stroke acute management in 2019web.brrh.com/msl/im2019/im sunday/sunday - 6... · ©2013 mfmer |...
TRANSCRIPT
©2013 MFMER | slide-1
Stroke – Acute Management in 2019
Kevin M Barrett MD FAAN Associate Professor & Vice-Chair
Department of Neurology, Mayo Clinic Florida
©2013 MFMER | slide-2
©2011
MFMER |
slide-2
Disclosure
Relevant Financial Relationship(s)
NONE
Off Label Usage
NONE
©2013 MFMER | slide-3
©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
©2013 MFMER | slide-4
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
©2013 MFMER | slide-5
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
©2013 MFMER | slide-6
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%
©2013 MFMER | slide-7
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
©2013 MFMER | slide-8
TNK molecule
©2013 MFMER | slide-9
TNK
• Greater fibrin specificity
• Increased resistance to PAI-1
• Longer half-life allowing for bolus administration
©2013 MFMER | slide-10
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
©2013 MFMER | slide-11
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
©2013 MFMER | slide-12
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%*
©2013 MFMER | slide-13
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
©2013 MFMER | slide-14
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
©2013 MFMER | slide-15
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)
©2013 MFMER | slide-17
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.
©2013 MFMER | slide-18
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
©2013 MFMER | slide-19
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
©2013 MFMER | slide-20
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
©2013 MFMER | slide-21
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
©2013 MFMER | slide-22
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
©2013 MFMER | slide-23
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
Parsons M et al. N Engl J Med 2012;366:1099
©2013 MFMER | slide-24
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 (
%)
Parsons M et al. N Engl J Med 2012;366:1099
©2013 MFMER | slide-25
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.
©2013 MFMER | slide-26
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
©2013 MFMER | slide-27
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
©2013 MFMER | slide-28
Characteristics of the 202 Patients at Baseline.
Campbell BCV et al. N Engl J Med 2018;378:1573-1582
©2013 MFMER | slide-29
Outcomes.
Campbell BCV et al. N Engl J Med 2018;378:1573-1582
©2013 MFMER | slide-30
Modified Rankin Scale Scores at 90 Days in the Intention-to-Treat Population.
Campbell BCV et al. N Engl J Med 2018;378:1573-1582
©2013 MFMER | slide-31
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.
©2013 MFMER | slide-32
©2011
MFMER |
slide-32 ©2011 MFMER | slide-32
Illustrative Case
• 85 yo woman with transient left sided visual disturbance x 1 hour
• NIHSS = 0
• Normal neurological examination
• BP 167/84
©2013 MFMER | slide-33
©2011
MFMER |
slide-33
©2013 MFMER | slide-34
©2011
MFMER |
slide-34 ©2011 MFMER | slide-34
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
©2013 MFMER | slide-35
©2011
MFMER |
slide-35 ©2011 MFMER | slide-35
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
©2013 MFMER | slide-36
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
©2013 MFMER | slide-37
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
©2013 MFMER | slide-38
Retinal
TIAs
Hemispheric
TIAs
Anatomic Classification of Transient Ischemic Attacks
TIAs
Posterior
circulation TIAs
Anterior
circulation TIAs
©2013 MFMER | slide-39
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
©2013 MFMER | slide-40
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
©2013 MFMER | slide-41
©2011
MFMER |
slide-41 ©2011 MFMER | slide-41
Positive Symptoms
• Visual: sparkles, flashes, colors, formed and unformed figures, etc.
• Sensory: Tingling or marching paresthesias
• Motor: Tonic or clonic movements
©2013 MFMER | slide-42
©2011
MFMER |
slide-42 ©2011 MFMER | slide-42
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)
©2013 MFMER | slide-43
©2011
MFMER |
slide-43 ©2011 MFMER | slide-43
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
©2013 MFMER | slide-44
©2011
MFMER |
slide-44 ©2011 MFMER | slide-44
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)
©2013 MFMER | slide-45
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
©2013 MFMER | slide-46
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
©2013 MFMER | slide-47
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
©2013 MFMER | slide-48
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)
©2013 MFMER | slide-49
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.
©2013 MFMER | slide-50
©2011
MFMER |
slide-50
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]
©2011 MFMER | slide-50
Giles, et al. Neurology 2011
©2013 MFMER | slide-51
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.
©2013 MFMER | slide-52
©2011
MFMER |
slide-52
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
©2013 MFMER | slide-53
Baseline & 90 day brain MRI in TIA patient
©2013 MFMER | slide-54
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
©2013 MFMER | slide-55
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
©2013 MFMER | slide-56
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
©2013 MFMER | slide-57
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
©2013 MFMER | slide-58
CHANCE – Stroke Free Survival
©2013 MFMER | slide-59
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
©2013 MFMER | slide-60
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
©2013 MFMER | slide-61
©2013 MFMER | slide-62
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.
©2013 MFMER | slide-63
©2013 MFMER | slide-64
©2013 MFMER | slide-65
Efficacy Outcomes
©2013 MFMER | slide-66
Major Hemorrhage
©2013 MFMER | slide-67
Safety Outcomes
©2013 MFMER | slide-68
Primary Outcome by Time Period
©2013 MFMER | slide-69
So what do we do?
• Treatment x 21-30 days is evidence based approach to balance benefit with risk of hemorrhage
©2013 MFMER | slide-70
Amarenco P et al. N Engl J Med 2018
©2013 MFMER | slide-71
Amarenco P et al. N Engl J Med 2018
©2013 MFMER | slide-72
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
©2013 MFMER | slide-93