Prof. Ovidiu Bajenaru, MD
• Professor of neurology at the University of medicine and pharmacy
• Chairman and head of the Neurology department of the University hospital of mergency Bucharest
• President of the Romanian Society of neurology
• Focuses on stroke, dementia and neurodegenerative diseases, multiple sclerosis
Current stroke management:
from prevention of first to
prevention of recurrent stroke
Prof. Ovidiu Bajenaru, MD, PhD
University of Medicine and Pharmacy ―Carol Davila‖ Bucharest
Chair and Department of Neurology – University Emergency Hospital Bucharest
RISK FACTORS FOR STROKE
• NON-MODIFIABLE • AGE
SEX ( M > F )
• LOW BIRTH WEIGHT
• ETNICITY / RACE ( blacks, latin/ hispano-americans )
• GENETIC
• MODIFIABLE • HTA
• CIGARETTE SMOKING
• DIABETES MELLITUS
• DYSLIPIDEMIA
• ATRIAL FIBRILLATION
• ASYMPTOMATIC CAROTID ARTERY
STENOSIS
• DIET and NUTRITION
• SICKLE CELL DISEASE
• POSTMENOPAUSAL HORMONE
THERAPY
• ORAL CONTRACEPTIVES
• PHYSICAL INACTIVITY
• OBESITY and BODY FAT
DISTRIBUTION
6
5
3
2
1
0
4
Incidence (%)
7
STOP-1
SHEP
STONE SYST-
EUR
SYST-
China
HOT
CAPPP
STOP-2
NICS
NORDIL
INSIGHT
Stroke
MI
Kjeldsen et al 2001
Stroke more common than MI
in hypertension trials
0
10
20
30
40
50
60
70
80
90
74- 119
140- 159
180- 300
Men Events/ 1000 pts.
TAS
Women
0
10
20
30
40
50
60
70
80
90
74- 119
140- 159
180- 300
Events/ 1000 pts.
TAS
120- 139
160- 179
120- 139
160- 179
Vokonas et al 1988
65-94 y-o 35-64 y-o
Hypertension and CV risk
in older people
HTA – major risk factor for:
Cerebrovascular & cardiovascular diseases
Associated disorders (co-morbidities)
Dementia ( Alzheimer, vascular, mixed)
modified after Miia Kivipelto, MD, PhD and Alina Solomon, MD - NEUROLOGY
2009;73:168-169
HTA treatment is associated :
Reduced CV mortality and morbidity Reduced stroke incidence (30-40%) Reduced coronary events (20%) Significant reduction of heart failure Benefits are even more important for patients with diabetes mellitus
Ghidul pentru managementul HTA 2007 al ESH si al ESC; Revista Romana de Cardiologie, vol.XXII, nr 3, 2007
Reappraisal of European Guidelines on Hypertension Management: a European Society of Hypertension Task Force document Giuseppe Mancia, Journal of
Hypertension 2009, 27:2121-2158; HTA = hipertensiune arteriala; AVC = accident vascular cerebral; CV =cardiovascular
Current AHA/ ASA guidelines for primary prevention of stroke recommend a
systolic/diastolic BP goal of 140/90 mm Hg in the general population and
130/80 mm Hg in persons with DM
Whether a lower target BP has further benefits is uncertain
To prevent stroke most effectively, blood-pressure-lowering drugs should
reduce mean blood pressure without increasing variability; ideally they should
reduce both ( CCB superior to beta-blockers )
Rothwell P. et al – Lancet Neurology, 2010, 9(5): 469 - 480
Stroke Risk Stratification Schemes for
Patients With Atrial Fibrillation
The risk of ischemic stroke is significantly increased in AF patients, and
there is evidence of a graded increased risk of stroke associated with
advancing age Marinigh R et al - J Am Coll Cardiol, 2010; 56:827-837
Ischemic stroke risk vs. bleeding risk
Guidelines for the management of atrial Fibrillation European Heart Journal 2010
• Adjusted-dose warfarin (target INR, 2.0 to 3.0) is recommended for all patients with
nonvalvular atrial fibrillation deemed to be at high risk and many deemed to be at
moderate risk for stroke who can receive it safely (Class I; Level of Evidence A).
