ED Ischemic Stroke Patient Neuroprotection: What neuroprotection strategies do we utilize and what might be the role of NXY-059?

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ED Ischemic Stroke Patient Neuroprotection
What neuroprotection strategies do we utilize
and what might be the role of NXY-059?
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2006 Advanced Emergency Acute Care Medicine and
Technology Conference
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Emergency Medicine AssociatesAtlantic City,
NJSeptember 26-27, 2006
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Edward P. Sloan, MD, MPH FACEP
ProfessorDepartment of Emergency
MedicineUniversity of Illinois College of
MedicineChicago, IL
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Attending PhysicianEmergency
MedicineUniversity of Illinois HospitalOur
Lady of the Resurrection HospitalChicago, IL
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Disclosures

• NovoNordisk, King Pharmaceuticals, UCB Pharma
  Advisory Boards
• Eisai Speakers Bureau
• ACEP Clinical Policies Committee
• ACEP Scientific Review Committee
• Executive Board, Foundation for Education and
  Research in Neurologic Emergencies

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Global Objectives

• Maximize patient outcome
• Utilize health care resources well
• Optimize evidence-based medicine
• Enhance ED practice

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Sessions Objectives

• State key questions and concepts
• Why perform neuroprotection?
• What global neuroprotections?
• What specific therapies?
• What lies ahead?

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Case Presentation

• 64 year old presents to ED
• Trouble using L hand and speech
• Symptoms for last 90 minutes
• No headache or trauma
• History of TIA x 1, similar symptoms
• Hx DM, smoker
• No recent illness

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ED Neuroprotection Key Concepts

• Outcome related to infarct volume
• Need to limit infarct size
• Aggressively Rx ischemic penumbra
• ED MD is the best neuroprotectant
• Specific neuroprotectants tested
• SAINT-I clinical trial showed benefit
• Specific questions to be addressed

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ED Neuroprotection Key Concepts

• Outcome related to infarct volume

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Stroke Volume and Outcome

• Vessel occlusion
• Infarct core
• Ischemic penumbra
• How large is the core in the ED?
• What is the penumbra conversion?
• Do ED therapies limit infarct growth?

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ED Neuroprotection Key Concepts

• Outcome related to infarct volume
• Need to limit infarct size

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Limiting Stroke Volume
the astonishing results

• Enhance perfusion
• Treat hypoxia, hypotension
• Limit ischemic cascade effects
• Prevent complications

Compare the results with a conventional training
protocol. Most people do at least two exercises
per muscle group, perform three sets and perhaps
12 or 15 reps per set. Allowing just five seconds
per rep, that makes for at least 36 minutes of
exercise per workout. This is usually done three
times per week. So in six weeks, a conventional
program would involve 648 minutes of exercise.
That's 42 times more than the subjects in our
study. Are your results in the last six weeks 42
times better than theirs? I doubt it.
performance improvement

Remember, these golfers were exercising in a way
that did not involve stretching or moving the
weight over a full range of motion. So how did
this affect a full range of motion activity like
a golf drive? Every one of them showed an
improvement. The increase in drive distance
varied from 5 to 31 yards. Keep in mind that
these subjects had been golfing for up to 40
years and had handicaps as low as eleven. So
getting any improvement in golfers who already
play at this level is impressive. Getting it with
14 minutes of exercise spread over six weeks is
truly revolutionary. The fact is every sport --
even a finesse sport like golf -- is improved by
an increase in strength. Muscles are responsible
for all movement in the body and stronger muscles
deliver more power to every aspect of movement,
irrespective of its range of motion. Since this
study, I've gone on to improve this method of
training. Further research showed that static
hold times could be reduced to even less than
what the golfers used. Workouts can be spaced
further apart as a trainee gets stronger. I work
with advanced trainees who train once every six
weeks, yet they gain strength on every exercise
each time they work out. The weights they hoist
are enormous. I believe the time is coming when
most people will have a better understanding of
the role of proper, efficient strength training
methods and frequency. For the guy who wants
maximum results with minimum time invested, an
ultra-brief but ultra-intense workout will be
performed about as often as he gets a haircut.
Anything more is just lifting weights as a busy
work hobby. Train smart!
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ED Neuroprotection Key Concepts

• Outcome related to infarct volume
• Need to limit infarct size
• Aggressively Rx ischemic penumbra

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Aggressively Rx Ischemic Penumbra

• Maximize cerebral perfusion
• Provide optimal substrates, O2
• Avoid cell death
• Maintain intact blood brain barrier

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Cerebral Perfusion

• CPP MAP - ICP
• Cerebral perfusion pressure
• Mean arterial pressure
• Intracranial pressure

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Cerebral Perfusion

• CPP MAP - ICP
• If MAP 110 mmHg, ICP 10 mmHg
• CPP then equals 100 mmHg
• Cerebral blood flow auto-regulation
• CPP maintained over range of MAPs
• Pathological ICP elevations limited

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Mean Arterial Pressure

• 120 / 75 MAP 90 mmHg
• 210 / 120 MAP 150 mmHg
• 180 / 110 MAP 97 mmHg
• How much MAP therapy is OK?
• What agents provide best Rx?
• How to avoid watershed infarct?

