Acute Management of Stroke due to Intracranial Steno-occlusion. Joon-Tae Kim, MD, PhD Department of Neurology Chonnam National University Hospital

Acute Management of Stroke due to Intracranial Steno-occlusion Joon-Tae Kim, MD, PhD Department of Neurology Chonnam National University Hospital

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Contents Current status of acute management in AIS with LVO Endovascular therapy AIS with ICAD Characteristics Acute management of ICAD

Current status of acute management in AIS with LVO Endovascular therapy AIS with ICAD Characteristics Acute management of ICAD

The recent success of 5 RCTs of endovascular thrombectomy (EVT) for treating acute ischemic stroke (AIS) had resulted in EVT being considered as the standard care treatment in clinical practice. IMS-3 MR-RESCUE SYNTHESIS 2013 NEJM MR-CLEAN EXTEND-IA ESCAPE SWIFT-PRIME REVASCAT 2015 NEJM Main reasons for the success of recent RCTs 1. strict selection of patients with favorable imaging profiles; 2. quality control to decrease intra-hospital time delay esp. onsetto-groin puncture time; 3. development of modern up-to-date thrombectomy devices with increase in successful reperfusion

Lancet. 2016 5 RCTs Pooled data for 1287 patients; 634 EVT vs 653 standard therapy Time from onset to random; 3h 16m Of 570 patients assigned EVT, 71% had mtici 2b-3

26.5% 46.0% mrs 0-2 at 90d: adjusted OR 2.71 (2.07-3.55; p<0.0001); NNT 5.1 NNT to have reduced disability of at least 1 point on mrs: 2.6 For the primary outcome, pooled data showed reduced chance of disability at 90d in patients assigned to thrombectomy vs those assigned to control (adjusted cor 2.49, 95% CI 1.76 3.53). The number needed to treat for one patient to have reduced disability of at least 1 point on mrs was 2.6.

Endovascular thrombectomy is of benefit to most patients with acute ischemic stroke with anterior large vessel occlusion, irrespective of patient characteristics or geographical location.

About 30% of patients treated with EVT do not achieve substantial reperfusion EVT failures of reperfusion may result from 1) anatomical problems (tortuosity) 2) large clot amounts 3) tandem occlusion 4) clot characteristics 5) different pathomechanisms (embolic vs athero)

The lack of effectiveness of retrievable stents in patients with atherothrombotic stroke compared with the other etiologies. Although retrievable stents were the first choice device, intrinsic characteristics of atherothrombotic lesions usually determined the need to use other devices. Matias-Guiu JA, et al. JNIS 2012

When we encounter AIS patients with dica or MCA occlusion, we can presume two possible mechanisms, embolic from heart or proximal artery or thrombotic occlusion in the parent artery or From heart From carotid artery MCA occlusion In situ thrombosis

Current status of acute management in AIS with LVO Endovascular therapy AIS with ICAD Characteristics Acute management of ICAD

Intracranial atherosclerotic diseases Common in Asians, Hispanics, and non-white people in the USA. ICAS is estimated to account for 33-50% of stroke in Chinese populations, 47% in Thailand, and 28-60% in Korea. In the USA, the relative rate of strokes associated with ICAS is about 5.0 times higher for Hispanics and 5.85 times higher for black people compared with white people. Kim JS, Intracranial Atherosclerosis Wong LKS, Int J Stroke 2006 Nam HS et al. Neurology 2006 Bang OY et al. Neurology 2005

Intracranial atherosclerotic diseases Common in Asians, Hispanics, and non-white people in the USA. ICAS is estimated to account for 33-50% of stroke in Chinese populations, 47% in Thailand, and 28-60% in Korea. In the USA, the relative rate of strokes associated with ICAS is about 5.0 times higher for Hispanics and 5.85 times higher for black people compared with white people. Thus, acute occlusion due to ICAD should not be ignored in non-white people, especially Asian patients. Kim JS, Intracranial Atherosclerosis Wong LKS, Int J Stroke 2006 Nam HS et al. Neurology 2006 Bang OY et al. Neurology 2005

