Acute ischemic stroke treatment in a nutshell

Acute ischemic stroke treatment
in a nutshell
Deidre De Silva
Neurology, SGH campus, NNI

Acute ischaemic stroke treatment strategies
Limit damage
from incident
stroke
Reperfusion
Antithrombotic
BP & glucose control
Prevent and
manage
complications
Stroke Units
Specific
complications

REPERFUSION
TIME IS BRAIN
An estimated 1.2 billion brain cells, including 58 million neurons, die for
each hour that an average stroke goes untreated. (Jeff Saver, ULCA)

Recanalization of
arterial occlusion

Reperfusion of
salvageable tissue

Attenuation of
Infarct Growth

Improved neurological
& functional outcomes

Reperfusion Strategies
• Acute intravenous thrombolyis
– Alteplase
– Desmoteplase
– Tenecteplase
• Acute intra-arterial thrombolysis
• Mechanical Thrombectomy
• Acute angioplasty and stenting

Acute intravenous alteplase

Specific guidelines

• BENEFIT
RCT EVIDENCE

RCT 3 to 4.5 hours
• ECASS III
• BENEFIT At 3 months, mRS 0-1
– 52.4% tPA, 45.2% Placebo
– OR 1.34 (1.02- 1.76), ARR 7.2%, NNT 14
• RISKS
– sICH 7.9% vs 3.5%, p=0.006
Hacke, NEJM, 2008

TIME IS BRAIN
• At 3 months, OR for good outcome
– 0-90 2.2 (1.8 to 4.5)
– 91-180 1.6 (1.1 to 2.2)
– 181-270 1.4 (1.1 to 1.9)
– 271-360 1.2 (0.9 to 1.5)
Hacke, Lancet 2004

Intravenous thrombolysis (IVT)
• 0-4.5 hours
– Intravenous alteplase 0.9 mg/ kg BW
• Treat as early as possible
• Beyond 4.5 hours
– Consider other intravenous thrombolytic agents in
trial setting
Eg. DIAS III intravenous desmoteplase within 9 hrs

Antithrombotic therapy: Antiplatelet
• Initiation within 48 hours of onset
• AST and CAST studies
• Benefits
– ARR 1% for recurrent stroke in first 2 weeks
– NNT 83 to prevent death or significant disability
– Low cost, easy administration, non toxic
• Mechanism:
– Early secondary prevention
– Possibly penumbral salvage

Acute ischaemic stroke treatment strategies
Limit damage
from incident
stroke
Reperfusion
Antithrombotic
BP & glucose control
Prevent and
manage
complications
Stroke Units
Specific
complications

Stroke Unit Management
• What is a stroke unit
– geographically defined area
– multidisciplinary team with training in stroke care
• Benefit
– reduces mortality: At 1 yr OR 0.79, NNT 26
– improves functional outcomes: At 1 yr death & dependency
OR 0.82
– advantages extending to 10 years after stroke
– benefits replicated outside trial setting
– cost-effective manner
– applicable to all patients
• Risks: None

How does stroke unit management
improve outcome
COMBINATION OF FACTORS including:
• screening for dysphagia
• prophylaxis of deep vein thrombosis and other complications
• lipid profile during hospital stay
• diagnosis of pathological mechanism and tailored secondary prevention
• encouragement to stop smoking
• stroke education for patients and family
• early coordinated planing of rehabilitation/discharge (physical, occupational,
speech)
• start of antithrombotic medications within 48 h
• prescription of antithrombotic medication at discharge
• prescription of anticoagulants at discharge
• access to vascular and neurosurgeons

Acute ischaemic stroke treatment strategies
Limit damage
from incident
stroke
Reperfusion
Antithrombotic
BP & glucose control
Prevent and
manage
complications
Stroke Units
Specific
complications

Anti-thrombotic therapy in longterm
secondary stroke prevention
Deidre De Silva
Neurology, SGH campus, NNI

