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IV tPA: 1996 to Present

Where We’ve Come From & What We’ve Learned

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Many of the things that seem impossible now will become

realities of tomorrow….

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Streptococcus Discovered back in the 1930s

Activates fibrinolytic system, potential to treat stroke with plasmin recognized

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The Thrombolytic Timeline

Urokinase extracted from human urine

in 1940s

Tillett & Garner

dissolve fibrin with SK in

1933

First use of a thrombolytic to treat stroke in

1958

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JAMA, 1958

No CT scanners around for at

least ~15 years! How do you rule out

hemorrhage?

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The Thrombolytic Timeline

tPA discovered in 1979

Plasmin vs Placebo over 3 days in MCA

strokes in 1963

CT scanners Available in Mid-1970s

Urokinase extracted from human urine

in 1940s

Tillett & Garner

dissolve fibrin with SK in

1933

First use of a thrombolytic to treat stroke in

1958

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Quid Pro Quo

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The Thrombolytic Timeline

tPA discovered in 1979

Tenecteplase shown to have a higher fibrin specificity than

tPA in 1994

The big NINDS trial is published

1995

Research begins on

desmoteplase in 1991

Recombinant tPA produced

in 1983

Plasmin vs Placebo over 3 days in MCA

strokes in 1963

CT scanners Available in Mid-1970s

Urokinase extracted from human urine

in 1940s

Tillett & Garner

dissolve fibrin with SK in

1933

First use of a thrombolytic to treat stroke in

1958

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Breathed new life into the stroke paradigm…

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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

✣0-3 → 0-4.5 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; 42:1775.7

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I always like to look on the optimistic side of life, but I am

realistic enough to know that life is a complex matter…

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

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Alternative Pharmacologic Lysis Agents

✣Plasminogen activators ✣Glycoprotein IIb/IIIa inhibitors ✣Direct thrombin inhibitors

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Alternative Plasminogen activators

✣DESMOTEPLASE ⨳Fibrin-specific platelet activator

✣DIAS-3 trial (Lancet Neurol 2015: 14: 575–84) ⨳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

I have incredible fibrin

specificity!

I have a long half-

life!

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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

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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;366:1099-107.

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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: 769-774

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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?

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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 sICH @ 36 hrs ✣Unique choice for primary efficacy outcome @ 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?

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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

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Direct Thrombin Inhibitors

✣Thrombin causes cell death via the protease-activated 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

⨳sICH = 4.6%, (95% CI 0.9-12.9) ⨳61% of pts achieved full or partial recanalization by 24 hrs

Baretto AD et al. Stroke 2012;43:3 770-775

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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

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ARTSS-2

✣No significant difference in sICH ✣79% probability of benefit when looking at combined argatroban dosing groups vs. IV tPA alone

Percent with mRS 0-1

IV tPA

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%

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

future...

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Mechanical Adjuncts to Lytic Agents

Overcome the stagnant flow barrier

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Mechanical augmentation

✣CLOTBUSTER ✣Sonothrombolysis

✣Magnetically enhanced diffusion ⨳Iron oxide microbeads drawn through stagnant blood towards thrombus via large magnet, draws tPA along with them.

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

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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