Stroke Updates

8/2/2019 Stroke Updates

1/72
http://www.neuro.org.my/index.php


2/72

Prof Dr Hamidon Basri

UPDATE ON STROKE
http://www.neuro.org.my/index.phphttp://www.neuro.org.my/index.php


3/72

Stroke- 3rd leading causeof death

Major cause of disability

Incidence: 1 in 2000population

Decreasing trend indeveloped countries

Better preventiontreatment and aftercaremanagement


4/72

75%

25%

INCIDENCEISCHAEMIC STROKE

HEMORRHAGIC STROKE

010203040

MORTALITY

ISCHAEMIC STROKE

HAEMORRHAGIC STROKE

30DA

YMORTALITY(%

)

8%-12%

36%-37%

Hamidon BB et al. Neurology Asia2003

American Heart Association Heart Disease and Stroke Statistics-2005 Update


5/72

Rapidlydeveloping clinical neurologicalsignsof focal (or global) disturbance ofcerebral function, with symptoms lasting 24hoursor longer or leading to death, with noapparent cause other than of vascularorigin

Transient Ischaemic Attack (TIA) < 24 hours


6/72

Assessed by imaging- absence of end organ injury


7/72

Cumulative risk of stroke after TIA or minor stroke


8/72

ABCD2 Score


9/72


10/72

Before and After trial

Phase 1: Referral system, delay in treatment

Phase 2: Seen and treated immediately. Reduced

treatment delays Urgent assessment

Early initiation of a combination of existingpreventative treatments

TIA and Minor Stroke- EXPRESS Trial


11/72

EXPRESS trial- What made the difference?


12/72

80% reduction inrisk of stroke at90 days

Favouring early& aggressivetreatment group

TIA and Minor Stroke


13/72


14/72

Aspirin ASAPRisk Factor control

Thrombolysis

Neurosurgery


15/72


16/72

Cultural/belief

- minor, overcome

- TCM Social - staying alone

- ignorance

Geographical location, remote areas, traffic

Organisational in-hospital delays

Zamri M, Hamidon BB


17/72

75% pre-hospitaldelays

65% ignorant of strokesymptoms

78% depend on otherfamily members to

decide on seekingtreatment

Rahmah MA, Hamidon BB

Delays in Stroke


18/72

6 large RCTs

European Cooperative Acute StrokeStudy (ECASS I and II)

NINDS (1 and 2)

ATLANTIS A and B


19/72

Pooled analysis of individual patient data (n=2775) from 6 trials of i.v.alteplase vs placebo showed that the effective treatment window mayextend to 4.5 hours

Time Interval from onset of symptoms to treatment initiation [min]

A

djustedoddsratio

1.5h

OR2.8

3h

OR1.5

4.5h

OR1.4

6h

OR1.2

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.54.0

60 120 180 240 300 360

OR, odds ratio

Hacke et al. Lancet2004; 363: 768774.


20/72

To assess efficacy and safety of alteplasebetween 3 and 4.5 hours after stroke onset in

the European setting, collecting additionalconfirmatory prospective data


21/72

Randomised, placebo-controlled, double-blindclinical trial

CT pre-randomisation to exclude ICH or major

ischaemic infarction 1:1 randomisation by IVRS to i.v. alteplase (0.9

mg/kg bodyweight) or placebo Alteplase administration: bolus (10% of total dose) in

1-2 min, remaining 90% infused i.v. over 60 min

CT, computed tomography; ICH, intracranial haemorrhage;IVRS, interactive voice randomisation system


22/72

Age 1880 yr

Acute ischaemic stroke, after excluding ICH

Onset of stroke symptoms 34.5 h prior toinitiation of study drug

Identical to the European Summary of ProductCharacteristics (ESPC) of alteplase for ischaemicstroke, except for treatment time window

ICH, intracranial haemorrhage


23/72

Overall mortality (day 90)

Any ICH

Symptomatic ICH (ECASS 3 definition)

Any blood in the brain or intracranially associated with aclinical deterioration 4 points on the NIHSS for whichthe haemorrhage has been identified as the dominatingcause

