Transcript 8 Stroke Research Updates_Chang

Stroke Research 2016
Jeanne Carroll, RN, BA, CCRC2
Ivorine Yu, PhD1
Fen-Lei Chang, MD, PhD1,2,3
University School of Medicine – Fort Wayne
2Parkview Neuroscience and Stanley Wissman Stroke
Center
3Fort Wayne Neurology
1Indiana
May 18, 2016
Disclosures:
FC: Genentech, Biogen, Boehringer-Ingelheim and
AstraZeneca: Principal Investigator for clinical trials
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Neuroprotection
Overcoming Failure of Translational Research
from Bench to Bedside
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More than 1000 peer-reviewed publications on successful neuroprotection against stroke neural
damage in various stroke models, but none so far proven to be useful in human clinical trials.
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Proposed reasons
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Difference of stroke in human and animal models
(Difference in immunological mechanisms between human and mice)
Heterogeneity of stroke in human
Lack of sensitivity of outcome measures in human stroke research
Lack of clinical relevance of basic research such as pre-treatment, early reperfusion, and unrealistic dosing
Needs for combination treatment with efficacy on blocking multiple ischemic pathways
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Indiana University School of Medicine – Fort Wayne
Translational Stroke Research
• First animal stroke model focused on
penumbra, not on ischemic core
• Clinically relevant time window after
stroke onset
• MCA occlusion, brain slice, and cell
culture models
• Combination Rx:
– Lamotrigine
– Lovastatin
– Minocycline
S260-2 ISH-Il1b & IHC-HP1 R CPU (core) 40x
• Translational research
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ComboRx Reduced Necrosis and Apoptosis of Cultured
Hippocampal Neurons After OGD
while Minocycyline reduced apoptosis, and Lovastatin and Lamotrigine reduced necrosis
necrosis
apoptosis
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ComboRx Reduced Necrosis and Apoptosis of Cultured
Hippocampal Neurons After OGD
while Minocycyline reduced apoptosis, and Lovastatin and Lamotrigine reduced necrosis
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Model for Cardiac Arrest
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Model for Cardiac Arrest
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Model for Cardiac Arrest
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Model for Cardiac Arrest
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Acute Ischemic Stroke Model
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Acute Ischemic Stroke Model
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Acute Ischemic Stroke Model
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Acute Ischemic Stroke Model
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Acute Ischemic Stroke Model
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Opportunity for Translational Research
• Safe – medications on the market with
extensive experience
• Pre-clinical evidence of efficacy efficacy
• Making sense for patients and family members
– Lovastatin: statin with proven neuro-protective benefits
– Lamotrigine: anti- seizure medication to prevent seizures
– Minocycline: antibiotics to prevent infection and fever
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PRISMS
• Phase IIIb, double-blind study
to evaluate Alteplase in patients
with mild stroke
• Within 3 hours of stroke onset
• NIHSS < 5 and not clearly
disabling
• Why? Many of these patients
(around 30%) were significantly
disabled upon evaluation at 3
months (mRS 2-6)
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PRISMS
So Why So Many People with Significant Disability
After Initial Mild Deficits??
• Stroke Progression from lost
collaterals and/or increased
thrombus
• Under-measured cognitive
deficits by NIHSS
• Under-appreciated effect of
deficits at time of presentation
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SOCRATES
Acute Stroke Or Transient IsChemic Attack TReated
with Aspirin or Ticagrelor and Patient OutcomES
Evaluate ASA vs Ticagrelor
for patients with mild stroke
(NIHSS < 5) or high risk
TIA on vascular outcome
including
1. Stroke
2. MI
3. Vascular death
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SOCRATES
• Ticagrelor (Brilinta) is a platelet aggregation inhibitor
• Ticagrelor is more effective than clopidogrel to prevent CV
death, MI, and stroke after acute coronary syndrome, The PLATO
trial
[Wallentin et al., N. Engl. J. Med. 2009, 361 (11): 1045–57]
• NIHSS < 5
• ASA or Ticagrelor starts
within 24 hours of stroke onset
** Study was completed, and failed to demonstrate better efficacy
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Embolic Strokes of Undetermined Source: The
Case for a New Clinical Construct
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Hart et al., Lancet Neurology, 2014, 13, 429-438
Embolic Strokes of Undetermined Source (ESUS): The
Case for a New Clinical Construct
• Cryptogenic: vague, negatively defined
• ESUS: non-lacunar strokes without an identified
cardioembolic source or due to occlusive atherosclerosis
• Embolic sources – usually low risk
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LV dysfunction
Mitral annular calcification
Patent foramen ovale
Left atrial stasis associated with atrial tachycardia
Non-stenotic atherosclerotic carotid plaques
Aortic arch atheroma
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Embolic Strokes of Undetermined Source
(ESUS): The Case for a New Clinical Construct
• Prior studies showed no benefit due to
– Less well defined patient population
– Coumadin with increased bleeding risk
• New clinical trial to include
– ESUS platform
– New generation oral anticoagulant
– May provide a valid treatment options
for this group of patients
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PRIMARY OBJECTIVE:
• To assess the clinical effects of natalizumab versus placebo in acute ischemic
stroke on clinical measures of functional independence and activities of daily
living.
