1. health and fitness
2. therapy

From IV thrombolytics and Beyond
Disclosure
• None
Dolora R. Wisco, MD
Stroke Staff
Cerebrovascular Center
Cleveland Clinic
Objectives
• First line acute stroke therapy: IV tPA
• Telestroke role in delivering IV tPA
• Second line acute stroke therapy: endovascular
stroke therapy
Stroke is a major problem
• Annual incidence ~795,000 strokes each year
• 3rd leading cause of death
• Leading cause of disability
• Direct and indirect cost ~$73.7 billion per year
• By 2030, an additional 4 million will have had stroke.
• 24.9% increase in prevalence from 2010
What are the Types of Stroke?
• Ischemic Stroke
(Blockage)
o Caused when there is a
blockage in the blood
vessels to the brain
• Hemorrhagic Stroke
(Bleeding)
o Caused by burst or
leaking blood vessels in
the brain
Stroke Mechanism:
• Ischemic (87%) TOAST classification:
• Large-artery atherosclerosis (thrombosis and artery-toartery embolism)
• Cardioembolism (Afib, left ventricle thrombus, etc)
• Small artery occlusion (lacune/lipohyalinosis)
• Stroke of other determined cause (dissection, infective
endocarditis, vasculitis etc)
• Stroke of undetermined cause (a.k.a. cryptogenic)
• Hemorrhagic (13%):
• Intraparenchymal hemorrhage (10%)
• Subarachnoid Hemorrhage (3%), SAH
Time is Brain!
Neurons
Lost
Synapses
Lost
Accelerated
Aging
Per Stroke
1.2 billion
8.3 trillion
36 yrs
Per Hour
120 million
830 billion
3.6 yrs
Per Minute
1.9 million
14 billion
3.1 weeks
Per Second
32,000
230 million
8.7 hrs
(Total number of neurons in the average human brain is 130 billion)
Penumbra concept
• There is tissue is
ischemic but not
infarcted—”Tissue at
risk” around a “core”
o Blood flow dependence
o Time dependence
Stroke. 2004;35[suppl I]:2662-2665
Donnan et al, Lancet Neurol 2009
Stroke 2006;37:263-266
Time is Brain!
ƒ Normal blood flow 50ml/min/100grams brain tissue
ƒ Ischemia: 0-4 min
ƒ (blood flow <20ml/min/100grams brain tissue)
ƒ Infarction = irreversible cell death: >10 min
ƒ (blood flow <10ml/min/100g)
ƒ Penumbra: area at risk surrounding infarct
ƒ In the CNS, the areas served by the major vessels are also
served by collateral circulation; therefore, the areas of
infarction and penumbra vary patient-to-patient and the
timing of infarction may likewise vary.
ƒ Acute stroke treatment goal is to save the
penumbral area and minimize the size of the
infracted brain.
SUDDEN ONSET …
Stroke symptoms...
UNILATERAL:
-Loss of vision
- Visual field cut
-Weakness
-Numbness
-Tingling
-Aphasia
-Facial droop
-Loss of balance
-Slurred speech
-Difficulty swallowing
-Double vision
-Sudden coma
Time of Onset or Last Know Well
Stroke Assessment
• If witnessed symptom onset: Time of onset
• If not witnessed symptom onset: Last seen at
baseline health/function
• Woke up with symptoms: Last seen at
baseline – usually when pt went to bed, or in
middle of night if patient witnessed to be
normal
• Times of reference
• ABC
• Finger stick for blood glucose – hypoglycemia symptoms
can mimic stroke
• Get Vitals
• Focused history
o Television
o The time the basketball game started
o Recent events – stroke, MI, trauma, surgery, bleeding
o List of patient meds
o Look specifically for anticoagulants (warfarin, apixiban,
pradaxa, rivaroxiban, etc) , antiplatelet (aspirin, Plavix,
Aggrenox) , insulin and antihypertensive use
• Comorbid conditions – HTN, DM, AFib
- Neurological examination …
NIHSS
Acute Stroke Treatment Options
• Time Dependent
• Acute stroke thrombolysis treatment
windows:
o IV thrombolysis with IV tPA
• < 3 hrs (IV t-PA) Æ and up to 4.5 hours in some instances
o Endovascular Therapy
• 6 hrs (IA thrombolytics)
• < 8hrs (Mechanical thrombolysis)
• >?hrs (Basilar occlusion)
