Acute Ischemic Stroke - Swedish Medical Center/media/Images/Swedish/CME1... · 2016-09-16 ·...

Sixth Annual Intensive Update in Neurology 9/15-16/2016

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Acute Ischemic Stroke:Updates to the Science and Art

of Acute Stroke CareRavi Menon, MD

June 16, 2016

Intensive Update in Neurology

Swedish Cherry Hill

Seattle, WA


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Disclosures

• None

• No financial disclosures

• Clinical trial involvement: Former site PI Ticagrelor clinical trial (SOCRATES); SubInvestigator for PRISMS, iCAS

• Will discuss nonFDA approved use clinical trial study of alteplase, argatroban, clinical trials of imaging selection


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Objectives

• Analyze the expanded use of IV alteplase for acute ischemic stroke

• Review diagnostic and therapeutic considerations in the acute management of ischemic stroke• Interventional considerations

• Discuss therapeutic dilemmas in the care of the hospitalized stroke patient


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1996


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1996

• Artist … actor


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1996

• Artist/actor …

• Tom Cruise

• Jerry Maguire

• Mission Impossible series

• Mission Impossible 1


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1996

• Jerry Maguire

• Mission Impossible series

• Mission 1

• 2000 MI 2

• 2006 MI 3

• 2011 Ghost Protocol

• 2015 Mission Impossible:Rogue Nation

• What could stroke neurologists have learned from Tom Cruise?


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IV alteplase stroke trials

Cheng and Kim 2015


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2015 IV alteplase

• Inclusion and exclusion criteria on the alteplase label do not match up well with clinical experience

• Limited population helped by limited use in which only ~25% pts eligible 3 hr window

• FDA not approve 3-4.5 hour window

• IV alteplase

• 0-3 hours NINDS

• 3-4.5 hours ECASS3

• FDA revision of eligibility

• 2015 Scientific Statement from AHA/ASA

• Updates to package labelling


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Cheng and Kim 2015


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Historical Contraindications/Warnings to IV alteplase for acute ischemic stroke (NINDS)

• SBP >185 or DBP >110 mmHg [despite medical intervention to lower it]

• Seizure at onset • Recent surgery/trauma (less than 15 days) • Recent intracranial or spinal surgery, head trauma, or stroke (less than 3 months)

• History of intracranial hemorrhage or brain aneurysm or vascular malformation or brain tumor

• Active internal bleeding (less than 22 days) [including arterial puncture at a non-compressible site]

• Platelets less than 100,000, PTT greater than 40 sec after heparin use, or PT greater than 15 or INR greater than 1.7, or known bleeding diathesis

• Suspicion of subarachnoid hemorrhage [by imaging or clinical presentation] CT findings (ICH, SAH, or major acute infarct signs) [e.g. hypodensity greater than 1/3 cerebral hemisphere]


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Historical Contraindications/Warnings to IV alteplase for acute ischemic stroke (NINDS)

• Stroke severity - too severe NIHSS >22

• Glucose less than 50 or greater than 400 mg/dl [if residual deficits are due to the altered metabolic state rather than to ischemia. If rapid diagnosis of vascular occlusion can be made, treatment may be given.]

• Left heart thrombus documented

• Increased risk of bleeding due to any of the following: • Acute pericarditis Subacute bacterial endocarditis (SBE); Hemostatic defects including those secondary to

severe hepatic or renal disease, Pregnancy, Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions; Septic thrombophlebitis or occluded AV cannula at seriously infected site

• Patients currently receiving oral anticoagulants, e.g., Warfarin sodium [and INR greater than 1.7]

• Advanced age

• Rapid improvement

• Stroke severity too mild [e.g. anticipate ability to discharge to home]

• Life expectancy less than 1 year or severe co-morbid illness or CMO on admission


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2013 Fugate and Rabinstein


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• FDA not approved for 3-4.5 hour window

• AHA/ASA endorses IV alteplase 0-4.5 hours

• ECASS III exclusions

AHA/ASA Scientific Statement 2015


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Age > 80 years

• Only 0.5% included in clin trials over age 80- unknown

• Age independent risk factor for poor outcome independent of IV alteplase tx

• Age>85 short/longterm mortality 2x younger

• Observational- limited age<80

• > mortality; similar rates symptomatic ICH

• IST-3 >1600pts over age 80- randomized alteplase or asa w/in 6 hrs-• Overall no benefit but age>80 > benefit


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Updates to IV alteplase Exclusion Criteria

• IV alteplase is recommended for eligible patients age 80 and higher

• “For otherwise medically eligible patients ≥18 years of age, intravenous alteplaseadministration within 3 hours is equally recommended for patients 80 years of age. “

• Older age is an adverse prognostic factor in stroke but does not modify the treatment effect of thrombolysis.

