IV tpa: 1996 to Present

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Derrick Thompson
6 years ago
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1 IV tpa: 1996 to Present Where We ve Come From & What We ve Learned 1

2 Many of the things that seem impossible now will become realities of tomorrow. 2

3 Streptococcus Discovered back in the 1930s Activates fibrinolytic system, potential to treat stroke with plasmin recognized 3

4 The Thrombolytic Timeline Tillett & Garner dissolve fibrin with SK in 1933 First use of a thrombolytic to treat stroke in 1958 Urokinase extracted from human urine in 1940s 4

5 No CT scanners around for at least ~15 years! How do you rule out hemorrhage? JAMA,

6 The Thrombolytic Timeline Tillett & Garner dissolve fibrin with SK in 1933 First use of a thrombolytic to treat stroke in 1958 CT scanners Available in Mid-1970s tpa discovered in 1979 Urokinase extracted from human urine in 1940s Plasmin vs Placebo over 3 days in MCA strokes in

7 Quid Pro Quo 7

8 The Thrombolytic Timeline Tillett & Garner dissolve fibrin with SK in 1933 First use of a thrombolytic to treat stroke in 1958 CT scanners Available in Mid-1970s tpa discovered in 1979 Research begins on desmoteplase in 1991 The big NINDS trial is published 1995 Urokinase extracted from human urine in 1940s Plasmin vs Placebo over 3 days in MCA strokes in 1963 Recombinant tpa produced in 1983 Tenecteplase shown to have a higher fibrin specificity than tpa in

9 Breathed new life into the stroke paradigm 9

10 Challenges with IV tpa Only 15-30% of clots recanalize Recanalization partially dependent upon length and location Clots longer than 8mm, <1% likelihood of recanalization. 6.4% ICH rate hour time window Site of Occlusion Early Recanalization after IV tpa ICA terminus 5% MCA M1 30% MCA M2 42% Basilar 11% Overall 42% Riedel et al, Stroke 2011; 42:

11 I always like to look on the optimistic side of life, but I am realistic enough to know that life is a complex matter 11

12 Alternative lytic agents Improving the fibrin specificity and lowering the hemorrhage rates 12

13 Alternative Pharmacologic Lysis Agents Plasminogen activators Glycoprotein IIb/IIIa inhibitors Direct thrombin inhibitors 13

Alternative Plasminogen activators I have incredible fibrin specificity! DESMOTEPLASE Fibrin-specific platelet activator I have a long halflife!

14 Alternative Plasminogen activators I have incredible fibrin specificity! DESMOTEPLASE Fibrin-specific platelet activator I have a long halflife! DIAS-3 trial (Lancet Neurol 2015: 14: ) Desmoteplase vs. placebo in 3-9 h time window Occluded IC vessel Treated w/in 60 min of imaging No improved outcome at 90 days 14

15 A small treatment effect in patients with small infarct core (< 25 ml) measured on MRI only, post-hoc Similar to post-hoc results seen in EPITHET and DEFUSE-2 15

16 Alternative Plasminogen activators TENECTEPLASE Fibrin-specific platelet activator derived from Chinese hamster ovaries *higher fibrin specificity, longer t1/2 *more resistant to plasmin activator *more rapid and more complete reperfusion *lower ICH rates Comparison of tpa to TNKase (2 doses, phase 2b trial) *<6 hrs after stroke, mostly < 4.5 hrs *Intracranial LVO w/perfusion deficit *TNKase (higher dose) better than tpa at % reperfusion clinical outcome at 24 hrs and 90 days without increase in ICH Parsons M et al. NEJM 2012;366:

17 TEMPO-1 Trial (phase 2) Thrombolysis for Minor Ischemic Stroke With Proven Acute Symptomatic Occlusion Using TNK-tPA Focus on minor stroke NIHSS <6, mrs 0-1, treated out to 12 hours (62% < 4.5hrs) IV tpa vs. 2 different doses of TNKase Higher rate of recanalization in TNKase (52% in highest dose) Recanalization associated with better clinical outcomes Low (4%) rate of ICH Pts were shown to have LVO on CTA, primarily M2s Tempo-2 trial currently recruiting, phase III Coutts, SB et al. Stroke. 2015; 46:

18 Glycoprotein IIB/IIIA inhibitors Eptifibatide Derived from the venom of the southeastern pygmy rattlesnake Short half-life, renal elimination Useful for rapid early reperfusion without triggering the ICH issues seen with abciximab? 18

19 CLEAR Trials Phase II safety trials Standard 0-3 hour IV tpa vs. low dose IV tpa + IV eptifibatide Bolus and 2 hour infusion escalating dose IV tpa 0.3, 0.45, 0.6 mg/kg Primary safety outcome 36 hrs Unique choice for primary efficacy 90 days: mrs 0-2 OR return to baseline mrs Allowed inclusion of pts w/ prior disability What would results be with 0.9 mg/kg tpa combo? 19

20 CLEAR Trials CLEAR-FDR enrolled 27 patients with full dose IV tpa + eptifibatide No significant difference in sich Pooled analysis of all CLEAR trials also no significant difference in sich Progressive increase in OR of favorable clinical outcome with increasing dose of IV tpa without worsening safety concerns 20

21 Direct Thrombin Inhibitors Thrombin causes cell death via the proteaseactivated receptors found in endothelial cells, astrocytes, neurons short half life, may augment tpa ARTSS-1 trial in 2012: IV tpa (full dose) + argatroban DTI bolus x 48 hrs No control group (planned to c/w CLOTBUST controls) <4.5 hrs with proximal LVO on TCD/CTA Took seven years to complete, hard to recruit Baretto AD et al. Stroke 2012;43: sich = 4.6%, (95% CI ) 61% of pts achieved full or partial recanalization by 24 hrs 21

22 ARTSS-2 Phase IIb open label trial (blinded to imaging and clinical outcomes) for safety and efficacy Compared IV tpa (control) vs. combo IV tpa with low dose or high dose argatroban NIHSS > 10, or any NIH + prox LVO on imaging Trial ended early due to endovascular trials Only 90 of 105 patients recruited 22

23 ARTSS-2 No significant difference in sich 79% probability of benefit when looking at combined argatroban dosing groups vs. IV tpa alone IV tpa Percent with mrs 0-1 IV tpa + low dose argatroban IV tpa + high dose argatroban 21% 30% 32% Percent with mrs 0-1 IV tpa IV tpa + argatroban 21% 31% 23

24 Time and conditions change so rapidly that we must keep our aim constantly focused on the future... 24

25 Mechanical Adjuncts to Lytic Agents Overcome the stagnant flow barrier 25

26 Mechanical augmentation CLOTBUSTER Sonothrombolysis Magnetically enhanced diffusion Iron oxide microbeads drawn through stagnant blood towards thrombus via large magnet, draws tpa along with them. 26

27 An intervention for everyone: IV fibrinolytics? Other IV thrombolysis? Mechanical adjuncts? Endovascular retrieval? 27

28 Credits Thank you to the cerebrovascular dreamers and the thought leaders, who keep the our world of stroke ever changing. And thank you to Mr. Walt Disney, for always reminding us to look towards the future. Special thanks to all the people who made and released these awesome resources for free: Presentation template by SlidesCarnival Photographs by Unsplash Paper texture by GraphicBurguer 28

Clinical Study Synopsis for Public Disclosure

abcd Clinical Study Synopsis for Public Disclosure This clinical study synopsis is provided in line with s Policy on Transparency and Publication of Clinical Study Data. The synopsis - which is part of