Symptomatic oedema

Brain oedema with mass effect as the dominatingpathology for clinical deterioration

Serious adverse eventsICH, intracranial haemorrhage;NIHSS, National Institutes of Health Stroke Scale


24/72

0

5

10

15

20

25

30

Any ICH Fatal ICH

Patients(%)

27.0

2.4

0.3 0.70.0

17.6

p=0.001

p=0.008

6.9 7.2

p=0.9

Symptomaticoedema

SymptomaticICH

Alteplase

Placebo

p=0.7

7.78.4

Overallmortality


25/72

Primary endpoint: Disability @ day 90 mRS dichotomised on a favourable (mRS 01) versus

unfavourable outcome (mRS 26)

Secondary endpoint Global outcome analysis* @ day 90, combining:

mRS score of 01

Barthel Index score 95

NIHSS score of 01 (including distal motor function) Glasgow Outcome Scale score of 1

*NINDS. N Engl J Med1995;333:1581-1587.

mRS, modified Rankin Scale;NIHSS, National Institutes of Health Stroke Scale


26/72

Day 90: mRS 0,1 Excellent recovery

Analysis Alteplasen/N (%)

Placebon/N (%)

OR

(95% CI)

P

Unadjusted 219/418(52.4%)

182/403(45.2%)

1.34(1.021.76)

0.038

Adjusted* 1.42(1.021.98)

0.037

*Adjusted for prognostic variables: treatment, baseline NIHSS, smoking history, stroke onset to treatment time, and prior hypertension

0.5 1 1.5

Favours Placebo Favours Alteplase


27/72

*stratified on CochranMantelHaenszel test, adjusted for baseline NIHSS scores and time-to-treatment onset

0% 20% 40% 60% 80% 100%Patients

p=0.016*

Per-protocol population

Alteplase(n=375)

mRS score

Placebo(n=355)

1 2 30 4 5 6

29.1 10.114.425.9 8.8 6.15.6

22.3 11.816.923.1 14.9 4.2 6.8

p=0.024*

Intent-to-treat population

Alteplase(n=418)

mRS score

Placebo(n=403)

1 2 30 4 5 6

27.5

23.321.8 16.4

9.314.124.9

13.7

9.3

8.2

6.78.1

11.4 5.2

Method as per Lees et al. N Engl J Med2006;354:588-600.


28/72

Co-Authors and Writing Committee


29/72

IV alteplase 34.5 h after stroke symptoms Effective treatment with no increase in ICB

compared with Rx


30/72

having more time does not mean we shouldtake more time

Treatment of patients- as early as possible

with alteplase, to maximise the benefit

There may be more time for the patients,

but not for the treating physicians


31/72


32/72

Experienced physician/neurologist instroke management

24-hours radiological support (CT/MRI) Neurosurgical support

Stroke care unit

Not minor deficits (NIHSS>6)

Normal brain CT or early changes < 1/3 orASPECT Score


33/72


34/72

Thrombolysis

Intravenous alteplase

(rtPA) 0.9 mg/kg 10% asbolus, remaining 90% over1 hour


35/72

TranscranialDoppler

Ultrasound enhanced

thrombolysis(CLOTBUST trial) 49%vs 30% (control)achieved completerecanalisation


36/72

Intra-arterial (PRO-ACT II)- 6 hours

MRI/CT perfusion- better selection onsalvageable penumbral tissues

Mechanical devices


37/72


38/72

Thrombolysis Prevention of early

complications eg.aspiration

Better nutrition Standardized

control of riskfactors: BG, BP,

Cholesterol Early & focused

rehabilitation

Acute Stroke Care Unit


39/72


40/72

Routine coagulationmonitoring

Slow onset/offset of action

Warfarin resistance

Numerous drugdrug

interactions

Numerous fooddruginteractions

Narrow therapeutic

window(INR range 2.03.0)

INR = International normalized ratio; VKA = vitamin K antagonist.Ansell J, et al. Chest2008;133;160S-198S. Umer Ushman MH, et al. J Interv Card Electrophysiol2008;22:129-137.

