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

University College London (UCL)

Status: Active, not recruiting

Conditions: Atrial Fibrillation; Stroke, Acute

Treatments: Drug: Direct oral anticoagulant (DOAC)

Study type: Interventional

Funder types: Other

Identifiers

NCT03759938

18/0316

Details and patient eligibility

About

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.

Full 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.

Enrollment: 3,648 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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3,648 participants in 2 patient groups

Early initiation of DOAC

Experimental group

Description:

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

Treatment:

Drug: Direct oral anticoagulant (DOAC)

Standard Initiation of DOAC

Active Comparator group

Description:

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).

Treatment:

Drug: Direct oral anticoagulant (DOAC)