Antithrombotic agents
• Antiplatelets
• Anticoagulants
– Heparin
• Unfractionated
• LMW
• Heparinoids
– Warfarin
– Novel agents
• Direct thrombin inhibitors
• Factor Xa inhibitors

Antiplatelets
Dosing
Cost
Side effects
Aspirin
OM
$0.05 per 100 mg
($0.05 per day)
PUD
Clopidogrel
OM
$1.28 per tab
($1.28 per day)
Ticlopidine
BD
$0.11 per tab
($0.22 per day)
Neutropenia
Dipyridamole
TDS
$0.05 per tab
($0.30 per day)
Headache
Many tablets
Cilostazol
BD
Not available
Headache, palpitations,
dizziness, diarrhoea

Antiplatelets in long-term secondary
stroke prevention
Any antiplatelet therapy
Which Antiplatelet
Combination

Any antiplatelet therapy
Anti-thrombotic Trialists’ Collaboration
• Antiplatelet therapy among patients with
previous ischemic stroke/ TIA
– Significantly reduced vascular events
– Over 2 years per 1000 patients,
• 36 fewer serious vascular events
• 25 fewer recurrent ischemic strokes
• 6 fewer non-fatal myocardial infarction

Which antiplatelet
Acceptable options
Aspirin + Dipyridamole
Aspirin alone
Clopidogreal alone
Ticlopidine alone

Which antiplatelet better
• Ticlopidine slightly better than aspirin post-stroke /TIA
(TASS)
– NNT 40 over 39 months for stroke
– Side effects of ticlopidine
• Clopidogrel may be better than aspirin for pts with MI/
Stroke/ PAD (CAPRIE)
– NNT 200 over 23 mths for MI/ischemic stroke/
vascular death in composite group
– No significant difference for ischemic stroke
subgroup

Which antiplatelet better-Combinations
• Aspirin and dipyrimadole better than aspirin post-stroke (ESPS II,
ESPRIT)
- NNT 104 per year for vascular death, MI, ischemic stroke, major
bleed
• Aspirin and Clopidogrel higher risk than clopidogrel post-stroke
(MATCH)
– Similar rates for ischemic stroke/ MI
– Higher rates for ICH/ ,major bleeding
– Not advised for ischemic stroke indication
– Special situations eg. post coronary intervention
- Aspirin + dipyridamole vs clopidogrel post-stroke (PROFESS)
- Not superior
- Cannot say if inferior or not

NEW COMERS
Cilostazol
Terutroban

Cilostazol (CSPS II)
• Randomised, double blind
• Inclusion: cerebral infarction within 26 wks
• Cilostazol 100 mg BD vs Aspirin 81 mg OM
• Not inferior
• Lower rates of ICH/ major bleeding
At mean of 29 mths
Cilostazol
Aspirin
RRR
Stroke- ischemic or
hemorrhagic
6.1%
8.9%
0.74 (0.56-0.98)
for non-inferiority
ICH, other major bleeding
1.7%
4.3%
P=0.004

TERUTROBRAN
(Thromboxane receptor antagonist):
PERFORM study
• Randomized, double-blind
• Inclusion: recent history of stroke or TIA
• Versus aspirin or aspirin + dipyridamole
• Did not fulfill non-inferiority

Anticoagulation in long-term
secondary stroke prevention
– Cardioembolic stroke

Anticoagulants
– Heparin: activates AT III
• UF, LMW, heparinoid
– Warfarin: Vit K antagonist
– Direct thrombin inhibitor: Dabigatran
– Direct Factor Xa inhibitor: Rivaroxaban, Apixaban

Anticoagulants
Dosing
Monitoring
SE
UF Heparin
6H
PTT
IV
LMW Heparin
OM, BD
No need
SC
(Anti-Xa)
Coumadin
TDS
INR
Variable dose
Interactions
Dabigatran
BD
No need
Just registered by HSA
Rivaroxaban
OM
No need
Not FDA approved yet
Apixaban
BD
No need
Not FDA approved yet

