Stroke Acute Management in 2019web.brrh.com/msl/IM2019/IM Sunday/Sunday - 6... · ©2013 MFMER |...

©2013 MFMER | slide-1

Stroke – Acute Management in 2019

Kevin M Barrett MD FAAN Associate Professor & Vice-Chair

Department of Neurology, Mayo Clinic Florida


©2011

MFMER |

slide-2

Disclosure

Relevant Financial Relationship(s)

NONE

Off Label Usage

NONE


©2011

MFMER |

slide-3 ©2011 MFMER | slide-3

Learning Objectives

• Recognize alternative systemic thrombolytic agents for acute ischemic stroke

• Implement evidence-based acute treatment strategies for minor ischemic stroke/TIA

• Manage hyperglycemia in the acute setting following ischemic stroke


Acute Ischemic Stroke Intervention

• Approximately 800,000 incident and recurrent strokes in the U.S. each year

• Stroke is the second leading cause of death worldwide

• 1996 IV rtPA received FDA approval for treatment of stroke within a 3 hour window

• ECASS III extended the window to 4.5 hours and was supported by the AHA/ASA however has not received FDA approval


Recombinant tissue plasminogen activator (rt-PA)

• Multidomain serine protease

• 1980’s – demonstrated fibrin-stimulated clot lysis and utility in treating thrombotic disorders

• Rapid clearance from the circulation necessitates administration as an infusion to achieve thrombolysis

• Remains only FDA-approved medical treatment for acute ischemic stroke


rt-PA therapy

• Limitations in stroke treatment

• ~6% incidence of symptomatic intracranial hemorrhage

• Recanalization rates achieved by tolerable doses are suboptimal (30-50%)

• Estimates of recanalization of proximal vascular occlusions ≤ 20%


Tenecteplase (TNK)

• Genetically engineered form of wild-type form of rt-PA

• Developed specifically for increased safety and efficacy

• Modified rt-PA molecule with targeted mutagenesis at three sites:

• Threonine → asparagine (T) @ 103

• Asparagine → glutamine (N) @ 117

• Lysine, histidine, arginine x 2 → alanine x 4 (K) @ 296-299


TNK molecule


TNK

• Greater fibrin specificity

• Increased resistance to PAI-1

• Longer half-life allowing for bolus administration


TNK in rabbit embolic stroke model

0

10

20

30

40

50

60

% animals with ICH

Control

(n = 6) rt-PA

(n = 6)

TNK

(n = 34)

50%

33%

13%*

* - p < 0.05 Thomas, et al: Stroke 1994


TNK for Acute Coronary Syndrome

ASSENT – 2: Phase III - TNK vs. rt-PA in STEMI

Results published in 1999

16,950 patients randomized to weight-optimized TNK bolus or standard rt-PA infusion within 6 hours of symptom onset

30-day mortality nearly identical (6.16% TNK vs 6.18 rt-PA)

TNK approved by FDA for acute coronary syndrome based on these results


ASSENT - 2 Bleeding Complications

0.95%

4.7% 4.3%

0

1

2

3

4

5

6

7

= TNK (n =8461)

= rt-PA (n = 8488)

* = p< 0.001 vs. TNK

sICH

Major

Bleeding

Transfusions

% Patients

0.94%

4.7%

ASSENT-2 Inv.: Lancet 1999

5.9%* 5.5%*


TNK in Acute Ischemic Stroke (TNK-S)

• NINDS-funded pilot, dose-finding study – enrollment began 6/00

• Standard NINDS eligibility for rt-PA (<3h)

• Randomized to 0.1, 0.2, 0.4, 0.5mg/kg TNK vs. 0.9mgkg rt-PA

• Dose Tier Size = 25 patients

• Safety outcome: sICH reviewed at each tier before continuing (halted if >2 sICH/tier)

• Activity measured by MNI defined as ≥ 8 point decrease in NIHSS score at 24 hours


TNK-S: Results

• 6/00 – 4/03: 88 patients

• 4 dose tiers: 0.1, 0.2, 0.4, 0.5 mg/kg

• No symptomatic ICHs in 1st three tiers

• 2/13 with symptomatic ICH at 0.5 mg/kg

• Increasing ICH with increasing dose (8% - 38%)

