UPDATE ON STROKE

Prof Dr Hamidon Basri

 Stroke- 3rd leading cause of death Major cause of disability Incidence: 1 in 2000 population Decreasing trend in developed countries Better prevention treatment and aftercare management

INCIDENCE
HEMORRHAGIC STROKE

MORTALITY
30 DAY MORTALITY (%)

ISCHAEMIC STROKE

40 30 20 10 0
8%-12%

36%-37%

25%

75%

ISCHAEMIC STROKE HAEMORRHAGIC STROKE Hamidon BB et al. Neurology Asia 2003 American Heart Association Heart Disease and Stroke Statistics-2005 Update

 Rapidly developing clinical neurological signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death, with no apparent cause other than of vascular origin

Transient Ischaemic Attack (TIA) < 24 hours

Assessed by imaging- absence of end organ injury

Cumulative risk of stroke after TIA or minor stroke

ABCD2 Score

TIA and Minor Stroke- EXPRESS Trial

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 existing preventative treatments

EXPRESS trial- What made the difference?

TIA and Minor Stroke

80% reduction in risk of stroke at 90 days Favouring early & aggressive treatment group

Aspirin ASAP Risk Factor control

Neurosurgery

Thrombolysis

Cultural/belief - minor, overcome - TCM Social - staying alone - ignorance Geographical location, remote areas, traffic Organisational in-hospital delays

Zamri M, Hamidon BB

Delays in Stroke

75% pre-hospital delays 65% ignorant of stroke symptoms 78% depend on other family members to decide on seeking treatment
Rahmah MA, Hamidon BB

6 large RCTs European Cooperative Acute Stroke Study (ECASS I and II) NINDS (1 and 2) ATLANTIS A and B

Pooled analysis of individual patient data (n=2775) from 6 trials of i.v. alteplase vs placebo showed that the effective treatment window may extend to 4.5 hours
4.0

Adjusted odds ratio

3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 60

OR 2.8

OR 1.5

OR 1.4

OR 1.2

120

180

240

300

360

1.5h
OR, odds ratio

3h

4.5h

6h

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

Hacke et al. Lancet 2004; 363: 768774.

To assess efficacy and safety of alteplase between 3 and 4.5 hours after stroke onset in the European setting, collecting additional confirmatory prospective data

Randomised, placebo-controlled, double-blind clinical 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

Age 1880 yr Acute ischaemic stroke, after excluding ICH Onset of stroke symptoms 34.5 h prior to initiation of study drug
Identical to the European Summary of Product Characteristics (ESPC) of alteplase for ischaemic stroke, except for treatment time window

ICH, intracranial haemorrhage

Overall mortality (day 90) Any ICH Symptomatic ICH (ECASS 3 definition) Any blood in the brain or intracranially associated with a clinical deterioration 4 points on the NIHSS for which the haemorrhage has been identified as the dominating cause Symptomatic oedema Brain oedema with mass effect as the dominating pathology for clinical deterioration Serious adverse events

ICH, intracranial haemorrhage; NIHSS, National Institutes of Health Stroke Scale

30

p=0.001 27.0

Alteplase Placebo

25

Patients (%)

20
17.6

15
p=0.7

10
p=0.008 2.4 0.3 0.7 0.0

p=0.9 6.9 7.2 7.7

8.4

Any ICH

Symptomatic ICH

Fatal ICH

Symptomatic oedema

Overall mortality

Primary endpoint: Disability @ day 90

Secondary endpoint
mRS dichotomised on a favourable (mRS 01) versus unfavourable outcome (mRS 26)

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

mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale *NINDS. N Engl J Med 1995;333:1581-1587.

Day 90: mRS 0,1 Excellent recovery

Analysis Alteplase n/N (%) Placebo n/N (%) OR (95% CI) 1.34 (1.021.76) P

Unadjusted

219/418 (52.4%)

182/403 (45.2%)

0.038

Adjusted*

1.42 (1.021.98)
0.5 1 1.5

0.037

Favours Placebo

Favours Alteplase

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

Intent-to-treat population
mRS score Alteplase (n=418) Placebo (n=403)
0 27.5 1 24.9 2 14.1 3 9.3 4 9.3 5 6

8.1 6.7

p=0.024*
21.8 23.3 16.4 11.4 13.7 5.2 8.2

Per-protocol population
mRS score Alteplase (n=375) Placebo (n=355) Patients 0%
0 29.1 1 25.9 2 14.4 3 10.1 4 8.8 5 6

5.6 6.1

p=0.016*
22.3 23.1 16.9 11.8 14.9

4.2 6.8

20%

40%

60%
Method

80%

100%

*stratified on CochranMantelHaenszel test, adjusted for baseline NIHSS scores and time-to-treatment onset as per Lees et al. N Engl J Med 2006;354:588-600.

