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 2

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 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;80:420-433; 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. 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;80:420-433. Mayer SA, Rincon F. Treatment of inracerebral haemorrhage. Lancet Neurol. 2005;4:662-672. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001;344:1450-1460. Taylor TN, Davis PH, Torner JC, Holmes J, Meyer JW, Jacobson MF. Lifetime cost of stroke in the United States. Stroke. 1996;27:1459-1466. Reed SD, Blough DK, Meyer K, Jarvik JG. in-patient costs, length-of-stay, and mortality for cerebrovascular events in community hospitals. Neurology. 2001;57:305-314. 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.

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: 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, 1996. http://www.ninds.nih.gov/news_and_events/proceedings/stroke_proceedings/recs-emerg.htm. Accessed November 8, 2007; Adams et al. Stroke. 2007;38(5):1655-1711. 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 5

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

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,

# 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

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: 1.5-2.9) for a favorable clinical outcome at 3 months

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; 369:275-282. 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? Yes 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 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 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 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: Do not transport Transport to the closest hospital 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? 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 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.

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? 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? Nothing Intravenous t-PA 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 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. 2007.

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):1655-1711.

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.

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: The plaintiff 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 27