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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
ABCD2 Score
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
80% reduction in risk of stroke at 90 days Favouring early & aggressive treatment group
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
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
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
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
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
8.4
Any ICH
Symptomatic ICH
Fatal ICH
Symptomatic oedema
Overall mortality
mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale *NINDS. N Engl J Med 1995;333:1581-1587.
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.
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
Thrombolysis Prevention of early complications eg. aspiration Better nutrition Standardized control of risk factors: BG, BP, Cholesterol Early & focused rehabilitation
Unpredictable response
VKA therapy has several limitations that make it difficult to use in practice
Warfarin resistance
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 practice2,3
66%
9%
<2.0 2.03.0 INR >3.0
In ACTIVE-W trial1
Rate of major bleeding (% per year) 4 4
P=0.53
3
P=0.9
3
0
Oral anticoagulation N=3,371 Clopidogrel + Aspirin N=3,335
0
Warfarin 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
PARENTERAL INDIRECT
ROCKET
Va Xa
Fondaparinux
AT II AT
LMWH UFH
RELY
Dabigatran AZD 0837 Fibrinogen
IIa Fibrin
43
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.
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
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)
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.
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151
Trial
Design
Start date
Duration (mo) 15
# 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
26 23 17 24
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
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151
3.48 13 43 29 13 2 62 63 90 40 55 17
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
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151
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%
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
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
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
*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
Rocket AF
Rivaroxaban 20 mg Warfarin 3.60% / yr 3.45% / yr 0.92
*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
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151
Rocket AF Investigators, AHA 2010; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151
Favours warfarin
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