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Watershed Infarct

• watershed (wô t r-sh d) n.
• 1. A ridge of high land dividing two areas that
  are drained by different river systems. Also
  called water parting.
• 2. The region draining into a river, river
  system, or other body of water.
• 3. A critical point that marks a division or a
  change of course a turning point

watershed infarction n. Infarction of the cerebral cortex in an area of blood supply between two major cerebral arteries.
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ED Neuroprotection Key Concepts

• Outcome related to infarct volume
• Need to limit infarct size
• Aggressively Rx ischemic penumbra
• ED MD is the best neuroprotectant

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ED MD Best Neuroprotectant
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ED MD Best Neuroprotectant

• Available 24/7

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ED MD Best Neuroprotectant

• Available 24/7
• Effectively able to diagnose infarct

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ED MD Best Neuroprotectant

• Available 24/7
• Effectively able to diagnose infarct
• Systems expert able to make things happen
  quickly

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ED MD Best Neuroprotectant

• Available 24/7
• Effectively able to diagnose infarct
• Systems expert able to make things happen
  quickly
• Focus on acute interventions

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ED MD Best Neuroprotectant

• Available 24/7
• Effectively able to diagnose infarct
• Systems expert able to make things happen
  quickly
• Focus on acute interventions
• Know our limitations

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ED MD Best Neuroprotectant

• Available 24/7
• Effectively able to diagnose infarct
• Systems expert able to make things happen
  quickly
• Focus on acute interventions
• Know our limitations
• We can be trained

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ED MD Neuroprotection

• Manage the airway

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ED MD Neuroprotection

• Manage the airway
• ETI, rapid sequence induction

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ED MD Neuroprotection

• Manage the airway
• ETI, rapid sequence induction
• Manage hypotension

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ED MD Neuroprotection

• Manage the airway
• ETI, rapid sequence induction
• Manage hypotension
• Manage hypertension

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ED MD Neuroprotection

• Manage the airway
• ETI, rapid sequence induction
• Manage hypotension
• Manage hypertension
• Treat metabolic abnormalities

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ED MD Neuroprotection

• Manage the airway
• ETI, rapid sequence induction
• Manage hypotension
• Manage hypertension
• Treat metabolic abnormalities
• Diagnose and lower elevated ICP

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ED MD Neuroprotection

• Manage the airway
• ETI, rapid sequence induction
• Manage hypotension
• Manage hypertension
• Treat metabolic abnormalities
• Diagnose and lower elevated ICP
• Prevent and treat seizures

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ED MD Neuroprotection

• Manage the airway
• ETI, rapid sequence induction
• Manage hypotension
• Manage hypertension
• Treat metabolic abnormalities
• Diagnose and lower elevated ICP
• Prevent and treat seizures
• We first do no harm

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ED Neuroprotection Key Concepts

• Outcome related to infarct volume
• Need to limit infarct size
• Aggressively Rx ischemic penumbra
• ED MD is the best neuroprotectant
• Specific neuroprotectants tested

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Stroke Pathophysiology, Neuroprotectants
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Stroke Pathophysiology, Neuroprotectants
Lubeluzole Fosphenytoin Sipatrigine Riluzole Lamot
rigine Lifarizine Maxipost
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Stroke Pathophysiology, Neuroprotectants
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Stroke Pathophysiology, Neuroprotectants
Aptiganel Selfotel GV-150526 CP-101606 Eliprodil A
CPC ACEA 1021 Dizocilpine Dextromethorphan NBQX Ma
gnesium
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Stroke Pathophysiology, Neuroprotectants
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Stroke Pathophysiology, Neuroprotectants
GM1 Piracetam Tirilizad PEG SOD PNA Enlimomab Citi
coline CX295 Ceresine
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Stroke PathophysiologyFree Radical Formation
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Stroke PathophysiologyFree Radical Formation
Tirilazad Citicoline Ebselen NXY-059
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Neuroprotection 1955-2000
Trials of Neuroprotection Agents in
Stroke1955-2000
Neuroprotective Agents Tested 49
RCTs Performed 114
Patients Enrolled 21,445
Trials with Positive Results 0
This year, first positive primary endpoint trial
Kidwell CS et al. Stroke 32(6)1349-59.
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Why have neuroprotection agents failed in human
trials?

