RAIN 2020: Ischemic Stroke Disclosures NIH U24 NS 107229 (PI) - - PowerPoint PPT Presentation

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RAIN 2020: Ischemic Stroke

Wade S. Smith, MD, PhD

Chief, UCSF Neurovascular Division Professor, UCSF Department of Neurology

Disclosures

• NIH
• U24 NS 107229 (PI) NorCal RCC
• Founder:
• MindRhythm, Inc.

Wade S. Smith, MD, PhD

Chief, UCSF Neurovascular Division Professor, UCSF Department of Neurology 251 pts: Mild deficit LVO: ICA, M1, M2 < 24 hours,NIHSS < 6 Functional Independence: 77% v 89%, p=0.02 favoring BMM ICH rates: 18% vs 5%, favoring BMM Meta analysis: no change in functional independence

JAMA Neurol 2019 Sep 23

1028 pts with minor TIA (brief speech loss, minor motor symptoms, age >=40 y) 13% were DWI + so the ultimate diagnosis was stroke If stroke, RR of second stroke = 6.4 at 1 year DWI negative: 99.8% negative predictive value of recurrent stroke

JAMA Neurol 2019 Sep 23

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225 pts with stroke, between 4.5 and 9 hours with penumbra Good outcome alteplase v. placebo: 35% vs. 30%, p=0.04 Symptomatic ICH 6% vs 1%

Observation of 105 pts with stroke, and large core infarcts, < 6 hours mRS 0-2: 31% of IAT, 15% of MM (OR 3.3, p=0.03) 40% per hour reduction in good outcome Cores > 100 cc: none had a good outcome 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

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Tenecteplase

• 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 Thank You

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Neurocritical Care Potpourri

• J. Claude Hemphill III, MD, MAS

Kenneth Rainin Chair in Neurocritical Care Professor of Neurology and Neurological Surgery University of California, San Francisco Chief, Neurology Service & Director, Neurocritical Care Zuckerberg San Francisco General Hospital Past-President, Neurocritical Care Society

Disclosures Consultant: Biogen

Neurocritical Care Potpourri 2020

• Intracerebral hemorrhage

– Factor Xa inhibitor reversal – Re-evaluation of MISTIE III

• Status epilepticus

– ESETT

• Head trauma

– Tranexamic acid

• Coma and prognostication

– Cognitive motor dissociation and circuits – Curing Coma Campaign

• Overarching theme – moving from ”one size fits all” to

precision medicine

Saraf Postgrad Med J 2014

FFP PCC idarucizumab

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
• 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 – Good or excellent hemostasis at 12 hours after end of infusion » For intracranial bleeding, this meant no more than 35% increase in hematoma volume on follow-up CT or MRI

Connolly NEJM 2019

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Connolly NEJM 2019

• 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?

• Current status – heterogeneity

and controversy over whether to stock and use andexanet alfa (Peled NCC 2019)

• No at ZSFG
• Yes at UCSF (used?)

The Lancet

• Randomized clinical trial, n=499
• ICH with hematoma volume > 30 ml, stable size on 6

hour scan, GCS < 14

• Catheter placed into hematoma, t-PA injected
• Favorable outcome at 1 year – mRS < 3 (ambulatory)

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

• 5. Stop t-PA when hematoma volume

< 15 ml (goal hematoma volume)

Hanley Lancet 2019

• No difference in primary outcome – medical 45%, surgical 41% (P=0.33)
• Decreased mortality in surgical group
• Conclusion – save lives, does not improve patients. Did not work. Nothing to

see here. Please move on.

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• Better functional outcome in surgical group IF hematoma volume < 15 ml achieved

(10.5% effect size, P=0.03)

• Less intracranial pressure elevation in surgical group
• Greater surgeon and site experience associated with avoiding poor hematoma
• evacuation. Major emphasis on training of surgeons in procedure.
• This should not be surprising. What is surprising is that this expectation has not been

part of surgical ICH trials previously.

