Bridging Thrombolysis Versus Direct Mechanical Thrombectomy in Acute Ischemic Stroke

Study Overview
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Brief Summary
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Intravenous thrombolysis with recombinant tissue-type plasminogen activator (IV t-PA) has been the only proven therapy for acute ischemic stroke (AIS) for almost 20 years. Whether IV t-PA prior to endovascular clot retrieval is beneficial for AIS patients with a proximal vessel occlusion in the anterior circulation has currently become a matter of debate and is a relevant unanswered question in clinical practice. The main objective is to determine whether subjects experiencing an AIS due to large intracranial vessel occlusion in the anterior circulation will have non-inferior functional outcome at 90 days when treated with direct mechanical thrombectomy (MT) compared to subjects treated with combined IV t-PA and MT. The secondary objectives are to study causes of mortality, dependency and quality of life in these AIS patients.

Detailed Description
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Intravenous thrombolysis with recombinant tissue-type plasminogen activator (IV t-PA) has been the only proven therapy for acute ischemic stroke (AIS) for almost 20 years. Since December 2014 a new era in acute stroke treatment has begun: randomized controlled studies have consistently shown that endovascular clot retrieval in addition to best medical treatment (± IV t-PA) improves outcome in acute anterior circulation stroke patients with proximal vessel occlusion compared to best medical treatment alone. Whether pre-treatment with IV t-PA prior to endovascular clot retrieval is beneficial has now become a matter of debate. A pooled analysis of 5 RCTs (MR CLEAN, SWIFT-PRIME, EXTEND IA, ESCAPE and REVASCAT) suggested that the treatment effect size of MT does not differ between patients receiving intravenous thrombolysis (IVT) and those treated with MT alone (p interaction: 0.4311). Besides post-hoc RCT analyses, there are a myriad of observational studies reporting on rates of successful reperfusion and functional outcome stratified according to IV t-PA pretreatment status. There is evidence that reperfusion rates after IV t-PA in patients with occlusions of the internal carotid artery and the main stem of the middle cerebral artery are low, but may reach more than 80% after mechanical thrombectomy (MT). Therefore the most important factor for vessel recanalization, which is linked with favorable outcome, is MT. No randomized controlled trial has ever assessed whether direct MT in patients with AIS is equally effective as MT in combination with IV t-PA (bridging thrombolysis). In a patient-level pooled analysis of five randomized controlled studies (HERMES collaboration) similar rates of functional independence and mortality at 90 days were observed between patients who received IV t-PA+MT and those who received direct MT. However, patients in the direct MT group had contraindications for IV t-PA. Two larger studies based on registries compared the outcome of patients after bridging thrombolysis with direct MT in patients eligible for IV t-PA. In both studies, the outcome of patients after bridging thrombolysis and direct MT was similar. For these reasons the investigators hypothesize that immediate and direct MT is not inferior and might even be superior to bridging thrombolysis in patients directly referred to a stroke center with rapid access to endovascular procedures. In this trial all commercially available stent-retriever revascularization devices manufactured by Medtronic (e.g. Solitaire™) will be used as tool for direct MT. The investigators aim to provide conclusive information on the efficacy and safety of direct MT, in comparison with bridging thrombolysis. If direct MT in patients with AIS would not be inferior to bridging thrombolysis, the organization of acute stroke management would change essentially. Direct MT would then be the therapy of choice in stroke centers with endovascular facilities. Furthermore, this trial could have an impact on healthcare guidelines and costs. However, this trial does not address the question, whether patients arriving in stroke units with no endovascular facilities should be pre-treated with IV t-PA or whether they should directly be referred to stroke centers with endovascular facilities.