• Antiplatelet therapy with aspirin is recommended for low-risk and some moderate-
risk patients with atrial fibrillation, based on patient preference, estimated
bleeding risk if anticoagulated, and access to high-quality anticoagulation
monitoring (Class I; Level of Evidence A).
• For high-risk patients with atrial fibrillation deemed unsuitable for anticoagulation,
dual antiplatelet therapy with clopidogrel and aspirin offers more protection against
stroke than aspirin alone but with increased risk of major bleeding and might be
reasonable (Class IIb; Level of Evidence B).
• Aggressive management of BP coupled with antithrombotic prophylaxis in elderly
patients with atrial fibrillation can be useful (Class IIa; Level of Evidence B).
ACTIVE A: benefit in stroke reduction
when adding clopidogrel to aspirin
Significant reduction by clopidogrel + aspirin versus aspirin alone is primarily due to reduction in stroke (no or only weak differential treatment effects for subgroups) after median follow-up of 3.6 years
Connolly SJ, et al. N Engl J Med 2009;360:2066-78
RR -28%
p<0.001
RR -3%
p=0.69
2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial
Fibrillation (Updating the 2006 Guideline): A Report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice
Guidelines
The ACTIVE Investigators.N Engl J Med 2009;360:2066-78.
Circulation. 2011;123:104-123.
Authorized indication in EU
― In adult patients with atrial fibrillation who have at
least one risk factor for vascular events, are not
suitable for treatment with Vitamin K antagonists
(VKA) and who have a low bleeding risk,
CLOPIDOGREL IS INDICATED IN COMBINATION
WITH ASA for the prevention of atherothrombotic
and thromboembolic events, including stroke‖
ANTIPLATELETS in PRIMARY
PREVENTION OF STROKE
ESO Recommendations ( 2009 )
Low-dose aspirin is recommended in women aged 45 years or more who are not at
increased risk for intracerebral haemorrhage and who have good gastro-intestinal
tolerance; however, its effect is very small (Class I, Level A)
Antiplatelet agents other than aspirin are not recommended for primary stroke prevention
(Class IV, GCP)
AHA/ ASA Recomandations ( 2010 )
• Aspirin (81 mg daily or 100 mg every other day) can be useful for prevention of a first
stroke among women whose risk is sufficiently high for the benefits to outweigh the risks
associated with treatment (Class IIa; Level of Evidence B).
• Aspirin is not useful for preventing a first stroke in persons at low risk (Class III; Level of
Evidence A).
• Aspirin is not useful for preventing a first stroke in persons with diabetes or diabetes
plus asymptomatic peripheral artery disease (defined as an ankle brachial pressure index
<0.99) in the absence of other established CVD (Class III; Level of Evidence B).
• The use of aspirin for other specific situations (eg, atrial fibrillation, carotid artery
stenosis) is discussed in the relevant sections of guidelines.