• Identifying targets to improve procedural success
• This is what happened with embolectomy for ischemic stroke. Better devices,

systems of care, practitioners. (And patient selection) Awad Neurosurgery 2019

Recent ZSFG Patient – right hemiplegia

• Initial data from

multiple small

• bservational studies

suggest integrity of corticospinal tract as strong marker of motor recovery

• Potential patient

selection criteria for surgical hematoma evacuation

• Hemiparesis

with intact CS tract – due to mass effect

• Hemiparesis

with damaged CS tract – due to direct transection

corticospinal tract completely intact

Ritsma Case Reports in Neurological Medicine 2014

Three ongoing minimally invasive ICH surgery clinical trials with various devices and goal of improved patient selection

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 – Levetiracetam 60 mg/kg

• Phase III NIH-sponsored randomized clinical trial
• Primary outcome – clinical seizure cessation and improved

consciousness at 60 minutes without other anticonvulsants

• N=384, ~40% children
• Results – no difference (fos 45%, VPA 46%, LEV 47%)
• More hypotension in children with fosphenytoin

Kapur NEJM 2019

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Lancet 2019

• Large “pragmatic” mega-trial. N=12,737.

175 hospitals in 29 countries

• Tranexamic acid (anti-fibrinolytic agent) – 1 gm

bolus then 1 gm over 8 hours

• Treatment within 3 hours of TBI injury onset
• Author conclusions – it works, give it to everybody
• TBI/NCC community – this does not seem to do much, why bother
• No data on hematoma/contusion expansion (presumed mechanism by which it would help)
• This may be important in resource-challenged areas of the world where access to

neurosurgery and (neuro)critical care is limited to non-existent.

• Does bring up the concept that trial results may have differing relevance depending on

practice environment Difference in death but not disability in mild-moderate TBI patients treated within 3 hours but not severe TBI patients

• 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

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Claassen NEJM 2019

CMD No CMD

Default mode network functional connectivity Stroke 2019 Diffusion tensor tractography of ARAS

Assessing specific mechanisms

• f coma and recovery in

individual patients not just clinical description of current state

Curing Coma Campaign

• Neurocritical Care Society research initiative to address the grand

challenge of improving the care for patients with acute coma/disorders of consciousness (launched October 2019)

– Disorders of consciousness are central to what all of us do in some fashion in neurocritical care. Researchers and clinicians. – Decreased consciousness in acute neurological conditions is the prime driver of decisions regarding ongoing care (prognostication) – The journal Science identified “what is the biological basis of consciousness?” as the 2nd 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

Curing Coma Campaign – 2020 initiatives

• NIH Symposium – September 9-10, 2020
• Common Data Elements Project – NIH/NINDS
• World Coma Day

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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.

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2/13/2020 1

Secondary Prevention 2020: Some Clarity in an Ever-Changing World

• S. Andrew Josephson MD

Carmen Castro Franceschi and Gladyne K. Mitchell Neurohospitalist Distinguished Professor Chair, Department of Neurology Founder, Neurohospitalist Program University of California, San Francisco

The speaker has no disclosures

Antiplatelet Options

• 1. ASA

– 50mg to 1.5g equal efficacy long-term

• 2. Aggrenox

– 25mg ASA/200mg ER Dipyridamole

• 3. Clopidogrel (Plavix)

– Multiple secondary prevention studies (CHARISMA, SPS3) show no long-term benefit in combination with ASA

Law of Transitivity: Secondary Prevention

• Aggrenox is better than ASA
• Aggrenox and Clopidogrel are equal
• Therefore, Clopidogrel is likely better

than ASA Clopidogrel + ASA: POINT Trial

• Selected those with only minor or no deficits

(NIHSS 3 or less or ABCD2 of 4 or more) for short-term treatment

• Nearly 5000 TIA or minor stroke patients assigned

to 90d of daily ASA + Placebo versus daily ASA + Clopidogrel following 600mg load

• Modestly improved efficacy (1.5%)
• Minimally (0.5%) more hemorrhage

Johnston SC et al: N Engl J Med 379:215, 2018

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Dual Antiplatelets in TIA or Minor Stroke: How Long?

• POINT was 90 days, CHANCE was 21 days
• Most recurrent events in POINT were in the first

week and over 80% were in the first 30 days

• Hemorrhagic risk was low and consistent

throughout the trial (0.9% vs 0.2%)

– Most were gastrointestinal (only 0.1% ICH)

• Likely it is not necessary to expose patients to a

full 90 days of increased (small) hemorrhagic risk when most of the efficacy is in the first month

Johnston SC et al: N Engl J Med 379:215, 2018 Tillman H et al: JAMA Neurology 76:774, 2019

