Implications for Clinical Practice
Jeffrey L. Saver, MD
Professor of Neurology
Director, UCLA Stroke Center
UCLA Stroke Center
--All slides in presentation are freely available under a Creative Commons “Share Freely
with Attribution” License – Saver
Talk Outline
• Implications for clinical
practice guidelines
» Statistical significance
• Implications for
clinicians at bedside
» Clinical significance
» Systems of care
• Implications for future
UCLA Stroke Center
Guidelines
UCLA Stroke Center
European EUSI Recommendations 2006
UCLA Stroke Center
US AHA/ASA Guidelines 2010
UCLA Stroke Center
INTERACT 2: A Near Win Trial
Trial
INTERACT 2
UCLA Stroke Center
Intervention
OR
P
primary
P
ordinal
BP↓ for ICH
0.87 (0.75-1.01)
0.06
0.04
Stroke and Near Win Trials
Trial
Intervention
OR
P
primary
P
ordinal
BP↓ for ICH
0.87 (0.75-1.01)
0.06
0.04
TPA to 6 hours
1.13 (0.95-1.35)
0.18
0.001
BP↓ prevent
recurrent stroke
0.81 (0.64-1.03)
0.08
INTERACT 2
IST 3
SPS3 BP Arm
UCLA Stroke Center
Meta-Analysis of INTERACT 1, 2 and
ATACH Trials
UCLA Stroke Center
UCLA Stroke Center
Clinical Significance
“A difference, to be a
difference, must make a
difference”
UCLA Stroke Center
INTERACT 2
UCLA Stroke Center
INTERACT 2
UCLA Stroke Center
INTERACT 2
UCLA Stroke Center
Benefit on Dichotomized Outcome
• 52.0% vs 55.6%
• ARR 3.6%
• Benefit per Thousand: 36
• NNT: 27.8
UCLA Stroke Center
INTERACT 2
UCLA Stroke Center
INTERACT 2
UCLA Stroke Center
Automated Algorithmic Joint Outcome
Table Analysis
--Saver et al, Stroke 2009;40:2433-7
UCLA Stroke Center
Benefit Over All Health State
Transitions
• Benefit per Thousand: 81
• NNT: 12.3
UCLA Stroke Center
Benefit in INTERACT 2 vs Other
Acute Stroke Interventions
Intervention
TPA under 3h
IA Pro-UK
Coiling in SAH
TPA 3-4.5h
BP lowering for ICH
Clinician worthwhile
Socioeconomic model worthwhile
UCLA Stroke Center
Net Benefit per Thousand
290
208
169
136
81
50
20
--Samsa et al, Am Heart J 1998;136:703-13
--Saver, Stroke 2007;38:3055-3062
--Saver et al, Stroke 2009;40:2433-7
Door to BP Control in Community
Practice in ICH
•
•
•
•
100 patients, 32 Emergency
Departments
At ED arrival
»
»
»
54% received BP therapy in ED
Among the 48 patients with SBP ≥
180
»
»
»
UCLA Stroke Center
NIHSS 18
Time from LKW 63 mins
Mean BP 176/94
Control (<180) never achieved in
19%
Median door to control 118 mins
Door to control ≤ 90m in 31%
--Sanossian et al, Ann Emerg Med 2012;60: S56
Other Treatment Recommendations
for ICH
•
•
•
•
•
•
ICU monitoring
Antipyretics in febrile patients
Early mobilization
ICP management
»
»
Head of bed, analgesia, sedation
Osmotic diuretics, CSF drainage,
hyperventilation
Maintain serum glucose < 185
Seizures
»
»
»
Prophylactic antiepileptics for lobar
ICH
Antiepileptics for clinical seizures
Antiepileoptics for electrographic
seizures
•
•
•
•
DVT prophylaxis
»
»
Intermittent compression on arrival
SQ LMWH or UH after 3-4d
For DVT, consider vena cava filter
Reversal of coagulopathies
»
»
Protamine for heparin
Vitamin K, PCC, rF7 for warfarin
Surgery
»
»
»
Definite for select cerebellar
Consider for lobar
Consider minimally invasive for
deep
--Morgenstern et al, Stroke 2010
UCLA Stroke Center
ICH Critical Pathway
NINDS
Time Goals
Identify Signs of Possible Stroke
Monitor Blood Glucose
and Treat (if needed)
Critical EMS Assessments & Actions
BP Management
Immediate General Assessment/Stabilization
ICP Management
Immediate Neurologic Assessment
(stroke team or designee)
Seizure Prevention and
Management
Does CT scan show
hemorrhage?
