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Stroke Therapy

World Congress of Neurology Teaching Course


Joung-Ho Rha
Inha University Hospital, Incheon, Korea
No Conflict of Interest to Disclose
Learning Objectives
Antiplatelet Therapy for Stroke Prevention

Anticoagulation Therapy for Cardioembolic Stroke Prevention

Thrombolytic Therapy for Hyperacute Stroke


Considering Factors in
Antithrombotic Therapy for Stroke Prevention

Stroke Mechanism TOAST Classification

Large Artery Atherosclerosis

Small Vessel Disease

Cardioembolism

- Anticoagulation

Undetermined

- Cryptogenic / Embolic Stroke of Undetermined Source (ESUS)

Recurrent Stroke While On Antithrombotics

Ischemic Stroke with Previous Hemorrhagic Stroke / Microbleeds PICASSO Trial


Currently Available Antiplatelets
Aspirin

Ticlopidine

Clopidogrel

Aggrenox (Aspirin + Dipyridamole ER)

Cilostazol *

Triflusal

(Ticagrelor, Prasugrel)

Dual Anti-Platelet Therapy (DAPT)


Dual Antiplatelet (DAPT) Trials
for Stroke Prevention
CHANCE:
DAPT for 3 wks Only
Spectrum of Small Vessel Disease
Lacune
WMH
Cerebral Microbleed
ICH (?)
DAPT Failed Efficacay
for Small Subcortical Infarct
(Lacune)

Only More Hemorrhagic


Complication
Case 75/M Acute Confusion

2017 2017 2007


Which Antiplatelet for This Patient?
Recur during Antiplatelet (Aspirin)

Multiple Risk Factor (HT, DM, Smoking, Dyslipidemia)

Compliance/Adherence and Risk Factor Control Status


Previous Patient (2007, 2017 Ischemic Stroke)
2012 Rt Temporal ICH on DAPT,
with Multiple Cerebral Microbleeds

2017 2017 2012


Recur during Antiplatelet (ASA)

ICH Hx with Cerebral Microbleeds

Antithrombotics for Previous ICH?


If Switch Antiplatelet, To Which One?
Introduction
Previous Macro- (Intracerebral hemorrhage) or micro-
cerebral hemorrhage (microbleeds)

Increases the risk of future cerebral hemorrhage


Reflects fragile small perforating arteries
Detection rate increases as stroke population ages and the use of GRE/SWI increases
Optimal antiplatelet treatment for these patients are still unclear
Design Paper

Int J Stroke 2015;10(7):1153


Inclusion and Exclusion criteria
Patients inclusion criteria
1 patients with non-cardioembolic ischemic stroke or TIA within 180 days
2 patients older than 20 years of age
3 had a previous ICH based on clinical or radiologic findings or multiple
CMBs

Key exclusion criteria


patients with
1 recent cerebral hemorrhage within 6 months,
2 contraindicated for long-term use of antiplatelet agent,
3 with severe cardiomyopathy or congestive heart failure, and
4 diagnosed as myocardial infarction or have coronary artery procedures within 4
weeks prior to screening
Primary Outcome; Efficacy
Kaplan-Meier Analysis of the efficacy (composites of vascular
events; Stroke, MI and Vascular death

HR (90% CI): 0.80 (0.60-1.05)


Primary Outcome; Safety
Kaplan-Meier Analysis of Safety (Intracerebral and
subarachnoid hemorrhage)

P=0.0916 by log rank test


HR (95% CI): 0.51 (0.23-1.13)
Multivariable analysis
Adjusted HR* p
(two-sided 95% CI)

Primary endpoints

Time to composites of vascular events 0.79 (0.59-1.06) 0.005** / 0.10***

Time to cerebral hemorrhage 0.54 (0.23-1.27) 0.16

Secondary endpoints

Time to Stroke 0.67 (0.48-0.91) 0.01

Time to ischemic stroke 0.72 (0.51-1.02) 0.07

Time to myocardial infarction 4.47 (0.94-21.25) 0.06

Time to cardiovascular death 1.31 (0.39-4.38) 0.66

Time to other vascular events 0.75 (0.37-1.51) 0.42

Used marginal cox model


Adjusted for general medical history, pulse and baseline mRS; Hazard ratio for Cilostazol versus Aspirin
**p-value for non-inferiority; ***p-value for superiority
Conclusion

Cilostazol demonstrate non-inferiority to aspirin in composite of


cardiovascular event in ischemic stroke patients with extensive small
vessel disease presented by
macro andmicro cerebral hemorrhages.