• “Although older patients have poorer outcomes, higher mortality, and higher rates of sICH than those <80 years of age, compared with control subjects, intravenous alteplase provides a better chance of being independent at 3 months across all age groups (Class I;Level of Evidence A). “


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Nonogenarians: Age >= 90

• GWTG quality improvement registry Jan2009 – Apr 2013

• 7% of 35708 pts >=90 yrs vs 18-89

• Less alteplase used w/o documented contraindication (67% vs 84%; p<0.0001)

• Discharge outcomes:

• Discharge home/acute rehabilitation in 31.4%

• Independent ambulation at discharge in 13.4%

• sICH 6.1 %; in-hospital mortality/hospice 36.4%

• Frailty component

Rohan Arora et al. Stroke. 2016;47:2347-2354


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Surgery/Invasive Procedure

• Subclavian central line?

• Femoral line large bore?

• Lumbar surgery?

• Just put in a drain…

2013 Fugate and Rabinstein


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Updates: IV Alteplase Exclusion CriteriaSurgery/GI Bleed

• Recent Intracranial/Spine Surgery in the past 3 months: “potentially harmful” (III, C)

• Recent Surgery in the past 14 days (other than spine or intracranial surgery)• 2015 guidelines: “warning” and not an absolute contraindication • “may be considered” (IIb, C)

• Recent Dural Puncture- may be considered if lumbar dural puncture <7 days (IIb, C)

• Recent GI Bleed• FDA update =Warning; No exact time restrictions

• may be reasonable (Reported literature details low bleeding risk with past GI/GU bleeding) (IIb, C)

• Structural GI malignancy or recent bleeding event within 21 days of their stroke = considered high risk, and intravenous alteplase administration is potentially harmful (III, C)



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Updates: IV Alteplase Exclusion CriteriaRecent Stroke

• FDA updated guidelines: removed recent stroke within the past 3 months as an exclusion

• AHA updated guidelines:

• Prior ischemic stroke within 3 months may be harmful (III, B)

• Potential for increased risk of sICH and associated morbidity and mortality exists but not well established (IIb,B)

• Potential risks should be discussed during thrombolysis eligibility deliberation and weighed against the anticipated benefits during decision making (I,C)



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Updates: IV alteplase Exclusion CriteriaAnticoagulants

Anticoagulation – relatively unchanged

Updated AHA guidelines

Not recommended: LMWH previous 24 hours for Tx and Ppx dose (III, B)

Direct thrombin inhibitors/Direct factor Xa inhibitors: not established/may be harmful (III;C)

Not recommended unless: aPTT, INR, platelet count, ecarin clotting time, thrombin time

OR appropriate direct factor Xa activity assays are normal)

OR no dose x >48 hours & normal renal function

Reasonable = h/o warfarin use and an INR ≤1.7 (IIb,B)

Not Recommended: history of warfarin use and an INR >1.7 (III,B)AHA/ASA Scientific Statement 2015


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Updates to IV alteplase Exclusion Criteria

• Seizure• FDA labeling removed seizure as a contraindication or warning

• Updated AHA guideline:• Intravenous alteplase is reasonable in patients with a seizure at the time of onset of acute stroke if

evidence suggests that residual impairments are secondary to stroke and not a postictal phenomenon (Iia, C)

• Pregnancy• may be considered in pregnancy (anticipated benefit vs risk)(IIb, C)

• Safety/efficacy early post-partum (<14 days) not well established (IIb, C)

• Urgent consultation with OB-Gyn, potentially perinatologist (I, C)



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Updates to IV alteplase Exclusion CriteriaExtended 3-4.5 hour window

• IV alteplase recommended in carefully selected patients meeting ECASS III criteria = txw/in 3-4.5 hrs (I,B)

• Age ≥80 IV alteplase= Safe & As effective as in younger patients (Class IIa,B).

• Warfarin + INR <1.7 IV alteplase treatment appears safe and may be beneficial (Class IIb,B).

