The SWIFT DIRECT trial


Solitaire™ With the Intention For Thrombectomy Plus Intravenous t-PA Versus DIRECT Solitaire Stent-retriever Thrombectomy in Acute Anterior Circulation Stroke (SWIFT DIRECT).


Bridging Thrombolysis Versus Direct Mechanical Thrombectomy in Acute Ischemic Stroke.

Please find more information on www.clinicaltrials.gov

 

Introduction

Intravenous thrombolysis (IVT) with recombinant tissue-type plasminogen activator (tPA) has been the only proven therapy for acute ischemic stroke (AIS) for almost 20 years.1 Since December 2014 a new era in acute stroke treatment has begun: randomized controlled trials (RCTs) have consistently shown that endovascular clot retrieval in addition to best medical treatment (with and without intravenous thrombolysis with recombinant tissue-type plasminogen activator (IV t-PA) improves outcome in acute anterior circulation stroke patients with proximal vessel occlusion compared to best medical treatment alone.2-9 The main reason for the differences in outcome was endovascular clot retrieval, since proportions of patients receiving IV t-PA did not significantly differ in both groups.10 Whether pre-treatment with IV t-PA prior to endovascular clot retrieval is beneficial has now become a matter of debate.

Previous clinical trials (MR CLEAN, SWIFT-PRIME, EXTEND IA, ESCAPE and REVASCAT)2-6 suggested that the treatment effect size of mechanical thrombectomy (MT) does not differ between patients receiving intravenous thrombolysis (IVT) and those treated with MT alone, questioning a beneficial treatment interaction between IVT and MT.11, 20 As a consequence there is an ongoing scientific debate as to whether IVT before MT is still needed.12

 

State of Evidence

IVT has a lot of benefits as well as constraints.12, 20 So far, some observational studies have reported poorer outcome of patients treated with direct MT, and a recent meta-analysis aligns with these results.13 However, another meta-analysis has failed to reproduce these findings14 and there is a considerable uncertainty due to heavy selection bias15. Most of the studies included only direct MT patients who were ineligible for IVT, thus representing a patient cohort with a genuine poorer outcome.13,16

Recently, three observational studies assessing the safety and efficacy of direct MT in patients eligible for IVT were published.17-19 These data provided first evidence that direct MT may be equally or even superiorly safe and effective as compared to IVT + MT, further questioning if the poorer outcome of IVT ineligible patients treated with direct thrombectomy should be interpreted as a treatment effect of IVT.

Because recanalization rates after IVT and prior to MT are reasonable for patients secondly transferred to thrombectomy facilities and patients with distal intracranial occlusion, the study population will be confined to patients with proximal occlusions and direct access to thrombectomy.

We hypothesize that immediate and direct MT is not inferior and might even be superior to bridging thrombolysis in patients with a proximal LVO directly referred to a stroke center with rapid access to endovascular procedures.

 

SWIFT DIRECT – the protocol

Objectives

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 MT compared to subjects treated with bridging thrombolysis.

The secondary objectives are to study the causes of mortality, the dependency and the quality of life in these AIS patients.

Furthermore, the trial aims to provide conclusive information on the efficacy and safety of direct MT in comparison with bridging thrombolysis.

Protocol

Please check the key inclusion and exclusion criteria (http://swiftdirect.web.ctu-bern.ch/) and whether your center is among the 30 Major European and North American Stroke Centers that carry out the trial  (http://swiftdirect.web.ctu-bern.ch/participating-sites/).

Treatment Groups

 

Trial flow chart and time lines

Patients randomized to the direct MT group will receive treatment according to the instructions manual of the commercially available stent-retriever revascularization devices manufactured by Medtronic (e.g. Solitaire™). Patients randomized to the combined IV t-PA and MT group will receive treatment according to institutional and manufacturer’s instructions of IV t-PA and MT (e.g. Solitaire™).

A total number of 404 subjects will be included in the trial, which will last 3 years.

Outcomes

A treatment-blinded person will assess the primary outcome which is functional independence at 90 days after randomization. Favourable outcome is defined as a modified Rankin Score (mRS) of 0 to 2, unfavourable outcome as mRS score of > 2.

Secondary outcome measures will include the assessment of mortality, dependency and a quality of life assessment after AIS.

 

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.

 

Steering Committee

  • Prof. Jan Gralla, MD
  • Prof. Urs Fischer, MD
  • Prof. Vitor Mendes Pereira, MD
  • Prof. Jeffrey Saver, MD
  • Prof. René Chapot, MD
  • Prof. Adnan H. Siddiqui, MD
  • Prof. Michael T. Froehler, MD
  • Prof. Christoph Cognard, MD
  • Prof. Anthony Furlan, MD

Data Safety Monitoring Board

  • Prof. Rüdiger von Kummer, MD
  • Prof. Tim Friede, PhD
  • Prof. Bruce Campbell, MD

Neurocenter Bern

The Neurocenter Bern is a leading international neurovascular center with the largest number of highly-specialized interventions in Switzerland, including the endovascular clot retrieval after ischemic stroke. The new treatment concept of bridging thrombolysis versus direct mechanical thrombectomy in acute ischemic stroke has retrospectively been studied by Broeg-Morvay et al. (2016)12 evaluating the clinical and radiological outcomes of patients treated with bridging thrombolysis compared to IV t-PA-eligible patients treated with direct MT.12 The analysis showed that the new treatment of direct mechanical intervention seems to be equally effective in patients with large anterior circulation stroke as bridging thrombolysis.12 A RCT comparing direct MT with bridging therapy is warranted.12 Based on these results and lively discussions among specialists in our network, we initiated a prospective RCT on this new treatment concept.

