Direct Intra-arterial Thrombectomy in Order to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals

Study Overview
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Brief Summary
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Background: Intravenous thrombolysis (IVT) combined with mechanical thrombectomy (MT) has been proven safe and effective in patients with acute ischemic stroke (AIS) of anterior circulation large vessel occlusion (LVO). Despite recanalization, a considerable proportion of patients do not recover. The incidence of symptomatic intracerebral hemorrhage (sICH) was similar between combined IVT plus MT and IVT, suggesting that this complication could not be attributed to the MT, but rather to pre-treatment with IVT. Meanwhile, the incidence of intracranial atherosclerosis stenosis (ICAS) is higher in Asians. It is not clear whether patients with ICAS benefit from pretreatment with alteplase or not and how ICAS modifies treatment effect. Objective: To assess whether direct MT is non-inferior compared to combined IVT plus MT in patients with AIS due to an anterior circulation LVO, and to assess treatment effect modification by presence of ICAD. Study design: This is a parallel group, RCT of direct MT compared to combined IVT plus MT, using a non-inferiority design. The trial has observer blinded assessment of the primary outcome and of neuro-imaging at baseline and follow up. The trial will be executed in collaboration with MRCLEAN NO-IV investigators. Study population: Patients with AIS of anterior circulation VLO confirmed by CTA. Initiation of IVT must be feasible within 4.5 hours from symptom onset. Age must be 18 or over and NIHSS 2 or more. Main outcomes: The full distribution of the mRS at 3 months. Secondary outcomes: 1. death within 90 +/- 14 days; 2. pre-interventional reperfusion assessed on first intracranial DSA; 3. eTICI19 score on final angiography of MT; 4. score on the NIHSS at 24 +/- 6 hours and 5-7 days, or at discharge; 5. recanalization rate at 24-72h by CTA; 6. Final lesion volume at 5-7 days on NCCT20; 7. score on the EuroQoL 5-dimensions 5-level (EQ5D-5L)21 and Barthel index22 at 90 +/- 14 days; 8. dichotomous clinical outcome on the mRS at 90 +/- 14 days.

Detailed Description
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Protocol title: Direct Intra-arterial thrombectomy in order to Revascularize AIS patients with large vessel occlusion Efficiently in Chinese Tertiary hospitals: a Multicenter randomized clinical Trial (DIRECT-MT) Rationale: Mechanical thrombectomy (MT) by means of retrievable stents has been proven safe and effective in patients with acute ischemic stroke (AIS) with confirmed large vessel occlusion of the anterior circulation and in whom the procedure can be started within 6 hours from onset. Despite recanalization, a considerable proportion of patients do not recover. This can be attributed to potential adverse effects of the intravenous treatment (IVT) prior to MT. These effects could include neurotoxicity, blood brain barrier leakage and thrombus fragmentation through softening of the thrombus. Another reason for non-recovery in MRCLEAN was the occurrence of symptomatic intracranial hemorrhage (sICH) in 7% of patients, which was fatal in 65%. sICH occurred as often in the intervention as in the control group, suggesting that this complication could not be attributed to the MT, but rather to pre-treatment with IVT. Therefore, the investigators hypothesize that direct MT may lead to a 8% absolute increase in good outcome compared to MT preceded by IVT. Objective: To assess whether direct MT is non-inferior compared to combined IVT plus MT in patients with AIS due to an anterior circulation LVO, and to assess treatment effect modification by presence of ICAD. Study design: This is a multicenter, prospective, open label parallel group trial with blinded outcome assessment (PROBE design) assessing non-inferiority of direct MT compared to combined IVT plus MT. Study population: Patients with acute ischemic stroke and a confirmed anterior circulation occlusion by CTA. Initiation of IVT must be feasible within 4.5 hours from symptom onset. Age must be 18 or over and NIHSS 2 or more. INCLUSION CRITERIA a clinical diagnosis of acute ischemic stroke, caused by a large vessel occlusion of the anterior circulation (intracranial carotid artery or middle M1/proximal M2) cerebral artery confirmed by CTA, CT or MRI ruling out intracranial hemorrhage, eligible for IVT and MT (within 4.5 hours after symptom onset), a score of at least 2 on the NIH Stroke Scale, age of 18 years or older, written informed consent. EXCLUSION CRITERIA Pre-stroke disability which interferes with the assessment of functional outcome at 90 days, i.e. mRS >2 Any contra-indication for IVT, according to guidelines of the American Heart Association, i.e.: arterial blood pressure exceeding 185/110 mmHg blood glucose less than 2.7 or over 22.2 mmol/L cerebral infarction in the previous 6 weeks with residual neurological deficit or signs of recent infarction on neuro-imaging serious head trauma in the previous 3 months major surgery or serious trauma in the previous 2 weeks gastrointestinal or urinary tract hemorrhage in the previous 3 weeks previous intracerebral hemorrhage use of anticoagulant with INR exceeding 1.7 known thrombocyte count less than 100 x 109/L treatment with direct thrombin or factor X inhibitors treatment with heparin (APTT exceeds the upper limit of normal value) in the previous 48 hours. Intervention: The intervention group will undergo immediate MT using a stent retriever, as recommended by the steering committee. The standard care group will receive IVT 0.9 mg/kg with a maximum dose of 90 mg in one hour, followed by MT using a stent retriever. the investigators strive to reduce delays associated with IVT administration to a minimum to adequately assess the effect of IVT itself with MT. Main study parameters/outcomes: The primary outcome is the score on the modified Rankin Scale assessed blindly at 90 (+/- 14) days. An common odds ratio, adjusted for the prognostic factors (age, NIHSS, collateral score), representing the shift on the 6-category mRS scale measured at 3 months, estimated with ordinal logistic regression, will be the primary effect parameter. Secondary outcomes: 1. death within 90 +/- 14 days; 2. pre-interventional reperfusion assessed on first intracranial DSA; 3. eTICI19 score on final angiography of MT; 4. score on the NIHSS at 24 +/- 6 hours and 5-7 days, or at discharge; 5. recanalization rate at 24-72h by CTA; 6. Final lesion volume at 5-7 days on NCCT20; 7. score on the EuroQoL 5-dimensions 5-level (EQ5D-5L)21 and Barthel index22 at 90 +/- 14 days; 8. dichotomous clinical outcome on the mRS at 90 +/- 14 days.

