Tissue Plasminogen Activator 20 Years Later Randall C Edgell, MD, FSVIN Professor of Neurology Vascular and Interventional Neurology Saint Louis University Tissue Plasminogen Activator 20 Years Later

Hypothesis: A mechanical device can allow human flight Leonardo da Vinci – 1452 - 1519 1840 to 1890’s Set Backs Hypothesis: A mechanical device can allow human flight Wright Brothers: 1903 High Performance /Efficiency Evolution of Technique/Technology

Hypothesis: Reperfusion of ischemic neuronal tissue with thrombolytic will limit permanent neuronal loss and improve neurological recovery

Modified Rankin Score (mRS) 0 No symptoms at all 1 No significant disability despite symptoms; able to carry out all usual duties and activities 2 Slight disability; unable to carry out all previous activities, but able to look after own affairs Modified Rankin Score (mRS) 3 Moderate disability; requiring some help, but able to walk without assistance 4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance 5 Severe disability; bedridden, incontinent and requiring constant nursing care and attention 6 Dead

Early Work Considered Early Cardiology Template SK 1965 Urokinase 1976 Cardiology Template Success in treatment of acute myocardial infarction Streptokinase followed by tissue plasminogen activator Streptokinase Trials (1292) Australian Streptokinase Trial (ASK) Multicenter Acute Stroke Trial (MAST)E and I 6 hour time window All 3 terminated for safety Higher Mortality Higher sICH Trend to better outcome w/in 3 hours Meyer JS, et al. Randomized evaluation of intravenous streptokinase. In: Siekert W, Whisnant JP, eds. Cerebral vascular diseases. New York: Grune & Stratton, 1965:200-13. Fibrinolytic Therapists Trialists' (FTT) Collaborative Group.  Lancet 1994;343:311-322 Cornu C, et al. Meta-analysis Streptokinase. Stroke. 2000 Jul;31(7):1555-60. Fletcher AP, et al. A pilot study of urokinase therapy in cerebral infarction. Stroke 1976;7:135-142

European Cooperative Acute Stroke Study (ECASS) Part I 6 hours 620 patients planned 1.1mg tPA/kg Disability at 90 days Trend favoring tPA Higher sICH in tPA Part II 6hours 308 patients 0.9mg/kg mRS < 1 at 90 days No diff in primary outcome Lower death and disability 8.8 vs 3.4 sICH Hacke W et al. ECASS II. Lancet 1998: 352:1245–51. Hacke W, et al, for the ECASS Study Group. JAMA. 1995; 274: 1017–1025.

Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) Part A 6 hours 24hr and 30d NIH Stopped in 1993 by DSMB Concern about safety 5- 6hours Part B 613 0.9mg/kg tPA 5 hours (3-5 hours after NINDS) NIH 0-1 at 90 days No diff in Primary outcome 61 pt w/in 3 hrs sig benefit 1.1 v 7 sICH Albers GW, et al. 2002 Feb;33(2):493-5. Clark WM, et al. ATLANTIS. JAMA. 1999; 282: 2019–2026.

National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Study Part 1 291 pts Decrease in NIH by 4 or more points at 24 hours Trend toward benefit; NS Part 2 333 pts mRS < 2 at 90 days 50% treated w/in 90min 12% absolute increase in mRS < 2(p=0.008) 32% relative increase at 90d 1.7 odds ratio of good outcome 6% sICH v 1.5% NINDS Stroke Study Group. N Engl J Med. 1995; 333: 1581–1587.

The Cleveland Area Experience Initial Prospective cohort 3948 patients 1.8% (71pts) received tPA 11 (15.7%) sICH Assoc with protocol deviation Follow up Retrospective chart review 1923 patients 18.8% of pts arriving w/in 3 hours received tPA 6.4% sICH Lower protocol deviation rates Katzan IL, et al. the Cleveland area experience. JAMA. 2000 Mar 1;283(9):1151-8. Katzan IL, et al. a Cleveland update. Stroke. 2003 Mar;34(3):799-800.

Confirmation Safe Implementation of Thrombolysis in Stroke – Monitoring Study (SITS- MOST) Prospective, single arm 6483 sICH primary outcome 1.7% The Standard Treatment with Alteplase to Reverse (STARS) Study Prospective, single arm 389 Primary outcome sICH 3.3% 35% favorable outcome at 90d Hacke W, et al. ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-774 Albers GW, et al. 2002 Feb;33(2):493-5. Wahlgren N, et al. SITS-MOST: an observational study. Lancet 2007;369:275-282 Albers GW, et al. STARS study. JAMA. 2000 Mar 1;283(9):1145-50.