Official Title
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Solitaire™ With the Intention For Thrombectomy Plus Intravenous t-PA Versus DIRECT Solitaire™ Stent-retriever Thrombectomy in Acute Anterior Circulation Stroke

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Device: Stent-retriever thrombectomy with revascularization device of the Solitaire™ type
* Drug: Intravenous thrombolysis with recombinant tissue-type plasminogen activator (IV t-PA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent as documented by signature Age ≥ 18 Clinical signs consistent with an acute ischemic stroke Neurological deficit with a NIHSS of ≥ 5 and < 30 (deficits judged to be clearly disabling at presentation) Patient is eligible for intravenous thrombolysis Patient is eligible for endovascular treatment Randomization no later than 4 hours 15 minutes after stroke symptom onset and initiation of IV t-PA must be started within 4 hours 30 minutes of stroke symptoms onset (onset time is measured from the time when the subject was last seen well) Occlusion (TICI 0-1) of the intracranial internal carotid artery (ICA), the M1 segment of the middle cerebral artery (MCA), or both confirmed by CT or MR angiography, accessible for MT Core-infarct volume of Alberta Stroke Program Early CT Score (ASPECTS) greater than or equal to 4 (≥ 4) based on baseline CT or MR imaging (MRI) (a region has to have diffusion abnormality in 20% or more of its volume to be considered MR-ASPECTS positive) Exclusion Criteria: Acute intracranial hemorrhage Any contraindication for IV t-PA Pre-treatment with IV t-PA In-hospital stroke Pregnancy or lactating women. A negative pregnancy test before randomization is required for all women with child-bearing potential. Known (serious) sensitivity to radiographic contrast agents, nickel, titanium metals, or their alloys Known current participation in a clinical trial (investigational drug or medical device) Renal insufficiency as defined by a serum creatinine > 2.0 mg/dl (or 176.8 µmol/l) or glomerular filtration rate (GFR) < 30 mL/min or requirement for hemodialysis or peritoneal dialysis Severe comorbid condition with life expectancy less than 90 days at baseline Known advanced dementia or significant pre-stroke disability (mRS score of ≥2) Foreseeable difficulties in follow-up due to geographic reasons (e.g. patients living abroad) Comorbid disease or condition that would confound the neurological and functional evaluations or compromise survival or ability to complete follow-up assessments. Subject currently uses or has a recent history of illicit drug(s) or abuses alcohol (defined as regular or daily consumption of more than four alcoholic drinks per day). Known history of arterial tortuosity, pre-existing stent, other arterial disease and/or known disease at the femoral access site that would prevent the device from reaching the target vessel and/or preclude safe recovery after MT Radiological confirmed evidence of mass effect or intracranial tumor (except small meningioma) Radiological confirmed evidence of cerebral vasculitis CTA or MRA evidence of carotid artery dissection Evidence of additional distal intracranial vessel occlusion in another territory (i.e. A2 segment of anterior cerebral artery or M3, M4 segment of MCA) on initial NCCT/MRI or CTA/MRA

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
Interventional Model Description: Prospective, randomized, open label, blinded endpoint (PROBE)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Direct mechanical thrombectomy<br>Treatment with direct mechanical thrombectomy with a commercially available stent-retriever revascularization device of the Solitaire™ type. | Device: Stent-retriever thrombectomy with revascularization device of the Solitaire™ type<br>* Mechanical thrombectomy with a stent-retriever revascularization device<br>|
| Active Comparator: Combined intravenous thrombolysis and mechanical thrombectomy<br>Treatment with intravenous thrombolysis with recombinant tissue-type plasminogen activator (IV t-PA) followed by mechanical thrombectomy with a commercially available stent-retriever revascularization device of the Solitaire™ type. | Device: Stent-retriever thrombectomy with revascularization device of the Solitaire™ type<br>* Mechanical thrombectomy with a stent-retriever revascularization device<br>Drug: Intravenous thrombolysis with recombinant tissue-type plasminogen activator (IV t-PA)<br>* Bridging thrombolysis (IV t-PA plus mechanical thrombectomy) according to current European and North American stroke guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Score in modified Rankin Scale (mRS) |  | 90 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality |  | 90 days after randomization | 
| Modified Rankin Scale (mRS) shift analysis |  | day 0 and 90 days after randomization | 
| National Institute of Health Score Scale (NIHSS) |  | day 0 and day 1 after randomization | 
| Thrombolysis in Cerebral Infarction (TICI) scale |  | day 0 and day 1 after randomization | 
| Serious adverse events |  | day 0 until 90 days after randomization | 
| Intracranial hemorrhage |  | day 1 after randomization | 
| Quality of life assessed by questionnaire |  | 90 days after randomization | 
| Overall costs incurred during hospitalisation |  | 90 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intravenous thrombolysis, Endovascular treatment, Mechanical thrombectomy, Bridging thrombolysis, Acute ischemic stroke