1. Stroke Systems of Care V.T. Doss, D.O.
Stroke Medical Director, BMH-Memphis
Assistant Professor, Neurology & Neurosurgery, UTHSC

2. Intro Neurological emergency Ischemic vs. Hemorrhagic
TOAST classification
thrombosis /embolism due to atherosclerosis of a large artery
cardioembolic origin
occlusion of a small blood vessel
other determined cause (CSVT, vasculitis, trauma)
undetermined cause (two possible causes, no cause identified, or incomplete investigation)
thrombosis or embolism due to atherosclerosis of a large artery, (2) embolism of cardiac origin, (3) occlusion of a small blood vessel, (4) other determined cause (5) undetermined cause (two possible causes, no cause identified, or incomplete investigation).

3. Memphis- the capitol of atherosclerosis?

4. Stroke death rates, 2000–2006: adults ≥35 years of age, by county.
Stroke death rates, 2000–2006: adults ≥35 years of age, by county. Rates are spatially smoothed to enhance the stability of rates in counties with small populations. International Classification of Diseases, 10th Revision codes for stroke: I60–I69. Data source: National Vital Statistics System and the US Census Bureau.
Writing Group Members et al. Circulation 2012;125:e2-e220
Copyright © American Heart Association

5. US Stats
 95% of strokes at age >45, and 2/3 of strokes occur in those >65
leading cause death/disability
10% deaths worldwide
795,000 strokes/yr, 610,000 of these are first strokes. About 185,000 people who survive a stroke go on to have another
In 2010, stroke cost the US $53.9 billion
Someone in the United States has a stroke every 40 seconds. Every four minutes someone dies of stroke
This total includes the cost of health care services, medications, and missed days of work.
Compared to whites, African Americans are at nearly twice the risk of having a first stroke. Hispanic Americans' risk falls between the two. Moreover, African Americans and Hispanics are more likely to die following a stroke than are whites.
SE has highest mortality rates

6. According to the WHO, 15 million people suffer stroke worldwide each year.
Of these, 5 million die and another 5 million are permanently disabled.
Stroke is the second single most common cause of death in Europe: accounting for almost 1.1 million deaths each year.
Over one in seven women (15%) and one in ten men (10%) die from the disease.

7. Why is Time Important?
The area peripheral to a core infarct where metabolism is active but blood flow is diminished is called the ischemic penumbra
This is salvageable tissue that is at risk for infarction.
The penumbra lies in a 'no-man's land' between a zone of low blood flow that is < 25 ml/100 mg brain tissue/min and a zone where brain tissue is undergoing necrosis/death, flow of < 8-10 ml/100 mg/min1
Without restoration of blood flow/oxygen, the ischemic penumbra will convert to ischemic core or tissue death
Core Infarct
Ischemic Penumbra
Brain 1-

8. Time is Brain !!
Neurology Dec 12;55(11):

9. IV TPA APPROVED by FDA in 1996
NOW THE ACCEPTED STANDARD OF CARE THROUGHOUT US, EUROPE AND ASIA
RPCT – TPA v. Placebo < 3 hours (Dose .9mg/kg IV)
Inclusion Criteria: Stroke with clear time of onset, CT without ICH, & measurable deficit on NIHSS
Exclusion Criteria:
Recent GI or GU Bleed w/in 21 days, Ischemic stroke within 3 months,hx of ICH, recent arterial puncture at a noncompressible site w/in 7 days, SBP > 185 or DBP > 110 that can’t be controlled, INR > 1.5, platelets < 100K, glucose > 400 or < 50 Seizure at onset
Phase I (N=291): TPA clinical 24 hours NIHSS improvement of >/= 4
47% TPA vs. 39% placebo, p= 0.21
Phase II (N=333): Primary Outcomes (MRS < 2) at 90 days, ARR 12%, NNT = 8
SICH 6.4 % vs % (P < 0.001)

10. Number Needed to Treat = 14
Expanded time window for milder strokes, NIHHS < 25 with less than 1/3 of MCA territory on CT
N=821
Primary endpoint: MRS < 90 days. 52.4% vs. 45.2, P = 0.04
Number Needed to Treat = 14

11. Modified Rankin Scale 0 - No symptoms.
1 - No significant disability. Able to carry out all usual activities, despite some symptoms.
2 - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
3 - Moderate disability. Requires some help, but able to walk unassisted.
4 - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
5 - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
6 - Dead.