Outer Limit of Efficacy?

European Cooperative Acute Stroke Study (ECASS) III Thrombolysis btwn 3 and 4.5 hours RTC 821 pts 0.9mg/kg tPA Primary end point mRS < 1 at 90 days 1.34 Odds ratio of good outcome with tPA 2.4% sICH Hacke W, et al. ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008 Sep 25;359(13):1317-29.

Grotta J, ISC, Feb 2019, with permission

Grotta J, ISC, Feb 2019, with permission

Guidelines American Heart Association Canadian Stroke Association European Stroke Organization American College of Emergency Medicine Physicians Boulanger JM, et al. Canadian Stroke Best Practice Recommendations for Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care, 6th Edition, Update 2018. Int J Stroke. 2018 Dec;13(9):949-984. Powers WJ, et al. American Heart Association Stroke Council. 2018 Guidelines Stroke. 2018 Mar;49(3):e46-e110. doi: 10.1161/STR.0000000000000158. Epub 2018 Jan 24. Review. Erratum in: Stroke. 2018 Mar;49(3):e138. European Stroke Organisation (ESO. Cerebrovasc Dis. 2008;25(5):457-507.

Relative Contraindications Powers WJ, et al. American Heart Association Stroke Council. 2018 Guidelines Stroke. 2018 Mar;49(3):e46-e110. doi: 10.1161/STR.0000000000000158. Epub 2018 Jan 24. Review. Erratum in: Stroke. 2018 Mar;49(3):e138.

Medico-Legal 33 cases involving tPA in 2008 50% emergency physicians 20% neurologists 2/3 Failure/Delay in diagnosis of stroke 88% claim failure to treat with IV tPA 9% claim tPA causes injury Bruce NT, et al. Medico-legal aspects. Curr Treat Options Cardiovasc Med. 2011 Jun;13(3):233-9.

Perfusion Selection

Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke RTC 4.5 to 9 hour time window or upon awakening Primary outcome mRS < 1 225 patients 1.44 odds of better outcome if tPA given 6% sICH Ma H, et al. EXTEND 9 Hour. N Engl J Med 2019; 380:1795-1803 Thomalla G, et al. WAKE UP. N Engl J Med 2018;379:611-22.

Tenecteplase

Tenectaplase Grotta J, ISC, Feb 2019, with permission

ELVO Distal M1 Carotid T/L Driver of morbidity and mortality in ischemic stroke Leading cause disability 5th cause of death Caused by proximal arterial embolic occlusion Up to 40% of Ischemic Stroke: 2-300,000/yr Proximal M1 M2 80% of blood flow and emboli in anterior circulation Lead to mass effect, herniation, and death (60-80%) Cervical ICA Goyal M et al N Engl J Med. 2015 Feb 11.

Utility of IV tPA in LVO Limited Bhatia R, et al. Stroke. 2010 Oct;41(10):2254-8

Thrombectomy

Extended Time Window

Bayesian probability of superiority 11/14/2019 Co-primary endpoints Trevo MM Treatment benefit (95% CI) Bayesian probability of superiority Day 90 weighted mRS 5.5 ± 3.8 3.4 ± 3.1 2.1 (1.20, 3.12) >0.9999* Day 90 mRS (0-2) 48.6% 13.1% 35.5% (23.9%, 47.0%) NNT for 90-day functional independence = 2.8 *Similar to p<0.0001

Reasons for Failure Hypothesis is wrong Details of Execution Wrong Reperfusion of ischemic neuronal tissue with thrombolytic will limit permanent neuronal loss and improve neurological recovery Details of Execution Wrong Streptokinase 6 hours time window too long: ECASS I/II; ATLANTIS A/B Bar for Success Wrong 24 hour recovery: NINDS I mRS < 1 at 90 days: ECASS

Reasons for Success Hypothesis is wrong Details of Execution Reperfusion of ischemic neuronal tissue with thrombolytic will limit permanent neuronal loss and improve neurological recovery Details of Execution 3 then 4.5 window Bar for Success mRS < 2 at 90 days

Meta-analysis of Randomized Trials Emberson et al, Lancet 2014Lees et al, Stroke 2016 9 RCTs; 6756 patients Meta-analysis of Randomized Trials NINDS 1995 ECASS III 2008 Multiple RTCs Single RTCs NINDS 1995 Prospective Cohort Studies STARS 2000 SIT-MOST 2007 Retrospective Cohort Studies Retrospective Case Reports Personal Experience/ Anecdote

Earlier Delivery More Patients Greater Safety