OPTIMAS: OPtimal TIMing of Anticoagulation After Acute Ischaemic Stroke : a Randomised Controlled Trial

Atrial Fibrillation Clinical Trial

— OPTIMAS  

Official title:

OPtimal TIMing of Anticoagulation After Acute Ischaemic Stroke: a Randomised Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03759938
• Other study ID #: 18/0316
• Status: Recruiting
• Phase: N/A
• Start date: June 18, 2019
• Est. completion date: April 30, 2024

Study information

• Verified date: March 2023
• Source: University College, London
• Contact: Marisa Chau
• Phone: +44 20 7670 4618
• Email: ctu.optimas[@]ucl.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

OPTIMAS is a large, prospective, partially blinded randomised controlled trial of early (within ≤4 days [96hrs]) or standard (between day 7 and day 14 after stroke onset) initiation of anticoagulation after stroke in patients with atrial fibrillation (AF), using any licensed dose of a direct oral anticoagulant (DOAC). The trial will use a non-inferiority gatekeeper approach to test for non-inferiority of early anticoagulation followed by a test for superiority, if non-inferiority is established.

Description:

Current guidelines do not provide clear recommendations on the timing of OAC after acute AF-related stroke. Current United Kingdom (UK) guidelines for anticoagulation state that "delay for an arbitrary 2-week period is recommended" for "disabling" stroke and that anticoagulation can be started "no later than 14 days" for other strokes, at the prescriber's discretion. OPTIMAS will investigate whether early initiation of DOAC treatment, within 4 days (96hrs) of onset, in patients with acute ischaemic stroke and AF is as effective as, or better than, standard initiation of DOAC treatment, no sooner than day 7 (>144hrs) and no later than day 14 (<336hrs) after onset, in preventing recurrent ischaemic stroke, systemic embolism and symptomatic intracranial haemorrhage (sICH)? Participants will be randomised 1:1 to the intervention or control. The exact timing of initiating treatment within each group is at the discretion of the treating clinician.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3478
• Est. completion date: April 30, 2024
• Est. primary completion date: April 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Aged 18 years or over

2. Clinical diagnosis of acute ischaemic stroke

3. AF, confirmed by any of:

1. 12-lead ECG recording

2. Inpatient ECG telemetry

3. Other prolonged ECG monitoring technique (e.g. Holter monitor)

4. Known diagnosis of atrial fibrillation verified by medical records (e.g. primary care records, letter from secondary care)

4. Eligibility to commence DOAC in accordance with approved prescribing recommendations confirmed by treating physician

5. Uncertainty on the part of the treating physician regarding early versus standard initiation of DOAC.

Exclusion Criteria:

1. Contraindication to anticoagulation:

1. Coagulopathy or current or recent anticoagulation with vitamin K antagonist (VKA) leading to INR =1.7 at randomisation.

2. Thrombocytopenia (platelets < 75 x 10?/L)

3. Other coagulopathy or bleeding tendency (based on clinical history or laboratory parameters) judged to contraindicate anticoagulation by treating clinician

2. Contraindication to early anticoagulation

1. Known presence of haemorrhagic transformation with parenchymal haematoma occupying >30% of the infarct volume and exerting significant mass effect (i.e. PH2) (NB: HI1, HI2 and PH1 are not considered contraindications)

2. Presence of clinically significant intracranial haemorrhage unrelated to qualifying infarct

3. Any other contraindication to early anticoagulation as judged by the treating clinician

3. Contraindication to use of DOAC:

1. Known allergy or intolerance to both Factor Xa inhibitor and direct thrombin inhibitor

2. Definite indication for VKA treatment e.g. mechanical heart valve, valvular AF, antiphospholipid syndrome

3. Severe renal impairment with creatinine clearance (Cockcroft & Gault formula) <15 mL/min (i.e. 14 mL/min or less)

4. Liver function tests ALT > 2x ULN

5. Cirrhotic patients with Child Pugh score equating to grade B or C

6. Patient is taking medication with significant interaction with DOAC, including:

• Azole antifungals (e.g. ketoconazole, itraconazole)
• HIV protease inhibitors (e.g. ritonavir)
• Strong CYP3A4 inducers (e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort)
• Dronedarone

4. Pregnant or breastfeeding women

5. Presence on acute brain imaging of non-stroke pathology judged likely to explain clinical presentation (e.g. mass lesion, encephalitis)

6. Inability for patient to be followed up within 90 days of trial entry

7. Patient or representative refusal to consent to study procedures, including the site informing GP and healthcare professional responsible for anticoagulation care of participants

8. Any other reason that the PI considers would make the patient unsuitable to enter OPTIMAS. Note that current DOAC treatment is NOT an exclusion criterion, as long as the treating physician considers it appropriate to restart (or continue) according to the timings specified in the OPTIMAS trial protocol. Continuation of the DOAC would be recorded as a start time of zero hours.