Characteristics of ICAS-related occlusion Clinical Imaging

Mechanisms of ischemic stroke and TIA in patients with ICAS Mechanism Frequency Patterns of infarcts Number of infarcts In situ thrombotic occlusion Uncommon Large subcortical Sometimes with BZ Rarely, whole territory A-to-A embolism Common Small cortical and subcortical Impaired clearance of emboli Branch occlusive disease Common Common Small, scattered, alongside the BZ region Small subcortical, lacunelike Single Sometimes enlarging Multiple Multiple Single Hemodynamic Uncommon Borderzone Multiple Kim JS, Intracranial Atherosclerosis

Hwang et al. Stroke 2016 Hwang et al. reported the baseline and follow-up characteristics of residual stenosis after EVT in relation to stroke pathogenesis 40 of 163 patients (24.5%) were found to have in-situ thrombotic occlusion (IST)

Baseline Characteristics, Imaging, and Clinical Outcomes Based on the Operationally Defined Target Arterial Lesion Pathogeneses Hwang et al. Stroke 2016

ICAS-related occlusion MH Perez, et al. Stroke. 2017.

The arteries that reoccluded had such a severe stenosis that most patients showed a residual stenosis of 50%. The degree of stenosis was significantly higher for patients with reocclusion than those without. Heo JH et al. Neurology 2003 It is essential to determine whether a remnant focal stenosis is significant following primary thrombectomy (underlying ICAS) Hwang YH et al. 21.6% Lee JS et al. 17% Yoon W et al. 23%

Acute management of stroke due to ICAD Irrespective of mechanism of large vessel occlusion, Early recanalization/reperfusion is strongly associated with improved functional outcome and reduced mortality Rha JH, Saver JL, Stroke 2007

Therapeutic strategy for acute occlusion due to ICAD No RCTs Primary therapy could be mechanical thrombectomy (IVT+EVT, if possible)

Therapeutic strategy for acute occlusion due to ICAD No RCTs Primary therapy could be mechanical thrombectomy (IVT+EVT, if possible) Among 53 patients underwent EVT with the Solitaire FR device, ICAS-related LVO was observed in 9 (17%) Immediate reperfusion (mtici 2b-3); 7 (77.8%) Partical recanalization (AOL 2-3); 6 (66.7%) Lee JS et al. J Stroke 2017

Therapeutic strategy for acute occlusion due to ICAD No RCTs Primary therapy could be mechanical thrombectomy (IVT+EVT, if possible) In situ thrombi could be removed well by recent thrombectomy devices, and partial revascularization was achieved in most cases. Stent retrieval could work well as the primary EVT Lee JS et al. J Stroke 2017

Therapeutic strategy for acute occlusion due to ICAD No RCTs Primary therapy could be mechanical thrombectomy (IVT+EVT, if possible) However, there are concerns regarding endothelial damage if an acute LVO is due to ICAD. The intrinsic atherosclerotic pathology and the severity of target artery lesion may be pivotal factors associated with re-occlusion after EVT Lee JS et al. J Stroke 2017 Cao X et al. Stroke 2016

in situ thrombosis in ICAS lesion Stent retrieval for ICAS-O. Routine firstline thrombectomy can effectively eliminate the major portion of in situ thrombi. Endothelial cells are still inflamed and may cause re-occlusion. Lee JS et al. J Stroke 2017

Therapeutic strategy for acute occlusion due to ICAD (2) Anti-thrombotics such as GP IIb/IIIa inhibitor Abciximab Tirofiban

Therapeutic strategy for acute occlusion due to ICAD (2) Anti-thrombotics such as GP IIb/IIIa inhibitor Prospective study from a single center IA-thrombolysis Recanalized arteries were re-examined 20 min later Systematically administrated abciximab was associated with dissolution of the thrombus in all reocclusion patients with 30-40 min after the bolus. 29 (13 men, 64yr) were treated with IAT/IV+IAT. Initial recanalization was achieved in 18 (62%), but unsuccessful in 11 patients. Re-occlusion occurred in 4 of 18 patients (22%). Heo JH et al. Neurology 2003

prospectively collected data of consecutive patients with AIS in whom mechanical thrombectomy was perfomed in the years 2006 to 2011. In endovascular stroke therapy, additional treatment with the GP-IIb/IIIa inhibitor tirofiban is associated with increased risk of fatal ICH and poor outcome.

tirofiban was given within a standard operational procedure stating, if stenting is performed or relevant endothelial damage is feared, eg, because of multiple thrombectomy passages. - the bias resulting in increased ICH was introduced by the interventionalist administering tirofiban in patients felt to be at higher risk of unfavorable outcome during the intervention.