• Uncertain benefit of IV alteplase administration for baseline NIHSS >25 (Class IIb,C).

• Prior stroke + diabetes mellitus, IV intravenous alteplase as effective as 0- to 3-hour window and may be a reasonable option (Class Ib,B)



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Updates: No longer Exclusions

• CT Early ischemic changes (NOT frank hypodensity)

• Age> 80

• High NIHSS

• Low NIHSS but disabling symptoms

• Rapidly improving but disabling symptoms still present

• Unable to give consent but clear established last known normal (2 physician consent)


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Strong Recommendation Against Using Alteplase• Symptom onset >4.5 hours

• Symptoms resolved

• Clinical Suspicion of SAH

• Intracranial hemorrhage on CT (SAH, ICH, IVH, SDH, EDH)

• INR > 1.7 (if there is no history of OAC use and no suspicion of abnormal INR, INR evaluation should not delay Alteplase)

• Platelet Count <100K (if there is no clinical suspicion of low platelets based on PMHx, then CBC should not delay Alteplase)

• Significant head/spine surgery or trauma within the past 3 months

• History of ICH

• Active internal bleeding

• GI/GU Bleeding within 21 days

• GI Malignancy

• Endocarditis

• Intra-axial brain tumor

• Aortic dissection

• Current uncontrolled HTN > 180/105 not stabilized by IV drugs

• Large, unsecured aneurysms > 10mm

• Use of LMWH within 24 hours

• CT demonstrates “frank hypodensity”

• Use of Factor Xa Inhibitor within 48 hours and elevated Thrombin Time

• Life expectancy < 6 months or very poor quality of life


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May consider use of IV alteplase

• Seizure at the onset

• 3-4.5 hour window including age > 80, DM & prior clinical CVA, and INR < 1.7

• Cardiac Conditions: Concurrent MI (risk of tamponade), Pericarditis, LV Thrombus, Intracardiac Mass, MI w/in 3 months)

• Left Ventricular Assist Device (LVAD) patients. MUST consult LVAD team STAT and evaluate INR and platelets prior to decision

• Hyperglycemia if symptoms persist despite lowering glucose to < 400 mg/dL

• Hypoglycemia if symptoms persist despite raising blood glucose above 50 mg/dL

• Lumbar Puncture within 7 days

• Major trauma not involving spine or brain within 14 days

• Hemorrhagic retinopathy

• Pregnancy (Need emergent OB consult)

• Major surgery within 14 days

• Post angiogram stroke

• Cerebral microbleeds

• Extra-axial neoplasm

• Cerebral unruptured, unsecured aneurysm < 10mm

• Advanced dementia


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Not Well Established Contraindications

• Sickle Cell disease

• Current malignancy

• Arterial Puncture at non-compressible site within 7 days

• Intracranial arterial dissection

• Ischemic stroke within 3 months

• Unruptured AVM

• Pediatric patients (Age <18)


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Risk:Benefit in low NIHSS/`mild’ stroke• Mild Stroke- less defined benefit:risk

• What is mild?• Opera singer/Public figure mild dysarthria (nihss 2)

• Athlete with ataxia (nihss 1)

• The IRS auditor with acalculia (improved nihss 0)


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Risk:Benefit in low NIHSS/`mild’ stroke• Mild Stroke- less defined benefit:risk

• What is mild?• Opera singer/Public figure mild dysarthria (nihss 2)

• Athlete with ataxia (nihss 1)

• The IRS auditor with acalculia (improved nihss 0)

• Clinical Trials in Mild Stroke• PRISMS- Patients with Rapidly Improving Symptoms and Minor Neurologic

DeficitS

• MaRISS- Mild and Rapidly Improving Stroke Study


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Marshall NEJM 2015


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IV alteplase adjunctive tx/trials

• ARTSS-2 Argatroban

• ICTuS-2 Hypothermia


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Alteplase + what else?


