1. Beyond the Basics of Stroke Evaluation
Rebbeca Grysiewicz, DO
Director, Comprehensive Stroke Center
Beaumont Health System- Royal Oak

2. Disclosures
None

3. Objectives Discuss brief overview of stroke epidemiology
Review endovascular reperfusion therapy updates
Analyze the role of stroke mobile units

4. During a stroke 32,000 neurons die per second…

5. The brain ages 3.6 years each hour without treatment during an ischemic stroke.

6. Epidemiology Annually, 15 million people worldwide suffer a stroke
One-third of these individuals die and another one- third are left permanently disabled
The World Health Organization (WHO) estimates that a stroke occurs every 5 seconds

7. Epidemiology
In the United States, approximately 795,000 people have a new or recurrent stroke each year
About 600,000 are new strokes and 195,000 are recurrent strokes
A stroke occurs approximately every 40 seconds, which is 2160 strokes per day

8. Epidemiology
In the U.S., stroke is the primary cause of long term disability with an estimated 6.5 million survivors among adults age 20 and older (2.6 million males and 3.9 million females)
The estimated 2015 direct and indirect cost of stroke is $95 billion

9. Epidemiology Stroke mortality extends beyond 150,000 people annually
Stroke is now the fifth leading cause of death in the U.S., and the second leading cause of death globally
Stroke accounts for nearly 1 out of every 16 deaths in the U.S. and approximately 10% of all deaths worldwide

10. Epidemiology
Stroke can either be ischemic (an occlusion of a blood vessel) or hemorrhagic (a rupture of a blood vessel)
Hemorrhagic strokes include intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH)

11. Epidemiology

12. Epidemiology
Of all strokes in the U.S., 87 percent are ischemic, 10 percent are ICH and 3 percent are SAH
Ischemic strokes are further classified into subtypes according to the mechanism of injury

13. Pathophysiology
The degree of damage is dependent on duration of ischemia and degree of collateral flow
Normal cerebral blood flow is greater than 50mL/100mg/min, but if blood flow is decreased to less than 10mL/100mg/min, irreversible neuronal death occurs quickly

14. Pathophysiology
Blood flow between 11 and 20 mL/100mg/min is thought to represent the ischemic penumbra
This is an area of neurons that are ischemic, but still viable if blood flow is restored
The ischemic penumbra is the target of most acute stroke interventions in which recanalization of a vessel should theoretically restore perfusion to the penumbra

15. Pathophysiology

16. Acute management: thrombolysis
IV thrombolysis with recombinant tissue plasminogen activator (rt-PA) is the only FDA approved drug treatment for acute ischemic stroke
Endogenous tissue-plaminogen activators convert plasminogen to plasmin, an enzyme that catalyzes fibrin breakdown
Fibrinolysis is strongly enhanced by rt-PA

17. Acute management: thrombolysis

18. Acute management: thrombolysis
Double blinded placebo-controlled trial with 624 patients randomized to IV rt- PA or placebo
Patients who received rt-PA within 3 hours had more favorable outcomes and were 30% more likely to have minimal or no disability at 3 months (odds ratio 1.7, 95% CI 1.2 to 2.6)

19. Modified Rankin Scale (mRS)
The scale runs from 0-6, running from perfect health without symptoms to death.
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.

20. Acute management: thrombolysis
Only a select group of patients are eligible to received rt-PA
The major adverse affect of rt-PA is hemorrhage
The symptomatic intracranial hemorrhage rate in the NINDS trial was 6.4%
Symptomatic ICH was seen primarily from hemorrhagic transformation of the ischemic infarct

21. Acute management: thrombolysis
An additional landmark study was the European Cooperative Acute Stroke Study (ECASS) III published in the New England Journal of Medicine in September 2008
It is a double-blinded placebo-controlled study with 821 patients randomized to IV rt-PA or placebo

22. Acute management: thrombolysis
Patients who received intravenous rt-PA administered between 3 and 4.5 hours after the onset of symptoms had statistically significant improved clinical outcomes compared with placebo (52.4% vs. 45.2%; P=0.04)
The incidence of symptomatic ICH was higher with rt- PA than placebo (2.4% vs. 0.2%; P=0.008), but mortality did not significantly differ between the two groups

23. Acute management: thrombolysis
In May 2009, the American Heart Association/ American Stroke Association released a Science Advisory recommending the expansion of the time window for treatment of acute ischemic stroke with rt-PA from 3 hours to 4.5 hours after onset of symptoms

24. Acute management: thrombolysis
However, the FDA has declined to extend the approved time window for IV-tPA administration beyond 3 hours

25. Acute management: endovascular thrombolysis
Endovascular therapy for acute ischemic stroke includes intra-arterial fibrinolysis, mechanical clot retrieval or a combination of the two
There has been a 6 fold increase in endovascular treatment from 2004 to 2009 (0.1% vs 0.6%; P<0.001)
Mortality decreased (OR=0.7; P=0.007), but moderate to severe disability increased from (OR=1.4; P=0.0002)

26. Acute management: endovascular thrombolysis
4 mechanical devices with FDA clearance: Merci Retrieval System (2004), the Penumbra System (2007), the Solitaire Flow Restoration Device (2012), and the Trevo Retriever (2012)
Devices are cleared as mechanical means for recanalization of acutely occluded arteries based on studies without noninterventional control groups

27. Acute management: endovascular thrombolysis

28. Acute management: endovascular thrombolysis

29. Acute management: endovascular thrombolysis
Retrievable stent device; deployed within the thrombus to displace it radially, incorporate it within the stent’s struts and extract it

30. Acute management: endovascular thrombolysis

31. Acute Management: endovascular thrombolysis
3 endovascular thrombectomy trials were highlighted at the International Stroke Conference
IMS III
MR RESCUE
SYNTHESIS Expansion

32. Acute Management: endovascular thrombolysis
All 3 trials failed to show a statistically significant difference between the endovascular therapy group and the best medical management group (which could include IV-tPA) as measured by an mRS of 2 or less

33. MR CLEAN: A Randomized Trial of Intra-arterial Treatment for Acute Ischemic Stroke
Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands
Published January 1, 2015
500 patients with large vessel occlusion(LVO) confirmed by CTA were randomized to intra-arterial treatment (n=233) or medical management (n=267) within 6 hours of symptom onset
32.6% of patients who received endovascular treatment achieved a good functional outcome (mRS 0-2) compared to 19.1% of patients who received medical management
Berkhemer OA et al. N Engl J Med 2015;372:11-20.

