1. 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

2. 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

3. 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

4. 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 strokes / year
% Ischemic
% Hemorrhagic or SAH
% Mortality within 3 months
Leading cause of disability 2

5. 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

6. ICH High Mortality / Limited Recovery
6-month, 30%-50%
1-year, 50%
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)
Intracerebral hemorrhage (ICH) has been traditionally associated with dismal mortality and morbidity rates and high costs. In some reports, the 6-month mortality rate is 30% to 50%.1-3 Only 20% of patients regain functional independence at 6 months.2
ICH also results in substantial medical costs due to acute hospital and chronic care expenses and loss of productivity.2,4-7 An epidemiologic model of stroke incidence, survival, and recurrence based on a review of the literature found that the lifetime cost per person of first strokes occurring in 1990 was estimated to be $123,565 for ICH, with an aggregate lifetime cost of $6.0 billion. Indirect costs accounted for 58.0% of lifetime costs. Acute-care costs incurred in the 2 years following a first stroke accounted for 45.0%, long-term ambulatory care accounted for 35.0%, and nursing home costs accounted for 17.5% of aggregate lifetime costs of stroke.4
A recent US managed care cost-of-illness study found that the total direct annual costs of ICH (in-patient, out-patient, physician and pharmacy costs) approached $45,000. In-patient costs and length of stay were greater for patients with ICH than for patients with ischemic stroke.6
Overall, ICH represents a substantial medical and cost burden. However, advances in treatment modalities (medical and surgical) as well as implementation of stroke pathways hold the promise of improving outcomes and reducing costs.
Manno EM, et al. Mayo Clin Proc. 2005;80: ; Mayer SA, Rincon F. Lancet Neurol. 2005;4: ; Qureshi AI, et al. N Engl J Med. 2001;344: ; Taylor TN, et al. Stroke. 1996;27: ; Reed SD, et al. Neurology. 2001;57:
Manno EM, Atkinson JL, Fulgham JR, Wijdicks EFM. Emerging medical and surgical management strategies in the evaluation and treatment of intracerebral hemorrhage. Mayo Clin Proc. 2005;80:
Mayer SA, Rincon F. Treatment of inracerebral haemorrhage. Lancet Neurol. 2005;4:
Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:
Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke. 1996;27:
Reed SD, Blough DK, Meyer K, Jarvik JG. in-patient costs, length-of-stay, and mortality for cerebrovascular events in community hospitals. Neurology. 2001;57:
Russell M, Boulanger L, Ashish J, et al. The economic burden of intracerebral hemorrhage: a US managed care cost-of-illness study. Poster presented at: 18th World Congress of Neurology (WCN); November 5-11, 2005; Sydney, Australia.
Russell M, Boulanger L, Ashish J, et al. Intracerebral Hemorrhage versus ischemic stroke: differences in hospitalization outcomes. Poster presented at: 18th World Congress of Neurology (WCN); November 5-11, 2005; Sydney, Australia.

7. 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, )
No increase in mortality and a decrease in hospital stay

8. NIH-Recommended Emergency Department Response Times
The “golden hour” for evaluating and treating acute stroke
Door-to-needle time ≤60 minutes
Minutes: 10 15 25 45 60
Suspected stroke patient arrives at ED
Initial MD evaluation
Stroke team notified
CT scan initiated
CT & labs interpreted
tPA given if patient is eligible
As we have just discussed, the AHA/ASA guidelines recommend that assessment of a suspected patient with acute ischemic stroke be performed rapidly and a decision regarding treatment be made within 60 minutes of arrival in the Emergency Department (ED)
At a National Institutes of Health (NIH) national symposium, a panel of experts developed recommendations for in-hospital time intervals to allow the most expedient evaluation and treatment of stroke patients
The NIH recommendations include the following time intervals from the time of patient arrival at the ED
ED arrival to initial physician evaluation: within 10 minutes
ED arrival to stroke team notification: within 15 minutes
ED arrival to CT scan initiation: within 25 minutes
ED arrival to interpretation of CT: within 45 minutes
In addition, the NIH panel recommended that 80% of eligible stroke patients presenting to the ED should be treated with tPA within 60 minutes
Practices that may facilitate expeditious care of the patient include the following:
Establishment of stroke teams
Prenotification of the ED and/or the stroke team directly, whenever possible, while the patient is in transit
Regular, periodic code stroke drills
Establishment of standing orders for patients
Ongoing training programs for ED and EMS personnel and the stroke team
Transport of the patient by EMS directly to CT
Interpretation of CT scan on the console
Expeditious evaluation and assessment of the patient will facilitate timely administration of the appropriate stroke treatment
NINDS Proceedings of a National Symposium on Rapid Identification and Treatment of Acute Stroke, December 12-13, Accessed November 8, 2007; Adams et al. Stroke. 2007;38(5):
NINDS Proceedings of a National Symposium on Rapid Identification and Treatment of Acute Stroke, December 12-13, Accessed November 8, 2007.