• Inverse dose-response: 0.1 – 36% MNI, 0.2 – 24% MNI, 0.4 – 16% MNI


32%

32%

36%

39%

26%

24%

32%

36%

21%

25%

28%

12%

16%

23%

27%

16%

24%

12%

17%

21%

TNK Tier 3

TNK Tier 2

TNK Tier 1

NINDS t-PA

NINDS-placebo

Rankin 0-1 Rankin 2-3 Rankin 4-5 Rankin 6 (death)


TNK-S2B: Dose Refinement protocol

• NINDS-funded Phase II clinical trial

• Patients with at least a serious, measurable deficit on the NIH Stroke Scale

• language (aphasia score > 1),

• motor power (arm or leg > 1),

• vision (best visual score > 2),

• attention (attention score > 2).

• Must arrive at participating hospital and treatment begun within 3 hours of the onset of symptoms.

Must be 18 years of age or older.


TNK-S2B

• Dose Selection Procedure

• Randomized: 0.1 mg/kg, 0.25 mg/kg, 0.4 mg/kg TNK or 0.9 mg/kg rt-PA

• Sequential design: MNI – ICH

• Up to 600 patients (150 each group)

• Trial terminated early due poor recruitment after 112 patients without a clear signal of safety or efficacy


TNK-S2B: 3 Month and 24 Hour Outcomes by Treatment Group

TNK 0.1 mg/kg

(n=31)

TNK 0.25 mg/kg

(n=31)

TNK 0.4 mg/kg

(n=19)

rtPA 0.9 mg/kg

(n=31)

Rankin good, no. (%) 14 (45.2%) 15 (48.4%) 7 (36.8%) 13 (41.9%)

Rankin poor, no. (%) 7 (22.6%) 11 (35.5%) 6 (31.6%) 10 (32.3%)

MNI, no. (%) 7 (22.6%) 11 (35.5%) 4 (21.1%) 5 (16.1%)

TNK indicates tenecteplase

Haley E et al. Stroke 2010;41:707


TNK-S2B: Safety Data by Treatment Group TNK

0.1 mg/kg (n=31)

TNK 0.25 mg/kg

(n=31)

TNK 0.4 mg/kg

(n=19)

rtPA 0.9 mg/kg

(n=31)

Symptomatic ICH, no. (%)

0 (0) 2* (6.5) 3 (15.8) 1 (3.2)

Asymptomatic ICH, no. (%)

3 (9.7) 2 (6.5) 2 (10.5) 4 (12.9)

All ICH, no. (%) 3 (9.7) 4 (12.9) 5 (26.3) 5 (16.1)

Major systemic bleeding, no. (%)

0 (0) 1 (3.2) 0 (0) 0 (0)

Death within 3 months, all causes, no. (%)

2 (6.5) 7 (22.6) 3 (15.8) 8 (25.8)

* N.B.: Neither of these 2 ICHs is depicted in the Figure as a score of “0” because 1 also had MNI and the second was readjusted from asymptomatic to symptomatic by the independent adjudicator after the sequential score had been recorded per protocol TNK indicates tenecteplase.

Haley E et al. Stroke 2010;41:707


Original Article A Randomized Trial of Tenecteplase versus

Alteplase for Acute Ischemic Stroke

Mark Parsons, M.D., Neil Spratt, M.D., Andrew Bivard, B.Sc., Bruce Campbell, M.D., Kong Chung, M.D., Ferdinand Miteff, M.D., Bill O'Brien, M.D., Christopher

Bladin, M.D., Patrick McElduff, Ph.D., Chris Allen, M.D., Grant Bateman, M.D.,

Geoffrey Donnan, M.D., Stephen Davis, M.D., and Christopher Levi, M.D.

