Joshua N. Goldstein, MD, PhD - Controversies and...

Joshua N. Goldstein, MD, PhDAssociate Professor, Harvard Medical SchoolDirector, Center for Neurologic EmergenciesDepartment of Emergency MedicineMassachusetts General HospitalHarvard Medical SchoolBoston, MA

Disclosure: I have received research support from Portola, Pfizer, and consulting fees from CSL Behring, Octapharma

I. Prehospital CareII. Initial CareIII.Surgical therapyIV.Blood pressure controlV. Anticoagulation reversalVI.Supportive care

¡ ABCs¡ Cardiac monitoring¡ IV access¡ O2 as needed¡ Fingerstick glucose¡ NPO¡ Alert the receiving

ED§ Head CT if

possible!

CT in ambulance?

¡ Before diagnosis, this is the same as early stroke care.

¡ Airway management-Balance the risk:§ -losing the patient’s airway§ -losing the neurologic exam.

¡ Diagnosis – usually head CT

STICH I STICH II

Conclusion: No clear benefit to early surgical evacuation

¡ CLEAR III: Patients with ICH and IVH with EVD, randomized to intraventricular thrombolytics vs. placebo

Hanley DF et al, Lancet 2017

Conclusion: Lower mortality, but no change in “good outcome”

Fiorella D et al. J NeuroIntervent Surg2015

Labib MA et al. Neurosurgery 2017

¡ MISTIE II – Phase II randomized controlled trial of stereotactic catheter placement, intrahematomal rtPA, and hematoma drainage.§ Good outcome: ▪ 21% in medical group▪ 33% in MIS group

¡ MISTIE III – completed! § Results pending

Hanley DF et al, Lancet 2016

¡ Minimally Invasive Surgery

¡ Cerebellar ICH with neurologic deterioration§ (Class I, Evidence B).

¡ Supratentorial ICH in deteriorating patients might be considered as a life-saving measure§ (Class IIb, Evidence C)

¡ Early hematoma evacuation is not clearly beneficial compared with … when patients deteriorate § (Class IIb, Evidence A)

¡ Patients with intraventricularblood are at risk of obstructive hydrocephalus.

¡ Many recommend external ventricular drain placement.

¡ Unclear whether it is a cause or an effect.

¡ If, however, it is contributing to worse outcome, it is a tempting therapeutic target.

¡ INTERACT 2:§ 2839 patients with ICH within 6 hours randomized

to SBP<140 vs. SBP<180mmHg. Any BP medication was accepted.

¡ ATACH 2:§ 1000 patients with ICH within 4.5 hours of

symptom onset randomized to SBP<140 vs. SBP<180. Use of nicardipine plus labetalol.

Anderson et al NEJM 2013, Qureshi et al NEJM 2015

Majidi et al, Neurocrit Care 2016

Boulouis et al, JNNP 2017

Boulouis et al, JNNP 2017

¡ Question 1. Safety§ Radiologic studies show no pattern of harm§ Clinical trials show either no pattern of harm of

increased renal adverse events (9% vs 4%)¡ Question 2. Hematoma expansion

§ Primary analyses do NOT consistently show that BP reduction reduces risk of expansion

§ However, secondary analyses keep suggesting this.¡ Question 3. Clinical outcome

§ Primary analyses have NOT shown benefit.§ Secondary analyses are weighted in favor of benefit.

¡ In favor of lowering BP:§ INTERACT2 really compared SBP 150 vs. 140§ ATACH2 really compared SBP 140 vs. 120§ Maybe there is a threshold effect, and no one was

“allowed” to be hypertensive enough to see a difference.

¡ Against lowering BP:§ Three large adequately powered trials failed to

detect a difference in outcome.

§ Warfarin (Coumadin)§ Factor II Inhibitor (Dabigatran)§ Factor Xa Inhibitors (Rivaroxaban, Apixaban, Edoxaban)§ Aspirin, plavix?

¡ These patients are missing Factors II, VII, IX, and X.