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Time is brain…Quantified 2006


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Stroke care visionary…


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Interventional Trials

• MR CLEAN ==>

• ESCAPE

• EXEND-IA

• SWIFT PRIME

• REVASCAT

• FAST

• EFFECTIVE


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• HERMESHighly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration


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HERMESHighly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration

• MR CLEAN, ESCAPE, EXTEND IA, SWIFT PRIME, REVASCAT

• Identified 5 trials, modern devices

• IR definitive treatment Ant circ LVO

• Pooled analysis of individual patients would facilitate subgroup analysis via mixed effects model• > precision

• Subgroup analysis across trials


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HERMES

• Age, sex, occlusion, location, ASPECTS, tx alteplase, time from randomization

• Baseline characteristics similar: Avg NIHSS 17, ASPECTS 9

• Workflow- Upper quartile = Door to groin puncture 75 minutes, Imaging to Groin puncture 50 min (Quality goal)

• Overall Tx Effect• Intervention vs control, Risk difference, Rate ratio, OR, Adjusted Rate Ratio

and Adjusted Odds Ratio• NNT= 2.6 => round up to 3


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Additional IR trials

• PISTE: The Pragmatic Ischaemic Thrombectomy Evaluation• IVT vs IVT + IAT (CTA prior LVO)

• THRACE: Trial and Cost Effectiveness Evaluation of Intra-arterial Thrombectomy in Acute Ischemic Stroke• IVT vs IVT + IAT w/in 4 hours

• THERAPY: Assess the Penumbra System in the Treatment of Acute Stroke• IVT vs IVT+Penumbra

• All terminated early after HERMES


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Interventions

• 2012 FDA approved for alteplase ineligible/nonresponders

• 2016 Sept 2 – two stentrievers now FDA-approved for adjunct with alteplase


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M2 occlusions –understudied, disabling• M2 compared with M1 MCA occlusions in patients undergoing IR by assessing comprehensive MRI, angiography, and

clinical data

• UCLA M2 occlusions => disabling strokes => death or moderate-severe disability ~50% of patients at discharge

• Compared with M1 occlusions, M2 occlusions achieved similar Thrombolysis in Cerebral Infarction (TICI) 2b/3 recanalization rates, with significantly less hemorrhage

• M2 occlusions presented with smaller infarct and hypoperfused volumes and had smaller final infarct volumes regardless of recanalization. TICI 2b/3 recanalization of M2 occlusions was associated with smaller infarct volumes compared with TICI 0–2a recanalization, as well as less infarct expansion, in patients who received IV tissue plasminogen activator as well as those that did not.

• Successful reperfusion of M2 =>improved discharge mRS

• Conclusions M2 occlusions =same consideration as M1 occlusions.

• IVT vs IVT+IR

• Graphic A- all patients with M2 occlusions

• Graphic B- subset patients receiving IV alteplase

• Successful recanalization IR => improved mRS

J Neurointerv Surg. 2015 Jul ;7(7):478-83

http://www.ncbi.nlm.nih.gov/pubmed/?term=M2+occlusions+as+targets+for+endovascular+therapy:+comprehensive+analysis+of+diffusion/perfusion+MRI,+angiography,+and+clinical+outcomes


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M2 occlusionSELECT Trial(Optimizing Patient’s Selection For Endovascular Treatment in Acute Ischemic Stroke)

• Retrospective cohort, pooled: 10 academic tertiary 1/2012-4/2015

• Inclusion criteria:• Acute ischemic stroke + LVO isolated to M2

• Treated within 8 hours from last known normal (LKN)

• Independence at baseline (mRS 0-2)

JAMA Neurol. Published online September 12, 2016.


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Date of download: 9/12/2016Copyright © 2016 American Medical

Association. All rights reserved.

From: Endovascular Therapy for Acute Ischemic Stroke With Occlusion of the Middle Cerebral Artery M2

Segment

JAMA Neurol. Published online September 12, 2016. doi:10.1001/jamaneurol.2016.2773

Modified Rankin Scale Scores at 90 DaysOutcomes are compared for the endovascular therapy (EVT) vs medical management

groups.

Figure Legend:


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Therapeutic considerations/dilemmas?

