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

Sponsor

University College, London (Other)

Overall Status

Recruiting

CT.gov ID

NCT03759938

Collaborator

(none)

3,478

Enrollment

Locations

Arms

39.4

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Stroke, Acute Atrial Fibrillation	Drug: Direct oral anticoagulant (DOAC)	N/A

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 Design

Study Type:

Interventional

Anticipated Enrollment :

3478 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Patients will be randomised in a 1:1 ratio to intervention or control arms of the study. Participants and their physicians will not be blinded to study arm allocation.The exact timing of anticoagulation within the period specified for the allocated study arm is at the discretion of the treating physician, as is the choice of DOAC. Apart from the timing of DOAC initiation, the DOAC should be prescribed in accordance with usual clinical practicePatients will be randomised in a 1:1 ratio to intervention or control arms of the study. Participants and their physicians will not be blinded to study arm allocation.The exact timing of anticoagulation within the period specified for the allocated study arm is at the discretion of the treating physician, as is the choice of DOAC. Apart from the timing of DOAC initiation, the DOAC should be prescribed in accordance with usual clinical practice

Masking:

Single (Outcomes Assessor)

Masking Description:

The Event Adjudication Committee is a study group (of at least three members) responsible for the review of clinical events to ensure consistent, standardized, objective and unbiased results throughout all participating sites and minimise the likelihood of discrepant interpretations. This group consists of a panel of experts who have the relevant therapeutic area expertise, are experienced in clinical trials, and have been trained on the specific study protocol. The Event Adjudication Committee will centrally review events reported using all available clinical and imaging data and evaluate efficacy and/ or safety endpoints in a blinded and unbiased manner on a regular basis to ensure accurate, consistent and standardized assessments of important study events such as recurrent symptomatic ischaemic stroke, systemic embolism and death.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 18, 2019

Anticipated Primary Completion Date :

Sep 30, 2022

Anticipated Study Completion Date :

Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Early initiation of 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	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. Other Names: dabigatran, apixaban, edoxaban, rivaroxaban
Active Comparator: Standard Initiation of 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).	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. Other Names: dabigatran, apixaban, edoxaban, rivaroxaban

Arm

Intervention/Treatment

Experimental: Early initiation of 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

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.

Other Names:

dabigatran, apixaban, edoxaban, rivaroxaban

Active Comparator: Standard Initiation of 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).

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.

Other Names:

dabigatran, apixaban, edoxaban, rivaroxaban

Outcome Measures

Primary Outcome Measures

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

All-cause mortality [At 90 days from randomisation]
All cause mortality 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
Incidence of systemic embolism [At 90 days from randomisation]
Any incidence of incidence of systemic embolism 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
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.
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.
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.
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.
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
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
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
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 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
Incidence of clinically relevant non-major bleeding [At 90 days from randomisation]
Incidence of clinically relevant non-major bleeding reported in both arms

Other Outcome Measures

Ongoing anticoagulation at 90 days [At 90 days from randomisation]
Ongoing anticoagulation at 90 days assessed by patient self-reporting and/ or follow up patient medical records if necessary.
Individual cognitive domain subscores [At 90 days from randomisation]
Individual cognitive domain subscores measured using the MoCA questionnaire

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Aged 18 years or over
Clinical diagnosis of acute ischaemic stroke
AF, confirmed by any of:
12-lead ECG recording
Inpatient ECG telemetry
Other prolonged ECG monitoring technique (e.g. Holter monitor)
Known diagnosis of atrial fibrillation verified by medical records (e.g. primary care records, letter from secondary care)
Eligibility to commence DOAC in accordance with approved prescribing recommendations confirmed by treating physician
Uncertainty on the part of the treating physician regarding early versus standard initiation of DOAC.

Exclusion Criteria:

Contraindication to anticoagulation:
Coagulopathy or current or recent anticoagulation with vitamin K antagonist (VKA) leading to INR ≥1.7 at randomisation.
Thrombocytopenia (platelets < 75 x 10⁹/L)
Other coagulopathy or bleeding tendency (based on clinical history or laboratory parameters) judged to contraindicate anticoagulation by treating clinician
Contraindication to early anticoagulation
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)
Presence of clinically significant intracranial haemorrhage unrelated to qualifying infarct
Any other contraindication to early anticoagulation as judged by the treating clinician
Contraindication to use of DOAC:
Known allergy or intolerance to both Factor Xa inhibitor and direct thrombin inhibitor
Definite indication for VKA treatment e.g. mechanical heart valve, valvular AF, antiphospholipid syndrome
Severe renal impairment with creatinine clearance (Cockcroft & Gault formula) <15 mL/min (i.e. 14 mL/min or less)
Liver function tests ALT > 2x ULN
Cirrhotic patients with Child Pugh score equating to grade B or C
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

