Interventional Stroke Treatment 2015 Sudipta Roychowdhury, MD Director of Interventional Neuroradiology Director of Magnetic Resonance Imaging Clinical Associate Professor of Radiology Rutgers-RWJ Medical School University Radiology Group

Stroke Therapy Timeline MR CLEAN SWIFT PRIME EXTEND IA ESCAPE REVASCAT THERAPY Solitaire Penumbra Trevo PROACT II IA tPA Angioplasty Stenting Level I Evidence Bridging IV/IA IV tPA MERCI ACE IV tPA (4.5h) Generation 1 Generation 2 Generation 3 1995 2000 2005 2010 2015 FDA Approved - Yellow Off-label - Red

Ischemic Stroke Interventions Ischemic Stroke Therapy FDA Small Series Large Trial Efficacy IV t-PA Yes IA t-PA No IV and IA t-PA MERCI Device Penumbra Device Solitaire Device Trevo Device Angioplasty/Stenting 3

NINDS tPA Trial NINDS tPA trial (1995) Benefit still seen 3-4.5 hours IV tPA vs Placebo < 3hrs Outcomes improved with all 4 outcomes Symptomatic hemorrhage 6.4% vs 0.6% Mortality 17% vs 21% placebo at 3 months Established IV tPA as gold standard < 3hrs Better for small rather than large occlusions Benefit still seen 3-4.5 hours NEJM 9/2008 European study

PROACT II PROACT II (1998) Dr. Irwin Keller NJ Investigator – IA Prourokinase < 6 hrs Favorable outcome 40% vs 25% control Recanalization 66% vs 13% control Mortality 25% vs 27% control Symptomatic hemorrhage 10% vs 2% control IA Prourokinase and tPA not FDA approved

Case 55 y/o M presents after 5 hours of onset of rapidly progressive quadriparesis, ataxia, and dysphagia. Head CT was normal.

Basilar Artery Occlusion

Basilar Angioplasty and Thrombolysis IA t-PA

Excellent Recanalization and Excellent Outcome

Case 77 y/o F presents after 4 hours of onset of slurred speech and ataxia rapidly progressing to loss of consciousness Head CT was unremarkable.

Basilar Artery Occlusion

Basilar Angioplasty/Stent & Thrombolysis IA t-PA

Futile Recanalization

MERCI Device MERCI 14

MERCI Trial MERCI (2005) – MERCI < 8 hrs; n=141; No control arm Recanalization 46% (66% PROACT II) Mortality 44% (25% PROACT II, 27% Control) Symptomatic hemorrhage 7.8% Primary outcome recanalization not outcome Results worse than PROACT II FDA approved but heavily criticized for approval before establishing efficacy

Multi-MERCI Trial Multi- MERCI (2006) – MERCI +/- IV tPA < 8 hrs; n=164; No control Recanalization 54% and 69% w IA tPA Mortality 31%; Symptomatic hemorrhage 9% Primary outcome recanalization not outcome Results still worse than PROACT II Still trying to establish efficacy after FDA approval!

Does the MERCI Device Work? “In summary, the MERCI study does not provide any evidence of improved outcomes or greater recanalization rates…. In addition, both clinically significant complications and mortality are higher than the results of other interventional trials…. the results do not support the proposal that the Merci retrieval device works by any definition.” Wechsler, Lawrence R. MD, Donnan, Geoffrey A. MD, FRACP; Davis, Stephen M. MD, FRACP Stroke Volume 37(5), May 2006, pp 1341-1342

MERCI: Defended Why high recanalization but not better outcomes? Comparing MERCI to PROACT II Different pt selection – MERCI trials included pts with poor functional status unlike PROACT II If adjust for patient selection, similar mortality and outcome 18

Case 38 y/o F presents with acute left sided hemiplegia presents at 4 hours. History of atrial fibrillation. Head CT was unremarkable.

MERCI

Penumbra Device Suction catheter with separator wire which prevents thrombus from clogging the tip 21

Penumbra Trial Penumbra – n=125; Recanalization 82% (PROACT II 66%) Mortality 32% (25% PROACT II, 27% Control) Symptomatic hemorrhage 11% Primary outcome recanalization 36% good outcome; No control arm 510k FDA approval – “equivalent” to MERCI

Case 44 y/o M presents with mental status changes and left leg weakness at 6 hours. Head CT was unremarkable.

Penumbra ACA Infarct

Stent Retrievers 3rd Generation endovascular stroke treatment Immediate flow restoration Trap thrombus within stent struts and retrieved Removable device so no anti-platelets needed Solitaire Trevo

Solitaire

Solitaire – SWIFT Trial SWIFT (SOLITAIRE With the Intention for Thrombectomy) Solitaire (S) versus Merci (M) randomized trial 200 intended pts but stopped at 144 by safety board Successful recanalization without symptomatic hemorrhage – occurred in 61% of the Solitaire group and 24% of the Merci group. Highly significant difference with a P value of .0001 Symptomatic intracranial hemorrhage (2% S vs. 11% M). All intracranial hemorrhage (17% S vs. 38% M). Good 90-day neurologic outcome (58% S vs. 33% M). 90-day mortality (17% S vs. 38% M). Solitaire was significantly better than Merci

Case 65 y/o M presents acute left sided hemiplegia at 4 hours and was on Coumadin for atrial fibrillation. Head CT was unremarkable.

