Stroke Research Center Bern

Clinical Trials

SWIFT DIRECT

The main objective o fthe SWIFT DIRECT trial is to determine whether subjects experiencing acute ischemic stroke 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 compared to subjects treated with bridging thrombolysis

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.

Key inclusion- and exclusion criteria

Inclusion criteria

  • Informed consent as documented by signature
  • Age ≥ 18
  • Acute ischemic stroke (AIS)
  • NIHSS ≥ 5 and <30 (deficits judged to be clearly disabling at presentation)
  • Patient is eligible for IV t-PA
  • Patient is eligible for endovascular therapy
  • 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
  • Occlusion (TICI 0-1) of the intracranial internal carotid artery (ICA) , 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
  • Known (serious) sensitivity to radiographic contrast agents, nickel, titanium metals or their alloys
  • Current participation in a clinical trial
  • Renal insufficiency
  • Life expectancy less than 90 days at baseline
  • Known advanced dementia or significant pre-stroke disability (mRS score of ≥ 2)

Outcomes

Primary outcome measures

  • Score in modified Rankin Scale (mRS) [ Time Frame: 90 days after randomization ]

Secondary outcome measures

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

Contact

Trial Core Team at SRCB

References

  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;48(10):2912-2918.