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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Atrial Fibrillation; Stroke, Acute
• Intervention / Treatment: Drug: Direct oral anticoagulant (DOAC)

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 Type: Interventional
• Enrollment (Anticipated): 3478
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marisa Chau; Phone Number: 64618 +44 20 7670 4618; Email: ctu.optimas@ucl.ac.uk

Study Locations

• United Kingdom
  • Aberystwyth, United Kingdom, SY23 1ER
    • Recruiting
    • Bronglais General Hospital, Hywel Dda University Health Board
    • Contact: Phil Jones
  • Bath, United Kingdom, BA1 3NG
    • Recruiting
    • Royal United Hospitals Bath NHS Foundation Trust
    • Contact: Lukuman Gbadamoshi
  • Birmingham, United Kingdom, B15 2TH
    • Recruiting
    • Queen Elizabeth Hospital,University Hospitals Birmingham NHS Foundation
    • Contact: Dom Sims
  • Bournemouth, United Kingdom, BH7 7DW
    • Recruiting
    • Royal Bournemouth Hospital, Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
    • Contact: Kamy Thavanesan
  • Bradford, United Kingdom, BD9 6RJ
    • Recruiting
    • Bradford Royal Infirmary, Bradford Teaching Hospitals NHS Foundation Trust
    • Contact: Stuart Maguire
  • Broomfield, United Kingdom, CM1 7ET
    • Recruiting
    • Broomfield Hospital, Mid Essex Hospital Services NHS Trust
    • Contact: Madan Meegada
  • Bury Saint Edmunds, United Kingdom, IP33 2QZ
    • Recruiting
    • West Suffolk Hospital, West Suffolk NHS Foundation Trust
    • Contact: Abul Azim
  • Cambridge, United Kingdom, CB2 0QQ
    • Recruiting
    • Addenbrooke's Hospital NHS Trust
    • Contact: Eoin O'Brien
  • Carmarthen, United Kingdom, SA31 2AF
    • Recruiting
    • Glangwili General Hospita, Hywel Dda University Health Boardl
    • Contact: Pagadala Sridhar
  • Chertsey, United Kingdom, KT16 0PZ
    • Recruiting
    • St Peter's Hospital, Ashford and St. Peter's Hospitals NHS Foundation Trust
    • Contact: Giosue Gulli
  • Derby, United Kingdom, DE22 3NE
    • Recruiting
    • Royal Derby Hospital, University Hospitals of Derby and Burton NHS Foundation Trust
    • Contact: Tim England
  • Exeter, United Kingdom, EX2 5DW
    • Recruiting
    • Royal Devon & Exeter NHS Foundation Trust
    • Contact: Martin James
  • Haverfordwest, United Kingdom, SA61 2PZ
    • Recruiting
    • Withybush General Hospital, Hywel Dda University Health Board
    • Contact: Christopher James
  • High Wycombe, United Kingdom, HP11 2TT
    • Recruiting
    • Wycombe Hospital, Buckinghamshire Healthcare NHS Trust
    • Contact: Maria Tuna
  • King's Lynn, United Kingdom, PE30 4ET
    • Recruiting
    • Queen Elizabeth Hospital Kings Lynn NHS Trust
    • Contact: Raj Shekhar
  • Leicester, United Kingdom, LE1 5WW
    • Recruiting
    • Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust
    • Contact: Eveson David
  • Liverpool, United Kingdom, L7 8XP
    • Recruiting
    • Royal Liverpool and Broadgreen University Hospitals NHS Trust
    • Contact: Aravind Manoj
  • Llanelli, United Kingdom, SA14 8QF
    • Recruiting
    • Prince Philip Hospital, Hywel Dda University Health Board
    • Contact: Senthil Subbarayan
  • London, United Kingdom, NW1 2BU
    • Recruiting
    • University College London Hospitals NHS Foundation Trust
    • Contact: David Werring; Phone Number: 020 3108 6255; Email: d.werring@ucl.ac.uk
  • London, United Kingdom, W6 8RF
    • Recruiting
    • Charing Cross Hospital, Imperial College Healthcare NHS Trust
    • Contact: Soma Banerjee
  • London, United Kingdom, SW17 0QT
    • Recruiting
    • St George's University Hospitals NHS Foundation Trust
    • Contact: Liqun Zhang
  • London, United Kingdom, E1 1FR
    • Recruiting
    • The Royal London Hospital, Barts Health NHS Trust
    • Contact: Sageet Amlani
  • London, United Kingdom, HA1 3UJ
    • Recruiting
    • Northwick Park Hospital, London North West Healthcare NHS Trust
    • Contact: Sumanjit Gill
  • Luton, United Kingdom, LU4 0DZ
    • Recruiting
    • Luton and Dunstable University Hospital NHS Foundation Trust
    • Contact: Lakshmanan Sekaran
  • Middlesbrough, United Kingdom, TS4 3BW
    • Recruiting
    • The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust
    • Contact: Samer Al Hussayni
  • Milton Keynes, United Kingdom, MK6 5LD
    • Recruiting
    • Milton Keynes University Hospital NHS Foundation Trust
    • Contact: Yousif Behnam
  • Nottingham, United Kingdom, NG7 2UH
    • Recruiting
    • Nottingham University Hospitals NHS Trust
    • Contact: Ashit Shetty
  • Plymouth, United Kingdom, PL6 8DH
    • Recruiting
    • Derriford Hospital University Hospitals Plymouth NHS Trust
    • Contact: Alex Shah
  • Poole, United Kingdom, BH15 2JB
    • Recruiting
    • Poole Hospital NHS Foundation Trust
    • Contact: Suzanne Ragab
  • Preston, United Kingdom, PR2 9HT
    • Recruiting
    • Royal Preston Hospital, Lancashire Teaching Hospitals
    • Contact: Hedley Emsley
  • Reading, United Kingdom, RG1 5AN
    • Recruiting
    • Royal Berkshire NHS foundation trust
    • Contact: Nagaratnam Kirubanathan
  • Salford, United Kingdom, M6 8HD
    • Recruiting
    • Salford Royal Hospital, Salford Royal NHS Foundation Trust
    • Contact: Amit Kishore
  • Salisbury, United Kingdom, SP2 8BJ
    • Recruiting
    • Salisbury District Hospital, Salisbury NHS Foundation Trust
    • Contact: Toby Black
  • Sheffield, United Kingdom, S10 2JF
    • Recruiting
    • Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust
    • Contact: Kirsty Harkness
  • Southampton, United Kingdom, SO16 6YD
    • Recruiting
    • University Hospital Southampton NHS Foundation Trust
    • Contact: Richard Marigold
  • Southend-on-Sea, United Kingdom, SS0 0RY
    • Recruiting
    • Southend University Hospital NHS Foundation Trust
    • Contact: Paul Guyler
  • Sutton in Ashfield, United Kingdom, NG17 4JL
    • Recruiting
    • Kings Mill Hospital, Sherwood Forest Hospitals NHS Foundation Trust
    • Contact: Martin Cooper
  • Swansea, United Kingdom, SA6 6NL
    • Recruiting
    • Morriston Hospital, Swansea Bay University Health Board
    • Contact: Manju Krishnan
  • Torquay, United Kingdom, TQ2 7AA
    • Recruiting
    • Torbay Hospital, Torbay and South Devon NHS Foundation
    • Contact: John France
  • Upton, United Kingdom, CH49 5PE
    • Recruiting
    • Arrowe Park Hospital, Wirral University Teaching Hospital NHS Foundation Trust
    • Contact: Brian Menezes
  • Watford, United Kingdom, WD18 0HB
    • Recruiting
    • Watford General Hospital, West Hertfordshire Hospitals NHS Trust
    • Contact: Mohit Bhandari
  • Winchester, United Kingdom, SO22 5DG
    • Recruiting
    • Royal Hampshire County Hospital, Hampshire Hospitals NHS Foundation Trust
    • Contact: Lucy Sykes
  • Wrexham, United Kingdom, LL 13 7TD
    • Recruiting
    • Wrexham Maelor Hospital, Betsi Cadwaladr University Health Board
    • Contact: Walee Sayed
  • York, United Kingdom, YO31 8HE
    • Recruiting
    • York Teaching Hospital NHS Foundation Trust
    • Contact: Ruhail Mir

