RAIN 2020: Ischemic Stroke Disclosures •NIH •U24 NS 107229 (PI) NorCal RCC •Founder: • MindRhythm, Inc. Wade S. Smith, MD, PhD Wade S. Smith, MD, PhD Chief, UCSF Neurovascular Division Chief, UCSF Neurovascular Division Professor, UCSF Department of Neurology Professor, UCSF Department of Neurology 1 2 JAMA Neurol 2019 Sep 23 1028 pts with minor TIA (brief speech loss, minor motor symptoms, age JAMA Neurol 2019 Sep 23 251 pts: >=40 y) Mild deficit LVO: ICA, M1, M2 < 24 hours,NIHSS < 6 13% were DWI + so the ultimate diagnosis was stroke Functional Independence: 77% v 89%, p=0.02 favoring BMM If stroke, RR of second stroke = 6.4 at 1 year ICH rates: 18% vs 5%, favoring BMM DWI negative: 99.8% negative predictive value of recurrent stroke Meta analysis: no change in functional independence 3 4 1
225 pts with stroke, between 4.5 and 9 hours with penumbra Observation of 105 pts with stroke, and large core infarcts, < 6 hours Good outcome alteplase v. placebo: 35% vs. 30%, p=0.04 mRS 0-2: 31% of IAT, 15% of MM (OR 3.3, p=0.03) Symptomatic ICH 6% vs 1% 40% per hour reduction in good outcome Cores > 100 cc: none had a good outcome 5 6 Randomized 50 pts following hemicraniectomy for malignant cerebral edema to moderate hypothermia vs. euthermia • Functional outcome at 12 months no different • 80% SAEs in hypothermia group vs. 43% euthermia • 19% mortality hypternmia, 13 % in euthermia 7 8 2
Tenecteplase Thank You • Single bolus • Non-inferior c/w t-PA by meta analysis (Burgos et al) • TIMELESS Trial: > 4.5 – 9 hours, perfusion selected, tnk + placebo f/b EVT University of California, San Francisco 9 10 3
Neurocritical Care Potpourri 2020 Neurocritical Care Potpourri • Intracerebral hemorrhage – Factor Xa inhibitor reversal J. Claude Hemphill III, MD, MAS – Re-evaluation of MISTIE III • Status epilepticus Kenneth Rainin Chair in Neurocritical Care – ESETT Professor of Neurology and Neurological Surgery • Head trauma University of California, San Francisco – Tranexamic acid Chief, Neurology Service & Director, Neurocritical Care • Coma and prognostication Zuckerberg San Francisco General Hospital – Cognitive motor dissociation and circuits Past-President, Neurocritical Care Society – Curing Coma Campaign • Overarching theme – moving from ”one size fits all” to Disclosures precision medicine Consultant: Biogen 1 2 Andexanet alfa • Modified recombinant inactive form of factor Xa • Binds and sequesters factor Xa inhibitors, thereby rapidly reducing anti–factor • Bolus over 15-30 minutes, then 2 hour infusion idarucizumab • Very expensive (single dose ~$45,000) [FDA approved] • Studied in single-arm clinical trial of 352 patients with major bleeding (64% intracranial [spontaneous or traumatic]) • Outcomes – Change in factor Xa activity after treatment FFP – Good or excellent hemostasis at 12 hours after end of infusion PCC » For intracranial bleeding, this meant no more than 35% increase in hematoma volume on follow-up CT or MRI Connolly NEJM 2019 Saraf Postgrad Med J 2014 3 4 1
• So 80% patients with intracranial hemorrhage did not enlarge their hematomas by more than 34%? • And 20% did? • Does this actually work? Is it better than natural history? The Lancet • Current status – heterogeneity and controversy over whether to stock and use andexanet • Randomized clinical trial, n=499 alfa (Peled NCC 2019) • ICH with hematoma volume > 30 ml, stable size on 6 • No at ZSFG hour scan, GCS < 14 • Yes at UCSF (used?) • Catheter placed into hematoma, t-PA injected • Favorable outcome at 1 year – mRS < 3 (ambulatory) Connolly NEJM 2019 5 6 MISTIE III –Surgical Approach Detailed surgical protocol (10-step protocol, including) 1. Image guided catheter placement 2. Clot aspiration 3. Post-placement CT 4. t-PA 1 mg every 8 hours for up to 9 doses • No difference in primary outcome – medical 45%, surgical 41% (P=0.33) 5. Stop t-PA when hematoma volume • Decreased mortality in surgical group < 15 ml (goal hematoma volume) • Conclusion – save lives, does not improve patients. Did not work. Nothing to see here. Please move on. Hanley Lancet 2019 7 8 2
