Clinical trial NCT03759938: OPTIMAS: OPtimal TIMing of Anticoagulation After Acute Ischaemic Stroke : a Randomised Controlled Trial
Official title: OPtimal TIMing of Anticoagulation After Acute Ischaemic Stroke: a Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Stroke, Acute
Atrial Fibrillation
Keywords: ischaemic stroke, atrial fibrilation
Lead sponsor: University College, London
Sponsor class: OTHER
First posted: 2018-11-30
Enrollment: 3648
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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 practice
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Composite outcome of the combined incidence of:recurrent symptomatic ischaemic stroke,symptomatic intracranial haemorrhage and systemic embolism
timeFrame: At 90 days from randomisation
Secondary outcomes:
measure: All-cause mortality
timeFrame: At 90 days from randomisation
measure: Incidence of vascular death
timeFrame: At 90 days from randomisation
measure: Incidence of recurrent ischaemic stroke
timeFrame: At 90 days from randomisation
measure: Incidence of systemic embolism
timeFrame: At 90 days from randomisation
measure: Incidence of venous thromboembolism (deep vein thrombosis [DVT], pulmonary embolism [PE], cerebral venous thrombosis [CVT])
timeFrame: At 90 days from randomisation
measure: Functional status assessed by the modified Rankin scale (mRS) in both arms
timeFrame: At 90 days from randomisation
measure: Cognitive ability assessed by the Montreal Cognitive Assessment (MoCA) questionnaire in both arms
timeFrame: At 90 days from randomisation
measure: Quality of life at 90 days assessed by EuroQol 5 Dimensions 5 level questionnaire [EQ-5D-5L] in both arms
timeFrame: At 90 days from randomisation
measure: Patient reported outcomes assessed by the Patient-Reported Outcomes Measurement Information System Global Health questionnaire (PROMIS-10) in both arms.
timeFrame: At 90 days from randomisation
measure: Ongoing anticoagulation
timeFrame: At 90 days from randomisation
measure: Time to first incidence of primary outcome component (recurrent ischaemic stroke, systemic embolism, or sICH)
timeFrame: At 90 days from randomisation
measure: Length of hospital stay for stroke-related care
timeFrame: At 90 days from randomisation
measure: Health and social care resource use
timeFrame: At 90 days from randomisation
measure: Incidence of symptomatic intracranial haemorrhage (sICH)
timeFrame: At 90 days from randomisation
measure: Incidence of major extracranial bleeding
timeFrame: At 90 days from randomisation
measure: Incidence of all major bleeding (intracranial and extracranial)
timeFrame: At 90 days from randomisation
measure: Incidence of clinically relevant non-major bleeding
timeFrame: At 90 days from randomisation
Other outcomes:
measure: Ongoing anticoagulation at 90 days
timeFrame: At 90 days from randomisation
measure: Individual cognitive domain subscores
timeFrame: At 90 days from randomisation
Locations:
city: Aberystwyth
country: United Kingdom
facility: Bronglais General Hospital, Hywel Dda University Health Board
city: Bath
country: United Kingdom
facility: Royal United Hospitals Bath NHS Foundation Trust
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital,University Hospitals Birmingham NHS Foundation
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital, Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust
city: Bradford
country: United Kingdom
facility: Bradford Royal Infirmary, Bradford Teaching Hospitals NHS Foundation Trust
city: Broomfield
country: United Kingdom
facility: Broomfield Hospital, Mid Essex Hospital Services NHS Trust
city: Bury Saint Edmunds
country: United Kingdom
facility: West Suffolk Hospital, West Suffolk NHS Foundation Trust
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital NHS Trust
city: Carmarthen
country: United Kingdom
facility: Glangwili General Hospita, Hywel Dda University Health Boardl
city: Chertsey
country: United Kingdom
facility: St Peter's Hospital, Ashford and St. Peter's Hospitals NHS Foundation Trust
city: Derby
country: United Kingdom
facility: Royal Derby Hospital, University Hospitals of Derby and Burton NHS Foundation Trust
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter NHS Foundation Trust
city: Haverfordwest
country: United Kingdom
facility: Withybush General Hospital, Hywel Dda University Health Board
city: High Wycombe
country: United Kingdom
facility: Wycombe Hospital, Buckinghamshire Healthcare NHS Trust
city: King's Lynn
country: United Kingdom
facility: Queen Elizabeth Hospital Kings Lynn NHS Trust
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust
city: Liverpool
country: United Kingdom
facility: Royal Liverpool and Broadgreen University Hospitals NHS Trust
city: Llanelli
country: United Kingdom
facility: Prince Philip Hospital, Hywel Dda University Health Board
city: London
country: United Kingdom
facility: The Royal London Hospital, Barts Health NHS Trust
city: London
country: United Kingdom
facility: Northwick Park Hospital, London North West Healthcare NHS Trust
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: St George's University Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Charing Cross Hospital, Imperial College Healthcare NHS Trust
city: Luton
country: United Kingdom
facility: Luton and Dunstable University Hospital NHS Foundation Trust
city: Middlesbrough
country: United Kingdom
facility: The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust
city: Milton Keynes
country: United Kingdom
facility: Milton Keynes University Hospital NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust
city: Plymouth
country: United Kingdom
facility: Derriford Hospital University Hospitals Plymouth NHS Trust
city: Poole
country: United Kingdom
facility: Poole Hospital NHS Foundation Trust
city: Preston
country: United Kingdom
facility: Royal Preston Hospital, Lancashire Teaching Hospitals
city: Reading
country: United Kingdom
facility: Royal Berkshire NHS Foundation Trust
city: Salford
country: United Kingdom
facility: Salford Royal Hospital, Salford Royal NHS Foundation Trust
city: Salisbury
country: United Kingdom
facility: Salisbury District Hospital, Salisbury NHS Foundation Trust
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust
city: Southend-on-Sea
country: United Kingdom
facility: Southend University Hospital NHS Foundation Trust
city: Sutton in Ashfield
country: United Kingdom
facility: Kings Mill Hospital, Sherwood Forest Hospitals NHS Foundation Trust
city: Swansea
country: United Kingdom
facility: Morriston Hospital, Swansea Bay University Health Board
city: Torquay
country: United Kingdom
facility: Torbay Hospital, Torbay and South Devon NHS Foundation
city: Upton
country: United Kingdom
facility: Arrowe Park Hospital, Wirral University Teaching Hospital NHS Foundation Trust
city: Watford
country: United Kingdom
facility: Watford General Hospital, West Hertfordshire Hospitals NHS Trust
city: Winchester
country: United Kingdom
facility: Royal Hampshire County Hospital, Hampshire Hospitals NHS Foundation Trust
city: Wrexham
country: United Kingdom
facility: Wrexham Maelor Hospital, Betsi Cadwaladr University Health Board
city: York
country: United Kingdom
facility: York Teaching Hospital NHS Foundation Trust
Study officials:
affiliation: UCL
name: David Werring, Prof
role: STUDY_CHAIR
References:
citation: 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.