Clinical trial NCT03192332: Bridging Thrombolysis Versus Direct Mechanical Thrombectomy in Acute Ischemic Stroke
Official title: Solitaire™ With the Intention For Thrombectomy Plus Intravenous t-PA Versus DIRECT Solitaire™ Stent-retriever Thrombectomy in Acute Anterior Circulation Stroke
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Ischemic Stroke
Keywords: Intravenous thrombolysis
Endovascular treatment
Mechanical thrombectomy
Bridging thrombolysis
Acute ischemic stroke
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Medtronic
First posted: 2017-06-20
Enrollment: 410
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomized, open label, blinded endpoint (PROBE)
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Informed consent as documented by signature
2. Age ≥ 18
3. Clinical signs consistent with an acute ischemic stroke
4. Neurological deficit with a NIHSS of ≥ 5 and \< 30 (deficits judged to be clearly disabling at presentation)
5. Patient is eligible for intravenous thrombolysis
6. Patient is eligible for endovascular treatment
7. 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)
8. 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
9. 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:

1. Acute intracranial hemorrhage
2. Any contraindication for IV t-PA
3. Pre-treatment with IV t-PA
4. In-hospital stroke
5. Pregnancy or lactating women. A negative pregnancy test before randomization is required for all women with child-bearing potential.
6. Known (serious) sensitivity to radiographic contrast agents, nickel, titanium metals, or their alloys
7. Known current participation in a clinical trial (investigational drug or medical device)
8. 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
9. Severe comorbid condition with life expectancy less than 90 days at baseline
10. Known advanced dementia or significant pre-stroke disability (mRS score of ≥2)
11. Foreseeable difficulties in follow-up due to geographic reasons (e.g. patients living abroad)
12. Comorbid disease or condition that would confound the neurological and functional evaluations or compromise survival or ability to complete follow-up assessments.
13. 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).
14. 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
15. Radiological confirmed evidence of mass effect or intracranial tumor (except small meningioma)
16. Radiological confirmed evidence of cerebral vasculitis
17. CTA or MRA evidence of carotid artery dissection
18. 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

Primary outcomes:
measure: Score in modified Rankin Scale (mRS)
timeFrame: 90 days after randomization
Secondary outcomes:
measure: Mortality
timeFrame: 90 days after randomization
measure: Modified Rankin Scale (mRS) shift analysis
timeFrame: day 0 and 90 days after randomization
measure: National Institute of Health Score Scale (NIHSS)
timeFrame: day 0 and day 1 after randomization
measure: Thrombolysis in Cerebral Infarction (TICI) scale
timeFrame: day 0 and day 1 after randomization
measure: Serious adverse events
timeFrame: day 0 until 90 days after randomization
measure: Intracranial hemorrhage
timeFrame: day 1 after randomization
measure: Quality of life assessed by questionnaire
timeFrame: 90 days after randomization
measure: Overall costs incurred during hospitalisation
timeFrame: 90 days after randomization
Other outcomes:
Locations:
city: Linz
country: Austria
facility: Keppler Universitätsklinikum
state: Oberösterreich
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Calgary
country: Canada
facility: University of Calgary, Alberta Health Services
city: Montréal
country: Canada
facility: Mc Gill University
city: Saskatoon
country: Canada
facility: Royal University Hospital, University of Saskatchewan
city: Toronto
country: Canada
facility: Toronto Western Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital
city: Brest
country: France
facility: Hôpital Cavale Blanche CHU Brest
state: Finistère
city: Reims
country: France
facility: CHU de Reims
state: Marne
city: Clermont-Ferrand
country: France
facility: CHU de Clermont-Ferrand
state: Puy-de-Dôme
city: Bordeaux
country: France
facility: CHU de Bordeaux
city: Caen
country: France
facility: CHU de Caen Normandie
city: Lille
country: France
facility: CHU de Lille
city: Limoges
country: France
facility: CHU de Limoges
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Montpellier
country: France
facility: CHU de Montpellier
city: Nancy
country: France
facility: CHRU Nancy
city: Nantes
country: France
facility: CHU de Nantes
city: Paris
country: France
facility: Hôpital Bicêtre
city: Paris
country: France
facility: GHU Paris Psychiatrie et Neurosciences, Sainte Anne
city: Paris
country: France
facility: Fondation Ophtalmologique A. de Rothschild
city: Rouen
country: France
facility: CHU Rouen Normandie
city: Strasbourg
country: France
facility: CHRU Strasbourg
city: Toulouse
country: France
facility: CHU de Toulouse
city: Tours
country: France
facility: CHU Tours
city: Suresnes