IV Tissue Plasminogen Activator
NINDS TPA & ECASS 3 Results
• Alteplase
o Recombinant tissue plasminogen activator (rt-PA)
o Only FDA approved treatment for acute ischemic stroke in 0-3 hour time
window
o Not FDA approved for 3-4.5 hour time window. However, this is
recommended by AHA/ASA
NINDS
TPA
Trial
0-3
hours
13%
ECASS 3
Trial
3-4.5
hours
IV tPA for cerebral ischemia within 3 hours of onset changes in outcome due to treatment
UCLA
7.3%
We also give tPA to non‐strokes
• In a retrospective study of tPA treated patients
o 12.5% of patients have no stroke on MRI
• 9% classified as TIA, 3.5% as non strokes
• Others report 3-14%
• Complications risk is low
Winkler et al, Stroke, 2009
Savitz et al, Neurology, 2010
Uchino et al, Cerebrovasc Dis, 2010
Barriers to IV tPA use
• Lack of recognition of stroke by patient/ family
• Lack of recognition of stroke by EMS, triage
personnel
• Lack of immediate notification of stroke team
• Lack of stroke team/ organized acute treatment
protocol
• Delays in imaging/ lack of 24-hour CT scanning
• Fear of IV t-PA by non-neuroloigst or non-stroke
trained physicians
Telestroke
• Video conferencing technology offers us the
opportunity to assess patients outside of PSCs,
with the potential to offer more patients acute
IV tPA therapy
LIMITATIONS OF IV TPA
Telestroke
• STARR registry (Arizona)
o 25% of patients received IV thrombolysis
• 6% hemorrhage rate
o Majority of patients were managed in the Spoke hospital (64%)
• Telestroke vs telephone
• Recanalization rate poor for larger arteries such as
ICA or proximal MCA
• Outcomes for persistent MCA occlusions poor
• Limited time window
o STRokE DOC: expert committee blinded to modality used
o Telestroke consult resulted in more accurate decision making
(98% vs. 82%)
40%
40%
35%
30%
25%
35%
31%
24%
20%
15%
10%
5%
0%
8%
All
ICA
MCA Stem MCA Divsn
MCA
Branch
Del Zoppo et al., Ann Neurol 1993
Beyond IV thrombolytics
o Patients with inelegible for IV tPA due to time window with severe
stroke and a large vessel occlusion.
o Patients who received IV tPA who have persistent large vessel
occlusion and a severe stroke.
o Endovascular Therapy
• 6 hrs (IA thrombolytics)
• < 8hrs (Mechanical thrombolysis)
• >?hrs (Basilar occlusion)
Endovascular Therapy for Acute Ischemic Stroke
• Advantages
o
o
o
o
Maximum delivery of lytic agent
Endpoint of clot lysis
Not given if spontaneous clot lysis
Availability of mechanical methods
• Disadvantages
o
o
o
o
Transfer to center with interventional capabilities
Time necessary to place catheter
Requires interventionalists
Emergent availability of angiography
Intra‐arterial Thrombolytics
40%
•
•
•
•
•
•
•
25%
PROACT II
Randomized multicenter
controlled trial
o 9 mg IA r-proUK + IV heparin
vs. IV heparin alone
Randomized 2:1 to treatment
vs. control
180 pts with M1 or M2 occlusion
by angio
Treatment started within 6 hours
of stroke onset
IA r-proUK infused over 2 hours
then repeat angio
Primary endpoint - mRS ≤ 2 at
90 days
Intra‐arterial Thrombolytics
• IMS II
• 81 subjects , NIHSS >10,
received IV tPA w/in 3 hours
of onset
• Pts with arterial occlusion on
angio received additional
IA tPA
• Feasibility and safety study
P=0.04
Furlan et al, JAMA 1999
Mechanical thrombectomy
o Allows further treatment of patient with large vessel
occlusion
• Stents/angioplasty
• Mechanical thrombolysis
o Trevo, Solitaire, Penumbra, Merci
• Multi-modal (chemical + mechanical
o Allows treatment of an expanded patient
population (larger time window,
postoperative patients)
Solitaire
Trevo
Merci pull
Merci
Penumbra
Mechanical Thrombectomy
Post Merci single pull
Penumbra
Figure. A, Basal agiogram with occlusion of middle cerebral artery.
