Expanding the Therapeutic Window for Acute Ischemic Stroke

Expanding the Therapeutic Window for Acute Ischemic Stroke: New Agents, New Approaches Andria L. Ford, MD Associate Professor Department of Neurology Division of Cerebrovascular Diseases

Disclosures • Research Support: • • • NIH NHLBI R 01 HL 129241 Washington University ICTS UL 1 TR 000448 Clay. Co Foundation • Consulting Relationships: none • Stock Equity >$10, 000: none • Speakers' Bureau(s): none

Expanding the Therapeutic Window for Acute Ischemic Stroke: New Agents, New Approaches § Over a decade, especially in the past 3 years, the individualization of acute stroke care has become complex § Concrete changes to acute care happening now § MRI-selection for patients with Wake-up Stroke Symptoms § Tenecteplase (TNK) challenging two decades of IV Alteplase § Some things haven’t changed: Time is Brain § How do we integrate the complexity and deliver best outcomes to the patients? § Collaboration across departments, institutions, and even hospital networks has become more important than ever

Acute ischemic stroke decision-making 1988 Stroke Symptoms Head CT Acute Ischemic Stroke Admit

Acute ischemic stroke decision-making 1998 Stroke Symptoms < 3 hrs from time Last Known Normal (LKN) Head CT Acute Ischemic Stroke Go to IV t. PA protocol - Eligible for IV t. PA? Yes Give IV t. PA No Admit

Acute ischemic stroke decision-making 2008 Stroke Symptoms < 4. 5 hrs from time Last Known Normal (LKN) Head CT Acute Ischemic Stroke Go to IV t. PA protocol - Eligible for IV t. PA? Yes Give IV t. PA No Admit

Stroke Symptoms < 24 hrs from time Last Known Normal (LKN) and Head CT without ICH Acute ischemic stroke decision-making Go to Wake-up / Unwitnessed Onset h. MRI Stroke Protocol Acute Ischemic Stroke Mimic vs. AIS Stroke Mimic Yes Wake-up / Unwitnessed stroke > 4. 5 hr from LKN, can get h. MRI and be treated with IV t. PA < 4. 5 hr from sx discovery? Go to IV t. PA protocol: LKN < 4. 5 hr and eligible for IV t. PA? received t. PA) No Triage per Prelim. Dx Yes No No (and has not No Go to Hyper. Acute MRI Protocol; DWI c/w AIS? Give IV t. PA Bridge to Endovascular Yes Perform RAPID / CTA. Go to Endovascular Protocol: Is LVO present and eligible for thrombectomy? Yes Thrombectomy 2018

Evolution of Acute Ischemic Stroke (AIS) Care over two decades 2015 < 4. 5 hr DEFUSE Alteplase 3 -6 hrs MRI-selected ASK Streptokinase 0 -4 hrs NINDS IV t. PA Alteplase 0 -3 hrs DIAS / DEDAS Desmoteplase 39 hrs MRI-selected DIAS-2 Desmoteplase 39 hrs MRI-selected 1996 2005 -2006 2009 1995 ECASS I Alteplase 0 -6 hr 1998 2008 ATLANTIS Alteplase 3 -5 hrs ECASS-3 Alteplase 3 -4. 5 hr ECASS II Alteplase 3 -6 hrs EPITHET Alteplase 3 -6 hr MRI-selected < 24 hr MR-WITNESS Alteplase 4. 5 -24 hr MRI-selected IMS III, MR RESCUE, SYNTHESIS Endovascular Early Devices < 5 -8 hr NOR-TEST Tenecteplase 0 -4. 5 hr 2013 2012 Tenecteplase vs. Alteplase 04. 5 hr CTPselected + LVO DAWN, DEFUSE 3 Endovascular 4. 5 -24 hr CTA-CTP selected 2017 2015 MR CLEAN, ESCAPE, EXTEND-IA, SWIFT-PRIME, REVASCAT Endovascular New Devices < 6 -12 hr WAKE-UP Alteplase > 4. 5 hr MRI-selected 2018 EXTEND-IA TNK Tenectoplase 0 -6 hr CTP-selected + LVO PRISMS Alteplase 0 -3 hr Non-Disabling