9. NINDS Proceedings: 1997 / 2002 Public education
Prehospital emergency response
Designated stroke centers
Emergency departments
Hospital stroke units
Rehabilitation 5

10. 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 8

11. 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

12. 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

13. 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,

14. # of patients treated with t-PA (# of placebo patients with ICH)
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 t-PA
(n=310)
# of Symptomatic ICH’s
(# of placebo patients with ICH)
Percentage (%)
114
2 (1)
1.8 1
144
7 (1)
4.9
> 1 52 11
21.2

15. 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 t-PA treatment measured by an adjusted t-PA to placebo global odds ratio of 2.1 (95% CI: ) for a favorable clinical outcome at 3 months

16. 4.6% symptomatic hemorrhage at 24 hours
Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST). Lancet 2007; 369:
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)

17. 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

18. Case PMHx: Hypertension Medications Enalapril, 10 mg Aspirin, 81 mg
Social Hx
Smoking - 1 pack per day

19. 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

20. Question 1
Can vertigo be the sole presenting complaint of posterior circulation ischemia?
Yes No

21. Posterior Circulation Stroke: Anatomy

22. 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

23. Lee et al. Cerebellar infarction presenting isolated vertigo
Lee et al. Cerebellar infarction presenting isolated vertigo. Neurology 2006; 67:
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”

24. Pitfalls in the diagnosis of cerebellar infarction
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

25. Pitfalls in the diagnosis of cerebellar infarction
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

26. 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

27. Question 2 Which of the following would you recommend to EMS:
Do not transport
Transport to the closest hospital
Transport to a designated stroke center

28. 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

29. 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

30. 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

32. 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

33. 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.

34. 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

35. Question 3 Which of the following would you recommend?
Discharge with PMD follow up
Discharge on increased aspirin
Discharge on clopidogrel
Discharge on ASA / dipyridamole
Admit to the hospital

36. 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:
371 consecutive patients with TIA
8% ischemic stroke in 30 days; ½ within 48 hours
12% in motor deficit group

37. Patients at highest risk for stroke after TIA
Age > 60
Blood pressure elevation
Clinical feature:
Focal weakness
Speech Impairment
Diabetes
Duration > 60 minutes

38. 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
Some patients, who will not have a change in their treatment after further evaluation, including those with prior TIA evaluation and those who are not candidates for CEA or anticoagulation, may be discharged home.

39. Case Discharge diagnosis: “Dizziness – resolved” Limit alcohol use
Return to ED if symptoms reoccur
Call your doctor in the am

40. 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

41. 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

42. Question 4 How would you manage the blood pressure? No BP intervention
Labetolol IV
Nicardipine IV
Nitroprusside IV
Nitroglycerin paste

43. 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

44. Question 5
CT showed no infarct, edema, or hemorrhage 3 hours and 30 minutes post symptom onset. Which of the following would you recommend?
Nothing
Intravenous t-PA
Intra-arterial t-PA / clot retrival

45. 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
tPA should be administered only to patients who are eligible
Indication and Usage
tPA is indicated for the management of acute ischemic stroke in adults for improving neurological recovery and reducing 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 cranial computerized tomography (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 therapy is bleeding
The type of bleeding associated with thrombolytic therapy can be divided into 2 broad categories: internal bleeding and superficial, or surface, bleeding, observed mainly at invaded or disturbed sites
These episodes occur because, as fibrin is lysed during tPA therapy, bleeding from recent puncture sites may occur. Therefore, thrombolytic therapy requires careful attention to all potential bleeding sites, including catheter insertion sites, arterial and venous puncture sites, cutdown sites, and needle puncture sites.
Intramuscular injections and nonessential handling of the patient should be avoided during treatment with tPA, and venipunctures should be performed carefully, and only as required
Should an arterial puncture be necessary during an infusion of tPA, it is preferable to use an upper extremity vessel that is accessible to manual compression. If bleeding occurs, pressure should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of further bleeding.
Should serious bleeding (not controllable by local pressure) occur, the infusion of tPA should be terminated immediately, appropriate work-up and treatment should be performed, and a neurosurgeon should be consulted
Each patient being considered for therapy with tPA should be carefully evaluated and anticipated benefits should be weighed against potential risks associated with therapy
Alteplase full Prescribing Information 2005; Rymer et al. The Stroke Center Handbook

46. Appropriate Treatment With tPA: Contraindications & Selected Eligibility Considerations
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)
Selected eligibility considerations
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).
This slide lists more in-depth elements to consider when identifying patients who are eligible for tPA therapy
Patients are ineligible if they experience any of the following:
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
Uncontrolled hypertension at time of treatment (ie, >185 mm Hg systolic or >110 mm Hg diastolic)
Seizure at the onset of stroke
Active internal bleeding
Intracranial neoplasm, arteriovenous malformation, or aneurysm
Known bleeding diathesis
Selected eligibility considerations for tPA treatment included in the AHA/ASA 2007 Guidelines:
Diagnosis of ischemic stroke causing measurable neurological deficit
No gastrointestinal or urinary tract hemorrhage in the 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 is being taken, an 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)
Alteplase full Prescribing Information 2005; Adams et al. Stroke. 2007;38(5):

47. 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
The risks of tPA therapy to treat acute ischemic stroke may be increased in patients with some conditions:
Severe neurologic deficits (NIHSS >22) at presentation
Patients with major and early infarct signs on a cranial CT scan
Patients greater than 75 years of age
Patients with blood glucose values of <50 mg/dL or >400 mg/dL
Patients with a minor strokes or rapidly resolving symptoms
Therefore, in these situations, the anticipated benefits should be weighed against the potential risks
Alteplase full Prescribing Information 2005.
Alteplase full Prescribing Information 2005.

48. 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

49. Do you want to take the case for:
The plaintiff
The defense

50. 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 27