N Engl J Med Volume 366(12):1099-1107

March 22, 2012


Characteristics of the Patients at Baseline Tenecteplase

Characteristic Alteplase

(n=25) 0.1 mg/kg

(n=25) 0.25 mg/kg

(n=25)

Clinical

Age – yr 70±8.4 72±6.9 68±9.4

Male sex – no. (%) 12 (48) 13 (52) 13 (52)

Hypertension – no. (%) 15 (60) 16 (64) 16 (64)

Diabetes mellitus – no. (%) 1 (4) 8 (32) 6 (24)

Blood glucose – mmol/liter 6.4±1.1 7.1±2.0 7.3±1.8

Hyperlipidemia – no. (%) 9 (36) 13 (52) 15 (60)

Atrial fibrillation – no. (%) 6 (24) 9 (36) 13 (52)

Current smoking – no. (%) 1 (4) 9 (36) 5 (20)

Current medications – no. (%)

Antiplatelet agent 11 (44) 11 (44) 12 (48)

Anticoagulant 1 (4) 1 (4) 1 (4)

NIHSS score 14.0±2.3 14.5±2.3 14.6±2.3

Time to treatment – hr 2.7±0.8 3.1±0.9 3.0±0.7

Parsons M et al. N Engl J Med 2012;366:1099


Characteristics of the Patients at Baseline Tenecteplase

Characteristic Alteplase

(n=25) 0.1 mg/kg

(n=25) 0.25 mg/kg

(n=25)

Imaging

Volume of infarct core – mL

Median 13 8 11

Interquartile range 2-41 1-25 1-35

Volume of perfusion lesion – mL

Median 76 80 79

Interquartile range 21-185 22-199 31-147

Occlusion site – no. (%)

Anterior cerebral artery 0 0 1 (4)

Proximal section of first segment of middle cerebral artery

11 (44) 6 (24) 8 (32)

Midsection of first segment of middle cerebral artery

2 (8) 4 (16) 4 (16)

Distal section of first segment of middle cerebral artery

5 (20) 10 (40) 7 (28)

Second segment of middle cerebral artery 4 (16) 2 (8) 4 (16)

Posterior cerebral artery 1 (4) 1 (4) 1 (4)

Terminal internal carotid artery 0 1 (4) 0

None 2 (8) 1 (4) 0



Alteplase 0.1 mg/kg 0.25 mg/kgAlteplase 0.1 mg/kg 0.25 mg/kg

Tenecteplase Tenecteplase

Distribution of Changes in NIHSS Scores Distribution of Reperfusion Rates

0

20

40

60

80

100

-15

-10

-5

0

5

10

Re

pe

rfu

sio

n (

%)

Re

pe

rfu

sio

n (

%)



Study Overview

• In this phase 2B trial involving 75 patients with acute ischemic stroke, tenecteplase was more effective than alteplase in achieving reperfusion and clinical improvement at 24 hours.

• Bleeding complications were similar in the two groups.


Original Article Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke

Bruce C.V. Campbell, Ph.D., Peter J. Mitchell, M.Med., Leonid Churilov, Ph.D., Nawaf Yassi, Ph.D.,

Timothy J. Kleinig, Ph.D., Richard J. Dowling, M.B., B.S., Bernard Yan, M.B., B.S., Steven J. Bush, M.B., B.S., Helen M. Dewey, M.D., Vincent Thijs, M.D., Rebecca Scroop, M.B., B.S., Marion Simpson, M.B.,

B.S., Mark Brooks, M.B., B.S., Hamed Asadi, M.B., B.S., Teddy Y. Wu, M.B., B.S., Darshan G. Shah, M.B., B.S., Tissa Wijeratne, M.D., Timothy Ang, M.B., B.S., Ferdinand Miteff, M.B., B.S., Christopher R.