No Hemorrhage
Possible
ischemic stroke
Fluid Management
Body Temperature
Management
Hemorrhage
• Consult neurologist or neurosurgeon
• If not available, consider transfer
Begin ICH Pathway
 Admit to stroke unit (if available) or ICU
 Monitor BP and treat (if indicated)
 Monitor neurologic status
(emergent CT if deterioration)
 Monitor blood glucose & treat (if needed)
 Supportive therapy
 Treat comorbidities
Surgical Treatment of ICH
 Cerebellar hemorrhage >3 cm with
neurologic deterioration or brain
stem compression and/or
hydrocephalus
 Consider in lobar clots <1 cm of
surface
AHA Adult Stroke Guidelines. Circulation. 2005;112(suppl 24):IV-111-IV-120; Broderick J,
et al. Stroke. 2007;38:2001-2023; Qureshi AI, et al. N Engl J Med. 2001;344:1450-1460.
ICH Critical Pathway Sample Checklist
Testing
Nursing
Assessment
EMS
ED (60 min)
ICU/NCCU
Surgical
Intervention
•Medical history (risk factors,
similar recent events)
•Determine any medications
currently taken
•Cincinnati Prehospital Stroke
Scale
•Los Angeles Prehospital Stroke
Screen
•ABCs
•Time of onset
•Medic Alert tag
•ABCs
•Vital signs
•Medical history
•Time of onset
•Blood pressure
•Neurologic status (GCSS)
•Blood glucose
•ABCs
•Vital signs
•Blood pressure
•Intracranial pressure
•Neurologic status
•Blood glucose
•Body temperature
•Routine evacuation of
supratentorial ICH
with standard
craniotomy within 96
hours not
recommended
•Surgical candidates
(cerebellar
hemorrhage >3 cm
with neurologic
deterioration;
consider with lobar
clots <1 cm from
surface)
•Vital signs
•Support ABCs (oxygen if
needed)
•Transport (consider triage to
stroke center)
•Vital signs
•Obtain IV access &
blood samples
•Support ABCs
•Intubation(?)
•Supportive therapy
•Treat comorbidities
•Vital signs
•Support ABCs
•Intubation(?)
•Supportive therapy
•Treat comorbidities
•Fluid management
(euvolemia)
•Positional factors (head at
midline, raise head of bed
30º)
•Blood glucose (if possible)
•12-lead ECG (if possible)
• CT/MRI
•Neurologic examination (NIH Stroke
Scale, Canadian Neurologic Scale)
•Blood pressure
•Electrolytes
•Blood glucose
•12-lead ECG on admission
•CBC, PT, aPTT, INR, electrolytes
•Toxicology
•Platelet function
•CXR
•Blood pressure – MAP, SAP,
CPP
•ICP (ventriculostomy,
fiberoptic ICP monitor, etc)
•Blood glucose
•12-lead ECG
•CT/MRI
ICH Critical Pathway Sample Checklist
EMS
ICH Critical Pathway Sample Checklist (cont.)
(60 min)
ICU/NCCU
ICHEDCritical
Pathway Sample
Checklist (cont.) Surgical
Intervention
•Oxygen (if hypoxemic)
•Treat blood glucose abnormalities
•Blood pressure (labetalol, esmolol,
nitroprusside, hydralazine, enalapril)
•Blood pressure (labetalol, esmolol, hydralazine,
enalapril, nicardipine)
•ICP (head elevation, osmotic diuretics, CSF
drainage; neuromuscular blockade,
hyperventilation)
•Seizures (lorazepam, diazepam, phenytoin, fosphenytoin)
•Warfarin coagulopathy (PCC, FFP, Vitamin K,
Factor VIIa)
•Treat blood glucose abnormalities
•Alert hospital
•Activate stroke team
•Consult neurologist or
neurosurgeon
•Consider transfer to stroke center
•Consult neurologist or neurosurgeon
•Begin stroke pathway
•Admit to stroke unit (if available) or
ICU
•Follow stroke pathway
Pathways Consults
Medications
•Oxygen
Adapted from AHA Adult Stroke Guidelines. Circulation. 2005;112(suppl 24):IV-111-IV-120; Broderick JP, et al. Stroke. 1999;30:905-915; Broderick J, et al.