34. MR CLEAN: A Randomized Trial of Intra-arterial Treatment for Acute Ischemic Stroke
Berkhemer OA et al. N Engl J Med 2015;372:11-20.

35. Acute Management: endovascular thrombolysis
3 endovascular thrombectomy trials were highlighted at the February International Stroke Conference in Nashville, TN
ESCAPE
EXTEND-IA
SWIFT PRIME

36. Acute Management: endovascular thrombolysis
All 3 trials showed a statistically significant difference between the endovascular therapy group and the best medical management group (which could include IV-tPA) as measured by an mRS of 2 or less

37. ESCAPE: Randomized Assessment of Rapid Endovascular Treatment Ischemic Stroke
Published February 11, 2015
Trial was stopped early because of efficacy
316 patients with proximal large vessel occlusion (LVO) and good collateral circulation confirmed by CTA were randomized to endovascular intervention (n=165) or medical management (n=150) within 12 hours of symptoms onset
Rates of functional independence (mRS 0-2) at 90 days was statistically significant for the endovascular intervention group compared to the control group (53.0% vs. 29.3%; p< 0.001)
Endovascular intervention was associated with reduced mortality (10.4% vs 19.0%; p=0.04)
Goyal M et al. N Engl J Med DOI: /NEJMoa

38. ESCAPE: Randomized Assessment of Rapid Endovascular Treatment Ischemic Stroke
Goyal M et al. N Engl J Med DOI: /NEJMoa

39. EXTEND-IA: Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection
Published February 11, 2015
Trial was stopped early due to efficacy
70 patients with internal carotid or middle cerebral artery occlusion, salvageable brain tissue, and ischemic core < 70 ml confirmed by CTP were randomized to endovascular thrombectomy with the Solitaire FR stent retriever (m=35) or alteplase alone (n=35) within 4.5 hours of symptom onset
The endovascular reperfusion group achieved greater reperfusion at 24 hours (median, 100% vs. 37%; p,0.001) and increased early neurologic improvement at 3 days (80% vs. 37%, p=0.002) as measured by the NIHSS
No significant difference in mortality or symptomatic ICH
Campbell BC et al. N Engl J Med DOI: /NEJMoa

40. EXTEND-IA: Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection
Campbell BC et al. N Engl J Med DOI: /NEJMoa

41. SWIFT PRIME Results presented at ISC on February 11, 2015
Trial was stopped early due to efficacy
196 patients with large vessel occlusion (LVO) confirmed by CTA or MRA were randomized to endovascular treatment with the Solitaire FR stent retriever (n=98) or alteplase alone (n=98) within 6 hours of symptom onset
The OR for mRS shift at 90 days in the endovascular treatment group compared to the alteplase alone group was statistically significant (p=0.0002), and good functional outcome (mRS 0-2) was achieved in 60.2% of the patients in the endovascular treatment group compared to 35.5% of the patients in the control group (p=0.0008)
Saver J. International Stroke Conference 2015 Invited Presentation. Presented February 11, 2015.

42. SWIFT PRIME: Secondary Endpoints
Endovascular Treatment
Control
P Value
mRS score of at 90 d (%)
60.2
35.5
.0008
Mortality (%)
9.2
12.4
.50
Mean improvement in NIHSS score at 27 h (points)
8.5
3.9
<.0001
Saver J. International Stroke Conference 2015 Invited Presentation. Presented February 11, 2015

43. Impact on acute stroke treatment
All 4 trials showed statistically significant evidence of endovascular treatment in select acute ischemic stroke patients
Selection of patients should be confirmed by vascular imaging
IV rt-PA should always be the first line treatment for eligible acute ischemic stroke patients
On average approximately 5% of stroke patients receive acute stroke treatment
We need to continue to improve community and physician awareness

44. Mobile Stroke Units
Mobile Stroke Units debuted in Cleveland and Houston during the past year
Units resemble a typical ambulance, but are equipped with a portal CT scanner, lab testing capabilities and the ability to administer IV-tPA
Mobile Stroke Units cost about $1 million and are staffed with a critical care nurse, a paramedic and CT technology expert
Physicians are able to remotely evaluate a patient with two-way video conferencing

45. Mobile Stroke Units
In Cleveland, the stroke unit operates from 8 am to 8 pm daily
Researchers found that on average patients received a CT scan 20 minutes faster than through the EC
There was also a significant reduction in average treatment time for the mobile stroke unit (64 minutes) compared to the emergency room (104 minutes)
Hussain MS. International Stroke Conference 2015.

46. More research is needed to determine if Mobile stroke units lead to overall better stroke outcomes and if they are cost effective in different locations.

47. Conclusion Every minute 1.9 million neurons die during a stroke
Just because we have 4.5 hours to administer IV rt-PA, does not mean that we should wait 4.5 hours to give IV rt-PA
Endovascular reperfusion therapy is beneficial for appropriately selected stroke patients
Time is brain!

48. Questions?
Thank you!