Solitaire

Trevo Trevo was significantly better than Merci Trevo 2 Trial : Trevo versus Merci retrievers for large vessel stroke Randomized Trevo Retriever group 88 patients and Merci Retriever group 90 pts 76 (86%) patients in the Trevo group and 54 (60%) in the Merci group met the primary endpoint after the assigned device. p<0·0001). Incidence of the primary safety endpoint did not differ between groups (13 [15%] patients in the Trevo group vs 21 [23%] in the Merci group; p=0·1826). Trevo was significantly better than Merci

Futile Recanalization Unfavorable outcome even with excellent endovascular recanalization

How do we select Stroke Patients to avoid Futile Recanalization? Time versus Penumbra versus Core Time Less than 6 hours for IA tPA (Anterior) Less than 8 hours for mechanical (Anterior) Unknown time for posterior circulation Penumbra – Potential stroke territory CT perfusion – very controversial Not accurate predictor of penumbra High radiation dose Fallen out of favor by MGH original CTP advocates Delayed CTA images for collaterals

How do we select Interventional Ischemic Stroke Patients? Core – Actual irreversibly infarcted brain tissue If less than 1/3 of MCA territory has been infarcted, better chance for good outcome with recanalization If the Core is smaller with larger penumbra, the patient may have good collaterals which will allow better outcome with recanalization. ASPECTS criteria MRI diffusion

ASPECTS Criteria Alberta Stroke Program Early CT score (ASPECTS) is a 10-point CT scan score ASPECTS predicts core of infarct A normal CT scan receives ASPECTS of 10 points.  To compute the ASPECTS, 1 point is subtracted from 10 for any evidence of early ischemic change for each of the defined regions OF MCA territory A score of 0 indicates diffuse involvement throughout the MCA territory  Patients with ASPECTS score of 8-10 had better outcomes than patients with 7 or less at both shorter (less 5 hours ) and longer (greater than 5 hours) recanalization

ASPECTS Criteria A normal CT scan receives ASPECTS of 10 points. To compute the ASPECTS, 1 point is subtracted from 10 for any evidence of early ischemic change for each of the defined regions OF MCA territory

MR Diffusion Criteria MR diffusion accurately predicts core of infarct If less than 1/3 MCA territory or less than 70ml volume, better outcome endovascular treatment (Volume = ABC/2) If brainstem infarcted in posterior circulation, poor outcome with basilar stroke. Takes additional time to obtain MR diffusion Diffusion (Core) PWI (Penumbra)

TICI Criteria for M1 Occlusion Grade 0 – No antegrade flow beyond occlusion Grade 1 – Open beyond obstruction but not distal Grade 2a – Less 50% MCA circulation Grade 2b – Greater than 50% MCA circulation Grade 3 – Entire MCA circulation open Grade 2B and 3 – Best neurological outcomes

Case 6 76 y/o F noted to have left arm/leg weakness 2 days after pelvic surgery. 38

Core: MR Diffusion MR Diffusion: less than 1/3 MCA core infarct Head CT MR Diffusion CTA – R M1 occlusion MR Diffusion: less than 1/3 MCA core infarct

CT Perfusion and MR Diffusion CBF TTP (Penumbra) Diffusion (Core) 40

Penumbra Device 41

CT Perfusion after Penumbra Thrombectomy TTP TTP after thrombectomy Diffusion 42

IMS III (2008-2012) Interventional Management of Stroke III NEJM March 2013 results – IV tPA only vs IV + IA tPA / Mechanical Trial stopped in 2012 as ongoing data could not show benefit of combined IV+ IA superior to IV tPA alone No distinction between small and large vessel strokes Large vessel occlusions did better with IA Limited by older endovascular devices No CTA, No ASPECTS criteria 43

SYNTHESIS Expansion Trials NEJM March 2013 – IV tPA only <3 hrs vs Combined IV + IA tPA and/or Mechanical Device < 6hrs Can we do better than IV tPA? Endocvascular Tx: Catheter & wire, Merci and Penumbra, minimal Stent-Retrievers Limited by older endovascular devices No difference in outcomes No distinction between large and small vessel strokes 44

Level I Interventional Evidence MR CLEAN ESCAPE EXTEND-IA SWIFT PRIME REVASCAT (THERAPY)