Asymptomatic carotid stenosis
• The presence of carotid stenosis is probably a marker of more advanced
atherosclerotic disease and of high risk
• The etiology of stroke is multifactorial and not only related to the presence
of carotid artery disease
• Better understanding of CEREBROVASCULAR DISEASES BIOLOGY
&
Increased efficacy of MEDICAL TREATMENT
↓
• Extended treatment of major RISK FACTORS:
– in particular: DM, HTA, DYSLIPIDEMIA
• New available drugs: better vascular protection
– antiplatelets: ASA +/ - CLOPIDOGREL
– ACEI
– much efficient and better tolerated statins
Guzman L.A. et al, Stroke. 2008;39:361-365; A. Abbott - METHANALYSIS Stroke 2009
Guidelines for Management of Ischaemic Stroke and
Transient Ischaemic Attack ESO - 2009
• Only centres with a perioperative complication rate of 3% or less should
contemplate surgery
• Patients with a high risk of stroke (men with stenosis of more than 80% and a life
expectancy of more than 5 years) may derive some benefit from surgery in
appropriate centres. All stenosis are graded following the NASCET- method (distal
stenosis)
Asymptomatic carotid stenosis
AHA / ASA Recommendations ( 2010 )
1. Patients with asymptomatic carotid artery stenosis should be screened for
other treatable risk factors for stroke with institution of appropriate
lifestyle changes and medical therapy (Class I; Level of Evidence C)
2. Prophylactic CEA performed with <3% morbidity and mortality can be
useful in highly selected patients with an asymptomatic carotid stenosis
(minimum 60% by angiography, 70% by validated Doppler ultrasound)
(Class IIa; Level of Evidence A). It should be noted that THE BENEFIT OF
SURGERY MAY NOW BE LOWER THAN ANTICIPATED based on
randomized trial results, and the cited 3% threshold for complication rates
may be high because of interim advances in medical therapy
3. The usefulness of CAS as an alternative to CEA in asymptomatic patients
at high risk for the surgical procedure is uncertain (Class IIb; Level of
Evidence C).
Asymptomatic carotid stenosis
- full evaluation is needed -
• ―Asymptomatic‖ carotid stenosis?
– only the grade of stenosis ?
– “silent strokes” ( ischemic, microbleeds ) ?
– co-existence of small vessel disease ? ( HTA, DM )
• increased coronary risk !
– BBB function ?
– cognitive deterioration ? gait deterioration ? urinary prblems ?
– genetic RF ?
– biological markers ?
• see LADIS study!
Other general recommendations
1. Each patient should undergo an assessment of stroke risk (Class I; Level of
Evidence A).
2. The use of a risk-assessment tool such as the FSP is reasonable because these
tools can help identify persons who could benefit from therapeutic interventions
and who may not be treated based on any single risk factor (Class IIa; Level of
Evidence B).
3. ACC/AHA practice guidelines providing strategies to reduce the risk of stroke in
patients with a variety of cardiac conditions, including valvular heart disease,
unstable angina, chronic stable angina and acute MI are emdorsed.
4. Screening for cardiac conditions such as PFO in the absence of neurological
conditions or a specific cardiac cause is not recommended (Class III; Level of
Evidence A).
5. It is reasonable to prescribe warfarin to post–STsegment elevation MI patients
with left ventricular mural thrombi or an akinetic left ventricular segment to
prevent stroke (Class IIa; Level of Evidence A).
~ 2/5 of the 18,843 patients with Cerebrovascular Disease also have
atherothrombotic disease in other arterial territories
RISK FACTORS
ONLY
8.4%
1.6%
1.2%
~ 2/5 of Patients with Cerebrovascular
Disease Have Polyvascular Disease1
1. Bhatt DL et al, on behalf of the REACH Registry Investigators.
JAMA 2006; 295(2): 180-189.
16.6%
Patients with
Cerebrovasc Dis =
27.8% of the REACH
Registry population
(%s are of total population)1
Coronary
Artery Dis
Cerebro-
vascular
Periph Art
Disease
Impact of Atherothrombosis on Life
Expectancy
Analysis of data from the Framingham Heart Study
AMI = Acute myocardial infarction
Atherothrombosis reduces life expectancy by approximately 8–12 years
in patients aged over 60 years*
Healthy History of
Cardiovascular Disease
History of
AMI
History of
Stroke
Average remaining life
expectancy at age 60 (men)