Official Title
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Parallel Group, Randomized Clinical Trial of Direct Intra-arterial Thrombectomy Versus Intravenous Thrombolysis With Intra-arterial Thrombectomy for Patients With Large Vessel Occlusion of the Anterior Circulation

Conditions
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Ischemic Stroke, Large Vessel Occlusion, Thrombectomy, Thrombosis, Alteplase

Intervention / Treatment
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* Procedure: intra-arterial thrombectomy
* Drug: Intravenous thrombolysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: a clinical diagnosis of acute ischemic stroke, caused by a large vessel occlusion of the anterior circulation (distal intracranial carotid artery or middle M1/proximal M2) cerebral artery confirmed by CTA, CT or MRI ruling out intracranial hemorrhage, eligible for IVT and IAT (within 4.5 hours after symptom onset), a score of at least 2 on the NIH Stroke Scale, age of 18 years or older, written informed consent. Exclusion Criteria: - Pre-stroke disability which interferes with the assessment of functional outcome at 90 days, i.e. mRS >2 Any contra-indication for IVT, according to guidelines of the American Heart Association, i.e.: arterial blood pressure exceeding 185/110 mmHg blood glucose less than 2.7 or over 22.2 mmol/L cerebral infarction in the previous 6 weeks with residual neurological deficit or signs of recent infarction on neuro-imaging serious head trauma in the previous 3 months major surgery or serious trauma in the previous 2 weeks gastrointestinal or urinary tract hemorrhage in the previous 3 weeks previous intracerebral hemorrhage use of anticoagulant with INR exceeding 1.7 known thrombocyte count less than 100 x 109/L treatment with direct thrombin or factor X inhibitors treatment with heparin (APTT exceeds the upper limit of normal value) in the previous 48 hours.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: Direct MT<br>Direct mechanical thrombectomy (MT) with no intravenous thrombolysis | Procedure: intra-arterial thrombectomy<br>* It is the emergency surgical removal of emboli which are blocking blood circulation. It usually involves removal of thrombi (blood clots)<br>|
| Active Comparator: IVT combine with MT<br>Intravenous thrombolysis before mechanical thrombectomy | Procedure: intra-arterial thrombectomy<br>* It is the emergency surgical removal of emboli which are blocking blood circulation. It usually involves removal of thrombi (blood clots)<br>Drug: Intravenous thrombolysis<br>* alteplase is used in the intravenous thrombolysis. It catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mRS (the modified Rankin Scale) | The mRS is an ordinal hierarchical scale ranging from 0 to 5, with higher scores indicating more severe disability. | 3 months after procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| eTICI score (Extended Treatment In Cerebral Ischemia) | The eTICI is an ordinal hierarchical scale ranging from 0 to 3, with higher scores indicating better antegrade reperfusion of the previously occluded target artery ischemic territory. | Immediately after procedure | 
| NIHSS (The National Institutes of Health Stroke Scale) | The NIHSS is an ordinal hierarchical scale to evaluate the severity of stroke by assessing a patient's performance. Scores range from 0 to 42, with higher scores indicating a more severe deficit. | at 24 hours and 5-7 days | 
| Recanalization rate | Recanalization rate at 24-48 hours after intra-arterial thrombectomy, assessed with CT angiography | at 24-48 hours after intra-arterial thrombectomy | 
| Final infarct volume | Final infarct volume will be assessed with the use of an automated, validated algorithm. | at 5-7 days | 
| sICH (symptomatic intracranial hemorrhage) rate | SICH means any hemorrhage with neurological deterioration, as indicated by an NIHSS score that was higher by ≥4 points than the value at baseline or the lowest value in the first 7 days or any hemorrhage leading to death. | 7 days after intra-arterial thrombectomy |