Secondary prevention of stroke for
patients with AF

WARFARIN
Secondary prevention: Prior TIA or minor stroke (EAFT)
• Warfarin (INR 2.5 to 4.0) vs placebo
Effective NNT over 2 y = 6-7
• Aspirin 300 mg om vs placebo
Safe alternative NNT over 2 y = 50
• Warfarin vs Aspirin
Warfarin superior NNT over 2 y =7-8
At 28
months
Warfarin
Placebo
P value
Aspirin
Placebo
P value
Stroke
8.9%
23.4%

NEW COMERS
Dabigatran
Rivaroxaban
Apixaban

DABIGATRAN
AF + high risk for embolism (20% prior stroke), RELY: randomised, unblinded
• Dabigatran 110mg BD vs warfarin (INR 2-3)
– Non-inferior for systemic embolisation and stroke
– Lower major bleeding rates
• Dabigatran 150mg BD vs warfarin (INR 2-3)
– Superior for systemic embolisation and stroke
– Similar major bleeding rates
• ** Higher risk of MI
• ** Renal impairment
At 2 years
Warfarin
Dabigatran 110
Dabigatran 150
Stroke + systemic embolism
1.69%
1.53%
1.11%
Major bleed
3.36%
2.71%
3.11%
Mortality
4.13%
3.75%
3.64%

DABIGATRAN
• 1000 stroke patients treated with dabigatran
over warfarin for 1 year
– 150 mg BD: 7 fewer strokes, same bleeding rate
– 110 mg BD: 5 fewer strokes, 14 fewer bleeds

RIVAROXABAN
AF + high risk for embolism (53% prior stroke)
ROCKET-AF: randomised, blinded
• RIVAROXABAN 20 mg OM vs warfarin (INR 2-3)
– Per protocol: stroke and non-CNS systemic embolism (1.70% vs.
2.15%, p=0.015), 21% relative risk reduction
• Non-interior
• No proof of superiority
– Intent to treat (ITT): (2.12% vs. 2.42%)
• Non-inferior
• Superior
• Any bleeding: No increased risk (14.91% vs. 14.52%, p=0.442)
• Major bleeding: Comparable (3.60% vs. 3.45%, p=0.576)
• ICH: Fewer (0.49% vs. 0.74%, p=0.019)

RIVAROXABAN
• 1000 stroke patients treated with rivaroxaban
over warfarin for 1 year
– 3 fewer stroke and systemin embolism
– 1 fewer major bleed

APIXABAN
AF patients could not tolerate warfarin (14% prior stroke) (AVERROES)
• Apixaban 5 mg BD vs Aspirin
– Stroke and systemic embolism (1.6% vs 3.7% per year)
P

APIXABAN
18 000 AF patients (ARISTOTLE trial)
• Apixaban 5 mg BD VS. Dose adjusted Warfarin
• Preliminary results “noninferior to the older
standard for the prevention of stroke and
systemic embolism”
• Full results out on August 28

Other indications for anticoagulation
Cardiomyopathy
Post MI
• Anterior wall MI
• Any MI with severe RWMA
LV thrombus
Mitral stenosis with or without AF
Prothrombotic states

Rationalising long-term therapy

Good Side: Beneficial Effects
• Retard/ reverse acute thrombotic process
• Prevention of recurrent ischemic stroke
• Prevention of other ischemic events
– IHD
– PVD
• Prevention of complications eg. DVT

Dark Side: Adverse effects
• Haemorrhage
– Intracranial
– Extracranial
• Allergic/ hypersensitivity
• Upper-GI toxicity (aspirin)
• Skin rash (thienopyridine)
• Diarrheoa (thienopyridines)
• Neutropenia, thrombocytopenia (Ticlopidine)
• Headache, giddiness (Dipyridamole: 1/3 discontinue)
• Monitoring (warfarin)
• Drug interactions
• Food interactions

One of many concerns
Don’t forget about
• Management of stroke complications
• Management of atherosclerotic risk factors
– Hypertension
– Diabetes
– Hyperlipidemia
– Smoking cessation
– Obesity management

