Second Enhanced Control of Hypertension and Thrombectomy Stroke Study (ENCHANTED2)

Objectives: To determine the effectiveness of more intensive BP lowering target (<120 mmHg) compared to higher BP management target (140-180mmHg) on functional outcome in patients with successful recanalization post-MT for AIS due to large vessel occlusion (LVO).

Inclusion Criteria:

1. Age ≥18 years;

2. Diagnosis of AIS with LVO confirmed by brain imaging;

3. Fulfill local criteria for MT therapy;

4. Achieve successful recanalization (TICI score ≥2b) after MT;

5. Provide written informed consent (or approved surrogate);

6. Persistent (2 readings <10 mins) systolic BP ≥140 mmHg <3 hours after recanalization;

7. No definite indication/contraindication to different intensities of BP lowering treatment;

Exclusion Criteria:

1. Unlikely to benefit from therapy (e.g. advanced dementia) or very high likelihood of early death post-MT, judged by responsible treating clinician.

2. Other medical illness that interferes with outcome assessments and follow-up (e.g. known significant pre-stroke disability (mRS scores 3-5), advance cancer and renal failure);

3. Specific contraindications to any of the BP agents to be used (eg, patients who are hypersensitive (allergic) to any of the ingredients);

4. Need for following concomitant medication, including phosphodiesterase inhibitors and monoamine oxidase inhibitors.

5. Patients with aortic isthmus stenosis and arteriovenous shunt (exception: patients with haemodynamically inactive dialysis shunt).

6. Women who are lactating.

7. Currently participating in another trial which would interfere with outcome assessments.

Outcome Measures Primary outcome: functional recovery, defined as a shift (improvement) in scores on the modified Rankin scale (mRS) at 90 days.

Secondary outcomes: any intracranial haemorrhage (ICH), symptomatic intracerebral haemorrhage (sICH), early neurological deterioration, imaging assessment (e.g. infarct size, edema volume), death, disability, HRQoL, duration of hospitalization, residence; and health service use for calculation of resources and costs.

Randomisation and intervention: Randomisation is via a central internet-based system, stratified by site, time from symptom onset to recanalization (<6, ≥6 hours), baseline neurological impairment on the National Institutes for Health Stroke Scale (NIHSS, <17 vs ≥17), to ensure balance in key prognostic factors.

Intensive BP lowering group: to commence intravenous BP lowering therapy immediately after randomization, with systolic BP target (<120 mmHg) achieved within 30 minutes, and maintained for at least 72 hours (or hospital discharge if earlier).

Control group: to receive guideline-recommended BP control strategy to maintain BP level <180 mmHg after MT procedure, but BP lowering treatment given only for BP ≥150 mmHg to achieve target ≥140 mmHg.

Substudies: Patients enrolled in main study can also be randomised into 2 substudies according to separate eligibility criteria. Both are pilot studies embedded in main trial to recruit as many patients to inform sample size estimates for a further main study.

Substudy #1: Timing of anticoagulation Objective: To determine the effectiveness of early initiation of anticoagulation (at Day 4±2 of stroke onset) compared with late initiation (at Day 12±2) on a composite outcome of recurrent AIS, sICH, systemic embolism and/or vascular death within 90 days in patients with AF-related AIS due to LVO who receive MT. Randomisation (allocation 1:1 ratio) via same system as main study and stratified by site, NIHSS score at 24 hours (<10 vs ≥10) and anticoagulation intent (warfarin vs DOACs). Randomised patients will be allocated to either early group of initiating OAC therapy at Day 4±2 day of stroke onset, or late group of initiating OAC therapy at Day 12±2 of stroke onset. Primary outcome: composite of recurrent AIS, sICH, systemic embolism and/or vascular death within 90 days after randomisation.

Substudy #2: Duration of dual antiplatelet therapy (DAPT):

Objective: To determine the effectiveness of short duration of DAPT (<6 weeks) compared with standard duration (3 months or more) on recurrence rate within 12 months in patients with AIS due to large artery atherosclerosis (LAA) who are eligible for DAPT post-MT. Randomisation (allocation 1:1 ratio) will be done via the same system as the main study and stratified by site, and NIHSS score at 24 hours (<10 vs ≥10). Randomised patients will be allocated to either short duration group of receiving DAPT (aspirin 100 mg and clopidogrel 75 mg per day) for 6 weeks, or standard duration group receiving DAPT for 3 months. DAPT is started <48 hours post-randomization, and maintained changed to antiplatelet monotherapy (aspirin or clopidogrel) thereafter. Primary outcome is new stroke event (AIS or ICH) over 12 months.