MR CLEAN Study Details Control – IV/Medical only versus Interventional arm - IA and IV MR CLEAN demonstrated a 71% improvement in good neurological outcomes for Interventional compared to medical management/TPA (32.6% (76/233) vs. 19.1% (51/267)) There was no safety difference in adverse events (47% vs. 42%) , ICH (7.8% vs. 6.4%) or 90 day mortality (21% vs 22%) between the two groups. Lower absolute rates of 90day mRS 0-2 and higher complication rates seen in MR CLEAN vs. prior studies reflect the ‘real-world’ experience in the Netherlands, particularly the relatively high rate of ICA lesions vs. prior studies like IMS3 (26% vs. 15%) Stent Retrievers used in 97% of interventions There was a improved mRS shift for Interventional vs Control First large scale study demonstrating interventional superiority

MR CLEAN mRS mRS (Modified Rankin Scale) 0 – No symptoms 1 – No significant disability 2 – Slight disability 3 – Moderate disability 4 – Moderate severe disability 5 – Severe disability 6 – Death

MR CLEAN Study Conclusion 4/21/2017 1:43 PM MR CLEAN Study Conclusion In patients with acute ischemic stroke caused by a large arterial occlusion of the anterior circulation, intraarterial treatment within 6 hours was effective and safe IA treatment leads to a clinically significant increase in the functional independence in daily life by 3 months, without an increase in mortality Triggered stoppage of multiple other trials: ESCAPE, SWIFT PRIME, Extend IA, REVASCAT, and THERAPY Add your key takeaways / perspective O.A. Berkhemer et. al. A Randomized Trial for Intraarterial Treatment for Acute Ischemic Stroke. N Eng J Med December 2014. V4

Merci Retriever®, EKOS, IA Lytic, Penumbra 24% pen (n=34) 27% nonp Trial Imaging Required to Confirm Occlusion Prior to Randomization? Device(s) Used in Intervention Arm TICI 2b/3 Revascularization Rate in the Intervention Arm mRS 0-2 Intervention Arm Control Arm IMS III No IA Lytic (138), Merci Retriever® (95), EKOS (22), Penumbra (54), Solitaire FR (5) 38% ICA 44% M1 44% M2 23% multi M2 40.8% (N=415) 38.7% (N=214) MR RESCUE Merci Retriever®, EKOS, IA Lytic, Penumbra 24% pen (n=34) 27% nonp (n=30) 21% pen (n=34) 17% nonp 26% pen (n=34) 10% nonp (n=20) MR CLEAN Head CT 97% Stent Retrievers, 2% other Mechanical 58.7% (N=196) 33% (N=233) 19% (N=267) ESCAPE CTA Collaterals, ASPECTS 86% Stent Retriever 72.4% (n=156) 53.0% (n=164) 29.3% (n=147) SWIFT PRIME CTP 100% Stent Retriever 88.0% (n=83) 60.2% (n=98) 35.5% (n=93) EXTEND-IA 86.2% (n=29) 71% (n=35) 40% REVASCAT ASPECTS 66% (n=102) 44% 28% (n=103) THERAPY CTA clot >8mm 100% Penumbra 38% (n=50) 30% (n=46)

4/21/2017 1:43 PM What does this mean? Interventional therapy (with IV tPA) may have become the gold standard for large vessel ischemic stroke in 2015. MR CLEAN, ESCAPE, SWIFT PRIME, REVASCAT, EXTEND-IA, THERAPY However, the selection criteria for interventional stroke treatment is not uniform. Head CT, ASPECTS, Diffusion MRI, CTA, Delayed CTA, CTP Medicolegal Implications: Large vessel ischemic stroke patients may need to have rapid access to Interventional tx. Add your key takeaways / perspective V4

Case 38 F who is 16 weeks pregnant presented with slurred speech and facial weakness to the ER after 8 hours. She became comatose after 24 hours after admission. MRI performed at 30 hours. Angiogram performed at 36 hours after emergency hospital privileges. 51

38 y/o Comatose F Angiogram at 36 hrs 52

Basilar Artery Angioplasty and Thrombolysis at 36 Hours 53

Ischemic Stroke Treatment Guidelines IV tPA (<4.5 hours) Add Interventional (IA) treatment if: Do CTA if MCA syndrome or NIHSS > 7 CTA shows large vessel occlusion Patient not a IV t-PA candidate Patient not improving with IV t-PA ASPECTS criteria 8-10 for MCA stroke MR diffusion shows small or no core infarct Transfer to comprehensive stroke center if large vessel stroke Need to await further results of trials “Do no harm…” 54

Interventional Stroke Treatment 2015 Sudipta Roychowdhury, MD Director of Interventional Neuroradiology Director of Magnetic Resonance Imaging Clinical Associate Professor of Radiology Rutgers-RWJ Medical School University Radiology Group

Stroke Therapy Timeline MR CLEAN SWIFT PRIME EXTEND IA ESCAPE REVASCAT THERAPY Solitaire Penumbra Trevo PROACT II IA tPA Angioplasty Stenting Level I Evidence Bridging IV/IA IV tPA MERCI ACE IV tPA (4.5h) Generation 1 Generation 2 Generation 3 1995 2000 2005 2010 2015 FDA Approved - Yellow Off-label - Red