atrial Flutter; Small Vessel Cerebrovascular Disease; Intracranial Hemorrhage, Hypertensive; Subdural Hematoma; Microhaemorrhage
• Intervention / Treatment: Drug: Apixaban; Drug: Rivaroxaban; Drug: Edoxaban; Drug: Dabigatran; Drug: Acenocoumarol; Drug: Phenindione; Drug: Warfarin

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.

• Study Type: Interventional
• Enrollment (Actual): 203
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZN
    • Aberdeen Royal Infirmary
  • Abergavenny, United Kingdom, NP7 7EG
    • Nevill Hall Hospital
  • Airdrie, United Kingdom, ML6 0JS
    • Monklands Hospital
  • Barnet, United Kingdom, EN5 3DJ
    • Barnet Hospital
  • Bath, United Kingdom, BA1 3NG
    • Royal United Hospital
  • Birmingham, United Kingdom, B9 5SS
    • Heartlands Hospital
  • Bournemouth, United Kingdom, BH7 7DW
    • The Royal Bournemouth Hospital
  • Bradford, United Kingdom, BD9 6RJ
    • Bradford Royal Infirmary
  • Bristol, United Kingdom, BS2 8HW
    • University Hospital Bristol
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrookes Hospital
  • Cardiff, United Kingdom, CF14 4XW
    • University Hospital of Wales/ /University Hospital Llandough
  • Colchester, United Kingdom, CO4 5JL
    • Colchester General Hospital
  • Derby, United Kingdom, DE22 3NE
    • Derby Royal Hospital
  • Derry, United Kingdom, BT47 6SB
    • Altnagelvin Hospital
  • Durham, United Kingdom, DH1 5TW
    • University Hospital North Durham
  • Enniskillen, United Kingdom, BT74 6DN
    • South West Acute Hospital
  • Exeter, United Kingdom, EX2 5DW
    • Royal Devon & Exeter Hospital
  • Frimley, United Kingdom, GU16 7UJ
    • Frimley Park Hospital
  • Gateshead, United Kingdom, NE9 6SX
    • Queen Elizabeth Hospital
  • Gillingham, United Kingdom, ME7 5NY
    • Medway Maritime Hospital
  • Glasgow, United Kingdom, G4 0SF
    • Glasgow Royal Infirmary
  • Glasgow, United Kingdom, G51 4TF
    • Queen Elizabeth University Hospital
  • Gloucester, United Kingdom, GL1 3NN
    • Gloucestershire Royal Hospital
  • Halifax, United Kingdom, HX3 0PW
    • Calderdale Royal Hospital
  • Harrow, United Kingdom, HA1 3UJ
    • Northwick Park
  • Hengoed, United Kingdom, CF82 7EP
    • Ystrad Mynach Hospital
  • Kirkcaldy, United Kingdom, KY2 5AH
    • Victoria Hospital Kirkcaldy
  • Lancaster, United Kingdom, LA1 4NU
    • Royal Lancaster Infirmary
  • Leeds, United Kingdom, LS13EX
    • Leeds General Infirmary
  • Liverpool, United Kingdom, L78XP
    • Royal Liverpool and Broadgreen University Hospital
  • Liverpool, United Kingdom, L9 7 AL
    • University Hospital Aintree
  • London, United Kingdom, E1 1BB
    • The Royal London Hospital
  • London, United Kingdom, SE1 7EH
    • St Thomas Hospital
  • London, United Kingdom, NW1 2BU
    • University College London Hospital
  • London, United Kingdom, E9 6SR
    • Homerton University Hospital
  • London, United Kingdom, N18 1QX
    • North Middlesex University Hospital
  • London, United Kingdom, SW17 OQT
    • St.George's Hospital
  • Luton, United Kingdom, LU4 0DZ
    • Luton & Dunstable University Hospital
  • Mansfield, United Kingdom, NG17 4JL
    • King's Mill Hospital
  • Middlesbrough, United Kingdom, Ts4 3Bw
    • James Cook University Hospital
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • Royal Victoria Infirmary
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham City Hospital
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital
  • Peterborough, United Kingdom, PE3 9GZ
    • Peterborough City Hospital
  • Poole, United Kingdom, BH15 2JB
    • Poole Hospital
  • Preston, United Kingdom, PR2 9HT
    • Royal Preston Hospital
  • Reading, United Kingdom, RG1 5AN
    • Royal Berkshire Hospital
  • Romford, United Kingdom, RM7 0AG
    • Queen' Hospital Romford
  • Salford, United Kingdom, M6 8HD
    • Salford Royal NHS Foundation Trust
  • Sheffield, United Kingdom, S10 2JF
    • Royal Hallamshire Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital
  • Stockton-on-Tees, United Kingdom, TS19 8PE
    • University Hospital of North Tees
  • Stoke-on-Trent, United Kingdom, ST4 6QG
    • Royal Stoke University Hospital
  • Sunderland, United Kingdom, SR4 7TP
    • Sunderland Royal Hospital
  • Swansea, United Kingdom, SA6 6NL
    • Morriston Hospital
  • Telford, United Kingdom, TF1 6TF
    • The Princess Royal Hospital
  • Torquay, United Kingdom, TQ2 7AA
    • Torbay District General Hospital
  • Truro, United Kingdom, TR1 3LJ
    • Royal Cornwall Hospital
  • Uxbridge, United Kingdom, UB8 3NN
    • Hillingdon Hospital
  • Wakefield, United Kingdom, WF1 4DG
    • Pinderfields Hospital
  • Westcliff-on-Sea, United Kingdom, SS0 0RY
    • Southend University Hospital NHS Foundation Trust
  • Winchester, United Kingdom, SO22 5DG
    • Royal Hampshire County Hospital
  • Wirral, United Kingdom, CH49 5EP
    • Arrowe Park Hospital
  • Wolverhampton, United Kingdom, WV10 0QP
    • New Cross Hospital
  • Yeovil, United Kingdom, BA21 4AT
    • Yeovil District Hospital
  • York, United Kingdom, YO31 8HE
    • York Hospital
  • Midlothian
    • Edinburgh, Midlothian, United Kingdom, EH16 4SB
      • Edinburgh Royal Infirmary