Nutescu EA, et al. Cardiol Clin2008;26:169-187.

VKA therapy hasseveral limitations

that make it difficultto use in practice

Frequent doseadjustments

Unpredictableresponse


41/72

Clinical trial1 Clinical practice2,3

3.0

Eligiblepatientsreceiv

ingWarfarin

(%)

38%

44%

18%

66%

9%

25%

INR


42/72

1. Connolly S for the ACTIVE Investigators. Lancet2006;367:1903-1912. 2. Mant J, et al. Lancet2007;370:493-503.

Rateofallmajorbleeding(%)

Rateofmajorbleed

ing(%peryear) 4

3

0

2

Oral anticoagulationN=3,371

Clopidogrel + AspirinN=3,335

Warfarin Aspirin

4

3

0

2

In ACTIVE-Wtrial1 In BAFTA trial

2

patients

75 yrs of age(N=973)

P=0.53 P=0.9

42% risk of strokewith oral anticoagulation

vs. clopidogrel + Aspirin

52% risk of stroke, intracranialhaemorrhage, systemic embolism

with warfarin vs. Aspirin

1 1

Superior strokeprevention withanticoagulation


43/72

43

UFHAT

ORALDIRECT

PARENTERALINDIRECT

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

RivaroxabanApixabanEdoxabanBetrixaban

LMWHAT

FondaparinuxAT

DabigatranAZD 0837

ROCKET

RELY


44/72

Atrial fibrillation1 Risk FactorAbsence of contra-indications951 centers in 44 countries

R

Warfarinadjusted(INR 2.0-3.0)N=6000

DabigatranEtexilate110 mg BIDN=6000

DabigatranEtexilate150 mg BIDN=6000

Blinded Event Adjudication.

Open Blinded

Patients were eligible if they had atrialfibrillation documented onelectrocardiography performed atscreening or within 6 months beforehandand at least one of the followingcharacteristics:

1. Previous stroke or transientischemic attack

2. a left ventricular ejection fraction ofless than 40%

3. New York Heart Association classII or higher heart-failure symptomswithin 6 months before screening

4. An age of at least 75 years or anage of 65 to 74 years plus diabetesmellitus, hypertension, or coronaryartery disease.

Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

(Randomized Evaluation of Long-Term AnticoagulantTherapy)


45/72

Rivaroxaban Warfarin

Primary Endpoint: Stroke or non-CNS Systemic Embolism

INR target - 2.5(2.0-3.0 inclusive)20 mg daily15 mg for Cr Cl 30-49 ml/min

Atrial Fibrillation

RandomizeDouble Blind /Double Dummy

(n ~ 14,000)

Monthly Monitoring

Adherence to standard of care guidelines

Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin

Kantagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation

Risk Factors CHF Hypertension Age 75 DiabetesOR Stroke, TIA or

Systemic embolus

At least 2 or 3required*

Rocket AF Investigators, AHA 2010


46/72

Both had non-inferiority to warfarin as primary endpoint

Rocket AF required 2 risk factors for entry, RE-LY 1 risk factor

Rocket AF capped CHADS2 = 2 early in the trial unless a patient scoredtwo points by having a prior stroke/TIA. This may account for the highrate of prior stroke in Rocket AF.

Both randomized trials

Rocket AF administered warfarin in a blinded fashion, RE-LY did not

There was a dose adjustment for impaired CrCl in Rocket AF

INR target range 2-3 in both

Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151


47/72

Trial Inclusion Design Start date Duration(mo)

Current / GoalEnrollment

#sites

ROCKET AF CHADS 3 or

stroke/TIA

(15% CHADS 2)

ShamINR

12/06 15 14,264 ~1200

ARISTOTLE CHADS 1

(50% VKA nave)

ShamINR

1/07 15 ~15,000 ~937

RE-LY CHADS 1

(30% VKA nave)

Openlabel

12/2005 26 18,113 706AMADEUS CHADS 1 Open

label9/2003 23 4576 165

SPORTIF V CHADS 1 ShamINR

8/2000 17 3922 409

ENGAGE CHADS > 2 ShamINR

10/2008 24 20,500 ~1400



48/72

RELY:

Primary Efficacy Evaluation: Stroke or non-CNS Embolism

Non-Inferiority: Intention-to-treat

Superiority: Intention-to-treat

Rocket AF:

Primary Efficacy Evaluation: Stroke or non-CNS Embolism Non-Inferiority: Protocol Compliant on treatment

Superiority: On Treatment, then by Intent-to-Treat

RE-LY used Intention to treatfor both non-inferiority and superioritytesting; Rocket AF used on treatment analysisfor first tests of non-inferiority and superiority



49/72

RELY: Primary Safety Evaluation: Major bleeding

Rocket AF: Primary Safety Evaluation: Major or non-Major

Clinically Relevant Bleeding



50/72

Characteristic Dabigatran 110mg Dabigatran 150mg WarfarinRandomized 6015 6076 6022Mean age (years) 71.4 71.5 71.6Male (%) 64.3 63.2 63.3CHADS2 score(mean)0-1 (%)2 (%)3+ (%)

2.132.634.732.7

2.232.235.232.6

2.130.937.032.1

Prior stroke/TIA (%) 19.9 20.3 19.8Prior MI (%) 16.8 16.9 16.1CHF (%) 32.2 31.8 31.9Baseline ASA (%) 40.0 38.7 40.6Warfarin Nave (%) 49.9 49.8 51.4



51/72

Rivaroxaban(N=7081)

Warfarin(N=7090)

CHADS2 Score (mean)2 (%)3 (%)4 (%)5 (%)6 (%)

3.48134329132

3.46134428122

Prior VKA Use (%) 62 63

Congestive Heart Failure (%) 63 62

Hypertension (%) 90 91

Diabetes Mellitus (%) 40 39

Prior Stroke/TIA/Embolism (%) 55 55

Prior Myocardial Infarction (%) 17 18

Based on Intention-to-Treat Population

Rocket AF: Baseline Demographics



52/72

Whereas 32.4% of patients in RE-LY were low risk CHADS 0-1, therewere none of these patients in Rocket AF

Whereas just over 32% of patients in RE-LY were high risk CHADSscore of 3 or more, over 85% of Rocket AF patients had a CHADS scoreof 3 or more

RE-LY patients were about 71.5 years old, and Rocket AF patients were73 years old

Prior stroke TIA embolism was about 20% in RE-LY and was 55% in

Rocket AF

About half of RE-LY patients were warfarin nave, whereas on 37.5% ofRocket AF patients were warfarin naive

Rocket AF was a Higher Risk Patient Population

C. Michael Gibson, M.S., M.D. Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151


53/72

RE-LY Rocket AFCountries 44 45

Patients 18,113 14,264

Median Duration ofFollow-Up

2 years (about 730days)

589 days ofexposure, 707days includingperiod off drug

during follow-upTime inTherapeutic Range(TTR)

64%67% warfarin-experienced61% warfarin-nave

57.8%

C. Michael Gibson, M.S., M.D. Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151


54/72

RE-LYDabigatran 110 mg 1.53% per yearDabigatran 150 mg 1.11% per yearWarfarin 1.69% per year

Rocket AFRivaroxaban 20mg 2.12% per yearWarfarin 2.42% per year

Primary Endpoint of Stroke or SystemicEmbolism: Non-inferiority Analysis

p


55/72

RE-LYDabigatran 110 mg 1.53% per yearDabigatran 150 mg 1.11% per yearWarfarin 1.69% per year

Rocket AFRivaroxaban 20mg 2.12% per yearWarfarin 2.42% per year

Primary Endpoint of Stroke or SystemicEmbolism: Superiority Analysis

p=0.117*

p


56/72

Dabigatran 110 mg 0.12% / yr 0.31


57/72

Dabigatran 110 mg 1.34% / yr 1.20 0.35Dabigatran 150 mg 0.92% / yr 0.76 0.03

Warfarin 1.20% / yr

HR

ITTP-value

Rivaroxaban 20 mg 1.62% / yr 0.99 0.92*

Warfarin 1.64% / yr

Rocket AF

RELY


*In an on treatment analysis in Rocket AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and 1.42%/ yr for warfarin, p=0.58. No on treatment analysis is available from RE-LY.