A retrospective study from a single center IAT; 30 patients IA tirofiban (Aggrastat ); 16 patients infused IA tirofiban with mechanical thrombolysis with microwire if there was no response to IA thrombolysis or suspicion of reocclusion of partially recanalized vessel. -TICI 2b-3; 13 of 16 patients -No procedure related complications -mrs 0-2 at 3m; 8/16 (50%) -Mortality; 3/16 (18.9%) -SICH; 1/16 (6.2%) IST; 30.3% (40/132) Instant reoclcusion; 65% (26/40) in the IST cohort vs 3.3% (3/92) in the non-ist cohort For the 35 patients with re-occlusion, - 85.7% (30/35) had TICI 2/3-74.3% (26/35) had mtici 2b/3 recanalization - Rescue stenting was inevitable for 5 (14.3%) - No SICH

a) Cerebral angiography revealed an occlusion at the M1 of the RMCA b) Suction thrombectomy with Penumbra reperfusion catheter was performed, and the following angiography showed a successful recanalization with focal significant residual stenosis at the occlusion site

The use of glycoprotein IIb/IIIa inhibitors appears to be potential treatment Limitations Retrospective analysis; neither randomized, nor blinded outcome measure Small sample No standard dose for IA/IV-antithrombotics; lower dose of IV-tirofiban (0.5-1mg) dicas/mca occlusion are occasionally refractory to GP IIb/IIIa inhibitors Concerns of bleeding still continue Further studies on GP IIb/IIIa inhibitor should be performed

Therapeutic strategy for acute occlusion due to ICAD (3) Angioplasty and stenting

Historical development of Endovascular technologies for acute recanalization Technology First human studies IA microcatheter lysis 1988 (1999) IA angioplasty 1994 IA aspiration thrombectomy 2001 (2009) IA ultrasound sonothrombolysis 2003 IA implanted stents 2003 IA laser clot destruction 2004 IA Archimedes screw 2004 IA coil retrievers 2004 IA basket/brush retrievers 2006 IA stent retrievers 2010 (2010)

Stroke. 2009 - prospective single-arm trial - Recanalization: in all 20 patients : 12 (60%) TIMI 3 : 8 (40%) TIMI 2 - Thirteen (65%) patients: improvement of 4 NIHSS - No SICH but the 1-month mortality rate was 25% (5 patients). These data appear to support the relative safety and angiographic efficacy of a primary stent-for-stroke treatment paradigm.

Stroke. 2016 Stroke. 2017 J Stroke. 2016 Neurosurgery. 2015

A, the right carotid angiography showed an occlusion (arrow) in the proximal M1 segment of the right MCA. B, angiography after 1 passage of the Solitaire stent revealed a severe stenosis (arrow) in the mid-m1 segment of the right MCA. C, angiography after intracranial angioplasty and stenting showed recanalization of the right MCA and complete reperfusion in the right MCA territory. Arrows indicate the proximal and distal end of the Wingspan stent. D, Maximum-intensity projection image of the follow-up CTA 1 week after the procedure showed that the stented segment of the right MCA appeared widely patent (arrows). Yoon W, Neurosurgery. 2015

Rescue therapy in patients with IST-related occlusion After EVT (multimodal) Hwang YH et al. 2016 Baek JH et al. 2016 Primary IAT failure 53/208 (25.5%) NA Yoon W et al. 2015 Lee JS et al. 2016 Adjuvant therapy GP IIb/IIIa inhibitor 15/20 (67%) 17/53 (32%) None 2/9 (22.2%) Angioplasty/Stenting 4/20 (20%) 17/45 (38%) 38/40 (95%) 5/9 (56%) mtici 2b-3 GP IIb/IIIa inhibitor NA NA NA Stenting NA 14/17 (83.3%) 36/38 (95%) mrs 0-2 at 3m GP IIb/IIIa inhibitor NA NA NA 2/2 (100%) Stenting 1/4 (25%) 6/17 (35%) 25/38 (65%) 2/5 (40%)