Co-Authors and Writing Committee

However

IV alteplase 34.5 h after stroke symptoms Effective treatment with no increase in ICB compared with Rx <=3 hrs A viable therapeutic option for the many patients previously excluded This finding opens a window of opportunity for later-arriving stroke patients

having more time does not mean we should take 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

Experienced physician/neurologist in stroke 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 or ASPECT Score <7

Thrombolysis

Intravenous alteplase (rtPA) 0.9 mg/kg 10% as bolus, remaining 90% over 1 hour

Transcranial Doppler

Ultrasound enhanced thrombolysis (CLOTBUST trial) 49% vs 30% (control) achieved complete recanalisation

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

MRI/CT perfusion- better selection on salvageable penumbral tissues Mechanical devices

Acute Stroke Care Unit

Thrombolysis Prevention of early complications eg. aspiration Better nutrition Standardized control of risk factors: BG, BP, Cholesterol Early & focused rehabilitation

Unpredictable response

Numerous fooddrug interactions

Narrow therapeutic window (INR range 2.03.0)

VKA therapy has several limitations that make it difficult to use in practice

Numerous drugdrug interactions

Slow onset/ offset of action

Warfarin resistance

Routine coagulation monitoring

Frequent dose adjustments

INR = International normalized ratio; VKA = vitamin K antagonist. Ansell J, et al. Chest 2008;133;160S-198S. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008;22:129-137. Nutescu EA, et al. Cardiol Clin 2008;26:169-187.

Clinical trial1 Eligible patients receiving Warfarin (%)

Clinical practice2,3

66%

44% 38% 25% 18%

9%
<2.0 2.03.0 INR >3.0

In ACTIVE-W trial1
Rate of major bleeding (% per year) 4 4

In BAFTA trial2 patients 75 yrs of age (N=973)

Rate of all major bleeding (%)

P=0.53
3

P=0.9
3

0
Oral anticoagulation N=3,371 Clopidogrel + Aspirin N=3,335

0
Warfarin Aspirin

Superior stroke prevention with anticoagulation

42% risk of stroke with oral anticoagulation vs. clopidogrel + Aspirin

52% risk of stroke, intracranial haemorrhage, systemic embolism with warfarin vs. Aspirin

1. Connolly S for the ACTIVE Investigators. Lancet 2006;367:1903-1912. 2. Mant J, et al. Lancet 2007;370:493-503.

ORAL DIRECT
X

TF/VIIa IX VIIIa IXa AT

PARENTERAL INDIRECT

ROCKET
Va Xa

Rivaroxaban Apixaban Edoxaban Betrixaban

Fondaparinux

AT II AT

LMWH UFH

RELY
Dabigatran AZD 0837 Fibrinogen

IIa Fibrin
43

(Randomized Evaluation of Long-Term Anticoagulant Therapy) Atrial fibrillation

1 Risk Factor Absence of contra-indications

Patients were eligible if they had atrial fibrillation documented on electrocardiography performed at screening or within 6 months beforehand and at least one of the following characteristics: 1. 2. 3. Previous stroke or transient ischemic attack a left ventricular ejection fraction of less than 40% New York Heart Association class II or higher heart-failure symptoms within 6 months before screening An age of at least 75 years or an age of 65 to 74 years plus diabetes mellitus, hypertension, or coronary artery disease.

951 centers in 44 countries

Blinded Event Adjudication.

4.