Levi, M.B., B.S., Edrich Rodrigues, M.B., B.S., Henry Zhao, M.B., B.S., Patrick Salvaris, M.B., B.S., Carlos Garcia-Esperon, M.D., Peter Bailey, M.D., Henry Rice, M.B., B.S., Laetitia de Villiers, M.B., B.S., Helen Brown, M.B., B.S., Kendal Redmond, M.B., B.S., David Leggett, M.B., B.S., John N. Fink, M.D., Wayne Collecutt, M.B., B.S., Andrew A. Wong, M.B., B.S., Claire Muller, M.B., B.S., Alan Coulthard, M.B., B.S.,

Ken Mitchell, M.B., B.S., John Clouston, M.B., B.S., Kate Mahady, M.B., B.S., Deborah Field, M.B., B.S., Henry Ma, Ph.D., Thanh G. Phan, Ph.D., Winston Chong, M.B., B.S., Ronil V. Chandra, M.B., B.S., Lee-

Anne Slater, M.B., B.S., Martin Krause, M.D., Timothy J. Harrington, M.B., B.S., Kenneth C. Faulder, M.B., B.S., Brendan S. Steinfort, M.B., B.S., Christopher F. Bladin, Ph.D., Gagan Sharma, M.C.A., Patricia M.

Desmond, M.D., Mark W. Parsons, Ph.D., Geoffrey A. Donnan, M.D., Stephen M. Davis, M.D., for the EXTEND-IA TNK Investigators

N Engl J Med Volume 378(17):1573-1582

April 26, 2018


EXTEND-IA TNK

• Eligibility:

• Occlusion of internal carotid, middle cerebral, or basilar artery

• Eligible for thrombectomy

• Onset of symptoms < 4.5 hours

• Randomized:

• Alteplase 0.9mg/kg (max 90mg)

• Tenecteplase 0.25mg/kg (max 25mg)

• Primary Outcome:

• Major reperfusion = >50% reperfusion of territory


Characteristics of the 202 Patients at Baseline.

Campbell BCV et al. N Engl J Med 2018;378:1573-1582


Outcomes.



Modified Rankin Scale Scores at 90 Days in the Intention-to-Treat Population.



Study Overview

• In a randomized trial involving patients with acute stroke, the incidence of revascularization was higher with tenecteplase than with alteplase for intravenous thrombolysis before endovascular thrombectomy.

• Cerebral hemorrhage occurred at the same rate in each group.


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MFMER |


Illustrative Case

• 85 yo woman with transient left sided visual disturbance x 1 hour

• NIHSS = 0

• Normal neurological examination

• BP 167/84


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MFMER |

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©2011

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TIA Definitions

• Classic TIA definition arbitrarily based on symptom duration < 24 hours

• Operational definition prior to the advent of advanced neuroimaging techniques

• Modern study of TIA has demonstrated:

• Most TIA’s are < 1 hour in duration

• 30-50% classically-defined TIA’s have evidence of infarction on DWI


©2011

MFMER |


TIA and Ischemic Stroke Definitions

• Revised Definitions:

• TIA: “A transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.”

• Ischemic Stroke: “An infarction of the central nervous system tissue.”

Easton JD, et al. Stroke 2009


TIA Epidemiology

• 2.3% estimated prevalence in U.S.

• ~5 million people

• 15% of strokes heralded by TIA

• True incidence unknown as misdiagnosis (migraine, seizure, syncope) and failure to report is common

• Disability (mRS > 2) increases from 14% → 23% at 5 years following TIA

• 11% risk of institutionalization at 5 years following TIA

Benjamin, EJ et al. Circulation 2017


Diagnosis of TIA

• TIA diagnosis is frequently difficult in clinical practice

• Objective findings have often resolved at time of assessment

• Difficulty recalling or describing resolved symptoms

• Provider difficulty in eliciting/interpreting the information provided

• Many non-cerebrovascular symptoms are often misclassified as TIA by specialists and non-specialists alike


Retinal

TIAs

Hemispheric

TIAs

Anatomic Classification of Transient Ischemic Attacks

TIAs

Posterior

circulation TIAs

Anterior

circulation TIAs


Cardinal Features of Carotid Territory TIA

Symptom Sign

1. Motor dysfunction Weakness, clumsiness, paralysis of 1 or both limbs on same side

2. Sensory Numbness, loss of sensation, and paresthesias of 1 or both limbs on same side; without spread or march

3. Speech/language Aphasia

4. Vision Loss in one eye or part of one eye

5. Vision Homonymous hemianopia

6. Multiple Combination of above

Heyman A et al. Stroke.1974;5:277


3 Cardinal Features of Brainstem TIA

• Cranial nerve deficit

e.g., diplopia

• Crossed deficits

e.g., right facial droop and left upper and left lower extremity weakness

• Simultaneous bilateral deficits

e.g., drop attacks


©2011

MFMER |


Positive Symptoms

• Visual: sparkles, flashes, colors, formed and unformed figures, etc.

