Transcript Working with the P&T Committee

Stroke: Lysis and Beyond
September 15, 2008
Andy Jagoda, MD, FACEP
Professor and Vice Chair of Emergency Medicine
Mount Sinai School of Medicine
New York, New York
Disclosures
• Advisory Board: The Medicines Company
• Speakers Bureau: Genentech
• Past Chair, ACEP Clinical Policies
Committee
• Executive Board, Brain Attack Coalition,
NINDS
• Executive Board, Foundation for Education
and Research in Neurologic Emergencies
www.ferne.org
Key Points
• A (documented) systematic neurologic
evaluation is critical to minimizing risk . . .
And providing good patient care
• EMS plays a pivotal role in acute stroke care
and thus is assuming increasing liability
associated with their decision making
• Alteplase is a FDA approved treatment for
acute ischemic stroke and therefore a
decision to not use it for qualified patients
must be supported in the medical record
Introduction
• Stroke is the 3ird most common cause of
death in the United States
 Second most common cause for
patients to be in a nursing home
• 500,000 - 800,000 strokes / year
 80 - 90% Ischemic
 10 - 20% Hemorrhagic or SAH
 10 - 20% Mortality within 3 months
• Leading cause of disability
The Facts: Ischemic Stroke
• TIAs
 20% – 50% of strokes preceded by a TIA
 75% resolve in <15 minutes; 97% <3 hours
 New definition: event lasting less than 1 hour
and not associated with changes on
neuroimaging
• Acute Ischemic stroke
 Hemorrhagic conversion within 36 hours: 1%
symptomatic, 4% asymptomatic
 30% have little or no disability at 3 months
 30% have mild to moderate disability at 3
months
 30% have severe disability
 10% dead at 3 months
ICH High Mortality / Limited Recovery
• Only 20% of ICH patients
are independent at 6
months vs 60% of
ischemic stroke patients
• Medical costs
• US$125,000 lifetime cost per
person (1990)
• Direct and indirect costs (lost
productivity + caregiver burden)
100%
90%
Proportion of patients (%)
• Mortality
 6-month, 30%-50%
 1-year, 50%
80%
70%
60%
50%
40%
30%
20%
10%
0%
ICH
Dead
Ischemic
Dependent
Manno EM, et al. Mayo Clin Proc. 2005;80:420-433; Mayer SA, Rincon F. Lancet Neurol.
2005;4:662-672; Qureshi AI, et al. N Engl J Med. 2001;344:1450-1460; Taylor TN, et al.
Stroke. 1996;27:1459-1466; Reed SD, et al. Neurology. 2001;57:305-314.
Independent
NINDS t-PA Acute Ischemic Stroke. NEJM
1995
• A two part, double blind study: 624 patients
 Randomized to t-PA or placebo
• “Favorable outcome” defined as normal or near
normal at 90 days
 4 outcome measures: Barthel Index, Modified
Rankin Scale, Glasgow Outcome Scale, NIHSS
• Adjusted t-PA to placebo global OR for favorable
outcome was 1.7 (95%CI,1.2-2.6)
 No increase in mortality and a decrease in
hospital stay
NIH-Recommended Emergency Department
Response Times
The “golden hour” for evaluating and treating acute stroke
Door-to-needle time ≤60 minutes
Minutes: 0
Suspected
stroke patient
arrives at ED
10
15
Initial MD
evaluation
25
45
60
CT scan
initiated
CT & labs
interpreted
tPA given if
patient is
eligible
Stroke team
notified
NINDS Proceedings of a National Symposium on Rapid Identification and Treatment of Acute Stroke, December 12-13, 1996.
http://www.ninds.nih.gov/news_and_events/proceedings/stroke_proceedings/recs-emerg.htm. Accessed November 8, 2007.