¡ Give Vitamin K IV 10mg, PLUS either:¡ FFP

§ Has multiple clotting factors in it. Must be thawed and type matched.

¡ 4-Factor PCC§ Concentrate of 4 coagulation factors. No

typing/screening.

Time to INR correction (INR ≤1.3)

Frac

tion

of p

atie

nts

wit

hout

IN

R c

orre

ctio

n

0.0

0.20.1

0.40.3

0.60.5

0.80.7

1.00.9

4F-PCC, N=87

Time since start of infusion, h

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Plasma, N=81

FFP PCC

Steiner et al Lancet Neurol 2016

INCH Trial: Randomized trial of FFP vs. PCC for warfarin-ICH

¡ 54 patients (26 vs. 28)

De Caterina et al 2012

Agent Factor II Factor VII Factor IX Factor X

Profilnine + Minimal + +

FEIBA + + + +

Kcentra + + + +

Novo7 - + - -

FFP + + + +

¡ Idarucizumab§ 2 IV boluses 15 min

apart¡ 10%

thromboembolism¡ 15% 30d mortality

Pollack et al, NEJM 2015

¡ Andexanet– Xa inhibitor antidote?

PRT064445 (r-Antidote)

S S

EGF1,2

S419A

fXa

S S

S419

EGF1,2Gla

Light Chain Heavy Chain

Catalytic Domain

X

¡ Clinical trial completed – FDA approved – available at BWH

¡ 18% of patients had thromboembolic events

¡ 14% mortality¡ $25k-$50k per dose

¡ Andexanet.

Connolly, SJ et al, NEJM 2016

¡ PATCH trial: Randomized 190 ICH patients to platelet tranfusion or not.

¡ Platelet transfusion led to significantly WORSE outcome!

Conclusion: Do not transfuse platelets Baharoglu M. et al Lancet June 2016

¡ It may be that there is no currently effective way to “reverse” antiplatelets.

¡ Some check platelet activity – not easy to do here.§ Consider platelet activation assays or TEG to guide

therapy if necessary.¡ Large observational studies:

§ GWTG analysis of 82,000 ICH patients, examining whether antiplatelet use was associated with outcome▪ Those on single antiplatelet - no difference in outcome ▪ Dual antiplatelet – worse outcome.▪ Perhaps only those on dual antiplatelets “need” reversal.

Khan NI al, Stroke 2017

¡ No randomized trials. No good data on how to treat – only expert opinion.

¡ Consider treatment within 24hours of tpa¡ Check fibrinogen level¡ Consider cryprecipitate 10 units

§ (goal Fg >150)¡ Consider amicar 5g IV bolus¡ Consider tranexamic acid 10mg/kg

¡ Randomized trial of 1696 patients in 19 stroke units.

¡ Patients with ischemic or hemorrhagic stroke randomized to standard care or FeSS (Fever, Sugar, Swallowing):§ T>=37.5C (99.5) treated with acetaminophen§ Glucose>140mg/dl treated with insulin§ Dysphagia screening

Middleton et al, Lancet Neurology 2011

P=0.002

¡ Hyperventilation is generally only helpful as a short term measure while the patient is going to the OR.

¡ Steroids and glycerol are probably ineffective¡ Mannitol and hypertonic saline have limited

evidence that they can reduce edema and temporarily reverse herniation.§ They are both reasonable to use but invasive ICP

monitoring should be considered to guide therapy

¡ HeadPoST Trial – cluster randomized¡ 11,093 patients with stroke (819 patients with ICH)

were randomized to lying flat vs. sitting up 30 degrees.

No difference in clinical outcomesNo difference in pneumonia or other SAEs.

Anderson CS, NEJM 2017

¡ Seizure risk: approximately 8% in first few days

¡ Most seizures occur within 24 hours.

¡ More commonly associated with lobar ICH

¡ Do seizures lead to worse outcome?§ Neuronal injury§ Nonconvulsive seizures

may contribute to coma§ However, no association

with worse long term outcome after adjusting for other predictors.

AHA Guidelines: Do NOT give anticonvulsants unless the patient has actually seized.