• Sensory: Tingling or marching paresthesias

• Motor: Tonic or clonic movements


©2011

MFMER |


Positive Symptoms

• Generally occur in:

• seizures

• transient migraine accompaniments

• transient events of cerebral amyloid angiopathy

• rarely in transient ischemic attacks (i.e. limb-shaking TIA)


©2011

MFMER |


Negative Symptoms

• Visual: Loss of vision, either monocular, or visual field

• Sensory: Numbness or loss of feeling

• Motor: Weakness; monoplegia or hemiplegia

• Language: Speech Arrest or Aphasia

• In TIA/Stroke: negative symptoms are generally seen and if more than one symptom is present they tend to all occur at the same time


©2011

MFMER |


Pattern Recognition in Diagnosing TIA

• The hallmark of TIAs is that the symptoms correlate with intermittent dysfunction in named vascular territories

• If there are a series of spells and they are stereotyped, they may represent recurrent TIAs distal to a single fixed stenosis

• TIAs do not have to be stereotyped (e.g. cardioembolic TIAs)


Clinical Situations Mimicking TIA/Stroke

Seizure History of seizures, witnessed seizure activity, post-ictal period

Hypoglycemia History of diabetes, low serum glucose, decreased level of consciousness

Migraine with aura History of similar events, preceding aura, headache

Hypertensive encephalopathy

Headache, delirium, significant hypertension, cortical blindness, cerebral edema, seizure

Wernicke’s encephalopathy

History of alcohol abuse, ataxia, ophthalmoplegia, confusion

CNS abscess History of drug abuse, endocarditis, medical device implant with fever

Drug toxicity Lithium, phenytoin, carbamazepine

Psychogenic Lack of objective cranial nerve findings, neurological findings in non-vascular distribution, inconsistent examination


TIA Near Term Risk

• 90 day stroke risk after TIA ~10-15%

• About half of this stroke risk is accrued in the first 48 hours after TIA

• Therefore, TIA is important to recognize and should be evaluated and treated expeditiously


TIA Risk Stratification

• ABCD2 score (0-7 points): • Age ≥ 60 [1 point]

• BP ≥ 140/90 mmHg [1 point]

• Clinical features:

• unilateral weakness [2 points]

• speech disturbance [1 point]

• Duration: ≥ 60 minutes [2 point]

10-59 minutes [1 point]

• Diabetes [1 point]

Johnston SC, et al. Lancet 2007 Johnston SC et al. Lancet. 2007;369(9558):283

Rothwell PM et al. Lancet. 2005;366(9479):29


Illustrative Case

• 72 y.o. woman with history of HTN and ↑lipids presents to the ED with an episode of right face, arm, and leg weakness x 20 minutes with spontaneous resolution.

• BP 167/84.

ABCD2 score = 5 (age, BP, clinical sx, duration)


High Risk 8.1%

Mod. Risk 4.1%

Low Risk 1.0%

ABCD2 score does not take into account neuroimaging that

has become a routine part of TIA evaluation.


©2011

MFMER |

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Tissue-based TIA definition & stroke risk

• Prospective cohort study (3,206 patients)

• DWI+ 7d stroke risk →7.1% [95% CI 5.5-9.1]

• DWI- 7d stroke risk → 0.4% [95% CI 0.2-0.7]


Giles, et al. Neurology 2011


Rationale for brain MRI after TIA

• DWI lesion rules in ischemia as the cause of symptoms

• DWI topography informs stroke mechanism

• DWI lesions inform risk of early recurrence

Non-contrast Head CT lacks necessary sensitivity to achieve

these goals in patients with transient symptoms.


