1. 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

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

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

4. 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

5. 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:
Fibrinolytic Therapists Trialists' (FTT) Collaborative Group.  Lancet 1994;343:
Cornu C, et al. Meta-analysis Streptokinase. Stroke Jul;31(7):
Fletcher AP, et al. A pilot study of urokinase therapy in cerebral infarction. Stroke 1976;7:

6. 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.

7. 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 Feb;33(2):493-5.
Clark WM, et al. ATLANTIS. JAMA. 1999; 282: 2019–2026.

8. 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.

10. 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 Mar 1;283(9):
Katzan IL, et al. a Cleveland update. Stroke Mar;34(3):

11. 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:
Albers GW, et al Feb;33(2):493-5.
Wahlgren N, et al. SITS-MOST: an observational study. Lancet 2007;369:
Albers GW, et al. STARS study. JAMA Mar 1;283(9):

12. Outer Limit of Efficacy?

13. 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 Sep 25;359(13):

15. Grotta J, ISC, Feb 2019, with permission

16. Grotta J, ISC, Feb 2019, with permission

17. 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 Int J Stroke Dec;13(9):
Powers WJ, et al. American Heart Association Stroke Council Guidelines Stroke Mar;49(3):e46-e110. doi: /STR Epub 2018 Jan 24. Review. Erratum in: Stroke Mar;49(3):e138.
European Stroke Organisation (ESO. Cerebrovasc Dis. 2008;25(5):

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

19. 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 Jun;13(3):233-9.

20. Perfusion Selection

21. 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:
Thomalla G, et al. WAKE UP. N Engl J Med 2018;379:

22. Tenecteplase

23. Tenectaplase
Grotta J, ISC, Feb 2019, with permission

24. 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.

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

31. Thrombectomy

33. Extended Time Window

35. 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

38. 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

39. 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

40. 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

41. Earlier Delivery
More Patients
Greater Safety