12. NINDS
NINDS randomized 624 subjects within 3 hours of stroke onset to receive 0.9 mg/kg of intravenous tPA or placebo
found that patients treated with tPA within 3 hours of onset had a substantially better chance of functional independence with minimal or no disability 3 months after treatment
The proportion of patients with minimal or no disability increased from 38% with placebo to 50% with tPA, a 12% absolute improvement
The NNT for 1 more patient to have a normal or near normal outcome was 8
NNT for 1 more patient to have an improved outcome was 3.1
Brain hemorrhages related to tPA caused severe worsened final outcome in 1% of patients
Overall, for every 100 patients treated within the first 3 hours, 32 had a better outcome as a result and 3 had a worse outcome.

13. ECASS III
821 pts, hr
no difference in mortality between the two groups (approximately 8%) 
sICH higher in tpa group (2.4%)
odds for a favorable outcome (MRS 0-1) after stroke were 28% higher with alteplase than with placebo
Time is tissue

14.  NINDS and ACLS Recommended Benchmarks for Potential Thrombolysis Candidate
Interval
Target
Door to doctor
10 min
Access to neuro expertise
15 min
Door to CT completion
25 min
Door to CT interpretation
45 min
Door to IV-rTPA
60 min
Admission to stroke unit or ICU
3 hours

15. Casting a wider net Expanding time window
Stroke centers- primary, comprehensive
Tele-stroke
Multi-modal imaging
New agents/devices
Less is more?
Neuroprotection

16. Direction/Innovations
EMS Advances
Telemedicine
Spoke and Hub Models

18. Tele-Stroke 24hr access to neuro specialist Avoids stroke mimickers
Allows smaller hospitals to keep these patients

19. CSC Physicians Vascular Neurology Vascular Neurosurgery
Infrastructure
Stroke Unit
Intensive Care Unit
Operating room staffed 24/7
Interventional staff available 24/7
Stroke registry
Diagnostic techniques
MRI with diffusion
MRA and MRV
Computed Tomography Angiogram (CTA)
Digital cerebral angiography
Transcranial dopplers
Carotid duplex ultrasound
TTE and TEE
Rehabilitation (PT/OT/ST)
Advanced Practice Nursing /Staff stroke nurses
Respiratory Therapists
Educational/research programs
Clinical research
Community education/prevention
Professional education
Physicians
Vascular Neurology
Vascular Neurosurgery
Vascular Surgery
Diagnostic radiology and neuroradiology
Interventional/endovascular physicians
Critical care medicine
Physiatrists
Surgical and interventional therapies
CEA
Intracranial aneurysm clipping
Surgical removal or draining of blood from the brain
Placement of EVD and intracranial pressure monitors
Endovascular treatment of aneurysms and arteriovenous malformations
Intra-arterial reperfusion therapy
Endovascular treatment of vasospasm
PSCs certified within the past 2 years, 72.7% of eligible patients received tPA. The longer a PSC was in the certification program, the higher its tPA participation rate. Hospitals in their second certification cycle achieved a 78.6% IV tPA participation rate, and those certified for a third 2-year cycle achieved 94.4% participation. Among teaching hospitals in their first certification cycle, the rate of IV tPA use for eligible patients was 81% compared with 70% of nonteaching hospitals. Most studies have found Tx at PSC you’re more likely to have a better outcome and lower mortality.

