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

University College, London3,648 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

3,648

Conditions

Stroke, Acute Atrial Fibrillation

Interventions

Direct oral anticoagulant (DOAC)DRUG

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (44)

Outcomes

Primary Outcomes

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.

Time frame: At 90 days from randomisation

Secondary Outcomes

All-cause mortality

All cause mortality reported in both arms

Time frame: At 90 days from randomisation

Incidence of vascular death

Any incidence of vascular death reported in both arms

Time frame: At 90 days from randomisation

Incidence of recurrent ischaemic stroke

Any incidence of recurrent ischaemic stroke reported in both arms

Time frame: At 90 days from randomisation

Incidence of systemic embolism

Any incidence of incidence of systemic embolism reported in both arms

Time frame: At 90 days from randomisation

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

Time frame: At 90 days from randomisation

Functional status assessed by the modified Rankin scale (mRS) in both arms

Data from ClinicalTrials.gov

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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 St 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

...and 34 more locations

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.

Time frame: At 90 days from randomisation

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.

Time frame: At 90 days from randomisation

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.

Time frame: At 90 days from randomisation

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.

Time frame: At 90 days from randomisation

Ongoing anticoagulation

Ongoing anticoagulation will be assessed based on patient self-reporting and follow up patient medical records if necessary in both arms

Time frame: At 90 days from randomisation

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

Time frame: At 90 days from randomisation

Length of hospital stay for stroke-related care

Length of hospital stay for stroke-related care in both arms

Time frame: At 90 days from randomisation

Health and social care resource use

Health and social care resources (assessed by a study specific questionnaire) in both arms

Time frame: At 90 days from randomisation

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

Time frame: At 90 days from randomisation

Incidence of major extracranial bleeding

Incidence of major extracranial bleeding reported in both arms

Time frame: At 90 days from randomisation

Incidence of all major bleeding (intracranial and extracranial)

Incidence of all major bleeding (intracranial and extracranial) reported during the study period, in both arms

Time frame: At 90 days from randomisation

Incidence of clinically relevant non-major bleeding

Incidence of clinically relevant non-major bleeding reported in both arms

Time frame: At 90 days from randomisation