Over a decade, especially in the past 3 years, acute stroke decision-making has become complex and increasingly individualized § First thrombolytic agent and time window defined across a population Alteplase, 4. 5 hours § Then endovascular device and time window defined across a population Stent-retrievers/suction catheters, 6 hours § Finally, imaging selection criteria defined who would benefit for extended time windows out to 24 hours from stroke onset CTA-CTP for endovascular therapy MRI FLAIR-DWI mismatch for thrombolysis

Expanding the Therapeutic Window for Acute Ischemic Stroke: Wake-up or Unwitnessed Stroke Onset § ~10% of stroke patients arrive within 4. 5 hours of symptom onset and can be treated with IV t. PA § Up to 1/3 of stroke patients wake-up with stroke symptoms or have unwitnessed onset § Historically, they are disqualified from acute treatments Unclear Onset Strokes ~ 30% of all Strokes Unknown Time of Onset While Awake Symptoms On Awakening Known Time of Onset J Stroke Cerebrovasc. Dis. 2011.

27 yo caucasian man was at the zoo; experienced sudden left hemiparesis, NIHSS=10 MRI performed at 2: 10 after onset FLAIR DWI ADC

27 yo caucasian man was at the zoo; experienced sudden left hemiparesis, NIHSS=10 MRI performed at 6: 00 after onset FLAIR DWI ADC

Positive DWI, Negative FLAIR may identify Strokes < 4. 5 hours old DWI FLAIR 90 min 125 min 130 min 282 min Thomalla et al. Ann Neurol. 2009.

WAKE-UP Stroke Trial Thomalla et al. NEJM 2018.

WAKE-UP Stroke Trial § Acute stroke with “last known normal” time > 4. 5 hrs (no upper time limit) § Met standard eligibility criteria for the use of alteplase § Had DWI-FLAIR mismatch (abnormal signal on DWI and no marked signal change on FLAIR in the region of the acute stroke). § Excluded: § Large strokes > 1/3 of MCA or NIHSS > 25 § Planned thrombectomy § The primary endpoint was favorable outcome, defined as m. RS = 0 -1 at 90 days § Randomized to Alteplase vs. Placebo within 4. 5 hrs of awakening or “symptom discovery” Thomalla et al. NEJM 2018.

WAKE-UP Stroke Trial Primary Outcome Alteplase: 53. 3% m. RS 0 -1 Placebo: 41. 8% m. RS 0 -1 P=0. 02 NNT = 8 Shift in distribution of m. RS scores of 90 day functional disability P = 0. 003 Thomalla et al. NEJM 2018.

Go to Wake-up / Unwitnessed Onset h. MRI Stroke Protocol Stroke Symptoms < 24 hrs from time Last Known Normal (LKN) and Head CT without ICH Acute Ischemic Stroke Mimic vs. AIS Stroke Mimic Yes Wake-up / Unwitnessed stroke > 4. 5 hr from LKN, can get h. MRI and be treated with IV t. PA < 4. 5 hr from sx discovery? Go to IV t. PA protocol: LKN < 4. 5 hr and eligible for IV t. PA? received t. PA) No Triage per Prelim. Dx Yes No No (and has not No Go to Hyper. Acute MRI Protocol; DWI c/w AIS? Give IV t. PA Bridge to Endovascular Yes Perform RAPID / CTA. Go to Endovascular Protocol: Is LVO present and eligible for thrombectomy? Education - Neurology MD - EM MD/RN - Radiology MD - MRI techs Yes Thrombectomy

EXTEND-IA TNK Trial Campbell et al. NEJM 2018.

EXTEND-IA TNK Trial Rationale § Both alteplase and tenecteplase are fibrinolytics § Tenecteplase (TNK) is a genetically modified form of alteplase with increased fibrin specificity and increased resistance to plasminogen activator inhibitor (PAI-1) thereby leading to a longer half-life. § TNK is given as a single bolus rather than a one hour infusion. § ~$3000 cheaper than alteplase, both made by Genentech § An agent with enhanced fibrinolytic activity, to reduce the need for thrombectomy, would be ideal. § TNK has replaced alteplase as standard fibrinolytic agent for acute myocardial infarction. alteplase tenecteplase Campbell et al. NEJM 2018.

EXTEND-IA TNK Methods § Hypothesis: alteplase - Tenecteplase is non-inferior to alteplase in achieving reperfusion at initial angiogram in patients planning to undergo endovascular therapy - Superiority testing if non-inferiority was met § Inclusion criteria: - Eligible for thrombolytics <4. 5 hours tenecteplase - Patients with LVO (ICA, M 1, M 2, or basilar artery) and could undergo thrombectomy in < 6 hours § Randomized TNK 0. 25 mg/kg or alteplase 0. 9 mg/kg § Primary outcome: Initial angiogram modified TICI reperfusion score Campbell et al. NEJM 2018.