country: France
facility: Hôpital Foch
state: Île De France
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim, Universität Heidelber
state: Baden-Württemberg
city: Osnabrück
country: Germany
facility: Klinikum Osnabrück GmbH
state: Niedersachsen
city: Aachen
country: Germany
facility: Universitätsklinikum RWTH Aachen
state: Nordrhein-Westfalen
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Campus Kiel
state: Schleswig-Holstein
city: Bochum
country: Germany
facility: Universitätsklinikum Knappschaftskrankenhaus GmbH Bochum
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen
city: Magdeburg
country: Germany
facility: Medizinische Fakultät der Otto-von-Guericke-Universität Magdeburg
city: München
country: Germany
facility: Klinikum rechts der Isar der Technischen Universität München
city: Recklinghausen
country: Germany
facility: Klinikum Vest GmbH
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Aarau
country: Switzerland
facility: Dept. of Neurology, Kantonsspital Aarau
state: Aargau
city: Lugano
country: Switzerland
facility: Dept. of Neurology, Ospedale Civo of Lugano
state: Ticino
city: Lausanne
country: Switzerland
facility: Dept. of Neurology, Centre hospitalier universitaire vaudois (CHUV)
state: Vaud
city: Bern
country: Switzerland
facility: Dept. of Neurology, Bern University Hospital
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires de Genève - HUG
city: Saint Gallen
country: Switzerland
facility: Kantonsspital St.Gallen
city: Zürich
country: Switzerland
facility: Dept. of Neuroradiology, UniversitätsSpital Zürich
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: London
country: United Kingdom
facility: St George's University Hospitals NHS Foundation Trust
city: Salford
country: United Kingdom
facility: Salford Royal
Study officials:
affiliation: Dept. of Neurology, Inselspital Bern
name: Urs Fischer, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: Dept. of Neuroradiology, Inselspital Bern
name: Jan Gralla, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mujanovic A, Eker O, Marnat G, Strbian D, Ijas P, Preterre C, Triquenot A, Albucher JF, Gauberti M, Weisenburger-Lile D, Ernst M, Nikoubashman O, Mpotsaris A, Gory B, Tuan Hua V, Ribo M, Liebeskind DS, Dobrocky T, Meinel TR, Buetikofer L, Gralla J, Fischer U, Kaesmacher J; SWIFT DIRECT investigators. Association of intravenous thrombolysis and pre-interventional reperfusion: a post hoc analysis of the SWIFT DIRECT trial. J Neurointerv Surg. 2023 Nov;15(e2):e232-e239. doi: 10.1136/jnis-2022-019585. Epub 2022 Nov 17.
citation: Meinel TR, Kaesmacher J, Buetikofer L, Strbian D, Eker OF, Cognard C, Mordasini P, Deppeler S, Mendes Pereira V, Albucher JF, Darcourt J, Bourcier R, Guillon B, Papagiannaki C, Costentin G, Sibolt G, Raty S, Gory B, Richard S, Liman J, Ernst M, Boulanger M, Barbier C, Mechtouff L, Zhang L, Marnat G, Sibon I, Nikoubashman O, Reich A, Consoli A, Weisenburger D, Requena M, Garcia-Tornel A, Saleme S, Moulin S, Pagano P, Saliou G, Carrera E, Janot K, Boix M, Pop R, Della Schiava L, Luft A, Piotin M, Gentric JC, Pikula A, Pfeilschifter W, Arnold M, Siddiqui A, Froehler MT, Furlan AJ, Chapot R, Wiesmann M, Machi P, Diener HC, Kulcsar Z, Bonati L, Bassetti C, Escalard S, Liebeskind D, Saver JL, Fischer U, Gralla J; SWIFT-DIRECT investigators. Time to treatment with bridging intravenous alteplase before endovascular treatment:subanalysis of the randomized controlled SWIFT-DIRECT trial. J Neurointerv Surg. 2023 Sep;15(e1):e102-e110. doi: 10.1136/jnis-2022-019207. Epub 2022 Jul 28.
citation: Fischer U, Kaesmacher J, Strbian D, Eker O, Cognard C, Plattner PS, Butikofer L, Mordasini P, Deppeler S, Pereira VM, Albucher JF, Darcourt J, Bourcier R, Benoit G, Papagiannaki C, Ozkul-Wermester O, Sibolt G, Tiainen M, Gory B, Richard S, Liman J, Ernst MS, Boulanger M, Barbier C, Mechtouff L, Zhang L, Marnat G, Sibon I, Nikoubashman O, Reich A, Consoli A, Lapergue B, Ribo M, Tomasello A, Saleme S, Macian F, Moulin S, Pagano P, Saliou G, Carrera E, Janot K, Hernandez-Perez M, Pop R, Schiava LD, Luft AR, Piotin M, Gentric JC, Pikula A, Pfeilschifter W, Arnold M, Siddiqui AH, Froehler MT, Furlan AJ, Chapot R, Wiesmann M, Machi P, Diener HC, Kulcsar Z, Bonati LH, Bassetti CL, Mazighi M, Liebeskind DS, Saver JL, Gralla J; SWIFT DIRECT Collaborators. Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial. Lancet. 2022 Jul 9;400(10346):104-115. doi: 10.1016/S0140-6736(22)00537-2.
citation: Fischer U, Kaesmacher J, S Plattner P, Butikofer L, Mordasini P, Deppeler S, Cognard C, Pereira VM, Siddiqui AH, Froehler MT, Furlan AJ, Chapot R, Strbian D, Wiesmann M, Bressan J, Lerch S, Liebeskind DS, Saver JL, Gralla J; SWIFT DIRECT study investigators. SWIFT DIRECT: Solitaire With the Intention For Thrombectomy Plus Intravenous t-PA Versus DIRECT Solitaire Stent-retriever Thrombectomy in Acute Anterior Circulation Stroke: Methodology of a randomized, controlled, multicentre study. Int J Stroke. 2022 Jul;17(6):698-705. doi: 10.1177/17474930211048768. Epub 2021 Oct 14.