0
2
4
6
8
10
12
14
16
18
20
Years
-7.4
years
-9.2
years
-12
years
*Peeters et al. Eur Heart J 2002; 23: 458–466
1. Adult Treatment Panel II. Circulation 1994; 89:1333–63. 2. Kannel WB. J Cardiovasc Risk 1994; 1: 333–9.
3. Wilterdink JI, Easton JD. Arch Neurol1992; 49: 857–63. 4. Criqui MH et al. N Engl J Med 1992; 326: 381–6.
*Sudden death defined as death documented within 1 hour and attributed to coronary heart disease (CHD) †Includes only fatal MI and other CHD death; does not include non-fatal MI
Increased risk vs general population (%)
Original event Myocardial infarction Stroke
Myocardial infarction
Stroke
Peripheral arterial disease
5–7 x greater risk1
(includes death) 3–4 x greater risk2
(includes TIA)
2–3 x greater risk2
(includes angina and
sudden death*)
9 x greater risk3
4 x greater risk4
(includes only fatal MI
and other CHD death†)
2–3 x greater risk3
(includes TIA)
Risk of a Second Vascular Event
Treatment Options for Long-Term
Secondary Prevention
• Risk Factor Management – Increase physical activity, smoking cessation, blood pressure
control, diabetes control, lipid reduction
• Surgical Treatment – Carotid Endarectomy (CEA): if symptomatic and substantial
carotid stenosis
– Carotid Stenting: investigating angioplasty + stenting
• Antithrombotic - pharmacologic management – Antiplatelets
• Clopidogrel
• Aspirin
• Extended-release dipyridamole + aspirin
– Anticoagulants
• Warfarin
TIA: ABCD2 score
• Age ≥ 60 ani) 1p
• Blood pressure, TAs > 140 mmHg / TAd ≥ 90 mm Hg): 1p
• Clinical manifestations:
– unilateral deficits = 2 p
– language disorder without motor deficit = 1 p
– no clinical signs = 0 p
• D 2
– Diabetes mellitus = 1 p
– Symptom Duration: 60 min = 2 p, 10- 59 min = 1 p, < 10 min = 0 p
– ABCD2 <4 allows some days delay (max.7) to investigate the patient;
– ABCD2 ≥4 or 2 TIA during the last 7 days: hospitalization in a stroke unit
and investigate the patient during the next 24 hours !
Ischemic stroke risk after TIA
Merwick Á. et al. Lancet Neurol 2010; 9: 1060–69.
The ABCD² score improves
stratification of patients with
transient ischaemic attack by
early stroke risk.
ABCD3 and ABCD3-I are two
new versions of the score: one
that was based on preclinical
information and one that was
based on imaging and other
secondary care assessments.
The ABCD³-I score can improve
risk stratification after transient
ischaemic attack in secondary
care settings.
However, use of ABCD³ cannot
be recommended without
further validation.
Although numerous randomized trials and meta-analyses support the
importance of treatment of hypertension for prevention of primary
cardiovascular disease in general and stroke in particular, few trials
directly address the role of BP treatment in secondary prevention among
persons with stroke or TIA
Lawes CM, Bennett DA, Feigin VL, Rodgers A. - Stroke. 2004;35:776 –785.
Rashid P, Leonardi-Bee J, Bath P. - Stroke. 2003;34:2741–2748
SECONDARY PREVENTION ( after stroke ):
In patients with TIA or STROKE,
TAd reduction with 5 – 6 mmHg
and
TAs reduction with 10- 12 mmHg,
DECREASE STROKE RECURRENCE RISK
with 19 – 30%
Lawes CM, Bennett DA, Feigin VL, Rodgers A. - Stroke. 2004;35:776 –785.
Rashid P, Leonardi-Bee J, Bath P. - Stroke. 2003;34:2741–2748
HTA reduction without CBF reduction
Dyker AG, Grosset DG, Lees K. Stroke. 1997;28:580-583.
BP control No adverse effect on
cerebral blood flow
Time since administration of drug
Diastolic blood pressure
110
100
90
80
70
mm
Hg
0 1 2 3 4 5 6 7 8 9 10 11 12 24
Hours cm
pe
r s
ec
on
d
0 1 2 3 4 5 6 7 8 9 10 11 12 24 2
Time since administration of drug
Mean flow velocity (middle cerebral artery)
60
40
20
0 Hours Weeks
Perindopril Placebo
• BP reduction is recommended for both:
- prevention of recurrent stroke
- prevention of other vascular events
in persons who have had an ischemic stroke or TIA and are
beyond the first 24 hours (Class I; Level of Evidence A)
• Because this benefit extends to persons with and without a documented
history of hypertension
- this recommendation is reasonable for all patients with ischemic
stroke or TIA who are considered appropriate for BP reduction
(Class IIa; Level of Evidence B).