EXTEND-IA TNK Results Primary Endpoint P = 0. 002 Non-Inferiority P = 0. 02 Superiority Secondary Endpoint P = 0. 04 Campbell et al. NEJM 2018.

EXTEND-IA TNK Conclusions § Superior reperfusion at initial angiogram § NNT 9 to avoid thrombectomy altogether § Faster infusion / Less expensive § However, giving TNK instead of alteplase to only thrombectomy candidates affects alteplase delivery to non-thrombectomy candidates as CTA must be performed prior to giving the thrombolytic to decide who will go on to thrombectomy and benefit from TNK § Current best application may be for OSH transferring patients in for thrombectomy § Two trials (TASTE and ATTEST-2) are enrolling patients for comparison of tenecteplase vs. alteplase in non-thrombectomy patients Campbell et al. NEJM 2018.

Expanding the Therapeutic Window for Acute Ischemic Stroke: Is Time Still Brain? Time to Alteplase and Favorable Clinical Outcome in 3000 Patients Combined data from ECASS I-III, NINDS, ATLANTIS; Lees et al, Lancet 375: 1695 -703, 2010. Saver et al, JAMA 2016.

Expanding the Therapeutic Window for Acute Ischemic Stroke: Is Time still Brain? Each minute destroys: • 1. 9 million neurons • 14 billion synapses • 7. 5 miles of myelinated fibers Saver. Stroke. 2006. 37(1): 263 -6. Yes, Time is Brain! However, Recent trials suggest the equation is more complex, non -linear, with greater inter-individual variability, now aided by Imaging selection. Metrics for Acute Stroke Treatment: • Onset-to-door time • Door-to-needle/puncture time • Onset-to-needle/puncture time

Expanding the Therapeutic Window for Acute Ischemic Stroke: Institutional Challenges Lean Manufacturing 80 70 Number of Patients Treated 60 50 40 Door-to-Needle Time 30 20 10 4 20 1 2 20 1 0 20 1 8 20 0 6 20 0 4 0 0 Consistent quality improvement methods to streamline care Treat-in-CT 90 20 0 § Protocol development with input across disciplines Bring-to-CT POC INR 100 8 § Frequent, repeated education of physicians and staff Resident-Based Protocol 19 9 § Work across departments Number of Patients Door-to-Needle Time (min) § Ford et al, Stroke. 2009; Ford et al, Stroke 2012. Curfman et al, Stroke 2014; Goyal et al. Stroke 2016.

Expanding the Therapeutic Window for Acute Ischemic Stroke: Network Challenges, Meeting Capacity • Distributive Stroke Network (DSN) with Missouri Baptist Hospital • Led by Jin-Moo Lee and Sheyda Namazie. Kummer at BJC-CCE • Hypothesis: For incoming telestroke calls requesting transfer from OSH, triaging low severity acute stroke patients to a primary stroke center will be safe, thereby providing additional volume to treat severe strokes at a Comprehensive Stroke Center Holder et al. ISC 2019. Submitted.

Expanding the Therapeutic Window for Acute Ischemic Stroke: Network Challenges § American Heart Association and The Joint Commission have helped push evidence to the forefront of practice § Setting up requirements for various levels of treating centers to meet current evidencebased standards to become certified § § Acute Stroke Ready Hospital (ASRH) Primary Stroke Center (PSC) Thrombectomy-Capable Stroke Center (TSC) Comprehensive Stroke Center (CSC) § Defined by acute stroke team availability, 24/7 imaging, thrombectomy capability, neurosurgical consultation Holder et al. ISC 2019. Submitted.

Expanding the Therapeutic Window for Acute Ischemic Stroke: New Agents, New Approaches § With the individualization of acute stroke care with a longer time window for treatment, we offer a greater proportion of patients discharge to home or inpatient rehabilitation instead of nursing home § However, to maintain optimal clinical outcomes achieved in clinical trials, substantial collaboration is required on both an institutional and system level. § We must think beyond departments, beyond institutions, and even beyond hospital networks.

Expanding the Therapeutic Window for Acute Ischemic Stroke: There is always room for improvement Kunz et al. Lancet Neurol 2016.