NINDS Proceedings: 1997 / 2002
• Public education
• Prehospital emergency response
• Designated stroke centers
• Emergency departments
• Hospital stroke units
• Rehabilitation
The Public Message
• WEAKNESS OR NUMBNESS ON ONE SIDE
OF THE BODY
• DIFFICULTY WITH VISION
• DIFFICULTY WITH SPEECH OR
UNDERSTANDING
• UNUSUALLY SEVERE HEADACHE
• DIZZINESS OR UNSTEADINESS
NINDS Trial Criticism
• External validity
• Imbalance of baseline NIHSS between
the t-PA and placebo groups
• Treatment effect favored those patients
treated within 90 minutes
• Unclear which patients were at risk for
intracerebral hemorrhage
NINDS Date Re-analysis Committee
• Kjell Asplund MD
Umeå
University,
Umeå, Sweden
• Lewis R. Goldfrank
MD
New
York University,
New York, USA
• Timothy Ingall MD
Mayo
Clinic
Scottsdale, Arizona,
USA
• Vicki Hertzberg PhD
Emory
University, Georgia,
USA
• Thomas Louis PhD
Johns
Hopkins Bloomberg
School of Public Health,
Maryland, USA
• Michael O’Fallon PhD
Mayo
Clinic Rochester,
Minnesota, USA
Committee Methods
• Concerns assessed included:
 Baseline NIHSS imbalance
 Time from symptom onset to treatment
 Risk factors for intracerebral hemorrhage
 Predictors of favorable outcome
• The analysis was adjusted for treating hospital,
time to treatment, age, baseline NIHSS,
diabetes,
ICH Analysis
Risk Factors for ICH:
 Baseline NIHSS > 20
 Age > 70 years
 Ischemic changes present on initial
CT
 Glucose > 300 mg/dl (16.7 mmol/L)
# of Risk
Factors
# of patients
treated with tPA
(n=310)
# of Symptomatic ICH’s
(# of placebo patients
with ICH)
Percentage
(%)
0
114
2 (1)
1.8
1
144
7 (1)
4.9
>1
52
11
21.2
NINDS Re-analysis
• Initial NIHSS <20, no diabetes, age <70, normal
CT predict best outcome from t-PA and low risk
for ICH
• The committee concluded, despite an increased
incidence of symptomatic intracerebral
hemorrhage in t-PA treated patients and
subgroup imbalances in baseline stroke severity,
there was a statistically significant benefit of tPA treatment measured by an adjusted t-PA to
placebo global odds ratio of 2.1 (95% CI: 1.52.9) for a favorable clinical outcome at 3 months
Thrombolysis with alteplase for acute ischaemic stroke
in the Safe Implementation of Thrombolysis in Stroke
Monitoring Study (SITS-MOST). Lancet 2007; 369:275282.
• Prospective, open, multicentre, multinational,
observational monitoring study established
as a condition by the European Union for
licensing
• 6483 patients
• 4.6% symptomatic hemorrhage at 24 hours
• 39% with no or mild disability at 3 months (vs
29% in pooled placebo)
The Case: Roseville, Illinois, 2003
63 year old male called EMS at 21:00 with a chief
complaint of feeling dizzy and weak. Vomited
once. No headache, no vision change.
Symptoms began after dinner; 2 cocktails and
2 glasses of wine
 Dizziness described as room spinning

Case
• PMHx:
 Hypertension
• Medications
 Enalapril, 10 mg
 Aspirin, 81 mg
• Social Hx
 Smoking - 1 pack per day
EMS called
• Upon arrival at 21:30 - symptoms
resolved
• BP 190 / 110, P 80, RR 14
• Alert, O x 3
 No facial droop
 No UE drift
 Speech fluent
Question 1
Can vertigo be the sole presenting complaint of
posterior circulation ischemia?
a) Yes
b) No
Posterior Circulation Stroke: Anatomy
Emergency Department Presentation
• Clinical Findings: Depends on the
syndrome
 Range: asymptomatic to comatose
• The 5 Ds: Dizziness, Diplopia,
Dysarthria, Dysphagia, Dystaxia
• Hallmarks: Crossed findings
 Cranial nerve deficits - Ipsilateral
 Motor / Sens deficits Contralateral
Lee et al. Cerebellar infarction presenting
isolated vertigo. Neurology 2006; 67:1178-1183
• 240 consecutive patients with confirmed
cerebellar infarction by MRI
• 25 patients presented with isolated
spontaneous prolonged vertigo with
imbalance
• “Cerebellar infarction simulating vestibular
neuritis is more common than previously
thought”
Pitfalls in the diagnosis of cerebellar infarction.
Acad Emerg Med 2007:14:63-68
• Retrospective chart review: 15 cases of
misdiagnosis
• 12 patients presented with “dizziness”
• 7 patients were younger than 50 and
presented with headache and dizziness
• Majority did not have gait / coordination
tested
Pitfalls in the diagnosis of cerebellar infarction.
Acad Emerg Med 2007:14:63-68
• All of the patients had initial CT read as
normal
• ED diagnosis
 migraine, gastroenteritis, presyncope
• Final diagnoses:
 4 vertebral artery dissections
 3 vertebral artery occlusions
 1 atrial thrombus
 1 patent foramen ovale
Can vertigo be the sole presenting complaint of
posterior circulation ischemia?