20. Mobile Stroke Unit Point-of-Care-based laboratory
compact CT scan results, reviewed remotely by hospital physicians
results in early pre-hospital IV-thrombolysis and subsequent bridging therapy later with IA recanalization in the hospital
A hospital system in Hamburg Germany developed a mobile stroke (treatment) ambulance to address the issue of suburban and rural stroke patient management and shorten time to treatment - bring the stroke care to the patient
They have been able to dramatically reduce Call-to-Lab time, Call to CT time and, most importantly, Call-to-Therapy Decision-Advanced Treatment time, reduced from 120 minutes (two hours), to just minutes.

21. Options for Patients Experiencing an Ischemic Stroke
IV tPA
Gold-standard in ischemic stroke care. Drug is designed to break apart the clot.
Endovascular Clot Removal
Mechanical disruption or removal of the clot using standard endovascular approaches
Bridging Therapy
Medical Management
Monitor vitals and provide secondary stroke prevention. Patient is send to rehab or a nursing facility when stable.

22. Endovascular Therapy Anterior 12 hours Posterior <24h NIHSS >7
Evidence of Large vessel occlusion, hemodynamically unstable
Large penumbra or clinical mismatch

23. 25% vs 42.9%## MCA Occlusion Basilar Occlusion
Recanalization rate IV TPA:
M1: 22%, M2:44%‡
Mortality:
25% vs 42.9%##
Recanalization rate with IV TPA: <10%
Mortality: 90%
(persistent occlusion)**
Internal Carotid Occlusion
Recanalization rate with IV TPA: <10%
Mortality: 73%
(persistent occlusion)^^
‡Alexandrov et al. Stroke
## Proact II: Jama 1999
**Meta analysis Furlan et al
^^ Flint et al. MERCI Registry Stroke 2008

24. The Importance of Recanalization
Recanalization is strongly associated with improved function outcomes and reduced mortality.

25. Meta-analysis shows a strong correlation between opening the blood vessel and patient good outcomes
Rha JH, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke Mar;38(3):

26. Clinical Trials
Most recent published EVT (endovascular therapy) trial results
Lessons learned
Current trial design

27. New EVT Stroke Trials IMS III MR RESCUE SYNTHESIS - EXPANSION
NEJM February 7, 2013

28. IMS III

29. IMS III: Interventional Management of Stroke 3
Patients who had received intravenous rt-PA within 3 hours after symptom onset were randomized 2:1 to:
IV tPA + IA therapy
IV t-PA alone
Primary outcome measure: 90-day mRS ≤ 2
Broderick JP. NEJM 2013;368:

30. Primary outcome: IMS III
mRS < 2 95% CI: -6.1% to +9.1%
40.8% with endovascular + IV rt-PA
38.7% with IV rt-PA alone
Broderick JP. NEJM 368: , 2013

31. MR RESCUE

32. MR RESCUE: Methods ≤ 8 hours of onset Anterior circulation LVO
Randomized to either EVT or Medical Mgmt
“penumbral” pattern by CT or MRI
Penumbra : “Small core” (<90 cc), large penumbra
Non-Penumbral: Large core and small/absent penumbra
IV tPA treated patients without recan were eligible if MRA or CTA showed persistent occlusion
Kidwell CS. NEJM 2013 Mar 7;368(10):914-23 32

33. MR RESCUE: 90-day mRS NO DIFFERENCE IN OUTCOMES
Endovascular vs. medical therapy
Penumbra vs. no penumbra
p=0.23
p=0.32
Kidwell CS. NEJM 368: , 2013

34. Synthesis Expansion

35. Synthesis Expansion: Outcomes
Primary Outcome (mRS < 1)
30.4% EVT
34.8% IV tPA
Death Rates
EVT: 14 (8%)
IV tPA: 11 (6%)
Italian Medicines Agency (AIFA)
“EVT is not superior to standard treatment with IV tPA”
Ciccone A. NEJM 368: , 2013