Open
Warfarin adjusted (INR 2.0-3.0) N=6000
Dabigatran Etexilate 110 mg BID N=6000

Blinded
Dabigatran Etexilate 150 mg BID N=6000

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

Risk Factors

Atrial Fibrillation
Rivaroxaban
20 mg daily
15 mg for Cr Cl 30-49 ml/min
Randomize Double Blind / Double Dummy (n ~ 14,000)

CHF Hypertension At least 2 or 3 required* Age 75 Diabetes OR Stroke, TIA or Systemic embolus

Warfarin
INR target - 2.5 (2.0-3.0 inclusive)

Monthly Monitoring Adherence to standard of care guidelines

Primary Endpoint: Stroke or non-CNS Systemic Embolism

Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin
K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation
Rocket AF Investigators, AHA 2010

 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 scored two points by having a prior stroke/TIA. This may account for the high rate 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

Trial

Inclusion CHADS 3 or stroke/TIA (15% CHADS 2) CHADS 1 (50% VKA nave)

Design

Start date

Duration (mo) 15

Current / Goal Enrollment 14,264

# sites ~1200

ROCKET AF

Sham INR Sham INR Open label Open label Sham INR Sham INR

12/06

ARISTOTLE

1/07

15

~15,000

~937

RE-LY

CHADS 1 (30% VKA nave) CHADS 1 CHADS 1 CHADS > 2

12/2005 9/2003 8/2000 10/2008

26 23 17 24

18,113 4576 3922 20,500

706 165 409 ~1400

AMADEUS SPORTIF V ENGAGE

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

RELY:
Primary Efficacy Evaluation: Stroke or non-CNS Embolism
Non-Inferiority: Superiority: Intention-to-treat 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-toTreat

RE-LY used Intention to treat for both non-inferiority and superiority testing; Rocket AF used on treatment analysis for first tests of noninferiority and superiority
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

RELY:
Primary Safety Evaluation: Major bleeding

Rocket AF:
Primary Safety Evaluation: Major or non-Major Clinically Relevant Bleeding

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

Characteristic
Randomized Mean age (years) Male (%) CHADS2 score (mean) 0-1 (%) 2 (%) 3+ (%) Prior stroke/TIA (%) Prior MI (%)

Dabigatran 110 mg
6015 71.4 64.3 2.1 32.6 34.7 32.7 19.9 16.8 32.2 40.0 49.9

Dabigatran 150 mg
6076 71.5 63.2 2.2 32.2 35.2 32.6 20.3 16.9 31.8 38.7 49.8

Warfarin
6022 71.6 63.3 2.1 30.9 37.0 32.1 19.8 16.1 31.9 40.6 51.4

CHF (%) Baseline ASA (%)

Warfarin Nave (%)

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

Rocket AF: Baseline Demographics

Rivaroxaban (N=7081) CHADS2 Score (mean) 2 (%) 3 (%) 4 (%) 5 (%) 6 (%) Prior VKA Use (%) Congestive Heart Failure (%) Hypertension (%) Diabetes Mellitus (%) Prior Stroke/TIA/Embolism (%) Prior Myocardial Infarction (%)
Based on Intention-to-Treat Population
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

Warfarin (N=7090) 3.46 13 44 28 12 2 63 62 91 39 55 18

3.48 13 43 29 13 2 62 63 90 40 55 17

Rocket AF was a Higher Risk Patient Population

Whereas 32.4% of patients in RE-LY were low risk CHADS 0-1, there were none of these patients in Rocket AF Whereas just over 32% of patients in RE-LY were high risk CHADS score of 3 or more, over 85% of Rocket AF patients had a CHADS score of 3 or more

RE-LY patients were about 71.5 years old, and Rocket AF patients were 73 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% of Rocket AF patients were warfarin naive

C. Michael Gibson, M.S., M.D.

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

RE-LY Countries Patients 44 18,113

Rocket AF 45 14,264

Median Duration of 2 years (about 730 589 days of Follow-Up days) exposure, 707 days including period off drug during follow-up
Time in Therapeutic Range (TTR) 64%
67% warfarin-experienced 61% 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

Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis Non Inferiorirty p vs warfarin RE-LY Dabigatran 110 mg 1.53% per year ITT Analysis p<0.001 Dabigatran 150 mg 1.11% per year p<0.001 Warfarin 1.69% per year Rocket AF Rivaroxaban 20mg Warfarin
Per Protocol Analysis