• An absolute target BP level and reduction are uncertain:
- should be individualized
- benefit has been associated with an average reduction of
approximately 10/5 mm Hg, and
- normal BP levels have been defined as 120/80 mm Hg
by JNC 7 (Class IIa; Level of Evidence B).
The optimal drug regimen to achieve the recommended level of
reduction is uncertain because direct comparisons between
regimens are limited. The available data indicate that diuretics or
the combination of diuretics and an ACEI are useful (Class I; Level of
Evidence A).
The choice of specific drugs and targets should be individualized
on the basis of pharmacological properties, mechanism of action,
and consideration of specific patient characteristics for which
specific agents are probably indicated (eg, extracranial
cerebrovascular occlusive disease, renal impairment, cardiac
disease, and diabetes) (Class IIa; Level of Evidence B). (New
recommendation).
Use of existing guidelines for glycemic control and BP targets in
patients with diabetes is recommended for patients who have had
a stroke or TIA (Class I; Level of Evidence B). (New
recommendation )
Use of angiotensin receptor blockers and risk of dementia in a
predominantly male population: prospective cohort analysis Li N-C, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B
Published 12 January 2010, BMJ 2010;340:b5465
European Stroke Organization
Guidelines - 2009
• Secondary prevention Optimal management of vascular risk factors
• Recommendations
It is recommended that blood pressure be checked regularly. Blood
pressure lowering is recommended after the acute phase,
including in patients with normal blood pressure (Class I, Level A)
• Large epidemiological studies in which ischemic and hemorrhagic
strokes were distinguishable have shown:
– a modest association of elevated total cholesterol or LDL – cholesterol
with increased risk of ischemic stroke
– and a relationship between low LDL-C and greater risk of ICH
• Other lipid subfractions - recent studies have independently linked:
– higher serum triglyceride levels with occurrence of ischemic stroke
and large-artery atherosclerotic stroke
– low HDL - cholesterol with risk of ischemic stroke
Ebrahim S et al - BMJ. 2006; 333:22; Freiberg JJ et al - JAMA. 2008;300:2142–2152; Bansal S et al - JAMA. 2007;
298:309 –316; Bang OY et al – Neurology. 2008;70:841–847; Sanossian N et al - Stroke. 2007;38: 1104–1109.
LIPID PROFILE & RISK FOR STROKE
Amarenco P. , Labreuche J. – The Lancet Neurology, 2009
Cholesterol Treatment Trialists' (CTT) Collaboration- The Lancet 2010: 1670- 1681
STATIN THERAPY IS THE MOST IMPORTANT ADVANCE IN
STROKE PREVENTION SINCE THE INTRODUCTION OF
ASPIRIN AND ANTIHYPERTENSIVE TREATMENTS Amarenco P. , Labreuche J. – The Lancet Neurology, 2009
LOWERING OF CHOLESTEROL concentrations with STATINS reduces the RISK
OF STROKE in:
- high-risk populations ( primary prevention )
- patients with non-cardioembolic stroke
- patients with TIA
Meta-analysis of randomised trials of statins shows that:
- EACH 1 mmol/l (39 mg/dl) decrease in LDL-CHOLESTEROL
equates to a REDUCTION IN RELATIVE RISK FOR STROKE of 21·1%
(95% CI 6·3—33·5, p=0·009)
In SECONDARY PREVENTION OF NON-CARDIOEMBOLIC STROKE, intense
reduction of LDL cholesterol by STATINS also significantly reduced the RISK
OF RECURRENT STROKE (relative risk 0·84, 0·71—0·99, p=0·03) and MAJOR
CARDIOVASCULAR EVENTS (0·80, 0·69—0·92, p=0·002)
Cholesterol Treatment Trialists' (CTT) Collaboration- The Lancet 2010: 1670- 1681
• Guidelines have proposed that high doses of generic
statins (eg, 80 mg simvastatin daily) be used to achieve
these benefits, but such regimens may be associated with
higher risk of myopathy
• Instead, these BENEFITS MAY BE ACHIEVED MORE
SAFELY with NEWER, MORE POTENT STATINS (eg,
80 mg ATORVASTATIN or 20 mg ROSUVASTATIN daily)
and, potentially, by combination of standard doses of
generic statins (eg, 40 mg simvastatin or pravastatin daily)
with other LDL-cholesterol-lowering therapies
AHA / ASA Recommendations ( 2010 )
1. 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 LDL-C level >100 mg/dL, and who are without known CHD
(Class I; Level of Evidence B)
2. For patients with atherosclerotic ischemic stroke or TIA and without
known CHD, it is reasonable to target a reduction of at least 50% in
LDL-C or a target LDL-C level of<70 mg/dL to obtain maximum
benefit (Class IIa; Level of Evidence B). (New recommendation)
3. Patients with ischemic stroke or TIA with elevated cholesterol or
comorbid coronary artery disease should be otherwise managed
according to the NCEP III guidelines, which include lifestyle
modification, dietary guidelines, and medication recommendations
(Class I; Level of Evidence A).