Recent ZSFG Patient – right hemiplegia Awad Neurosurgery 2019 • Initial data from multiple small observational studies suggest integrity of corticospinal tract as strong marker of motor • Better functional outcome in surgical group IF hematoma volume < 15 ml achieved recovery • Potential patient (10.5% effect size, P=0.03) selection criteria for • Less intracranial pressure elevation in surgical group surgical hematoma • Greater surgeon and site experience associated with avoiding poor hematoma evacuation • Hemiparesis evacuation. Major emphasis on training of surgeons in procedure. with intact CS tract – due to • This should not be surprising. What is surprising is that this expectation has not been mass effect • Hemiparesis part of surgical ICH trials previously. with damaged corticospinal tract • Identifying targets to improve procedural success CS tract – due to completely intact • This is what happened with embolectomy for ischemic stroke. Better devices, direct transection systems of care, practitioners. (And patient selection) 9 10 ESETT – Established Status Epilepticus Trial • What is best anticonvulsant to use for ongoing status epilepticus after adequate doses of benzodiazepines? – Fosphenytoin 20 mg/kg – Valproic acid 40 mg/kg Three ongoing minimally – Levetiracetam 60 mg/kg invasive ICH surgery • Phase III NIH-sponsored randomized clinical trial clinical trials with • Primary outcome – clinical seizure cessation and improved various devices and consciousness at 60 minutes without other anticonvulsants goal of improved patient • N=384, ~40% children selection • Results – no difference (fos 45%, VPA 46%, LEV 47%) • More hypotension in children with fosphenytoin Ritsma Case Reports in Neurological Medicine 2014 Kapur NEJM 2019 11 12 3
Difference in death but not disability in mild-moderate TBI patients treated within 3 hours but not severe Lancet 2019 TBI patients • Large “pragmatic” mega-trial. N=12,737. 175 hospitals in 29 countries • Author conclusions – it works, give it to everybody • TBI/NCC community – this does not seem to do much, why bother • Tranexamic acid (anti-fibrinolytic agent) – 1 gm • No data on hematoma/contusion expansion (presumed mechanism by which it would help) bolus then 1 gm over 8 hours • This may be important in resource-challenged areas of the world where access to neurosurgery and (neuro)critical care is limited to non-existent. • Treatment within 3 hours of TBI injury onset • Does bring up the concept that trial results may have differing relevance depending on practice environment 13 14 • 104 unresponsive patients assessed with EEG, machine learning used to evaluate response to standardized spoken motor commands • Assessed for brain activation by EEG (“cognitive motor dissociation” [CMD]) Claassen NEJM 2019 15 16 4
Stroke 2019 Assessing specific mechanisms of coma and recovery in individual patients not just clinical CMD No CMD description of current state Default mode network functional connectivity Diffusion tensor tractography of ARAS Claassen NEJM 2019 17 18 Curing Coma Campaign – 2020 initiatives Curing Coma Campaign • Neurocritical Care Society research initiative to address the grand challenge of improving the care for patients with acute • NIH Symposium – September 9-10, 2020 coma/disorders of consciousness (launched October 2019) – Disorders of consciousness are central to what all of us do in some • Common Data Elements Project – NIH/NINDS fashion in neurocritical care. Researchers and clinicians. – Decreased consciousness in acute neurological conditions is the prime driver of decisions regarding ongoing care (prognostication) • World Coma Day – The journal Science identified “what is the biological basis of consciousness?” as the 2 nd most important unanswered question • #1 – what is the universe made of? • Two major arms – Deep dive into science of coma assessment and treatment – Building the “Curing Coma Community” for research, education, advocacy, and implementation 19 20 5
Neurocritical Care Potpourri 2020 – Lessons Learned • Annexa-4 – it can be tricky to understand trial results with single arm design (done that way presumably for FDA approval reasons) – Really need clinical trial comparison with natural history or PCC • MISTIE III – it’s not whether a procedure was done. It’s whether it was done right. – Trials ongoing with improved techniques and patient selection • ESETT – sometimes it doesn’t matter what you do as long as you do something. – But in this case, that something is still not very effective. • CRASH 3 – one-size-fits-all megatrials can only get you so far. – But may be relevant to resource-challenged environments. • Coma – the neurological exam tells us what patients look like clinically now. But it does not really tell us why or whether they can recover. – Be humble and figure out the way forward. 21 6
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