1. The New Frontier In Stroke Care – Endovascular Intervention
Syed F Ali
Chief Resident, PGY3
Neurology, UAMS.

2. Saving lives, one clot at a time…
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3. Introduction
Stroke care has come a long way from mainly focusing on prevention and rehabilitation to actually ‘curing’ the disease.
Stroke has dropped from 4th leading cause of mortality in the US to the 5th in past decade but still responsible for nearly 130, 000 deaths every year.
Over the past 10 years, the death rate from stroke has fallen about 35% and the number of stroke deaths has dropped about 21%!
ITS AN EXCITING TIME TO BE A STROKE-OLOGIST!

4. How the natural course of disease changed
UC San Diego was the first to use IV tPA for stroke, a treatment developed in the laboratory of  Dr. Justin Zivin at UCSD!
ECASS Trial (JAMA – 1995): ‘intravenous thrombolysis cannot currently be recommended for use in an unselected population of acute ischemic stroke patients’
ECASS II Trial (Lancet – 1998): ‘the results do not confirm a statistical benefit for alteplase’
NINDS Trial (NEJM – 1995): ‘Despite an increased incidence of sICH, treatment with t-PA ≤ 3hr of ischemic stroke improved clinical outcome at three months’
ECASS III Trial (NEJM – 2008): ‘tPA administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes’

5. Initiatives to improve delivery of care
Focus then shifted to increasing the rates of tPA and decreasing the time to tPA.
Saver et al (Stroke – 2006) showed that ‘typical patient loses 1.9 million neurons each minute in which stroke is untreated!’
Target Stroke initiative, AHA/ASA/JACHO/GWTG/CMS/NQF all working towards improving DTCT, DTN, tPA rates
Telestroke initiative – first and only trial - STRokE DOC trial (Lancet – 2008) ‘more appropriate decisions, high rates of thrombolysis use, low rate of intracerebral haemorrhage, favourable time requirements all support the efficacy of telemedicine for making treatment decisions’

6. IV tPA
Ali et al. Circ Cardiovasc Qual Outcomes Sep 1;6(5): doi: /CIRCOUTCOMES Temporal trends in patient characteristics and treatment with intravenous thrombolysis among acute ischemic stroke patients at Get With The Guidelines-Stroke hospitals.

7. Do we need to do better than tPA?
Why?
Delayed treatment – no penumbra remaining?
IV tPA doesn’t always open the artery?
Kamalian et al. reported that clots > 8mm are less likely to dissolve with tPA (Stroke – 2013)
Proximal occlusion? – reported data has shown that distal branches has better recanalization success with tPA as compared to proximal occlusion.
Carotid terminus 5%, M1 30%, M2 42%

8. Intra-arterial thrombolysis
PROACT II (JAMA – 1999): ‘Despite an increased frequency of early sICH, treatment with IA r-proUK within 6 hours of the onset of acute ischemic stroke caused by MCA occlusion significantly improved clinical outcome at 90 days’
Why not just take the clot out!

9. Endovascular intervention era arrived…
A MERCI catheter in use.

10. IMS III – NEJM 2013
Full Name: Interventional Management of Stroke (IMS) III
Background: On the basis of preliminary work, first tested in the small - randomized Emergency Management of Stroke (EMS) trial during 1995 and and consecutive single-group trials (IMS I and II trials), the IMS III trial was organized to begin enrollment in 2006.
Objective: Comparison of IV tPA alone vs. IV tPA + EVT
Methods: Randomly assigned eligible patients who received IV tPA within 3hr to get additional EVT in a 2:1 ratio.

11. IMS III
Planned to enroll a maximum of 900 participants, at 58 centers in the United States, Canada, Australia, and Europe.
NIHSS ≥ 10, later revised to 8-9 with CTA finding of occlusion
No requirement to demonstrate arterial occlusion, all patients who were randomly assigned went for angio with EVT if needed.
Older devices - Merci retriever, Penumbra System, or endovascular delivery of t-PA by means of the MicroSonic SV infusion system [EKOS] or a standard microcatheter

12. IMS III
April 2012 – after 656/900 enrollments, study stopped due to futility.
No significant difference between the IV tPA vs. EVT + IV tPA in proportion of patients with mRS ≤ % vs. 38.7%
Predefined secondary analyses showed no significant differences among the subgroups.