STUDY TREATMENT:
• IV Natalizumab vs. Placebo up to 9 hrs from onset of stroke symptoms
RATIONALE:
• Experimental and pathologic data suggest that peri-infarct inflammation
contributes to secondary injury after brain ischemia and that blocking
inflammation reduces the volume of brain infarction and improves clinical
outcomes
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Natalizumab is a recombinant humanized monoclonal antibody that inhibits the
transmigration of leukocytes into inflamed parenchymal tissue
Mild & Rapidly Improving Stroke Study
PRIMARY OBJECTIVE:
• To clarify long-term outcomes of patients with mild and rapidly
improving stroke and examine the association with tPA treatment
STUDY TREATMENT:
• Observational study using patient questionnaires to measure long term
patient outcomes
RATIONALE:
• Mild and rapidly improving stroke symptoms are common presentations
of acute stroke. The great majority of these pts are not treated with
thrombolytics yet almost 1 in 3 are unable to return home or ambulate
independently at discharge.
• MaRISS will describe the long-term outcomes with a battery of outcome
measures and will elucidate predictors of poor outcome by analyzing
stroke baseline characteristics and early fluctuations.
path
Penn Alliance
For Therapeutic Hypothermia
Penn Alliance for Therapeutic
Hypothermia (PATH) Registry
PRIMARY OBJECTIVE:
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To provide hospitals with the ability to benchmark and
perform research around cardiac arrest care.
STUDY TREATMENT:
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Comprehensive data abstraction on every cardiac
arrest entering Parkview Regional Medical Center. All
data entered will be exportable in real time and
quarterly data summary reports will be available to all
users.
RATIONALE:
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With therapeutic hypothermia (TH) and more
aggressive post-arrest interventions and monitoring
becoming common, PATH addresses the need to track
and assess many different aspects of cardiac arrest.
The comprehensive data capture in PATH is ideal in
terms of both quality improvement and research
initiatives.
CAROTID REVASCULARIZATION & MEDICAL
MANAGEMENT
FOR ASYMPTOMATIC CAROTID STENOSIS
PRIMARY OBJECTIVE:
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To test the primary hypothesis that intensive
medical management (IMM) differs from Carotid
Endarterectomy (CEA) + IMM and Carotid Artery
Stenting (CAS) + IMM in preventing the primary
endpoint of stroke or death in pts with high-grade
asymptomatic carotid stenosis
STUDY TREATMENTS:
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Two parallel Studies:
• CEA + IMM versus IMM Alone
• CAS + IMM versus IMM Alone
RATIONALE:
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There have been substantial changes in MEDICAL
management in the past two decades that may
have substantially reduced the risk of stroke in
asymptomatic carotid stenosis. CREST-2 is
uniquely positioned to test the merits of CEA and
CAS in the context of the latest intensive medical
management treatment.
Thank You!
• Creating knowledge - Finding new treatment options
• Collaboration of
– Parkview Neuroscience Service Line
– Parkview Mirro Research and Innovation Center
– Parkview Center on Aging and Health – Fall Prevention Clinic
– Indiana University School of Medicine-Fort Wayne
– Fort Wayne Neurology
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