Antithrombotic therapy:
Considerations for individual patient
• Side effects
• Dosing, Compliance, Need for monitoring
• Cost
• Other indications
• Contra-indications
• Resistance
– no guidelines yet, much ongoing research
• Genetic polymorphisms
• Need for gastric protection
• Drug-drug interaction
• Drug-food interaction

Great population benefit in view of high
incidence of stroke
• ESPRIT (A+D vs A) ARR 3% over 3 years
– NNT to prevent vascular event/ bleeding in 3 years = 33
• In Singapore, 10000 ischemic stroke pts/ yr
– Assume 2/3 can be treated with A + D = 6666
– Number of potential events prevented for one year
cohort after 3 years = 202

Thank
you

Management of Hypertension,
Diabetes and Dyslipidemia for
Secondary Stroke Prevention
Jennifer Justice F. Manzano, MD
Stroke Fellow
Singapore General Hospital campus
National Neuroscience Institute

Hypertension
• Hypertension is the most modifiable stroke risk factor
• Systolic and diastolic BP are associated with recurrent
stroke
– But there is no clear threshold
• Should all post-stroke patients be given
antihypertensives
• Which antihypertensives to use
• What is the target BP

Should all post-stroke patients be given
antihypertensives
• PROGRESS Trial
- Significant reduction in recurrent stroke only for those
with baseline SBP ≥ 140 mm Hg
PROGRESS Collaborative Group, Lancet 2001

Should all post-stroke patients be given
antihypertensives
Mancia, et al, J Hypertens 2009

Should all post-stroke patients be given
anti-hypertensives
• No.
– Only start treatment if BP >140/90 mmHg
– Not certain for BP 130-140/80-90 mmHg
– Not for BP

Which antihypertensives to use
• Stroke risk reduction correlates with BP reduction
• No drug-class specific treatment effect
– Major antihypertensive drug classes do not
differ significantly in
• BP reduction
• Cardiovascular risk reduction

Which antihypertensives to use
Law, et al, BMJ 2009

Which antihypertensives to use
• Direct data that diuretics or diuretics + ACEI are
useful (AHA/ASA 2010 Guidelines)
• Individualized treatment
– Each drug class has specific indications,
contraindications, side effects

Which antihypertensive to use
- Combination therapy
• Effective BP control is often only achieved by combining
at least 2 antihypertensive drugs
• Combination therapy as initial treatment may have
advantages, especially in high-risk patients in which
early BP control is desirable
• CAUTION: Beta blocker + diuretic favors the
development of diabetes in predisposed patients

Which antihypertensive to use
- Combination therapy
Law, et al, BMJ 2009

Which antihypertensive to use
- Combination therapy
Law, et al, BMJ 2009

Which antihypertensive to use
- Combination therapy
Law, et al, BMJ 2009

What is the target BP – Upper limit
• JNC 7:

What is the target BP – Upper limit
• AHA/ASA (2010) and European (2009) guidelines:

What is the target BP – Lower limit
J-Curve Phenomenon
• In patients at high
cardiovascular risk,
antihypertensive
treatments that reduce
SBP to ≤ 120-125 mmHg
and DBP < 70-75 mm Hg
may be accompanied by an
increase in the incidence of
coronary events
Chrysant, World J Cardiol 2011

What is the target BP – Lower limit
J-Curve Phenomenon
• J-curve phenomenon exists even in placebo-treated
groups of many trials
• Between SBP 120-140 mmHg and DBP 70-80 mmHg,
the differences in achieved cardiovascular protection are
small
• Lower is not always better!
• No clear guidelines currently

Diabetes
• Diabetes is a risk factor for stroke, but its
relationship to recurrent stroke is unclear.
• Does good glycemic control translate to
reduction of stroke recurrence
• How tight should glycemic control in
diabetics

Does good glycemic control translate to
reduction of stroke recurrence
• DCCT and UKPDS : Good glycemic control
– Reduces microvascular complications
– No reduction in macrovascular complications
DCCT Research Group, N Engl J Med, 1993
UKPDS Group, Lancet 1998