13. SYNTHESIS Expansion – NEJM 2013
Objective: To investigate whether endovascular treatment, including the options of a mechanical device and intraarterial t-PA, is more effective than the currently available treatment with intravenous t-PA.
The study was funded by the Italian Medicines Agency (AIFA).
Methods: Administration of endovascular treatment within 6 hours after symptom onset.
Patients who were assigned to this treatment group did not receive intravenous t-PA while awaiting endovascular treatment, but they got IA tPA or EVT.

14. SYNTHESIS Expansion
Results: From February, 2008 till April, 2012 a total of 362 patients were randomized (181 to each group)
In EVT group 109 received just IA tPA and 56 had a device added.
~ 1 hr delay to when IV tPA was given vs. IA tPA
There were no significant differences between the groups with respect primary or secondary outcome measures, with adjustment.

15. MR RESCUE – NEJM 2013
The Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy trial.
Objective: Whether brain imaging can identify patients who are most likely to benefit from therapies for acute ischemic stroke and if endovascular thrombectomy improves clinical outcomes in such patients.
Methods: North American trial, patients with NIHSS of 6 – 29 who had large vessel, anterior circulation stroke were randomly assigned within 8hrs to undergo EVT vs. IV tPA.

16. MR RESCUE
EVT done by FDA-cleared embolectomy devices - Merci Retriever and the Penumbra System
MRI/CT Perfusion done but not a criteria for selection
Results: Among 118 eligible patients, the mean time to enrollment was 5.5 hours and 58% had a favorable penumbral pattern.
Revascularization in the embolectomy group was achieved in 67% of the patients.
Ninety-day mortality was 21%, and the rate of symptomatic intracranial hemorrhage was 4%; neither rate differed across groups.

17. MR RESCUE
Among all patients, mean scores on the mRS did not differ between embolectomy and standard care (3.9 vs. 3.9, P=0.99).
Embolectomy was not superior to standard care in patients with either a favorable penumbral pattern (mean score, 3.9 vs. 3.4; P=0.23)
Or a nonpenumbral pattern (mean score, 4.0 vs. 4.4; P=0.32)

18. wait ‘til next year…

19. How to improve? Faster is always better in the world of stroke!
Increase recanalization success – Newer, better devices, raise bar for success (TICI 2b/3)
Stop selecting everyone! – Better selection of patients for EVT, those with demonstrated LVO but still large penumbra to save
Exclude risky patients – those arriving too late, with large core infarct!

20. New Device!

21. MR CLEAN – NEJM 2015
Objective: In patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion, intraarterial treatment is highly effective for emergency revascularization.
Methods: The study was conducted at 16 centers in the Netherlands.
Initiation of intraarterial treatment had to be possible within 6 hours after stroke onset.
Eligible patients had an occlusion of the distal intracranial carotid artery, M1 or M2, A1 or A2, established with CTA, MRA, or DSA and a score of 2 or higher on the NIHSS, no penumbral selection
Use of newer devices – stent retrievers

22. MR CLEAN Well matched groups in terms of age and NIHSS
97% had EVT with newer devices
TICI 2b/3 was 58% (vs. 40% in IMS3 and 27% in MR RESCUE!)
Onset to tPA ~ 90mins, onset to groin puncture ~ 260 mins

23. MR CLEAN
A shift in the distribution of the primary- outcome scores in favor of the intervention
Adj. OR was 1.67 (95% confidence interval [CI], 1.21 to 2.30)
The shift toward better outcomes in favor of the intervention was consistent for all categories of the mRS , except for death
Significant NIHSS reduction at 24hrs and 7 d
Recanalization at 24hr – 33% vs 75%

24. SWIFT PRIME – NEJM 2015
The Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment (SWIFT PRIME) trial 
Objective:  to establish the efficacy and safety of rapid neurovascular thrombectomy with the stent retriever in conjunction with intravenous t-PA versus intravenous t-PA alone in patients with acute ischemic stroke. 
Methods:  39 centers in the United States and Europe
All the patients had confirmed LVO and an absence of large ischemic-core lesions.
Patients were randomly assigned in a 1:1 ratio to one of two treatment groups: intravenous t-PA plus stent retriever (intervention group) or intravenous t-PA alone (control group). 