Castaño C et al. Stroke. 2010;41:1836-1840
Copyright © American Heart Association, Inc. All rights reserved.
IMS III
•
•
•
Stopped prematurely because of
futility
656 participants
Patients who had received
intravenous t-PA within 3 hours after
symptom onset were randomized 2:1
to:
o
IV tPA + IA therapy
o
IV t-PA alone
Conclusion
No significant difference in
functional independence with
endovascular therapy after
intravenous t-PA, as compared
with intravenous t-PA alone
No difference in safety
The Importance of Recanalization
Recanalization is strongly
associated with improved
function outcomes and
reduced mortality.
Acute Stro
Stroke
ke
Eligible for
A Tx
Eligible
for IIA
Patient Selection Beyond IV tPA
• Non-contrast CT is important to rapidly rule out
hemorrhage and allow administration of IV tPA
• Time is Brain!
MRI Eligible
IV tPA Candidate
MRI
MRI Ineligible
IV tPA Ineligible
Inel igible
IV tPA Ineligible
Ineligible
or
or
Al ready Rec’
Already
Rec’d
d tPA
IV tPA Candidate
Candi date
o Systems of care should be organized to minimize delays
• Imaging beyond non-contrast CT is required
CT/CTA
CT/CTA
CT/CTA/CTP
CT/CTA/CTP
CT/CTA
CT/CTA
IV tPA
IV
tPA as Indicated
Indicated
IV tPA
tPA as Indicated
Indicated
CT/CTA/CTP
o CTA / CTP / MRI-DWI / MRI-PWI
LVO w/o Lg
Lg Infarct
Infarct
No LVO
LVO // Infarct
L VO w/o Lg Inf arct
No LVO
g Infarct
In farct
L VO / LLg
No L VO / Lg Infarct
No
VO / Lg Infarct
No LLVO
ACUTE MRI
ACUTE
MRI
STOP
ACUTE
ACUTE MRI
STOP
STOP
STOP
STOP
STOP
LVO w/o
w/o Lg Infarct
L VO w/o
LVO
w/o Lg Infarct
Inf arct
IA Tx
Tx
IA Tx
Lg Infarct
STOP
Lg Infarct
STOP
No Lg Infarct
IA Tx
IA
Tx
No Lg
Lg Infarct
IA TX
LVO: ICA, Prox
Prox MCA,
MCA, Bas
Bas
Lg Infarct: >?
Lg
NIHSS>DWI ? PWI
>? MCA, >70cm33, NIHSS>DWI
PWI
Hyperacute MRI Protocol
CT & CTA (+ MR)
• 84 y.o. female with known atrial fibrillation
• NIHSS 16
• LKW 4 hours
• Truncated MRI protocol:
o
o
o
o
o
DWI
FLAIR
PWI
Post-gad Ax T1
No need for SWI, MRA, etc
10 min
• Challenges:
o
o
o
o
o
Case example
Scheduling (interruption of other studies)
Time delay in traveling to and from MRI
Technologist availability
Safety screening
Inherent “chaos” of brain attack pts
Case Presentation
• 66 y/o LH male who awoke with symptoms of leftsided weakness; LKN 9 PM the night before (wake
up stroke)
• Our assessment at ~ 10 AM reveals:
o NIHSS = 11
o Head CT: hyperdense R MCA sign
o CTA: occlusion of distal Right M1
Right M1 distal occlusion
24 hrs post‐procedure
Case Presentation
• Given the clinical – diffusion mismatch & DWI – PWI mismatch,
patient RB taken to interventional angiography
• Successful recanalization of Right distal M1 occlusion
• Brain MRI 24 hrs post-procedure
o Persistent restricted diffusion in Right MCA territory as seen on
initial scan- No notable expansion of infarct
o Resolution of previous perfusion deficit
• At f/u visit (4 wks after ictus)- NIHSS = 3
Case
• Improved immediately post procedure, by next day
weakness resolved although expressive aphasia
remained
• At 1 month follow-up visit, patient had returned to
normal with no aphasia detected (NIHSS = 0)
Conclusion
• IV tPA is first line of stroke therapy
o Can be given quickly and easily
o Telestroke improves delivery of IV tPA
• Endovascular Stroke Therapy is a treatment option
for selected patients
o Large vessel occlusion
o Severe exam
o Tissue at risk present
Acknowlegement
• Dr. Uchino
• Dr. Hussain
Questions