36. IMS III Protocol Versus Contemporary Practice
The majority of patients included in the study
Were not imaged using modern approaches
Were not triaged using modern approaches
Were not treated using modern approaches

37. Imaging Assessment Basic Head CT only in most patients
More than 40% of IMS III patients had baseline CT with ASPECTS < 7

38. ASPECTS (Alberta Stroke Program Early CT Score)

39. ASPECTS Score - 4

40. Patient Selection Matters: Penumbra Pivotal Trial
Independent Blinded Retrospective Analysis Baseline NCCT Data Using ASPECTS
mRS ≤ 2
Large Infarct
8/53 pts
Small Infarct
15/30 pts
Goyal M. Stroke 2010

41. IMS III - Imaging Assessment
Patients with “large clear regions of hypodensity” (darker than white matter and brighter than CSF) on CT, greater than 1/3rd of MCA territory were excluded
Sulcal effacement and loss of grey-white matter differentiation were not contraindications
Many patients would have likely been excluded with more conservative CT reading (ASPECTS), CTA-SI (source image) ASPECTS, MR Diffusion ASPECTS, CT Perfusion or MR Perfusion

42. Imaging Based Selection: Perfusion Imaging

43. IMS III – EVT Arm Would ALL have been screened out with CTA
89 patients with ”no treatable or treated thrombus”
33 no thrombus seen
34 thrombus not treatable by EVT
12 with treatable thrombus but not treated
No reason (1)
Couldn’t safely cross occlusion (3)
Recanalization during angio (2)
Occlusion not responsible for clinical presentation (2)
No reason (2)
Would ALL have been screened out with CTA

44. Clot characteristics (length)
No Clot > 8mm recanalized with IV tPA
43% of large vessel occlusions have greater than 8 mm clot lengths1 44

45. IMS III: Baseline CTA Occlusion Present – 90 day mRS
van Elteren test p-value

46. IMS III: Baseline CTA Occlusion Present - NIHSS > 20
van Elteren test p-value

47. TICI Score Grade 0 No perfusion
Grade 1 Perfusion past the initial obstruction, but limited distal branch filling with little or slow distal perfusion
Grade 2a Perfusion of less than ½ of the vascular distribution of the occluded artery (e.g., filling and perfusion through 1 M2 division)
Grade 2b Perfusion of ½ or greater of the vascular distribution of the occluded artery (e.g., filling and perfusion through 2 or more M2 divisions)
Grade 3 Full perfusion with filling of all distal branches

48. Percentage of Patients Who Achieved a Functional Outcome in IMS III Based on Reperfusion Result (p=0.001)
In IMS III, independent functional outcome (mRS 0-2) was strongly associated with TICI 2b-3 revascularization.

49. IMS III ‘modern’ devices = 13% of endovascular cohort
Total endovascular treatments = 334/434
IA tPA
EKOS + tPA 22
Merci 38
Merci + tPA 57
Penumbra 16
Penumbra + tPA 38
Solitaire 2
Solitaire + tPA 3
‘modern’ devices
= 13% of endovascular cohort

50. IMS III IMS-III endovascular reperfusion rates: ≥ TICI 2a ≥ TICI 2b
ICA % %
M % %
M % %
Overall % %
TREVO2* 92% 68%
SWIFT* 94% 76%
*Both are high quality independent core lab adjudicated, published in Lancet

51. Systems and Process Issues in the Era of Comprehensive Stroke Center Designation
Relative to IMS I and II, the IMS III trial suffered from a dramatic delay between the initiation of iv tPA and endovascular therapy
At over two hours, this lag impedes the ability of reperfusion to realize clinical benefit.