25. SWIFT PRIME
Results: From December 2012 through November 2014, 196 patients underwent randomization
 Thrombectomy treatment was associated with a favorable shift in the distribution of global disability scores on the modified Rankin scale at 90 days 
The proportion of patients who were functionally independent (modified Rankin scale score, ≤2) at 90 days was higher in the intervention group than in the control group
The rates of serious adverse events and sICH did not differ significantly between the treatment groups 

26. SWIFT PRIME
Mortality at 90 days did not differ significantly between the intervention group and the control group
In the intervention group, substantial reperfusion (50 to 99%) or complete reperfusion (100%) at the end of the procedure occurred in 73 of the 83 patients (88%)

27. EXTEND IA – NEJM 2015
Extending the Time for Thrombolysis in Emergency Neurological Deficits — Intra- Arterial (EXTEND-IA) trial
Objective: to test the hypothesis that patients with anterior circulation ischemic stroke will have improved reperfusion and early neurologic improvement when treated with early endovascular thrombectomy with the use of the Solitaire FR after intravenous administration of alteplase, as compared with the use of alteplase alone
Methods: Planned to enroll 100 patients at 14 centers in Australia and New Zealand, stopped early due to MR CLEAN

28. EXTEND IA
From August 2012 through October 2014, a total of 70 patients underwent randomization 
Endovascular therapy led to greater early neurologic recovery at 3 and improved functional outcome in an ordinal analysis of the score on the mRS at 90 days
2.8 patients would NTT with EVT to achieve improvement of at least 1 mRS as compared to IV tPA alone

29. ESCAPE – NEJM 2015
The Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial 
Stopped early as well after MR CLEAN results

30. ESCAPE Primary end point showed an OR of 2.6 favoring the intervention
The proportion of patients with a modified Rankin score of 0 to 2 at 90 days was 53.0% in the intervention group and 29.3% in the control group 
Mortality at 90 days was 10.4% in the intervention group and 19.0% in the control group

31. ISC 2015

32. Summary of the EVT Trials

33. Experience at UAMS Year IV tPA at UAMS IV tPA at OSH EVT 2009 5 14 2
2010 13 43 1
2011 22 77 9
2012
110 20
2013 34
142 38
2014 36
182
2015 46
184 55
2016 60
152

34. Experience at UAMS

35. Experience at UAMS 2009-2010 (n=696) 2011-2012 (n=939) 2013-2014
(n=696)
(n=939)
(n=1260)
(n=827)
p-value
Age (years)*
70 (58, 81)
70 (58, 80)
69 (59, 80)
70 (59, 81)
0.95
Gender – Male
54.9%
53.1%
54.4%
53.4%
0.90
Race
Caucasian
79.7%
83.8%
81.0%
76.8%
0.07
African American
11.2%
10.8%
12.7%
13.3%
0.30
Ethnicity - Hispanic
5.6%
3.4%
3.5%
3.0%
0.06
Stroke Risk Factors
Hypertension
70.0%
73.1%
74.2%
70.9%
0.14
Diabetes Mellitus
23.1%
25.8%
24.0%
25.5%
0.56
Atrial Fibrillation
24.1%
23.7%
22.6%
20.8%
0.38
Coronary artery disease
23.4%
22.9%
0.98
Hyperlipidemia
44.0%
41.4%
45.0%
0.20
Previous Stroke
16.4%
19.6%
17.9%
18.6%
0.40
Smoker
14.9%
19.2%
17.7%
17.5%
0.17
NIHSS*
8 (4, 15)
8 (3, 16)
6 (2, 14)
7 (3, 16)
Door to CT (mins)*
46 (19, 200)
50 (19, 200)
41 (19, 171)
23 (12, 98)
0.001
In-hospital Acute Interventions
IV tPA at the center
12.4%
11.4%
11.5%
0.93
IV tPA at OSH
26.6%
34.3%
36.2%
38.9%
<0.001
Door to tPA (mins)#*
46 (30, 68)
53 (37, 69)
38 (28, 55)
45 (33, 58)
Endovascular Therapy
6.6%
7.8%
7.9%
13.9%
Door to EVT (mins)*
161 (95, 241)
125 (94, 160)
100 (63, 151)
78 (50, 126)
Symptomatic Intracranial Hemorrhage
2.6%
2.7%
2.4%
0.91