• Hyperacute phase

• Acute phase


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Imaging Selection for Intervention Candidates

• Imaging selection -> Tissue clock > Time clock

• DEFUSE-3– enroll up to 12hours

• MR WITNESS - imaging selection

• DWI vs FLAIR- Signal Intensity Ratio – select wakeup/last known normal unknown patients for tx IV alteplasew/in 4.5 hours of imaging

• DAWN DWI or CTP Assessment with Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention

• Posterior circulation Intervention

• Elderly outcomes/selection: 93 y oldest in ESCAPE


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tPA adjuncts

• ARTSS-2 - IVtPA + Argatroban

• ictus-2


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Update Trials

• ACT- 1

• Asymptomatic carotid stenosis = 1 yr & 5 yr f/u; carotid stenting non-inferior to CEA

• ACTION – Natalizumab- acute inflammation => insignificant reduction in infarct volume; secondary clinical: + benefit

• IRIS- pioglitazone Positive trial

• GAMES – glyburide; brain edema


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Early secondary prevention

• Ischemic stroke patient compliant with aspirin admitted with ischemic stroke

• ? Antiplatelet choice – Aspirin• Resistance – aspirin, clopidogrel assays for inhibition; medication interaction

• Trial Ticagrelor – no better than aspirin• Ticagrelor - SOCRATES (The Acute Stroke or Transient Ischaemic Attack Treated with

Aspirin or Ticagrelor and Patient Outcomes) vs. Aspirin• Negative trial- not superior in reducing 90 day rate of CVA/MI/Death

• Antithrombotic options• Aspirin, Clopidogrel, Dipyridamole/Aspirin


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Controversies remain controversial

• When to resume anticoagulation after ischemic stroke in the setting of atrial fibrillation?

• Volume considerations• Small = ~1 week

• Medium = ~2 weeks

• Large = ~4 - 6 weeks

• Hemorrhagic transformation

• Role of TCD emboli monitoring

• Clinical judgment paramount


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Clinical dilemmasCase

• 69 y/o RH man htn, dyslipidemia, obesity p/w new onset chest pain/dyspnea => new onset atrial fibrillation => IV heparin bolus

• 2 hours after bolus (last normal) RN calls code stroke: +left facial droop, left arm drfit, ?left neglect- onset after arising from bed; ? Confusion; glucose 143

• f/u exam/serial exam with Tagalog speaker slowly but appropriate

• Varying bedside exam by RN/internal medicine

• Neurology exam


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Clinical dilemmasCase

• 69 y/o RH man htn, dyslipidemia, obesity p/w new onset chest pain/dyspnea => new onset atrial fibrillation => IV heparin bolus

• ~2 hours after bolus (last normal) RN calls code stroke: +left facial droop, left arm drfit, ?left neglect- onset after arising from bed; ? Confusion; glucose 143 Varying bedside exam by RN/internal medicine

• NIHSS 3 = partial hemianopia1 (L sup quadrant +/- mid/lower) L face1 , LArm 1; EOM nl CN3 nl; unclear if baseline vs slowed speech per family

• CTA was obtained in addition to CT head on initial imaging


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Considerations…

• IV alteplase candidate?• Heparin bolus? Outright excluded vs check PTT and reeval?

• Disability?

• Localization P1 vs P2 with perfusion deficit• PCA occlusion with perfusion deficit

• Chronic occlusion?

• CTA obtained


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Considerations…

• IV alteplase candidate?• Heparin bolus? Outright n/a vs check PTT

• Disability?

• Localization P1 vs P2 with perfusion deficit• PCA occlusion with perfusion deficit

• Chronic occlusion?

• CTA obtained


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Considerations…

• Intervention candidate?• Proximal vs distal PCA syndrome?• Partial visual deficit vs Hemianopic?• How approach posterior circulation?• BP goals (hypoperfusion in setting of chronic?

• IR Trials studied mRS 0-2 – what ~ 3?

• Other patients/scenarios…


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Conclusions

• IV alteplase for acute ischemic stroke is of benefit in 0-4.5 hours with an expanded role and adjunctive therapies in the pipeline

• Think about interventional eligibility in appropriate ischemic stroke patients and think about it early

•Additional science continues to develop to advance the art of medicine


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References

• Cheng NT and AS Kim. Intravenous thrombolysis for acute ischemic stroke within 3 hours versus between 3 and 4.5 hours of symptom onset. The Neurohospitalist2015, Vol. 5(3) 101-109.

• Damaerschalk, B. et. al. Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2016;47:

• Fugate JE, Rabinstein AA Contraindications to intravenous rtPA for acute stroke: A critical reappraisal. Neurology Clinical Practice June 2013; 177-184.

• Marshall RS. Progress in Intravenous Thrombolytic Therapy for Acute Stroke. JAMA Neurol. 2015 Aug;72(8):928-34.

• The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study GroupTissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581–1587

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