3/28/2017© 2009, American Heart Association. All rights reserved.

EXPANSION OF THE TIME WINDOW FOR TREATMENT OF ACUTE ISCHEMIC STROKE WITH INTRAVENOUS TISSUE PLASMINOGEN ACTIVATOR An Advisory Statement from the Stroke Council, American Heart Association and American Stroke Association Gregory J. del Zoppo, MD, MS, FAHA; Jeffrey L. Saver, MD, FAHA; Edward C. Jauch, M.D, MS, FAHA; Harold P. Adams, Jr., MD, FAHA This science advisory reflects a consensus of expert opinion following thorough literature review that consisted of a look at clinical trials and other evidence related to the management of acute ischemic stroke. 3/28/2017© 2009, American Heart Association. All rights reserved. Information from the Expansion of the Time Window for Treatment of Acute Ischemic Stroke with IV TPA – Science Advisory

Stroke Council Professional Education Committee Slide presentation for developed by: Opeolu Adeoye MD Dawn Kleindorfer MD Key words included in the paper: ischemic stroke; tissue plasminogen activator; cerebrovascular disorders; hemorrhage; stroke 3/28/2017© 2009, American Heart Association. All rights reserved. Information from the Expansion of the Time Window for Treatment of Acute Ischemic Stroke with IV TPA – Science Advisory

Applying classification of recommendations and levels of evidence 3/28/2017© 2009, American Heart Association. All rights reserved.

Current Management rt-PA is recommended for treatment of ischemic stroke in selected patients However, rt-PA is only administered to less than 3% of ischemic stroke patients Delay in presentation contributes significantly to underutilization of rt-PA for stroke Extending time window for rt-PA administration beyond the current recommended 3 hrs might be beneficial. The European Cooperative Acute Stroke Study (ECASS 3), investigated rt-PA (alteplase) treatment in the 3.0 - 4.5 hour window 1. Adams HP, Jr., del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007;38(5):1655-1711. 3/28/2017© 2009, American Heart Association. All rights reserved. Information from the Expansion of the Time Window for Treatment of Acute Ischemic Stroke with IV TPA – Science Advisory

ECASS - 3 DESIGN AND METHODS Multicenter, prospective, placebo-controlled RCT Usual criteria for rt-PA eligibility within 3 hrs, exclusion criteria included: older than 80 years; baseline NIH Stroke Scale score >25; on oral anticoagulants; combo of a previous stroke & DM rt-PA (n = 418) or placebo (n = 403) given at 3.0 - 4.5 hrs from stroke symptom onset Dose = 0.9 mg/kg (max 90 mg); 10% as initial bolus & remainder infused over 1 hr. Primary outcome: modified Rankin Scale Score 0-1 (minimal or no disability) at 90 days after Tx. 3/28/2017© 2009, American Heart Association. All rights reserved. Information from the Expansion of the Time Window for Treatment of Acute Ischemic Stroke with IV TPA – Science Advisory

ECASS - 3 RESULTS Primary Outcome: mRS 0-1: rt-PA (52.4%) vs placebo (45.2%) (OR 1.34, 95% CI = 1.02-1.76; p = 0.04) Secondary Outcome: Global Favorable Outcome (mRS of 0-1, Barthel Index score >95, an NIHSS score of 0-1& Glascow Outcome Score of 1) ECASS – 3 = OR 1.28, 95% CI = 1.00-1.65) vs NINDS pool pts (enrolled 0-3hrs) = OR1.9, 95% CI 1.2-2.9 (Overlap in CI limits conclusions about these observations) 3/28/2017© 2009, American Heart Association. All rights reserved. Information from the Expansion of the Time Window for Treatment of Acute Ischemic Stroke with IV TPA – Science Advisory

ECASS - 3 RESULTS Symptomatic ICH (ECASS-3 definition) occurred in rt-PA n = 10 (2.4%) vs placebo n = 1 (0.2%) (OR 9.85, 95% CI 1.26-77.32, p = 0.008) Symptomatic ICH (NINDS study definition) occurred in rt-PA n = 33 (7.9%) vs placebo n = 14 (3.5%) (OR 2.38, 95% CI = 1.25-4.52, p = 0.006) Increased incidence of symptomatic ICH is consistent with the experience with rt-PA in other clinical trials with rt-PA Mortality in the two treatment groups did not differ significantly, although it was nominally higher among the subjects treated with placebo (7.7% vs. 8.4%, p=0.68) Information from the Expansion of the Time Window for Treatment of Acute Ischemic Stroke with IV TPA – Science Advisory 3/28/2017© 2009, American Heart Association. All rights reserved.

ECASS – 3 CONCLUSIONS The ECASS-3 trial is an important advance in treatment of acute ischemic stroke The results provide level B evidence that intravenous rt-PA can be given safely to carefully selected patients 3.0-4.5 hours after stroke These results are consistent with previous reports and confirmation of the ECASS-3 outcome in encouraged 3/28/2017© 2009, American Heart Association. All rights reserved. Information from the Expansion of the Time Window for Treatment of Acute Ischemic Stroke with IV TPA – Science Advisory

Recommendations Patients who are eligible for treatment with rt-PA within 3 hours of onset of stroke should be treated as recommended in the 2007 guidelines Delays in evaluation and initiation of therapy should be avoided because the opportunity for improvement is greater with earlier treatment 3/28/2017© 2009, American Heart Association. All rights reserved. Information from the Expansion of the Time Window for Treatment of Acute Ischemic Stroke with IV TPA – Science Advisory

Recommendations rt-PA should be administered to eligible pts within 3.0-4.5 hours after stroke (Class I Recommendation, LOE B) Eligibility criteria in this time period are similar to those for persons treated at earlier time periods with the following additional exclusion criteria: Age > 80 years; Oral anticoagulant use with INR ≤ 1.7*; baseline NIH Stroke Scale score > 25; a history of stroke and diabetes (*For the 3.0 – 4.5 hr window all pts receiving oral anticoagulant are excluded whatever their INR). The efficacy of IV rt-PA within 3.0 – 4.5 hours after stroke in pts with these exclusion criteria is not well-established & requires further study. (Class IIb Recommendation, LOE C) 3/28/2017© 2009, American Heart Association. All rights reserved. Information from the Expansion of the Time Window for Treatment of Acute Ischemic Stroke with IV TPA – Science Advisory

Summary rt-PA may be safely administered to ischemic stroke pts meeting strict inclusion & exclusion criteria in the 3.0-4.5 hr time window Ancillary care for pts receiving rt-PA at 3.0-4.5 hrs after ischemic stroke should be similar to that included in the 2007 AHA Stroke Guidelines 3/28/2017© 2009, American Heart Association. All rights reserved. Information from the Expansion of the Time Window for Treatment of Acute Ischemic Stroke with IV TPA – Science Advisory