©2011

MFMER |

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Timing of brain MRI following TIA/minor stroke

• 263 TIA/minor stroke (NIHSS ≤ 3) patients with MRI within 24 hours and at 90 days

• Stroke on baseline vs. 90d scan (68% vs. 56%, p=0.005)

• 30% subjects with negative 90d scans had stroke on baseline scan

Moreau F, Stroke 2013


Baseline & 90 day brain MRI in TIA patient


Timing of brain MRI following TIA/minor stroke

• Diagnostic yield of MRI decreases with time

• Late MRI should be interpreted with caution as false negative scans may occur

Neuroimaging evaluation within 24 hours of symptom onset –

MRI with DWI is preferred brain diagnostic imaging modality

(Class I; Level of Evidence B).

Jauch EC, Stroke 2013


Associated Factors with Acute Infarction Detected by DWI-MRI in all TIA Patients (n=3,724) Imaged with MRI Using Logistic Regression

Factors OR (95% CI) P

Regression

coefficient

Male sex 1.3 (1.1-1.5) 0.002 0.22

Motor weakness 2.3 (2.0-2.7) <0.001 0.85

Aphasia 1.7 (1.4-2.1) <0.001 0.53

Dysarthria 1.5 (1.3-1.9) <0.001 0.42

Atrial fibrillation 1.6 (1.3-2.0) <0.001 0.45

Abbreviations: CI = confidence interval; OR = odds ratio

Al-Khaled M, et al. Neurology 2013


TIA Acute Therapy

• CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events)

• 5170 patients within 24 hours after onset of minor ischemic stroke or high-risk TIA to:

Clopidogrel (300mg, followed by 75mg/d x 90days) + ASA (75mg/d x 21days)

OR

Placebo + ASA (75mg/d x 90 days)

Wang Y, et al. N Engl J Med 2013


CHANCE - Efficacy and Safety Outcomes

Outcome

Aspirin (n=2,586) Clopidogrel and

Aspirin (n=2,584)

HR (95% CI) P

Patients with event (no.)

Event rate (%)

Patients with Event (no.)

Event rate (%)

Primary outcome

Stroke 303 11.7 212 8.2 0.68 (0.57-0.81) <0.001

Secondary outcomes

Stroke, myocardial infarction, or death from cardiovascular causes 307 11.9 216 8.4 0.69-0.58-0.82) <0.001

Ischemic stroke 295 11.4 204 7.9 0.67 (0.56-0.81) <0.001

Hemorrhagic stroke 8 0.3 8 0.3 1.01 (0.38-2.70) 0.98

Myocardial infarction 2 0.1 3 0.1 1.44 (0.24-8.63) 0.69

Death from cardiovascular causes 5 0.2 6 0.2 1.16 (0.35-3.79) 0.81

Death from any cause 10 0.4 10 0.4 0.97 (0.40-2.33) 0.94

Transient ischemic attack 47 1.8 39 1.5 0.82 (0.53-1.26) 0.36

Safety outcomes

Bleeding*

Severe 4 0.2 4 0.2 0.94 (0.24-3.79) 0.94

Moderate 4 0.2 3 0.1 0.73 (0.16-3.26) 0.68

Mild 19 0.7 30 1.2 1.57 (0.88-2.79) 0.12

Wang Y, et al. N Engl J Med 2013


CHANCE – Stroke Free Survival


Probability of Survival Free of Stroke.

CHANCE – subgroup analysis

In contrast to treatment patterns in North America:

• 35% patients on anti-hypertensive

• 42% patients on lipid-lowering drugs


TIA Acute Therapy

• POINT (Platelet-oriented inhibition in new TIA and minor ischemic stroke)

• Patients <12 hours after onset of minor ischemic stroke or high-risk TIA to:

Clopidogrel (600mg, followed by 75mg/d x 90days) + ASA (50-325mg/d x 90days)

OR

Placebo + ASA (50-325mg/d x 90 days)

• Primary efficacy outcome is composite of ischemic stroke, myocardial infarction, or vascular death at 90d.