Why DM control in stroke patients
40% of stroke
patients in
Singapore
have DM
De Silva, et al, Cerebrovasc Dis 2005

Does good glycemic control translate to
reduction of stroke recurrence
• DCCT and UKPDS follow up after the study ceased
11 years
• No significant difference in HbA1c
• Significant reduction in cardiovascular events in those with good
glycemic control previously
DCCT Research Group, N Engl J Med, 1993
UKPDS Group, Lancet 1998

How tight should glycemic control be in
diabetics - ACCORD Study
10,251 patients with mean HbA1c 8.1% +
Previous cardiovascular event or at least 2 vascular risk
factors
Intensive therapy
(target HbA1c

How tight should glycemic control be in
diabetics - ACCORD Study
Outcome
Nonfatal
stroke
Fatal
stroke
Intensive
therapy
(HbA1c

How tight should glycemic control be in
diabetics - Other Studies
• ADVANCE and VADT: no significant difference in
- cardiovascular events
- mortality
Patel, et al, N Engl J Med 2008
Duckworth, et al, N Engl J Med 2009

How tight should glycemic control be in
diabetics
• Current recommendation: HbA1c

Dyslipidemia
• Modest relationship between high total cholesterol or LDL with
an increased risk of ischemic stroke.
• Link between high triglycerides and ischemic stroke
• Possible link between low LDL and ICH.
• Larger reduction in LDLc greater stroke reduction
– Meta-analysis of statin trials including >90,000
patients
• Should all post-stroke patients be on statins
• What is the target lipid level

Should all post-stroke patients be on
statins – SPARCL Trial
• 4371 persons with LDLc 100-190mg/dL
• Prior stroke (hemorrhagic or ischemic) or TIA, no hx of CAD
• Randomized to 80 mg Atorvastatin vs. Placebo
• Mean follow-up of 4.9 years
• Mean LDLc: 73 mg/dL Atorvastatin vs. 129 mg/dL
• Endpoint: fatal and nonfatal stroke
– Atorvastatin 11.2% vs Placebo 13.1%
– 5-yr absolute stroke risk reduction 2.2%, p=0.03, NNT = 45
– 5-yr absolute risk reduction in cardiovascular events 3.5%,
p=0.002, NNT= 29
– hemorrhagic strokes: Atorvastatin 55 vs. 33 Placebo
Amarenco, et al, Stroke 2007

Statins and ischemic stroke
- Meta-analysis
Amarenco, et al, Lancet Neurol 2009

Statins and hemorrhagic stroke
- Meta-analysis
Amarenco, et al, Lancet Neurol 2009

Should all stroke patients be on statins
What is the target LDL
Risk Factors
Recommendation - Lipids
Class/Level of
Evidence
Statin therapy with intensive lipid-lowering effects is recommended
to reduce risk of stroke and cardiovascular events among patients
with ischemic stroke or TIA who have evidence of atherosclerosis,
an LDLc level ≥100 mg/dl, and who are without known CHD.
For patients with atherosclerotic ischemic stroke or TIA and without
known CHD, it is reasonable to target a reduction of at least
50% in LDLc or a target LDLc level of

Cr: Ian Sayson

BP control
in secondary stroke prevention
• Should all post-stroke patients be given
antihypertensives
– Only start treatment if BP >140/90 mmHg
– Not certain for BP 130-140/80-90 mmHg
– Not for BP

Glycemic control
in secondary stroke prevention
• Does good glycemic control translate to
reduction of stroke recurrence
– No clear reduction in macrovascular
complications such as stroke
• How tight should glycemic control in diabetics
HbA1c

Lipid control
in secondary stroke prevention
• Should all post-stroke patients be on statins
No. Only if LDLc ≥100 mg/dl
• What is the target lipid level
– Reduce LDLc by at least 50% or
– Target an LDLc level of

µέτρον ἄριστον
Dbuma Chenpo
Cr: April Toh