Stroke. 2007;38:2001-2023; Marik PE, et al. Chest. 2002;122:699-711; Passero S, et al. Epilepsia. 2002;43:1175-1180; Qureshi AI, et al. Stroke.
2001;33:1916-1919.
ABCs = airway-breathing-circulation
aPTT = activated partial thromboplastin time
CBC = complete blood count
CPP = cerebral perfusion pressure
CXR = chest x-ray
ED = emergency department
FFP = fresh frozen plasma
GCSS = Glascow Coma Scale score
ICP = intracranial pressure
INR = international normalized ratio
MAP = mean arterial pressure
NCCU = neuro-critical care unit
PCC = prothrombin complex concentrate
PT = prothrombin time
SAP = systolic arterial pressure
Next Steps
UCLA Stroke Center
Time is Brain for Hemorrhagic Stroke
--Arima et al, Stroke 2012;43:2236-8
UCLA Stroke Center
Dynamics of Hyperacute Hematoma Growth
0-120 Minutes: Not Well Delineated
--Kazui et al, Stroke 1996;27:1783-1787
Intracerebral Hemorrhage and the
Golden Hour
•
•
•
Narrow therapeutic time
window
Early intervention critical
Prehospital personnel
» 35-70% of stroke patients
»
UCLA Stroke Center
arrive by ambulance
Unique position: first
medical professional to
come in contact with stroke
patient
45
CT scan
evaluated
Final Hematoma Volume
Established
40
Initial ED
Evaluation
Volume of Hematoma in mL
35
CT scan
obtained
EMS Arrival
in ED
30
Hospital
Treatment
initiated
EMS
Arrival
Activation
of EMS
25
20
15
10
Rupture of
blood vessel
5
Onset of
Symptoms
0
-15
-5
0
20
30
40
60
100
Time in minutes from onset of symptoms
160
200
360
Sanossian, FAST-BP Trial
45
CT scan
evaluated
Final Hematoma Volume
Established
40
Initial ED
Evaluation
Volume of Hematoma in mL
35
CT scan
obtained
EMS Arrival
in ED
30
Hospital
Treatment
initiated
EMS
Arrival
Activation
of EMS
25
Goal: Control Hematoma
expansion Earlier in
Course
20
15
10
Field Treatment
Initiated
Rupture of
blood vessel
5
Onset of
Symptoms
0
-15
-5
0
20
30
40
60
100
Time in minutes from onset of symptoms
160
200
360
Sanossian, FAST-BP Trial
45
CT scan
evaluated
Final Hematoma Volume
Established
40
Initial ED
Evaluation
Volume of Hematoma in mL
35
CT scan
obtained
EMS Arrival
in ED
30
Hospital
Treatment
initiated
EMS
Arrival
Activation
of EMS
25
Goal: Control Hematoma
expansion Earlier in
Course
20
15
10
Field Treatment
Initiated
Rupture of
blood vessel
--All hypertensive pts
--All severely hypertensive pts
--Likely ICH pts
5
Onset of
Symptoms
0
-15
-5
0
20
30
40
60
100
Time in minutes from onset of symptoms
160
200
360
Sanossian, FAST-BP Trial
Onset to Treatment Times in Recent
Trials Enrolling ICH Patients
Trial
Setting
Intervention
Onset to
Treatment
INTERACT 1
Hospital
Target SBP ≤ 140
4h 00m
ATACH 1
Hospital
Nicardipine
4h 17m
INTERACT 2
Hospital
Target SBP ≤ 140
4h 00m
RIGHT
Prehospital
Glyceryl trinitrate
55m
PIL-FAST
Prehospital
Lisinopril
FAST-MAG
Prehospital
Magnesium
UCLA Stroke Center
1h 17m
47m
Preserve / Treat / Cure
Condition
Acute ischemic
stroke
Acute
intracerebral
hemorrhage
UCLA Stroke Center
EMS
ED
OR/Cath Lab
Neuroprotection
TPA
Endovascular
recanalization
BP lowering
Hemostatic agent
Minimally
invasive hem
evacuation
Preserve / Treat / Cure
Condition
Acute ischemic
stroke
Acute
intracerebral
hemorrhage
UCLA Stroke Center
EMS
ED
OR/Cath Lab
Neuroprotection
TPA
Endovascular
recanalization
BP lowering
Hemostatic agent
Minimally
invasive hem
evacuation