Johnston SC, et al. Int J Stroke 2013


Key Inclusion Criteria

• Acute ischemic event:

Minor ischemic stroke (NIHSS <3), OR

High-risk TIA (ABCD2score >4)

• Randomized within 12 hours of event onset

• TIA symptoms not limited to numbness, visual changes,

dizziness/vertigo.

• No receipt of thrombolysis or thrombectomy.

• No planned endarterectomy.

• No indication for anticoagulation, aspirin, or clopidogrel, and no

contraindication for study drug.


Efficacy Outcomes


Major Hemorrhage


Safety Outcomes


Primary Outcome by Time Period


So what do we do?

• Treatment x 21-30 days is evidence based approach to balance benefit with risk of hemorrhage


Amarenco P et al. N Engl J Med 2018

Intensive versus Standard Treatment of Hyperglycemia in

Acute Ischemic Stroke

Karen Johnston, Askiel Bruno, Qi Pauls, Christiana Hall, Kevin Barrett, William Barsan, Amy Fansler,

Katrina Van de Bruinhorst, Scott Janis, Valerie Durkalski-Mauldin, for the NETT and

SHINE Investigators

Stroke Hyperglycemia Insulin Network Effort

The SHINE Trial

Financial Disclosures

• The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS) of NIH.

• Medical Decision Network LLC (Charlottesville, VA) provided, the GlucoStabilizer®, a computer decision support tool, at no cost.

• Rattan Juneja has received royalties from GlucoStabilizer®

• No Unlabelled/Unapproved use

Background

• Hyperglycemia in acute ischemic stroke common

• Preclinical/clinical data show hyperglycemia during acute cerebral ischemia is associated with worse outcome

• Severe hypoglycemia increases injury to ischemic brain

• Unclear if glucose lowering improves outcome

Background • GIST-UK Trial

– 933 patients (40% of planned), AIS/ICH, 24hr window

– Randomized to insulin or saline infusion

– Target 72-126 mg/dL (4-7 mmol/L)

– No difference in mortality

• 2 NIH-NINDS funded middle phase trials

– THIS/GRASP – safety and feasibility

– Phase III trial warranted

• Underpowered for efficacy

• Best glucose control approach remains unknown

Hypotheses

Efficacy

• Intensive glucose control to target range of 80-130 mg/dL with IV insulin infusion in hyperglycemic acute ischemic stroke patients within 12 hours of symptom onset will improve favorable outcome by absolute 7% as measured by mRS at 90 days after stroke.

Safety

• Intensive glucose control will be safe as measured by <4% increase in severe hypoglycemia (<40 mg/dL) compared to standard control in acute ischemic stroke patients treated up to 72 hours

Outcomes Primary Efficacy

• Severity adjusted favorable outcome (90 day mRS)

Primary Safety

• Severe hypoglycemia <40mg/dL (2.22 mmol/L) (treatment period)

Baseline NIHSS

90-day mRS

3-7 0

8-14 0-1

15-22 0-2

Design

• Prospective, multicenter, randomized, blinded

– 70 US sites, maximum of 1400 patients

• Randomization balance for NIHSS & tPA

• Single blind treatment

• Double blind outcome assessment

• Treatment (up to 72 hours)

– Intensive: Insulin drip – target 80-130 mg/dL

– Standard: SQ insulin q6 hr – target <180 mg/dL

• 4 planned interim analyses (500, 700, 900, 1100)

Main Eligibility Criteria

• Age 18 years or older

• Clinical diagnosis of ischemic stroke

• Randomization w/in 12 hours of LKW (last known well)

• Type 2 diabetes and glucose >110 mg/dL OR No known diabetes and glucose ≥150 mg/dL

• Baseline NIHSS score 3-22

Main Exclusion Criteria

• Type I Diabetes

• Pre-existing confounding conditions

• Renal dialysis

• Inability to follow the protocol including:

– Required insulin infusion

– Unable to follow up

SHINE Trial Sites • 70 participating sites

• 63 sites enrolled

• 1151 total patients enrolled (4/12 – 8/18)

SHINE Enrolling Site

NETT/Siren CCC - UM

NETT/Siren SDMC - MUSC

Top Enrolling Sites

1. NYP/Columbia

2. Emory/Grady

3. Ohio State

Baseline Characteristics

Characteristic Intensive (N=581)