2.12% per year 2.42% per year

p<0.001

Primary Endpoint of Stroke or Systemic Superiority Embolism: Superiority Analysis p vs warfarin ITT Analysis RE-LY Dabigatran 110 mg 1.53% per year p=0.34 Dabigatran 150 mg 1.11% per year p<0.001 Warfarin 1.69% per year
Rocket AF Rivaroxaban 20mg Warfarin

2.12% per year 2.42% per year

p=0.117*

RELY Dabigatran 110 mg Dabigatran 150 mg Warfarin 0.12% / yr 0.10% / yr 0.31 0.26

HR <0.001 <0.001

ITT P-value

0.38% / yr

Rocket AF

Rivaroxaban 20 mg
Warfarin

0.26% / yr
0.44% / yr

0.59

0.012*

*In an on treatment analysis in Rocket AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr for warfarin, p=0.024. No on treatment analysis is available from RE-LY.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151

RELY Dabigatran 110 mg Dabigatran 150 mg Warfarin 1.34% / yr 0.92% / yr 1.20 0.76

HR 0.35 0.03

ITT P-value

1.20% / yr

Rocket AF Rivaroxaban 20 mg Warfarin 1.62% / yr 1.64% / yr 0.99 0.92*

*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.

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

Major Bleeding RE-LY

Dabigatran 110 mg Dabigatran 150 mg Warfarin 3.36 2.71% / yr 3.11% / yr HR 0.8 0.93 ITT P-value 0.003 0.31

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

Rocket AF
Rivaroxaban 20 mg Warfarin 3.60% / yr 3.45% / yr 0.92

On Treatment P-value 0.58*

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

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

Conclusions: RE-LY vs Rocket AF Regarding Primary Endpoint of Stroke and/or Systemic Embolization
Primary Analysis of Non-Inferiority: Both drugs were non-inferior to Warfarin in reducing the primary 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; rivaroxaban was not.

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

Conclusions: RE-LY vs Rocket AF Regarding Stroke

Dabigatran 150 mg reduced the risk of hemorrhagic stroke (HR 0.26, p<0.001) as did rivaroxaban (HR 0.59, p=0.024).
Both drugs were therefore safer. Dabigatran 150 mg also reduced the risk of ischemic stroke (HR=0.76, p=0.03) while rivaroxaban did not (p=0.58)(dabigatran was associated with thrombotic efficacy)

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

Conclusions: RE-LY vs Rocket AF Regarding Bleeding

There was no difference in major bleeding associated with 150 mg of dabigatran therapy versus warfarin. There was statistically less major bleeding associated with 110 mg of dabigatran 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 had numerically more extracranial bleeds than warfarin

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

Meta-analysis of ischaemic stroke or systemic embolism

Warfarin vs. placebo

Warfarin vs. low dose warfarin Warfarin vs. ASA Warfarin vs. ASA + clopidogrel Warfarin vs. ximelagatran Warfarin vs. New Anticoagulants 0 0.3 0.6 0.9 1.2 1.5 1.8 2.1

Favours warfarin

Favours other treatment

Cerebrolysin
Amino acids and biologically active small peptides Products of enzymatic breakdown of lipid free brain products Experimental models demonstrated neuroprotective properties

The Safety and Efficacy of Cerebrolysin in Patients with Acute Ischaemic Stroke (CASTA)

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

Double-blind, placebo-controlled trial Nine stroke centres in France Ischaemic stroke and hemiplegia or significant hemiparesis Fugl-Meyer motor scale (FMMS) scores Fluoxetine (20 mg once per day, orally) or placebo for 3 months starting 510 days after the onset of stroke. Primary outcome measure- change on FMMS between day 0 and day 90 after the start of the study drug
The Lancet Neurology, 10:2; 123 - 130, February 2011

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

118 patients randomised to fluoxetine (n=59) or placebo (n=59), and 113 were included in the analysis (57 in the fluoxetine group and 56 in the placebo group) FMMS improvement at day 90 was significantly greater in the fluoxetine group (adjusted mean 340 points [95% CI 297384]) than in the placebo group (243 points [199287]; p=0003).
The Lancet Neurology, 10:2; 123 - 130, February 2011

New definition of TIA- tissue diagnosis Early and aggressive treatment using existing preventative treatment IV thrombolysis within 4.5 hours New oral anticoagulants as good or better than warfarin New agents- experimental