Neuro Clinical Trial Unit (NCTU)

The Neuro Clinical Trial Unit (NCTU) is a dynamic platform for clinical researchers in the discipline Neurology, Neuroradiology and Neurosurgery at the University Hospital Bern. The team of the NCTU consists of professionals in the management of investigator initiated clinical trials and takes over the managing part for this RCT.

 

Literature

  1. Tissue Plasminogen Activator for Acute Ischemic Stroke. New England Journal of Medicine. 1995;333(24):1581-1588.
  2. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. The New England journal of medicine. 2015;372(1):11-20.MR CLEAN
  3. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with perfusion-imaging selection. The New England journal of medicine. 2015;372(11):1009-1018.EXTEND IA
  4. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular treatment of ischemic stroke. The New England journal of medicine. 2015;372(11):1019-1030. ESCAPE
  5. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. The New England journal of medicine. 2015;372(24):2285-2295. SWIFT PRIME
  6. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in ischemic stroke. The New England journal of medicine. 2015;372(24):2296-2306. REVASCAT
  7. Bracard S, Ducrocq X, Mas JL, et al. Mechanical thrombectomy after intravenous alteplase versus alteplase alone after stroke (THRACE): a randomised controlled trial. The Lancet Neurology. 2016;15(11):1138-1147.
  8. Muir KW, Ford GA, Messow CM, et al. Endovascular therapy for acute ischaemic stroke: the Pragmatic Ischaemic Stroke Thrombectomy Evaluation (PISTE) randomised, controlled trial. Journal of neurology, neurosurgery, and psychiatry. 2017;88(1):38-44.
  9. Mocco J, Zaidat OO, von Kummer R, et al. Aspiration Thrombectomy After Intravenous Alteplase Versus Intravenous Alteplase Alone. Stroke; a journal of cerebral circulation. 2016;47(9):2331-2338.
  10. Grotta JC, Hacke W. Stroke Neurologist’s Perspective on the New Endovascular Trials. Stroke; a journal of cerebral circulation. 2015;46(6):1447-1452.
  11. Goyal M, Menon BK, Van Zwam WH, Dippel DWJ, Mitchell PJ, Demchuk AM, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387:1723–1731.
  12. Chandra R V, Leslie-Mazwi TM, Mehta BP, Derdeyn CP, Demchuk AM, Menon BK, et al. Does the use of IV tPA in the current era of rapid and predictable recanalization by mechanical embolectomy represent good value? J. Neurointerv. Surg. 2016;8:443–6.
  13. Mistry EA, Mistry AM, Nakawah MO, Chitale R V., James RF, Volpi JJ, et al. Mechanical Thrombectomy Outcomes With and Without Intravenous Thrombolysis in Stroke Patients. Stroke. 2017;48(9):2450-2456.
  14. Phan K, Dmytriw AA, Maingard J, Asadi H, Griessenauer CJ, Ng W, et al. Endovascular thrombectomy alone versus combined with intravenous thrombolysis. World Neurosurg. 2017
  15. Hui FK, Narayanan S, Cawley CM. Posterior-to-anterior circulation access using the Penumbra Stroke System for mechanical thrombectomy of a right middle cerebral artery thrombus. World Neurosurg. 2010;73(1):17-21.
  16. Huo Y, Phan K, Zhao D, Rao P, Phan S, Mortimer A. Endovascular therapy including thrombectomy for acute ischemic stroke: A systematic review and meta-analysis with trial sequential analysis. J. Clin. Neurosci. 2016;29:38-45.
  17. Weber R, Nordmeyer H, Hadisurya J, Heddier M, Stauder M, Stracke P, et al. Comparison of outcome and interventional complication rate in patients with acute stroke treated with mechanical thrombectomy with and without bridging thrombolysis. J. Neurointerv. Surg. 2017;9(3):229-233.
  18. Wang H, Zi W, Hao Y, Yang D, Shi Z, Lin M, et al. Direct endovascular treatment: an alternative for bridging therapy in anterior circulation large-vessel occlusion stroke. Eur. J. Neurol. 2017;24(7):935-943.
  19. Broeg-Morvay A, Mordasini P, Bernasconi C, Buehlmann M, Pult F, Arnold M, et al. Direct mechanical intervention versus combined intravenous and mechanical intervention in large artery anterior circulation stroke: A matched-pairs analysis. Stroke. 2016;47:1037–1044.
  20. Fischer U, Kaesmacher J, Mendes Pereira V, Chapot R, Siddiqui AH, Froehler MT, Cognard C, Furlan AJ, Saver JF, Gralla J. Direct Mechanical Thrombectomy Versus Combined Intravenous and Mechanical Thrombectomy in Large-Artery Anterior Circulation Stroke. Stroke. 2017;