• Wrong theoretical concept
• Treatment initiated too late
• Stroke heterogeneity
• Wrong drug action
• Doses too low
• Trials underpowered
• Wrong outcome measures
• Insensitive statistical techniques

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ED Neuroprotection Key Concepts

• Outcome related to infarct volume
• Need to limit infarct size
• Aggressively Rx ischemic penumbra
• ED MD is the best neuroprotectant
• Specific neuroprotectants tested
• SAINT-I clinical trial showed benefit

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NXY-059 (Cerovive)
2006354(6)588-600.
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NXY 059 Characteristics

• NXY-059 (Cerovive) is an intravenous,
  nitrone-based, free radical trapping agent
• Preclinical trials positive in rats/primates
• Effective after 4 hours of ischemia
• Significant dose response

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SAINT I Trial(Stroke Acute Ischemic NXY-059
Treatment)

• RCT Design
• 72 hr treatment window
• NXY-059 vs placebo
• Target plasma concentration 260 µM
• 158 centers across 24 countries
• Europe, Asia, Australia, New Zealand, South Africa

Lees KR et L. N Engl J Med 2006354(6)588-600.
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SAINT I Trial(Stroke Acute Ischemic NXY-059
Treatment)

• Eligibility
• CT/MR consistent with AIS
• Previous independence
• NIHSS 6 including limb weakness
• t-PA permitted
• lt 6hr ictus to treatment
• Forced allocation to achieve mean time from onset
  to start of treatment 4 hrs

Lees KR et L. N Engl J Med 2006354(6)588-600.
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SAINT I Primary Outcome VariableChange in
Modified Rankin Scale
At 90 Days
0
Symptom free
Symptom free
1
Symptomatic, but performing previous activities
Able to do all usual activities
2
Unable to do some previous activities, but
independent
Able to look after self
3
Requires some help, but can walk without
assistance
Able to walk without assistance
4
Needs assistance with walking and attending to
bodily needs
Not bedridden
Bedridden, incontinent, requires constant care
Bedridden / Death
5
Lees KR et L. N Engl J Med 2006354(6)588-600.
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SAINT I Secondary Outcome Variables

• mRS at 7 and 30 days
• NIHSS change on days 7 and 90
• Barthel Index on days 7, 30, and 90
• Safety
• Day 90 SIS-16 and Four Domains
• Day 90 EQ-5D

Lees KR et L. N Engl J Med 2006354(6)588-600.
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Primary Outcome (ITT)mRS at 90 Days
Lees KR et L. N Engl J Med 2006354(6)588-600.
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Primary Outcome (Per Protocol)mRS at 90 Days
Lees KR et L. N Engl J Med 2006354(6)588-600.
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NXY-059 Number Needed to Treat Benefit Using mRS
Shift Analysis
Lowest Possible 7.9
Highest Possible 16.7
Expert Panel 9.8
Expert Panel 8.7 10.9
Saver J. UCLA Stroke Center
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NXY-059 Number Needed to Treat Benefit Using
Outcome Dichotomy
mRS NNT
0 vs 1-6 23
0-1 vs 2-6 42
0-2 vs 3-6 48
0-3 vs 4-6 28
Saver J. UCLA Stroke Center
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SAINT I Clinical Endpoints
Endpoint P Value
Rankin shift 0.038
Rankin dichotomized 0.17
Improvement in NIHSS 0.86
Barthel Index dichotomized 0.14
Stroke Impact Scale 0.08
Euro QOL Index 0.06
QOL Visual Analogue Scale 0.05
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Nxy-059 Safety Adverse Events
Patients
AEadverse event SAEserious adverse event
DAEdiscontinued due to adverse event.
Lees KR, et al. New Engl J Med. 2006354588-600.
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ICH After IV tPA Thrombolysis (SAINT I Post
Hoc Analysis)
80
Asymptomatic ICH
27.3
70
Symptomatic ICH
60
50
20.9
52
15.4
Plt0.005(total ICH)
Patients (n)
40
30
12.9
31
20
10
6.4
16
P0.036
2.5
6
0
Placebo rt-PA (n249)
NXY-059 rt-PA (n240)
NINDS definition ICHintracerebral hemorrhage
Lees KR, et al. New Engl J Med. 2006354588-600.
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ED Neuroprotection Key Concepts

• Outcome related to infarct volume
• Need to limit infarct size
• Aggressively Rx ischemic penumbra
• ED MD is the best neuroprotectant
• Specific neuroprotectants tested
• SAINT-I clinical trial showed benefit
• Specific questions to be addressed

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Neuroprotectant Questions

• Will SAINT-II reproduce results?

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Neuroprotectant Questions

• Will SAINT-II reproduce results?
• Will the NNT be comparable?

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Neuroprotectant Questions

• Will SAINT-II reproduce results?
• Will the NNT be comparable?
• Will safety data be comparable?

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Neuroprotectant Questions

• Will SAINT-II reproduce results?
• Will the NNT be comparable?
• Will safety data be comparable?
• Will the tPA / ICH data compare?

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Neuroprotectant Questions

• Will SAINT-II reproduce results?
• Will the NNT be comparable?
• Will safety data be comparable?
• Will the tPA / ICH data compare?
• How to explain BBB information?

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Neuroprotectant Questions

• Will SAINT-II reproduce results?
• Will the NNT be comparable?
• Will safety data be comparable?
• Will the tPA / ICH data compare?
• How to explain BBB information?
• What cost will the results justify?

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Conclusions

• We provide neuroprotection
• Neuroprotection reduces infarct volume,
  complications
• New neuroprotection data
• Interesting data related to IV tPA
• Ischemic stroke care enhanced
• Patient outcomes improved

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Questions?
www.FERNE.org edsloan_at_uic.edu 312 413 7490
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