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Start oral anticoagulant (OAC); 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; The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.; Other Names: Eliquis; Drug: Rivaroxaban; The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.; Other Names: Xarelto; Drug: Edoxaban; The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.; Other Names: Lixiana; Drug: Dabigatran; The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.; Other Names: Pradaxa; Drug: Acenocoumarol; The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.; Other Names: Sinthrome; Drug: Phenindione; The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.; Other Names: Dindevan; Drug: Warfarin; The participant will be allocated to start this oral anticoagulant drug, if the participant's doctor indicated it before randomisation.; Other Names: Marevan; Coumadin
No Intervention: Do not start oral anticoagulant (OAC); 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?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of Symptomatic serious vascular events: (in the safety phase of the trial)	• 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.	1 year after randomisation
The number of Individual symptomatic vascular events: (in the safety phase of the trial)	Major haemorrhagic events (Bleeding Academic Research Consortium types 3-5)Recurrent symptomatic spontaneous intracranial haemorrhageExtracranial haemorrhage; Symptomatic ischaemic eventsischaemic strokemyocardial infarctionperipheral arterial occlusionmesenteric ischaemiacentral retinal arterial occlusiondeep vein thrombosispulmonary embolismcardiac 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-typeNon-fatal stroke, with brain imaging performed too late to distinguish haemorrhage from infarctionRapidly fatal stroke, but without radiographic or pathological confirmation	1 year after randomisation
Annual ratings of participant dependence completed by participant, their carer or nominated contact, or healthcare provider (e.g. general practitioner):	• Simplified modified Rankin Scale	1 year after randomisation
Ratings of participant quality of life completed by participant, their carer or or nominated contact	• The 5-level EQ-5D version (EQ-5D-5L) of the EuroQol	Randomisation and 1 year after randomisation

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: NHS Lothian
• Investigators: Principal Investigator: Rustam Al-Shahi Salman, MA PhD FRCP, University of Edinburgh

Publications and helpful links

General Publications

• Li L, Poon MTC, Samarasekera NE, Perry LA, Moullaali TJ, Rodrigues MA, Loan JJM, Stephen J, Lerpiniere C, Tuna MA, Gutnikov SA, Kuker W, Silver LE, Al-Shahi Salman R, Rothwell PM. Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies. Lancet Neurol. 2021 Jun;20(6):437-447. doi: 10.1016/S1474-4422(21)00075-2. Erratum In: Lancet Neurol. 2021 Jun 9;:
• SoSTART Collaboration. Effects of oral anticoagulation for atrial fibrillation after spontaneous intracranial haemorrhage in the UK: a randomised, open-label, assessor-masked, pilot-phase, non-inferiority trial. Lancet Neurol. 2021 Oct;20(10):842-853. doi: 10.1016/S1474-4422(21)00264-7. Epub 2021 Sep 3.

Helpful Links

• Trial website
• Chief investigator details

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2018
• Primary Completion (Actual): March 26, 2021
• Study Completion (Actual): March 26, 2021

Study Registration Dates

• First Submitted: May 10, 2017
• First Submitted That Met QC Criteria: May 12, 2017
• First Posted (Actual): May 15, 2017

Study Record Updates

• Last Update Posted (Actual): April 8, 2022
• Last Update Submitted That Met QC Criteria: March 31, 2022
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Oral anticoagulant; Vitamin K antagonist; Factor Xa inhibitors; Direct thrombin inhibitor; Antiplatelet drug
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Arrhythmias, Cardiac; Intracranial Hemorrhage, Traumatic; Atrial Fibrillation; Hemorrhage; Intracranial Hemorrhages; Subarachnoid Hemorrhage; Cerebrovascular Disorders; Atrial Flutter; Cerebral Small Vessel Diseases; Hematoma; Hematoma, Subdural; Intracranial Hemorrhage, Hypertensive; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Dabigatran; Apixaban; Edoxaban; Warfarin; Acenocoumarol; Phenindione
• Other Study ID Numbers: SoSTART2016; 2016-004121-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The Chief Investigator (Prof. Rustam Al-Shahi Salman) has established the Collaboration Of Controlled Randomised trials of Oral Antithrombotic drugs after intraCranial Haemorrhage (COCROACH) working towards a pre-planned individual patient data meta-analysis

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No