Related Conditions & MeSH terms

• Atrial Fibrillation
• Ischemic Stroke
• Stroke
• Stroke, Acute

Intervention

Drug:
• Direct oral anticoagulant (DOAC)
Any of the DOACs listed above may be used for treatment in either study arm. The DOAC will be supplied from normal hospital stock, using local hospital prescriptions.

Locations

Country	Name	City	State
United Kingdom	Bronglais General Hospital, Hywel Dda University Health Board	Aberystwyth
United Kingdom	Royal United Hospitals Bath NHS Foundation Trust	Bath
United Kingdom	Queen Elizabeth Hospital,University Hospitals Birmingham NHS Foundation	Birmingham
United Kingdom	Royal Bournemouth Hospital, Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust	Bournemouth
United Kingdom	Bradford Royal Infirmary, Bradford Teaching Hospitals NHS Foundation Trust	Bradford
United Kingdom	Broomfield Hospital, Mid Essex Hospital Services NHS Trust	Broomfield
United Kingdom	West Suffolk Hospital, West Suffolk NHS Foundation Trust	Bury Saint Edmunds
United Kingdom	Addenbrooke's Hospital NHS Trust	Cambridge
United Kingdom	Glangwili General Hospita, Hywel Dda University Health Boardl	Carmarthen
United Kingdom	St Peter's Hospital, Ashford and St. Peter's Hospitals NHS Foundation Trust	Chertsey
United Kingdom	Royal Derby Hospital, University Hospitals of Derby and Burton NHS Foundation Trust	Derby
United Kingdom	Royal Devon & Exeter NHS Foundation Trust	Exeter
United Kingdom	Withybush General Hospital, Hywel Dda University Health Board	Haverfordwest
United Kingdom	Wycombe Hospital, Buckinghamshire Healthcare NHS Trust	High Wycombe
United Kingdom	Queen Elizabeth Hospital Kings Lynn NHS Trust	King's Lynn
United Kingdom	Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust	Leicester
United Kingdom	Royal Liverpool and Broadgreen University Hospitals NHS Trust	Liverpool
United Kingdom	Prince Philip Hospital, Hywel Dda University Health Board	Llanelli
United Kingdom	Charing Cross Hospital, Imperial College Healthcare NHS Trust	London
United Kingdom	Northwick Park Hospital, London North West Healthcare NHS Trust	London
United Kingdom	St George's University Hospitals NHS Foundation Trust	London
United Kingdom	The Royal London Hospital, Barts Health NHS Trust	London
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	Luton and Dunstable University Hospital NHS Foundation Trust	Luton
United Kingdom	The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust	Middlesbrough
United Kingdom	Milton Keynes University Hospital NHS Foundation Trust	Milton Keynes
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United Kingdom	Derriford Hospital University Hospitals Plymouth NHS Trust	Plymouth
United Kingdom	Poole Hospital NHS Foundation Trust	Poole
United Kingdom	Royal Preston Hospital, Lancashire Teaching Hospitals	Preston
United Kingdom	Royal Berkshire NHS Foundation Trust	Reading
United Kingdom	Salford Royal Hospital, Salford Royal NHS Foundation Trust	Salford
United Kingdom	Salisbury District Hospital, Salisbury NHS Foundation Trust	Salisbury
United Kingdom	Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust	Sheffield
United Kingdom	University Hospital Southampton NHS Foundation Trust	Southampton
United Kingdom	Southend University Hospital NHS Foundation Trust	Southend-on-Sea
United Kingdom	Kings Mill Hospital, Sherwood Forest Hospitals NHS Foundation Trust	Sutton in Ashfield
United Kingdom	Morriston Hospital, Swansea Bay University Health Board	Swansea
United Kingdom	Torbay Hospital, Torbay and South Devon NHS Foundation	Torquay
United Kingdom	Arrowe Park Hospital, Wirral University Teaching Hospital NHS Foundation Trust	Upton
United Kingdom	Watford General Hospital, West Hertfordshire Hospitals NHS Trust	Watford
United Kingdom	Royal Hampshire County Hospital, Hampshire Hospitals NHS Foundation Trust	Winchester
United Kingdom	Wrexham Maelor Hospital, Betsi Cadwaladr University Health Board	Wrexham
United Kingdom	York Teaching Hospital NHS Foundation Trust	York

Sponsors (1)