When We Use Dual Antiplatelets

• NOT all the time!
• After minor stroke or TIA

– 600mg Clopidogrel load, then duals for only 21 days

• After a fresh carotid or coronary stent
• With severe intracranial atherosclerosis (>70%)

and stroke/TIA in that territory for only 90 days

• Still completely unclear if there is any role in

stroke for platelet inhibition testing

Secondary Prevention: Cholesterol

• SPARCL

– In patients with LDL >100 post stroke or TIA, those randomized to high-dose atorvastatin versus placebo had a significant reduction in stroke and major cardiovascular events over 5 years

• Led to most neurologists prescribing high-dose

statin to all stroke patients

• Risk of hemorrhage with ultra-low LDL likely
• verblown based on multiple studies
• Many PMDs stopped these medications: ?goal

SPARCL Investigators: N Engl J Med 355:549, 2006

Secondary Prevention: Cholesterol

• Treat Stroke to Target Trial

– Enrolled nearly 3000 patients with stroke or TIA and some evidence of atherosclerosis (CAD, aortic arch, intra- or extra-cranial vessel) – Randomized to target LDL <70 mg/dl vs 90-110 mg/dl with statin and/or ezetimibe; 3.5 year f/u

• Major cardiovascular events including stroke

significantly lower in intensive group

• Should now target 70 mg/dl post-stroke even if

another medication needs to be added

Amarenco P et al: N Engl J Med 382:9, 2020

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Shrinking Indications for Anticoagulation in Stroke

• 1. Atrial Fibrillation
• 2. Some other cardioembolic sources

– Thrombus seen in heart – ?EF<35 – ?PFO with associated Atrial Septal Aneurysm

• 3. Vertebral or Carotid dissection
• 4. Rare hypercoagulable states: APLS

Venous Sinus Thrombosis: A Different Beast

• Anticoagulate CVST if it is spontaneous for

at least 3-6 months even if resultant ICH

– Only ASA if post-surgical local phenomenon or trauma related – Consider longer duration if underlying risk is present that one can’t control

• New data that DOACs as good as warfarin

– Will become standard of care

Ferro J et al: JAMA Neurol [Epub Ahead of Print], 2019

SSRIs for Motor Recovery

• FLAME trial (2011) demonstrated in 118

patients that fluoxetine for 90 days vs. placebo led to enhanced motor recovery

– Widely adopted including by all of us

• FOCUS trial of nearly 3000 patients

showed no difference in motor recovery

– Improved depression – More bone fractures

FOCUS Trial Collaboration: Lancet 393:265, 2019

Where to do Outpatient Rehabilitation Post-Stroke?

• Patients who don’t qualify for inpatient

rehab post-stroke often (>50%) don’t complete outpatient rehab as prescribed

– Difficulties with access, transportation, cost

• 6 week course of intensive, dose-matched

rehab with telehealth shown to be just as effective as in-person rehab

– A major advance (if it can be paid for)

Cramer SC, et al.: JAMA Neurology 76:1079, 2019

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UPDATE ON BRAIN ANEURYSMS & VASCULAR MALFORMATIONS

Nerissa U. Ko, MD, MAS Recent Advances in Neurology February 13, 2020

THINGS THAT BLEED AND WHAT TO DO ABOUT THEM

Nothing to disclose

Current controversies

• Ruptured aneurysms: Subarachnoid hemorrhage
• Misdiagnosis is still problematic
• Predicting outcomes remains challenging
• Biomarkers for outcomes: magnesium?
• New MRI marker for risk of rupture?
• Unruptured aneurysms, AVMs, cavernomas
• New scoring systems for risk stratification
• Headache outcomes after treatment
• Does aspirin increase risk of bleeding from cerebral

cavernomas?

AHA Unruptured Aneurysm Guidelines

• Intracranial aneurysms are the leading cause of nontraumatic

subarachnoid hemorrhage (SAH). An estimated 3% of the general population has an unruptured intracranial aneurysm (UIA).

• Patients with UIAs should be counseled regarding smoking

cessation and should monitor blood pressure and undergo treatment for hypertension. (Class I, Level B)

• Computed tomographic angiography (CTA) and magnetic

resonance angiography (MRA) are useful for the detection and treatment of UIA. (Class I, Level B)

• Patients with two or more family members with intracranial

aneurysms or SAH should be offered screening by CTA or

• MRA. (Class I, Level B)
• Patients with aneurysms with documented enlargement during

follow-up should be offered treatment in the absence of prohibitive comorbidities. (Class I, Level B)

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AHA SAH Guidelines

• Surgical clipping and endovascular coiling of UIA should

be performed at high-volume centers (>20 procedures annually). (Class I, Level B)