Effects of statins on early and
late results of carotid stenting
• Statins use is associated with decreased perioperative
and late ischemic strokes risk and reduced mortality
rates in patients undergoing CAS
• Statins therapy should be considered part of the best
medical treatment in current CAS practice
Verzini F. et al -J Vasc Surg. 2011 ;53(1):71-9
STATINS and HEMORRHAGIC STROKE
Amarenco P. , Labreuche J. – The Lancet Neurology, 2009
Because of the increased incidence of haemorrhagic stroke seen in HPS
and SPARCL, we recommend caution when considering statin therapy in
patients with PRIOR CEREBRAL HAEMORRHAGE
Amarenco P. , Labreuche J. – The Lancet Neurology, 2009
Avoiding statins was favored over a wide range of values for many
clinical parameters, particularly in SURVIVORS OF LOBAR ICH without
prior cardiovascular events who are at highest risk of ICH recurrence
In patients with lobar ICH who had prior cardiovascular events, the
annual RECURRENCE RISK OF MYOCARDIAL INFARCTION would have
to exceed 90% to FAVOR STATIN THERAPY
Brandon Westover M. et al – Arch Neurol, 2011 ( published online January 10, 2011 )
Antiplatelet treatment:
possible options
• Aspirin monotherapy
• Aspirin + dipyridamole
• Clopidogrel
• Aspirin + clopidogrel
10 events avoided/1000 treated/1.9 yr (5/yr)
CAPRIE Steering Committee. Lancet. 1996;348:13291339.
0
2
4
6
8
10
Eve
nts
/ 1
.9 y
r (%
)
12
CV Death + MI + Stroke (primary combined endpoint)
ICH or fatal bleeding (secondary - safety)
Aspirin
n=3,198
10.6%
0.5%
11.1%
Clopidogrel
n=3,233
0.4% Decrease in bleeding
9.7%
Decrease in outcome
events
10.1% Net decrease in events
CAPRIE: Net Benefit
1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339. 2. Jarvis B, Simpson K. Drugs 2000; 60:
347–377. 3. Ringleb. Stroke 2004;35:528-532
152
200
238
141
172
204
0
50
100
150
200
250
300
All CAPRIE patients¹ (n=19,185)
Prior history of any ischemic event²
(n=8,854)
Prior history of major acute event (MI or stroke)3
(n=4,496)
Event ra
te* /1,0
00 p
atients
(avera
ge f
ollo
w-u
p,
2 y
ears
)