Especially, Cilostazol significantly decreased any stroke in


comparison to aspirin in this cohort, but increased MI and
therefore, failed to demonstrate superiority in reducing
composites of cardiovascular events

Future study verifying patients who may benefit from Cilostazol may
be needed.
Cardioembolic Stroke
Warfarin & 4 Commercially Available NOACs

Which NOAC to this particular patient?

When to start?

How to adjust dose?


Cryptogenic Stroke / Embolic Stroke of Undetermined Source (ESUS)

Paroxysmal Af

Patent Foramen Ovale

Aortic Arch Atheroma

Others

Role of NOAC?
Ongoing NOAC Trial for ESUS
RE-SPECT ESUS (Dabigatran)
Randomized Evaluation in Secondary stroke PrEvention Comparing the Thrombin
inhibitor dabigatran etexilate versus acetylsalicylic acid (ASA) in Embolic Stroke of
Undetermined Source

NAVIGATE ESUS (Rivaroxaban)


Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of
Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source

ATTICUS (Apixaban)
Apixaban for Treatment of Embolic Stroke of Undetermined Source
Summary - Antithrombotic Therapy
DAPT for Stroke Prevention
Negative for Long Term Prevention & Small Vessel Disease
Positive only for Short Term (<3 weeks), ICAS

Recurrent Stroke while on Aspirin


Switch to (or Add) Another Antiplatelet can be Considered

Ischemic Stroke with Previous ICH/Microbleeds


Cilostazol can be an Option, Caution for MI Risk Patient

NOAC Can be Individualized on Specific Situation

ESUS Antiplatelet vs. NOAC Ongoing


Thrombolytic Therapy
Dose & Ethnicity Issue of IV tPA in Asia

Conflicting, Inconclusive Results from Country to Country


Korea & China 0.9 vs. Japan & Taiwan 0.6 mg/kg

Standard (0.9) vs. Low (0.6mg/kg) tPA dose


Randomized, Head to Head Comparison is Required
ENCHANTED Trial
ENCHANTED Design
References

Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. The New England journal of
medicine. 2013;369:11-19

Liu L, Wong KS, Leng X, Pu Y, Wang Y, Jing J, et al. Dual antiplatelet therapy in stroke and icas: Subgroup analysis of chance. Neurology. 2015;85:1154-1162

Lee M, Saver JL, Hong KS, Rao NM, Wu YL, Ovbiagele B. Risk-benefit profile of long-term dual- versus single-antiplatelet therapy among patients with ischemic
stroke: A systematic review and meta-analysis. Annals of internal medicine. 2013;159:463-470

Wong KSL, Wang Y, Leng X, Mao C, Tang J, Bath PMW, et al. Early dual versus mono antiplatelet therapy for acute non-cardioembolic ischemic stroke or transient
ischemic attack: An updated systematic review and meta-analysis. Circulation. 2013;128:1656-1666

Investigators SPS, Benavente OR, Hart RG, McClure LA, Szychowski JM, Coffey CS, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar
stroke. The New England journal of medicine. 2012;367:817-825

Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to
ageing and neurodegeneration. The Lancet Neurology. 2013;12:822-838

Kim JT, Park MS, Choi KH, Cho KH, Kim BJ, Han MK, et al. Different antiplatelet strategies in patients with new ischemic stroke while taking aspirin. Stroke; a journal
of cerebral circulation. 2016;47:128-134

Ottosen TP, Grijota M, Hansen ML, Brandes A, Damgaard D, Husted SE, et al. Use of antithrombotic therapy and long-term clinical outcome among patients
surviving intracerebral hemorrhage. Stroke; a journal of cerebral circulation. 2016;47:1837-1843

Hong KS, Kim BJ, Kwon SU, Investigators P. Rationale and design of the prevention of cardiovascular events in ischemic stroke patients with high risk of cerebral
hemorrhage (picasso) study: A randomized controlled trial. International journal of stroke. 2015;10:1153-1158

Diener HC, Aisenberg J, Ansell J, Atar D, Breithardt G, Eikelboom J, et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual
patients with non-valvular atrial fibrillation: Part 2. European heart journal. 2016

Diener HC, Aisenberg J, Ansell J, Atar D, Breithardt G, Eikelboom J, et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual
patients with non-valvular atrial fibrillation: Part 1. European heart journal. 2016

Heidbuchel H, Hacke W, et al. Updated european heart rhythm association practical guide on the use of non-vitamin-k antagonist anticoagulants in patients with
non-valvular atrial fibrillation: Executive summary. European heart journal. 2016

Anderson CS, Robinson T, Lindley RI, Arima H, Lavados PM, Lee TH, et al. Low-dose versus standard-dose intravenous alteplase in acute ischemic stroke. The New
England journal of medicine. 2016

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