36. Experience at UAMS < 80yr ≥ 80yr p-value Age (years)* 60.6 ± 12.9
< 80yr
≥ 80yr
p-value
Age (years)*
60.6 ± 12.9
85.5 ± 3.6
<0.001
Gender – Male#
59.1%
38.6%
0.002
Race – Caucasian vs others#
76.9%
88.6%
0.03
Stroke Risk Factors
Atrial Fibrillation#
20.1%
60.4%
CAD/Prior MI#
18.2%
32.9%
0.008
Carotid Artery Stenosis#
0.8%
1.4%
0.60
Diabetes Mellitus#
22.9%
0.70
Hyperlipidemia
38.3%
0.96
Hypertension#
67.8%
81.4%
Previous Stroke
11.0%
10.0%
0.81
Smoker#
22.7%
4.3%
At Presentation
NIHSS*#
16 (12, 20)
17 (13, 21)
0.10
Weakness
80.0%
0.78
Aphasia
64.0%
58.6%
0.40
Altered level of consciousness
31.0%
37.1%
0.33
Acute Management
IV tPA (OSH)
51.9%
42.9%
0.18
IV tPA (MGH/UAMS)
22.3%
25.7%
0.56
Complications
sICH
8.0%
Pneumonia#
11.4%
2.9%
Outcomes
Good outcome (d/c to Home/IRF)
85.6%
61.5%
0.001
Disposition
Home
28.8%
8.6%
IRF
56.8%
52.9%
SNF
3.0%
Hospice
1.5%
In-hospital Mortality
9.8%
21.4%
0.01

37. AHA/ASA Update on Endovascular Therapy
Patients eligible for intravenous r-tPA should receive intravenous r-tPA even if endovascular treatments are being considered.
Rebuttal: Abilleria et al (Stroke 2017) and Coutinho et al. (in post-hoc analysis of SWIFT & STAR - JAMA Neurology) failed to show any difference in the safety and clinical outcomes of patients who received thrombectomy alone or thrombectomy combined with intravenous thrombolysis*

38. AHA/ASA Update on Endovascular Therapy
Patients should receive EVT if
Prestroke mRS score 0 to 1,
Acute ischemic stroke receiving IV tPA within 4.5 hours of onset
Causative occlusion of the internal carotid artery or proximal MCA
Age ≥18 years
NIHSS score of ≥6,
ASPECTS of ≥6
Treatment can be initiated (groin puncture) within 6 hours of symptom onset

39. AHA/ASA Update on Endovascular Therapy
Rebuttal:
Although guidelines recommend NIHSS > 6, but if the symptoms are severely disabling, e.g aphasia then EVT can still be considered.
There is no age cut-off in trials, and we showed in our regional analysis that EVT is safe in octogenarians and nonagenarians.
ASPECT > 6 is usually a good recommendations to follow to avoid sICH.
6hr cut-off is again debatable, we will see further trials on that aspect of EVT underway.

40. AHA/ASA Update on Endovascular Therapy
Quicker LKWT/door to groin puncture, better reperfusion to achieve TICI 2b/3.
Saver et al. reported in JAMA that earlier the EVT the better, as is with IV tPA and benefit becomes nonsignificant after 7.3 hrs.
Use of stent retrievers is indicated in preference to the MERCI device.
Angioplasty and stenting of proximal cervical atherosclerotic stenosis or complete occlusion at the time of thrombectomy may be considered but the usefulness is unknown
It might be reasonable to favor conscious sedation over general anesthesia during endovascular therapy for acute ischemic stroke.

41. AHA/ASA Update on Endovascular Therapy
If endovascular therapy is contemplated, a noninvasive intracranial vascular study is strongly recommended during the initial imaging evaluation of the acute stroke patient but should not delay intravenous r-tPA if indicated.
The benefits of additional imaging beyond CT and CTA or MR and MRA, such as CT perfusion or diffusion- and perfusion-weighted imaging, for selecting patients for endovascular therapy are unknown.

42. AHA/ASA Update on Endovascular Therapy
Patients eligible for intravenous r-tPA should receive intravenous r-tPA even if endovascular treatments are being considered.
*Although, Abilleria et al (Stroke 2017) and Coutinho et al. (in post-hoc analysis of SWIFT & STAR - JAMA Neurology) failed to show any difference in the safety and clinical outcomes of patients who received thrombectomy alone or thrombectomy combined with intravenous thrombolysis*

43. Future of Endovascular Intervention
DEFUSE3 -

44. SWIFT PRIME
Results: From December 2012 through November 2014, 196 patients underwent randomization
 Thrombectomy treatment was associated with a favorable shift in the distribution of global disability scores on the modified Rankin scale at 90 days 
The proportion of patients who were functionally independent (modified Rankin scale score, ≤2) at 90 days was higher in the intervention group than in the control group
The rates of serious adverse events and sICH did not differ significantly between the treatment groups 

45. SWIFT PRIME
Results: From December 2012 through November 2014, 196 patients underwent randomization
 Thrombectomy treatment was associated with a favorable shift in the distribution of global disability scores on the modified Rankin scale at 90 days 
The proportion of patients who were functionally independent (modified Rankin scale score, ≤2) at 90 days was higher in the intervention group than in the control group
The rates of serious adverse events and sICH did not differ significantly between the treatment groups