Standard (N=570)

Age (yr) - median (IQR) 66 (57-75) 66 (57-76)

Female sex – no. (%) 260 (44.8) 264 (46.3)

Race - no. (%)

Black 180 (31.0) 154 (27.0)

White 366 (63.0) 369 (64.7)

Ethnicity - no. (%)

Hispanic 87 (15.0) 91 (16.0)

Non Hispanic 460 (79.2) 449 (78.8)

Medical History - no. (%)

Previous Ischemic stroke 104 (17.9) 99 (17.4)

Diabetes mellitus (Type II) 468 (80.6) 455 (79.8)

Hypertension 513 (88.3) 502 (88.1)

Median eligibility glucose (mg/dL)- (IQR) 188 (153-250) 187 (155-248)

Baseline Characteristics

Characteristic Intensive (N=581)

Standard (N=570)

Final diagnosis - no. (%)

Ischemic stroke 542 (93.3) 524 (91.9)

Transient ischemic attack 8 (1.4) 12 (2.1)

Baseline NIHSS - median (IQR) 7 (5-12) 7 (5-13)

Baseline NIHSS category - no. (%)

Mild (NIHSS 3-7) 291 (50.1) 291 (51.1)

Moderate (NIHSS 8-14) 177 (30.5) 158 (27.7)

Severe (NIHSS 15-22) 113 (19.5) 121 (21.2)

Thrombolysis/thrombectomy - no. (%)

Intravenous tPA 372 (64.0) 353 (61.9)

Intraarterial drug therapy 14 (2.4) 21 (3.7)

Mechanical thrombectomy 74 (12.7) 72 (12.6)

Median time to randomization (Hour) - (IQR) 7.1 (4.8,9.4) 7.1 (4.9,9.7)

Blood Glucose Separation

179 mg/dL

OverallMean

118 mg/dL

Intensive target: 80-130 mg/dL Standard target: 80-179 mg/dL

Primary Results

• Stopped for futility at 4th interim analysis • 82% (1151/1400) of the planned maximum

number of patients were enrolled

• No safety boundary was crossed

Primary Results

Intention-To-Treat

N=1151

Intensive

N=581

Standard

N=570

Primary Efficacy Outcome- N (%) 119 (20.5) 123 (21.6)

Adjusted* Relative Risk 95% CI 0.97 (0.87, 1.08)

P value for adjusted analysis 0.55

Severe Hypoglycemia- N (%) 15 (2.6) 0

Risk Difference (%) (95% CI) 2.58 (1.29, 3.87)

*adjusted for baseline stroke severity and thrombolysis use

Additional Efficacy Outcomes

Intensive Standard

Favorable NIHSS (0 or 1) 43.7% 44.7%

Relative Risk (95% CI) 0.98 (0.83, 1.15)

Favorable Barthel Index (95-100) 55.2% 54.7%

Relative Risk (95% CI) 1.01 (0.90, 1.13)

SSQOL Median (IQ) 3.8 (3.0, 4.4) 3.7 (3.0, 4.5)

Full Range mRS (90 days) Stratified by stroke severity

Conclusions

• Successful & efficient completion of SHINE Trial

• Answered question of best glucose control for hyperglycemic AIS

• Intensive glucose control (80-130 mg/dL) does not improve 90 day functional outcome and increases risk of severe hypoglycemia

• SQ insulin with target <180 mg/dL is preferred

On behalf of the SHINE Leadership Team

Thank You

Patients Participating Site Teams

GlucoStabilizer®Team SHINE DSMB NIH-NINDS

NCT01369069

©2013 MFMER | slide-92 ©2011 MFMER | slide-92

Summary

• Early risk of stroke is high after TIA – expedited evaluation is warranted to identify high risk patients

• DWI is neuroimaging test of choice for TIA and should be performed as early as possible following symptoms

• Evidence supports early (<12 hours) dual anti-platelet treatment to reduce the risk of stroke following high-risk TIA and minor ischemic stroke


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