Lead Sponsor	Collaborator
University College, London

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Ongoing anticoagulation at 90 days	Ongoing anticoagulation at 90 days assessed by patient self-reporting and/ or follow up patient medical records if necessary.	At 90 days from randomisation
Other	Individual cognitive domain subscores	Individual cognitive domain subscores measured using the MoCA questionnaire	At 90 days from randomisation
Primary	Composite outcome of the combined incidence of:recurrent symptomatic ischaemic stroke,symptomatic intracranial haemorrhage and systemic embolism	OPTIMAS will investigate whether early initiation of DOAC treatment in patients with acute ischaemic stroke and atrial fibrillation is as effective as, or better than, standard initiation of DOAC treatment in preventing recurrent ischaemic stroke, systemic embolism and sICH.	At 90 days from randomisation
Secondary	All-cause mortality	All cause mortality reported in both arms	At 90 days from randomisation
Secondary	Incidence of vascular death	Any incidence of vascular death reported in both arms	At 90 days from randomisation
Secondary	Incidence of recurrent ischaemic stroke	Any incidence of recurrent ischaemic stroke reported in both arms	At 90 days from randomisation
Secondary	Incidence of systemic embolism	Any incidence of incidence of systemic embolism reported in both arms	At 90 days from randomisation
Secondary	Incidence of venous thromboembolism (deep vein thrombosis [DVT], pulmonary embolism [PE], cerebral venous thrombosis [CVT])	Any of Incidence of venous thromboembolism (deep vein thrombosis [DVT], pulmonary embolism [PE], cerebral venous thrombosis [CVT]) reported in both arms	At 90 days from randomisation
Secondary	Functional status assessed by the modified Rankin scale (mRS) in both arms	The Modified Rankin Scale measures the degree of disability and dependence following a stroke. The scale consists of 7 category descriptions, where 0 means no symptoms, 1 means no significant disability, 2 means slight disability, 3 means moderate disability, 4 means moderately severe disability, 5 means severe disability and 6 means death. The assessment is carried out by asking the participant or their carer about their activities of daily living.	At 90 days from randomisation
Secondary	Cognitive ability assessed by the Montreal Cognitive Assessment (MoCA) questionnaire in both arms	The Montreal Cognitive Assessment is a questionnaire widely used as a screening assessment for detecting cognitive impairment. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. An abbreviated version of the MoCA assessing attention, verbal learning, memory, executive functions/language and orientation can be performed over the phone. MoCA scores range between 0 and 30. A score of 26 or over is considered to be normal. In a study and people with mild cognitive impairment (MCI) scored an average of 22.1.	At 90 days from randomisation
Secondary	Quality of life at 90 days assessed by EuroQol 5 Dimensions 5 level questionnaire [EQ-5D-5L] in both arms	The EQ-5D-5L includes 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The EQ VAS records the respondent's self-rated health on a vertical, visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. In instances in which the participant struggles with giving answers on their own, the participant's next-of-kin or a friend who knows the participant well will be asked to complete the EQ-5D-5L proxy version. The proxy is asked to rate how they think the participant would rate their own health-related quality of life, if the participant were able to communicate it. In case a proxy is not available, the research team member who was looking after the participant will complete it on their behalf.	At 90 days from randomisation
Secondary	Patient reported outcomes assessed by the Patient-Reported Outcomes Measurement Information System Global Health questionnaire (PROMIS-10) in both arms.	The PROMIS Global-10 short form consists of 10 items that assess general domains of health and functioning including overall physical health, mental health, social health, pain, fatigue, and overall perceived quality of life. The scoring system of the PROMIS Global-10 allows each of the individual items to be examined separately to provide specific information about perceptions of physical function, pain, fatigue, emotional distress, social health and general perceptions of health where 0 means never experienced this problem or symptoms and 1 means always. The higher score for each response indicate better health.	At 90 days from randomisation
Secondary	Ongoing anticoagulation	Ongoing anticoagulation will be assessed based on patient self-reporting and follow up patient medical records if necessary in both arms	At 90 days from randomisation
Secondary	Time to first incidence of primary outcome component (recurrent ischaemic stroke, systemic embolism, or sICH)	Time to first incidence of primary outcome component (recurrent ischaemic stroke, systemic embolism, or sICH) reported in both arms	At 90 days from randomisation
Secondary	Length of hospital stay for stroke-related care	Length of hospital stay for stroke-related care in both arms	At 90 days from randomisation
Secondary	Health and social care resource use	Health and social care resources (assessed by a study specific questionnaire) in both arms	At 90 days from randomisation
Secondary	Incidence of symptomatic intracranial haemorrhage (sICH)	Incidence of symptomatic intracranial haemorrhage (sICH) classified according to site intracerebral haemorrhage (within the brain parenchyma); subdural haemorrhage; extradural haemorrhage; subarachnoid haemorrhage; and haemorrhagic transformation of a brain infarct, in both arms	At 90 days from randomisation
Secondary	Incidence of major extracranial bleeding	Incidence of major extracranial bleeding reported in both arms	At 90 days from randomisation
Secondary	Incidence of all major bleeding (intracranial and extracranial)	Incidence of all major bleeding (intracranial and extracranial) reported during the study period, in both arms	At 90 days from randomisation
Secondary	Incidence of clinically relevant non-major bleeding	Incidence of clinically relevant non-major bleeding reported in both arms	At 90 days from randomisation