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. 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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality	All cause mortality reported in both arms	At 90 days from randomisation
Incidence of vascular death	Any incidence of vascular death reported in both arms	At 90 days from randomisation
Incidence of recurrent ischaemic stroke	Any incidence of recurrent ischaemic stroke reported in both arms	At 90 days from randomisation
Incidence of systemic embolism	Any incidence of incidence of systemic embolism reported in both arms	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	At 90 days from randomisation
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
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
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
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
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
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
Length of hospital stay for stroke-related care	Length of hospital stay for stroke-related care in both arms	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	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	At 90 days from randomisation
Incidence of major extracranial bleeding	Incidence of major extracranial bleeding reported in both arms	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	At 90 days from randomisation
Incidence of clinically relevant non-major bleeding	Incidence of clinically relevant non-major bleeding reported in both arms	At 90 days from randomisation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Individual cognitive domain subscores	Individual cognitive domain subscores measured using the MoCA questionnaire	At 90 days from randomisation

Collaborators and Investigators

• Sponsor: University College, London
• Investigators: Study Chair: David Werring, Prof, UCL

Publications and helpful links

General Publications

• Best JG, Arram L, Ahmed N, Balogun M, Bennett K, Bordea E, Campos MG, Caverly E, Chau M, Cohen H, Dehbi HM, Dore CJ, Engelter ST, Fenner R, Freemantle N, Hunter R, James M, Lip GY, Murray ML, Norrving B, Sprigg N, Veltkamp R, Zaczyk I, Werring DJ; OPTIMAS investigators. Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for a randomized controlled trial. Int J Stroke. 2022 Jun;17(5):583-589. doi: 10.1177/17474930211057722. Epub 2022 Jan 12.

Study record dates

Study Major Dates

• Study Start (Actual): June 18, 2019
• Primary Completion (Anticipated): April 30, 2024
• Study Completion (Anticipated): April 30, 2024

Study Registration Dates

• First Submitted: November 27, 2018
• First Submitted That Met QC Criteria: November 29, 2018
• First Posted (Actual): November 30, 2018

Study Record Updates

• Last Update Posted (Actual): March 15, 2023
• Last Update Submitted That Met QC Criteria: March 14, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: ischaemic stroke, atrial fibrilation
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arrhythmias, Cardiac; Stroke; Ischemic Stroke; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Rivaroxaban; Dabigatran; Apixaban; Edoxaban; Anticoagulants
• Other Study ID Numbers: 18/0316

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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