• Endovascular coiling is associated with a reduction in

procedural morbidity and mortality over surgical clipping but carries an overall higher risk for intracranial aneurysm

• recurrence. (Class IIb, Level B)
• Multiple factors should be considered in the optimal

treatment of UIA, including size and location of the aneurysm, history of prior SAH, presence of multiple aneurysms, underlying conditions, patient age, and family history of aneurysms. (Class I, Level C)

• Stroke. 2012;43:1711–1737

Mi

• Misdiagnosis occurred in 25% (104/401) of cases
• Associated with delayed time to presentation and

diagnosis

• Lower clinical severity and less blood on imaging
• Poor outcome: OR 3.89, DCI: OR 2.47, treatment

complications: OR 2.27

• Stroke. 2019;50:3072-3076

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Unruptured Aneurysm Treatment Treatment scoring of UIAs

• Stroke. 2019: 50;2344-2350
• Stroke. 2019: 50;2344-2350

Treatment scoring of UIAs

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Epidemiology of BAVM

• Rare disease affecting both genders
• Prevalence: 10 - 18 / 100,000
• Incidence: 1.3 / 100,000 P-Y (Gabriel, Stroke 2010)
• Mean age of detection between 20-40 yrs
• Associated with neurological morbidity/mortality
• 30-50% morbidity
• 10-30% mortality, 1-3% mortality rate per year after ICH
• Primary presenting symptom is ICH (50%)
• Seizure (~25%), headache (~10%), neurological deficit
• Incidental 1/2000 (0.05%) (Morris, BMJ 2009)

ARUBA: A Randomized Trial of Unruptured Brain AVMs

Invasive therapy (n=114) Medical management (n=109)

HR=0.27 (95% CI: 0.14-0.54)

Mohr JP et al., Lancet 2014 Gross and Du, Neurosurg 2013

Death or Stoke (%) Months

ICH: 2.2% (0.9-4.5%)

Intent-to-treat analysis

Arteriovenous Malformations

• Stroke. 2019: 50;1703-1710

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Cerebral cavernomas

• Incidence: 0.56/100,000

per year in adults

• Affects both men and

women

• Sporadic (80%) solitary

lesion with associated developmental venous anomaly (DVA)

• Inherited or familial

(20%) multiple and bilateral lesions

• Brain, spinal cord, skin,

retina

• Mean age: 20-50 years
• Clinical sxs: Seizures

(50%), ICH (25%), focal deficits (25%)

• 20-50% asymptomatic

and incidental

• High risk for epilepsy

after 1st seizure

• Associated with prior

radiation exposure

Risk factors for CCM hemorrhage

• Overall risk of ICH 0.7
• 6%
• Any ICH 5%
• First ICH 0.4 - 2.4%
• Recurrent ICH 3.8 -

29.5%

• 5 year overall rate

15.8%

• Female gender, lesion

size, location, multiplicity

• Incidental CCM 0.08%
• ICH at presentation

associated with HR 5.6

• Brainstem location HR

4.4 (2-60% recurrence)

• Familial CCM 4.3-

6.5% especially with CCM3 mutation

CCM Management

• The primary treatment is surgery
• In nonrandomized studies, surgery associated with worse

functional outcome compared to conservative management.

• Risk of complications is strongly dependent on location
• Radiation therapy has not been effective
• Symptomatic hemorrhage or refractory seizures are

considerations for surgical resection.

• Medical management for symptoms (pain, HA, seizures)
• Other potential treatments: statins, beta blockers,

Vitamin D

Cavernous malformations

Lancet Neurology 2019;18:935-41

Antithrombotic therapy was associated with a lower risk of intracranial hemorrhage and focal neurological deficits (HR 0.12, IRR 0.25)

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Summary

• Misdiagnosis of SAH occurs in a quarter of

cases and is associated with worse

• utcomes
• Predicting outcomes after rupture remains

problematic

• Role for biomarkers, imaging
• Selecting patients at highest risk for rupture
• Role for new predictive tools, imaging
• Antithrombotic treatment may be safe for

some patients with vascular malformations

Thank you!

https://www.ucsfhealth.org/clinics/neurovascular-disease-and-stroke-center UCSF Center of Excellence for Cerebral Cavernoma (CCM) UCSF Center of Excellence for Hereditary Hemorrhagic Telangiectasia (HHT) UCSF Center for Cerebrovascular Research

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