52. IMS III patients further suffered a significant lag between groin access and initiation of IAT at the lesion Fourty-four minutes is far beyond reported standards with modern guide and distal access catheter technology

53. Time to Treatment IMS III Onset to arrival: 57 min
Arrival to IV tPA: 66 min
IV to groin puncture: 86 mins
Groin puncture to IA: 44 mins
MR RESCUE
Mean time from imaging to groin puncture:
2h 4 min
SYNTHESIS
Time from onset to start of treatment
EVT hrs
IV 2.75 hrs
130 mins between IV tPA and start of IA therapy
By comparison STAR registry:
Groin Puncture to guide cath placement: 12 mins
Guide cath to TICI 2B/3 flow: 20 mins
Critical as IA group did NOT receive IV tpa

54. Lessons Learned Endovascular Therapy is safe – as safe as IV rt-PA

55. Lessons Learned from Recent Ischemic Stroke Trials
It is not IV vs EVT
IV tPA is proven Class 1 – it should not be denied from patients
Future trials should compare best medical management versus best medical management + EVT
Only enroll patients with LVO (large vessel occlusion)
Excellent recanalization is needed
TICI 2B or 3
Time is Brain
Better determination of salvageable brain tissue
ASPECTS
CT Perfusion
MRI Diffusion/Perfusion
Set the stage for final portion of talk – can quickly review point 1 on this slide. We have already made the argument for point 2. Will then get into greater discussion of points 3-5 55

56. Merci Retriever
“Cork Screw”

57. Newer Technologies = Better Recanalization
Solitaire FR
Trevo
Separator 3-D
Penumbra Max System

60. Distal aspiration with retrievable stent assisted thrombectomy for the treatment of acute ischemic stroke
William Humphries1, Daniel Hoit1, Vinodh T Doss1, Lucas Elijovich1, Adam S Arthur1
Abstract
Objective Flexible large lumen aspiration catheters and stent retrievers have recently become available in the USA for the revascularization of large vessel occlusions presenting within the context of acute ischemic stroke (AIS). We describe a multicenter experience using a combined aspiration and stent retrieval technique for thrombectomy.
Design A retrospective analysis to identify patients receiving combined manual aspiration and stent retrieval for treatment of AIS between August 2012 and April 2013 at six high volume stroke centers was conducted. Outcome variables, including recanalization rate, post-treatment National Institutes of Health Stroke Scale (NIHSS) score, symptomatic intracranial hemorrhage, discharge 90 day modified Rankin Scale (mRS) score, and mortality were evaluated.
Results 105 patients were found that met the inclusion criteria for this retrospective study. Successful recanalization (Thrombolysis in Cerebral Infarction score 2B) was achieved in 92 (88%) of these patients. 44% of patients had favorable (mRS score 0–2) outcomes at 90 days. There were five (4.8%) symptomatic intracerebral hemorrhages and three procedure related deaths (2.9%).
Conclusions Mechanical thrombectomy utilizing combined manual aspiration with a stent retriever is an effective and safe strategy for endovascular recanalization of large vessel occlusions presenting within the context of AIS.
J NeuroIntervent Surg doi: /neurintsurg

61. Case 1 53yo male presented with L MCA syndrome NIHSS 21 Onset 1 hour
Received iv-tpa within 60 min from door

62. Pre-treatment

64. Post-treatment

65. Case 1 Dysfluency and hemiparesis d/c to rehab with mRS of 2
1 mo f/u mRS of 1

66. Case 2 75yo male consulted for acute stroke Pseudobulbar palsy
Post. circulation strokes 3 months prior, d/c mRS 0, was on ASA/plavix

67. April 2013
30% stenosis 67

71. 262 PRU

73. Case 3
35yo AA male presents with 2 hours of inability to produce speech and right sided weakness.
PMH: bipolar d/o
Exam: awake, not following commands, globally aphasic
Right hemiplaegia
NIHSS: 22

79. At Discharge: mRS- 0, NIHSS 1

80. Conclusions Stroke systems and patient selection critical to outcomes
EMS critical to triage, stabilizing and transporting to stroke center
Imperative to recognize signs and symptoms of stroke especially large vessel occlusion
IV-TPA standard of care
Endovascular treatment can be performed quickly and safely
Time is Brain!

81. Questions?