• Kerber et al. Stroke among patients with dizziness,
vertigo, imbalance in the ED: a population based
study. Stroke 2006:37:2484
 1666 patients presenting with dizziness, vertigo or
imbalance
 9 (0.7%) had a stroke or TIA
• If the neurologic exam is normal, including careful
assessment of gait and cerebellar function, it is
unlikely that isolated dizziness or vertigo is the result
of CNS ischemia
Question 2
Which of the following would you recommend
to EMS:
a) Do not transport
b) Transport to the closest hospital
c) Transport to a designated stroke center
Stroke Centers: The Thesis
• Thrombolytic and other interventions
are effective treatments in improving
outcomes from acute stroke
• Protocols facilitate efficient resource
utilization and lead to improved
outcomes
• Failure to adhere to protocols
increase morbidity and mortality
11 elements of a Primary Stroke Center
JAMA 2000; 283:3102-3109
•
•
•
•
•
•
•
•
•
•
EMS integrated into the acute stroke response
Acute stroke team available 24 / 7
Written care protocols
ED integrated into the acute stroke team
Stroke unit
Neurosurgical services available within 2 hours
Commitment from the institution
Neuroimaging done / interpreted within 45 min of arrival
Laboratory services with rapid turn around of tests
Quality improvement program including a database or
registry
• Continuing education program
JCAHO Disease Specific Care Certification
• Joint initiative between ASA and JCAHO
• Voluntary participation
 Approximately 1000 centers
certified(25%)
• Premise is that accreditation process will
drive quality measures and improve
outcomes
• No emergency medicine society has
endorsed this initiative
 t-PA controversy
 Overcrowding
 Medical legal implications
Is there a standard of care?
• Canadian Association of
Emergency Physicians
• American Academy of
Emergency Medicine
• Society for Academic
Emergency Medicine
• American College of
Emergency Physicians
American College of Emergency
Physicians
• IV t-PA may be an efficacious therapy for
the management of acute ischemic stroke
if properly used incorporating the
guidelines established by the NINDS
• The decision for an ED to use IV t-PA for
acute stroke should begin at the
institutional level with commitments from
hospital administration, the ED, neurology,
neurosurgery, radiology, and laboratory
services to ensure that the systems
necessary for the safe use of fibrinolytic
agents are in place.
Case
• Patient is transported to the closest
hospital
 BP- 190 / 110, P-80, RR-14, 98%, BS
110
 Alert, Ox3; NAD
 Heart and lungs: “normal”
 CN: “intact”
 Sensation: “intact”
 ECG: normal sinus rhythm
Question 3
Which of the following would you recommend?
a)
b)
c)
d)
e)
Discharge with PMD follow up
Discharge on increased aspirin
Discharge on clopidogrel
Discharge on ASA / dipyridamole
Admit to the hospital
TIA and Stroke
• Johnston, et al. JAMA 2000; 284:2901
 Follow-up of 1707 ED patients diagnosed
with TIA
 Stroke rate at 90 days was 10.5%
• Half of these occurred in the first 48 hours
after ED presentation
• Gladstone, et al. CMAJ 2004; 170:1099-1104
 371 consecutive patients with TIA
 8% ischemic stroke in 30 days; ½ within 48
hours
• 12% in motor deficit group
Patients at highest risk for stroke after TIA
• Age > 60
• Blood pressure elevation
• Clinical feature:
 Focal weakness
 Speech Impairment
• Diabetes
• Duration > 60 minutes
ED Disposition
• Consider ED discharge if:
 Further testing will not change
treatment
 Prior work-up
 Not a candidate for CEA or
anticoagulation
• ECG
• Cardiac echo
• Carotid ultrasound
Case
• Discharge diagnosis: “Dizziness – resolved”
 Limit alcohol use
 Return to ED if symptoms reoccur
 Call your doctor in the am
Case Continued
• 5 days later while visiting son, patient
acutely developed vertigo, left sided facial
droop, right sided weakness, slurred speech
• Lethargic with decreased gag
• BP 210 / 120, P 110, RR 14, POx 92% RA
• BS 110
• Transported to the same ED and arrived
within 45 minutes of symptom onset
Case
• CT obtained and showed no blood, no edema
• “Clot buster” treatment discussed with the
family who give consent for treatment
• t-PA box is opened and only contains
Retaplase
 There is no alteplase in the hospital
• Regional stroke center contacted and
arrangements made for aero-medical transport
• Patient is intubated
Question 4
How would you manage the blood
pressure?
a)
b)
c)
d)
e)
No BP intervention
Labetolol IV
Nicardipine IV
Nitroprusside IV
Nitroglycerin paste
Case
• The patient arrived at the stroke center 2
hours and 15 minutes from the onset of
symptoms)
• BP 160 / 90
• CT was not sent with the patient
 decision made to repeat the study
Question 5
CT showed no infarct, edema, or hemorrhage 3
hours and 30 minutes post symptom onset.