Pregnant or breastfeeding women
Presence on acute brain imaging of non-stroke pathology judged likely to explain clinical presentation (e.g. mass lesion, encephalitis)
Inability for patient to be followed up within 90 days of trial entry
Patient or representative refusal to consent to study procedures, including the site informing GP and healthcare professional responsible for anticoagulation care of participants
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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Bronglais General Hospital, Hywel Dda University Health Board	Aberystwyth	United Kingdom	SY23 1ER
2	Royal United Hospitals Bath NHS Foundation Trust	Bath	United Kingdom	BA1 3NG
3	Queen Elizabeth Hospital,University Hospitals Birmingham NHS Foundation	Birmingham	United Kingdom	B15 2TH
4	Royal Bournemouth Hospital, Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust	Bournemouth	United Kingdom	BH7 7DW
5	Bradford Royal Infirmary, Bradford Teaching Hospitals NHS Foundation Trust	Bradford	United Kingdom	BD9 6RJ
6	Broomfield Hospital, Mid Essex Hospital Services NHS Trust	Broomfield	United Kingdom	CM1 7ET
7	West Suffolk Hospital, West Suffolk NHS Foundation Trust	Bury Saint Edmunds	United Kingdom	IP33 2QZ
8	Addenbrooke's Hospital NHS Trust	Cambridge	United Kingdom	CB2 0QQ
9	Glangwili General Hospita, Hywel Dda University Health Boardl	Carmarthen	United Kingdom	SA31 2AF
10	St Peter's Hospital, Ashford and St. Peter's Hospitals NHS Foundation Trust	Chertsey	United Kingdom	KT16 0PZ
11	Royal Derby Hospital, University Hospitals of Derby and Burton NHS Foundation Trust	Derby	United Kingdom	DE22 3NE
12	Royal Devon & Exeter NHS Foundation Trust	Exeter	United Kingdom	EX2 5DW
13	Withybush General Hospital, Hywel Dda University Health Board	Haverfordwest	United Kingdom	SA61 2PZ
14	Wycombe Hospital, Buckinghamshire Healthcare NHS Trust	High Wycombe	United Kingdom	HP11 2TT
15	Queen Elizabeth Hospital Kings Lynn NHS Trust	King's Lynn	United Kingdom	PE30 4ET
16	Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust	Leicester	United Kingdom	LE1 5WW
17	Royal Liverpool and Broadgreen University Hospitals NHS Trust	Liverpool	United Kingdom	L7 8XP
18	Prince Philip Hospital, Hywel Dda University Health Board	Llanelli	United Kingdom	SA14 8QF
19	The Royal London Hospital, Barts Health NHS Trust	London	United Kingdom	E1 1FR
20	Northwick Park Hospital, London North West Healthcare NHS Trust	London	United Kingdom	HA1 3UJ
21	University College London Hospitals NHS Foundation Trust	London	United Kingdom	NW1 2BU
22	St George's University Hospitals NHS Foundation Trust	London	United Kingdom	SW17 0QT
23	Charing Cross Hospital, Imperial College Healthcare NHS Trust	London	United Kingdom	W6 8RF
24	Luton and Dunstable University Hospital NHS Foundation Trust	Luton	United Kingdom	LU4 0DZ
25	The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust	Middlesbrough	United Kingdom	TS4 3BW
26	Milton Keynes University Hospital NHS Foundation Trust	Milton Keynes	United Kingdom	MK6 5LD
27	Nottingham University Hospitals NHS Trust	Nottingham	United Kingdom	NG7 2UH
28	Derriford Hospital University Hospitals Plymouth NHS Trust	Plymouth	United Kingdom	PL6 8DH
29	Poole Hospital NHS Foundation Trust	Poole	United Kingdom	BH15 2JB
30	Royal Preston Hospital, Lancashire Teaching Hospitals	Preston	United Kingdom	PR2 9HT
31	Royal Berkshire NHS Foundation Trust	Reading	United Kingdom	RG1 5AN
32	Salford Royal Hospital, Salford Royal NHS Foundation Trust	Salford	United Kingdom	M6 8HD
33	Salisbury District Hospital, Salisbury NHS Foundation Trust	Salisbury	United Kingdom	SP2 8BJ
34	Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust	Sheffield	United Kingdom	S10 2JF
35	University Hospital Southampton NHS Foundation Trust	Southampton	United Kingdom	SO16 6YD
36	Southend University Hospital NHS Foundation Trust	Southend-on-Sea	United Kingdom	SS0 0RY
37	Kings Mill Hospital, Sherwood Forest Hospitals NHS Foundation Trust	Sutton in Ashfield	United Kingdom	NG17 4JL
38	Morriston Hospital, Swansea Bay University Health Board	Swansea	United Kingdom	SA6 6NL
39	Torbay Hospital, Torbay and South Devon NHS Foundation	Torquay	United Kingdom	TQ2 7AA
40	Arrowe Park Hospital, Wirral University Teaching Hospital NHS Foundation Trust	Upton	United Kingdom	CH49 5PE
41	Watford General Hospital, West Hertfordshire Hospitals NHS Trust	Watford	United Kingdom	WD18 0HB
42	Royal Hampshire County Hospital, Hampshire Hospitals NHS Foundation Trust	Winchester	United Kingdom	SO22 5DG
43	Wrexham Maelor Hospital, Betsi Cadwaladr University Health Board	Wrexham	United Kingdom	LL 13 7TD
44	York Teaching Hospital NHS Foundation Trust	York	United Kingdom	YO31 8HE