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

Not Applicable

Active, not recruiting

• Conditions: Stroke, Acute; Atrial Fibrillation
• Interventions: Drug: Direct oral anticoagulant (DOAC)

• Registration Number: NCT03759938
• Lead Sponsor: University College, London

Brief 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.

Detailed 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.

Study Timeline

• Study First Submitted: 2018-11-27
• Study First Submitted QC: 2018-11-29
• Study First Posted: 2018-11-30
• Study Start: 2019-06-18
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-13
• Last Update Posted: 2024-05-14
• Primary Completion: 2024-05-30
• Study Completion: 2024-10-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 3648

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 10⁹/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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Early initiation of DOAC	Direct oral anticoagulant (DOAC)	Early initiation of any direct oral anticoagulant (DOAC) at a dose licensed for stroke prevention in AF, within four days (96hrs) of onset of acute ischaemic stroke
Standard Initiation of DOAC	Direct oral anticoagulant (DOAC)	Standard initiation of any DOAC at a dose licensed for stroke prevention in AF, no sooner than day 7 and no later than day 14 after the onset of acute ischaemic stroke (i.e. between 144hrs and 336hrs from onset).

Primary Outcome Measures

Name	Time	Method
Composite outcome of the combined incidence of:recurrent symptomatic ischaemic stroke,symptomatic intracranial haemorrhage and systemic embolism	At 90 days from randomisation	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.

Secondary Outcome Measures

Name	Time	Method
All-cause mortality	At 90 days from randomisation	All cause mortality reported in both arms
Incidence of systemic embolism	At 90 days from randomisation	Any incidence of incidence of systemic embolism reported in both arms
Incidence of vascular death	At 90 days from randomisation	Any incidence of vascular death reported in both arms
Incidence of recurrent ischaemic stroke	At 90 days from randomisation	Any incidence of recurrent ischaemic stroke reported in both arms
Functional status assessed by the modified Rankin scale (mRS) in both arms	At 90 days from randomisation	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.
Quality of life at 90 days assessed by EuroQol 5 Dimensions 5 level questionnaire [EQ-5D-5L] in both arms	At 90 days from randomisation	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.
Incidence of symptomatic intracranial haemorrhage (sICH)	At 90 days from randomisation	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
Incidence of major extracranial bleeding	At 90 days from randomisation	Incidence of major extracranial bleeding reported in both arms
Incidence of clinically relevant non-major bleeding	At 90 days from randomisation	Incidence of clinically relevant non-major bleeding reported in both arms
Cognitive ability assessed by the Montreal Cognitive Assessment (MoCA) questionnaire in both arms	At 90 days from randomisation	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.
Incidence of all major bleeding (intracranial and extracranial)	At 90 days from randomisation	Incidence of all major bleeding (intracranial and extracranial) reported during the study period, in both arms
Time to first incidence of primary outcome component (recurrent ischaemic stroke, systemic embolism, or sICH)	At 90 days from randomisation	Time to first incidence of primary outcome component (recurrent ischaemic stroke, systemic embolism, or sICH) reported in both arms
Incidence of venous thromboembolism (deep vein thrombosis [DVT], pulmonary embolism [PE], cerebral venous thrombosis [CVT])	At 90 days from randomisation	Any of Incidence of venous thromboembolism (deep vein thrombosis \[DVT\], pulmonary embolism \[PE\], cerebral venous thrombosis \[CVT\]) reported in both arms
Ongoing anticoagulation	At 90 days from randomisation	Ongoing anticoagulation will be assessed based on patient self-reporting and follow up patient medical records if necessary in both arms
Length of hospital stay for stroke-related care	At 90 days from randomisation	Length of hospital stay for stroke-related care in both arms
Health and social care resource use	At 90 days from randomisation	Health and social care resources (assessed by a study specific questionnaire) in both arms
Patient reported outcomes assessed by the Patient-Reported Outcomes Measurement Information System Global Health questionnaire (PROMIS-10) in both arms.	At 90 days from randomisation	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.

Trial Locations

Locations (44)

St George's University Hospitals NHS Foundation Trust; 🇬🇧 London, United Kingdom

Royal Devon & Exeter NHS Foundation Trust; 🇬🇧 Exeter, United Kingdom

University College London Hospitals NHS Foundation Trust; 🇬🇧 London, United Kingdom

Charing Cross Hospital, Imperial College Healthcare NHS Trust; 🇬🇧 London, United Kingdom

Bronglais General Hospital, Hywel Dda University Health Board; 🇬🇧 Aberystwyth, United Kingdom

Royal United Hospitals Bath NHS Foundation Trust; 🇬🇧 Bath, United Kingdom

Bradford Royal Infirmary, Bradford Teaching Hospitals NHS Foundation Trust; 🇬🇧 Bradford, United Kingdom

Addenbrooke's Hospital NHS Trust; 🇬🇧 Cambridge, United Kingdom

Royal Bournemouth Hospital, Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust; 🇬🇧 Bournemouth, United Kingdom

Queen Elizabeth Hospital,University Hospitals Birmingham NHS Foundation; 🇬🇧 Birmingham, United Kingdom

West Suffolk Hospital, West Suffolk NHS Foundation Trust; 🇬🇧 Bury Saint Edmunds, United Kingdom

Glangwili General Hospita, Hywel Dda University Health Boardl; 🇬🇧 Carmarthen, United Kingdom

Broomfield Hospital, Mid Essex Hospital Services NHS Trust; 🇬🇧 Broomfield, 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

Withybush General Hospital, Hywel Dda University Health Board; 🇬🇧 Haverfordwest, 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

Wycombe Hospital, Buckinghamshire Healthcare NHS Trust; 🇬🇧 High Wycombe, United Kingdom

Queen Elizabeth Hospital Kings Lynn NHS Trust; 🇬🇧 King's Lynn, United Kingdom

Prince Philip Hospital, Hywel Dda University Health Board; 🇬🇧 Llanelli, United Kingdom

Northwick Park Hospital, London North West Healthcare NHS Trust; 🇬🇧 London, United Kingdom

The Royal London Hospital, Barts Health NHS 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

Derriford Hospital University Hospitals Plymouth NHS Trust; 🇬🇧 Plymouth, United Kingdom

Royal Berkshire NHS Foundation Trust; 🇬🇧 Reading, United Kingdom

Salisbury District Hospital, Salisbury NHS Foundation Trust; 🇬🇧 Salisbury, United Kingdom

Milton Keynes University Hospital NHS Foundation Trust; 🇬🇧 Milton Keynes, United Kingdom

Royal Preston Hospital, Lancashire Teaching Hospitals; 🇬🇧 Preston, United Kingdom

Poole Hospital NHS Foundation Trust; 🇬🇧 Poole, United Kingdom

Nottingham University Hospitals NHS Trust; 🇬🇧 Nottingham, United Kingdom

Salford Royal Hospital, Salford Royal NHS Foundation Trust; 🇬🇧 Salford, United Kingdom

University Hospital Southampton NHS Foundation Trust; 🇬🇧 Southampton, United Kingdom

Kings Mill Hospital, Sherwood Forest Hospitals NHS Foundation Trust; 🇬🇧 Sutton in Ashfield, United Kingdom

Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust; 🇬🇧 Sheffield, United Kingdom

Southend University Hospital NHS Foundation Trust; 🇬🇧 Southend-on-Sea, 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

Wrexham Maelor Hospital, Betsi Cadwaladr University Health Board; 🇬🇧 Wrexham, United Kingdom

York Teaching Hospital NHS Foundation Trust; 🇬🇧 York, 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