Which of the following would you
recommend?
a) Nothing
b) Intravenous t-PA
c) Intra-arterial t-PA / clot retrival
Appropriate Treatment With tPA:
Bleeding Risk
Indication and Usage
• tPA is indicated for the management of acute ischemic stroke in adults to improve
neurological recovery and reduce the incidence of disability
• Treatment should only be initiated within 3 hours after the onset of stroke
symptoms, and after exclusion of intracranial hemorrhage by a CT scan or
other diagnostic imaging method sensitive for the presence of hemorrhage
(see CONTRAINDICATIONS in the full Prescribing Information)
Bleeding Risk
• The most common complication encountered during tPA treatment is bleeding
• The rate of symptomatic intracranial hemorrhage* was 6.4% in the NINDS trials
• The type of bleeding associated with thrombolytic therapy can be divided into 2 broad
categories:


Internal bleeding, involving intracranial and retroperitoneal sites, or the
gastrointestinal, genitourinary, or respiratory tract
Superficial or surface bleeding, observed mainly at invaded or disturbed
sites (eg, venous cutdowns, arterial punctures, sites of recent surgical
intervention)
• Should serious bleeding (not controlled by local pressure) occur, the infusion of tPA should
be terminated immediately
Appropriate Treatment With tPA:
Contraindications & Selected Eligibility Considerations
Selected eligibility considerations
Contraindications
•
•
•
•
•
•
•
•
•
Evidence of intracranial hemorrhage on
pretreatment evaluation
Suspicion of subarachnoid hemorrhage
on pretreatment evaluation
Intracranial or intraspinal surgery, serious
head trauma, or stroke in the previous
3 months
History of intracranial hemorrhage
Active internal bleeding
Intracranial neoplasm, arteriovenous
malformation, or aneurysm
Known bleeding diathesis
Seizure at the onset of stroke
Uncontrolled hypertension at time of
treatment (ie, >185 mm Hg systolic or
>110 mm Hg diastolic)
Included in the AHA/ASA 2007 Guidelines
•
•
•
•
•
•
•
•
•
•
Diagnosis of ischemic stroke causing
measurable neurological deficit
No gastrointestinal or urinary tract
hemorrhage in previous 21 days
No major surgery in the previous 14 days
No arterial puncture at a noncompressible
site in the previous 7 days
Not taking an oral anticoagulant or, if
anticoagulant being taken, INR ≤1.7
If receiving heparin in previous 48 hours,
aPTT must be in normal range.
Platelet count ≥100,000/mm3
Blood glucose concentration ≥50 mg/dL
No seizure with postictal residual
neurological impairments
CT does not show a multilobar infarction
(hypodensity >1/3 cerebral hemisphere).
tPA Should Be Used With Caution
in Certain Patients
•
•
•
•
•
Patients with severe neurologic deficit (eg, NIHSS >22)
at presentation
Patients with major and early infarct signs on a cranial
CT scan (eg, substantial edema, mass effect, or
midline shift)
Patients of advanced age (eg, >75 years)
Due to the increased risk of misdiagnosis of acute
ischemic stroke, special diligence is required in making
this diagnosis in patients whose blood glucose values
are <50 mg/dL or >400 mg/dL
Patients with minor strokes or rapidly resolving
symptoms
Alteplase full Prescribing Information 2005.
Case Study: Outcome
• Patient did not receive t-PA
• 6 month modified Rankin scale score: 3
 Ambulate with walker
• Patient does well enough to sue:
 EMS for not taking him to a stroke center
 The first emergency physician for failure to
diagnose
 The second EP for not treating with t-PA
• EP sues hospital for not having alteplase
 Stroke Center physicians for delay in care
(repeated CT) and failure to treat
Do you want to take the case for:
a) The plaintiff
b) The defense
Conclusions
• A (documented) systematic neurologic
evaluation is critical to minimizing risk . . .
And providing good patient care
• EMS plays a pivotal role in acute stroke care
and is assuming increasing liability
associated with their decision making
• Alteplase is a FDA approved treatment for
acute ischemic stroke and therefore a
decision to not use it for qualified patients
must be supported in the medical record