Rescue therapy in patients with IST-related occlusion After EVT (multimodal) Hwang YH et al. 2016 Baek JH et al. 2016 Primary IAT failure 53/208 (25.5%) NA Yoon W et al. 2015 Lee Summary JS et al. 2016 Adjuvant therapy GP IIb/IIIa inhibitor 15/20 (67%) 17/53 (32%) None 2/9 (22.2%) Angioplasty/Stenting 4/20 (20%) 17/45 (38%) 38/40 (95%) 5/9 64/114 (56%) (56%) mtici 2b-3 GP IIb/IIIa inhibitor NA NA NA Stenting NA 14/17 (83.3%) 36/38 (95%) 50/55 (91%) mrs 0-2 at 3m GP IIb/IIIa inhibitor NA NA NA 2/2 (100%) Stenting 1/4 (25%) 6/17 (35%) 25/38 (65%) 2/5 34/64 (40%) (53%)

Stent retrieval for ICAS-O. Routine firstline thrombectomy can effectively eliminate the major portion of in situ thrombi. Endothelial cells are still inflamed and may cause re-occlusion. Gp IIb/IIIa inhibitor Gp IIb/IIIa inhibitor can stabilize the irritable endothelium. Angioplasty and stenting can crack the thrombus and plaque. Lee JS et al. J Stroke 2017

An organized (hard, fibrin-rich) clot is more resilient and less sticky than fresh (soft, red blood cell-rich) clots, causing less engagement with an SR and leading to clot missing during SR therapy Embolic occlusion ICAS-related occlusion Kim BM, J Stroke 2017

Possibly atherosclerotic plaque The organized clot may be refractory due to less engagement with the SR. If permanent stenting is conducted, the stented artery is likely more patent as the organized clot is less engaged inside the stent struts Kim BM, J Stroke 2017

Comparison of the efficacy between IA-GP IIb-IIIa inhibitor and angioplasty and stenting Pooled data from 2 stroke centers in S. Korea (CNUH+GUH) A; primarily angioplasty and stenting (N=72) B; primarily tirofiban IA infusion (N=68) Results A total of 140 patients (median age 67yr, male 65%) mtici 2b-3; 95% (133/140) mrs 0-2 at 3m; 60% (84/140) mortality; 8%(11/140) Unpublished data

Comparison of outcomes of patients from centers A and B. Rescue therapy Center A (N=72) Center B (N=68) P Angioplasty and stenting IA tirofiban Procedure time 37.5 (30-48) 53 (36-84) <0.001 Time to reperfusion 275 (205-400) 463 (274-647) <0.001 NIHSS 11 (9-15) 15 (11-20) <0.001 mtici 2b-3 69 (96%) 64 (94%) 0.71 mrs 0-2 at 3m 41 (57%) 43 (63%) 0.45 Mortality 7 (9.7%) 4 (5.9%) 0.53 Both intracranial angioplasty/stenting and intra-arterial infusion of a glycoprotein IIb/IIIa inhibitor may be effective and safe in the treatment of underlying severe ICAS in acute stroke patients with LVO. Unpublished data

Limitations of rescue angioplasty and stenting Experienced interventionists Neither randomized, nor blinded outcome measurement Antiplatelet medication after stenting? Increased risk of bleeding, eg. Intracerebral bleeding Branch occlusion during stenting? Further study will be warranted

Potential therapeutic strategies in ICAS-related occlusion Primary EVT (+) Significant residual stenosis in the parent artery B. Conservative therapy. 1) IA-glycoprotein IIb-IIIa inhibitor 2) Repeat f/u angiography A. rush to rescue therapy. 1) Rescue angioplasty/stenting +/- Glycoprotein IIb-IIIa inhibitor (+) reocclusion (-) reocclusion

Summary ICAS-related occlusion may not be uncommon in patients with acute ischemic stroke with large vessel occlusion The potential therapeutic strategies in ICAS-O could be primarily EVT, but it may not be sufficient to achieve the substantial reperfusion. Further study will be warranted, but based on studies from Korean researchers, rescue therapy including angioplasty and stenting or GP inhibitor might be considered.

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