Major Bleeding


58/72

Dabigatran 110 mg 2.71% / yr 0.8 0.003

Dabigatran 150 mg 3.11% / yr 0.93 0.31

Warfarin 3.36

150 mg Dabigatran vs 110 mg Dabigatran = HR of 1.16 (1.001.34) p = 0.052

Major Bleeding

HRITTP-valueRE-LY

Rivaroxaban 20 mg 3.60% / yr 0.92 0.58*

Warfarin 3.45% / yr

Rocket AF


*There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY.

On TreatmentP-value


59/72

Conclusions: RE-LY vs Rocket AF Regarding PrimaryEndpoint of Stroke and/or Systemic Embolization

Primary Analysis of Non-Inferiority:Both drugs were non-inferior to Warfarin in reducing theprimary endpoint of stroke and systemic embolism

Secondary Analysis of Superiority:Pre-specified secondary On Treatment analysis,rivaroxaban was superior to warfarin.

ITT - dabigatran 150mg superior to warfarin; rivaroxabanwas not.



60/72

Dabigatran 150 mg reduced the risk of hemorrhagic stroke(HR 0.26, p


61/72

There was no difference in major bleeding associated with 150 mg ofdabigatran therapy versus warfarin.

There was statistically less major bleeding associated with 110 mg ofdabigatran than warfarin.

While there was numerically more major bleeding with rivaroxaban,there was less fatal bleeding with rivaroxaban compared with warfarin.

Extracranial bleeding was numerically less with 110 mg of dabigatran

than warfarin, but both 150 mg of dabigatran and rivaroxaban hadnumerically more extracranial bleeds than warfarin

Conclusions: RE-LY vs Rocket AF RegardingBleeding



62/72

Meta-analysis of

ischaemic stroke or systemic embolism

Favours warfarin Favours other treatment

0 0.3 0.6 0.9 1.2 1.5 1.8 2.1

Warfarin vs. New Anticoagulants

Warfarin vs. placebo

Warfarin vs. low dose warfarin

Warfarin vs. ASA

Warfarin vs. ASA + clopidogrel

Warfarin vs. ximelagatran


63/72


64/72

Amino acids and biologically activesmall peptides

Products of enzymatic breakdown oflipid free brain productsExperimental models demonstratedneuroprotective properties

Cerebrolysin


65/72

The Safety and Efficacy of Cerebrolysin in

Patients with Acute Ischaemic Stroke (CASTA)


66/72


67/72


68/72


69/72

Fluoxetine for motor recovery after acute ischaemicstroke (FLAME): a randomised placebo-controlled trial

Double-blind, placebo-controlled trialNine stroke centres in FranceIschaemic stroke and hemiplegia or significant

hemiparesisFugl-Meyer motor scale (FMMS) scoresFluoxetine (20 mg once per day, orally) orplacebo for 3 months starting 510 days after theonset of stroke.Primary outcome measure- change on FMMSbetween day 0 and day 90 after the start of thestudy drug

The Lancet Neurology, 10:2; 123 - 130, February 2011


70/72

Fluoxetine for motor recovery after acute ischaemic stroke(FLAME): a randomised placebo-controlled trial

118 patients randomised to fluoxetine (n=59) orplacebo (n=59), and 113 were included in theanalysis (57 in the fluoxetine group and 56 in the

placebo group)FMMS improvement at day 90 was significantlygreater in the fluoxetine group (adjusted mean340 points [95% CI 297384]) than in theplacebo group (243 points [199287];

p=0003).

The Lancet Neurology, 10:2; 123 - 130, February 2011


71/72

New definition of TIA- tissuediagnosis

Early and aggressive treatment usingexisting preventative treatment IV thrombolysis within 4.5 hours New oral anticoagulants as good or

better than warfarin New agents- experimental


72/72

Date post:	05-Apr-2018
Category:	Documents
Upload:	hakimah-k-suhaimi
View:	221 times
Download:	0 times

Stroke Updates

Documents