ASA
Clopidogrel
11*
28*
34*
*Event rate of myocardial infarction, ischemic stroke, or vascular
death over a 3-year period
CAPRIE: Clopidogrel Is Shown to Provide Amplified
Benefits in Patients with Higher Vascular Risk1–3
*Events Prevented/1,000 Patients/3 Years over ASA
Superiority of Clopidogrel in patients with ACS with stroke history
*Number of events prevented/1,000 patients treated
**Terapia standard (inclusiv ASA)
1. Data on file, 2002, p87 internal CSR-EFC 3307.
11.0%
22.4%
17.9%
8.9%
0%
5%
10%
15%
20%
25%
Without strokehistory
With strokehistory
Clopidogrel +
Standard treatment**
21*
45*
Events prevented#/1000 patients, more than with ASA
# Stroke, Mi, vascular death
An
nu
alra
te o
fe
ven
ts(%
)
Standard treatment
alone**
RRR: 6.4% (p=0.244)
ASA*
Placebo*
IS, MI, VD, rehospitalization for acute ischemic event
Cu
mu
lati
ve e
ven
t ra
te
0.00
0.04
0.08
0.12
0.16
0.20
Months of follow-up
0 3 6 9 12 15 18
ASA showed a non-significant trend for the reduction in
major vascular events of in specific high risk cerebrovascular
patients*
* All patients received clopidogrel and other standard therapies
Primary Endpoint (ITT)
Overall Benefit Risk
• Efficacy:
– In absolute terms:
• 10 events prevented per 1000 patients (ITT)
• Safety
– In absolute terms , increased risk of life-threatening
bleeding of 13 additional events (including 4 PICH) per
1000 patients
• In secondary preventions in patients with stroke, association of ASA over CLOPIDOGREL does not bring supplemental benefits !
ESPS 2: Effects on Stroke–RRR
(Pairwise Comparisons)
ESPS 2 Group. J Neurol Sci. 1997;151(suppl):S1-S77.
37.0%
P < .001
16.3%
P =.039
18.1%
P =.013
23.1%
P =.006
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
32.0%
40.0%
RRR
ASA/ER-DP vs Placebo
ER-DP vs Placebo
ASA vs Placebo
ASA/ER-DP vs ASA
Antithrombotic Therapy
ESO Guidelines Ischaemic Stroke (2009)
Recommendations Patients should receive antithrombotic therapy (Class I, Level A)
Patients not requiring anticoagulation should receive antiplatelet
therapy (Class I, Level A). Where possible, combined aspirin and
dipyridamole, or clopidogrel alone, should be given.
Alternatively, aspirin alone, or triflusal alone, may be used
(Class I, Level A)
Prevention Regimen for Effectively Avoiding
Second Strokes (PRoFESS) trial
- a factorial design to address several
questions
- in a large population of 20,332 patients
from 695 sites in 35 countries
- a noncardioembolic ischemic stroke
within the previous 120 days
- randomized to receive:
aspirin (25 mg) plus extended-release
dipyridamole (200 mg) 2x / day
or,
clopidogrel (75 mg) once daily
-at the same time, patients were
randomized to receive either
80 mg/day of telmisartan or placebo
Recurrent Stroke or Intracranial Hemorrhage
Sacco RL et al. N Engl J Med 2008;359
1o endpoint: recurrent stroke
(non-inferiority test)
Non-inferiority of
ASA+ER-DP vs.
clopidogrel
0.8 1.0 1.2 1.4
Hazard Ratio
PRoFESS trial: summary of efficacy and safety
0.92 1.01
1.11
0.92
0.99
1.07 2o endpoint: stroke MI, vascular death
Major haemorrhagic event
1.6 1.8
All Intracranial haemorrhage
1.15 1.00 1.32
1.42
1.11 1.82
B) Safety endpoints
A) Efficacy endpoints
0.6
Non-inferiority of ASA+ER-DP
vs. clopidogrel not
demonstrated
[p=0.783]
[p=0.829]
[p=0.057]
[p=0.006]
MI, myocardial infarction; ASA, acetylsalicylic
acid; ER-DP, extended release dipyridamole
Meta-analysis of number of patients with at least one
microembolic signal (1) and of number of patients with
recurrent stroke (2) in CARESS and CLAIR studies
PRACTICAL ATITUDE ( in agreement with ESO Guidelines for 2009 ):
- First TIA / stroke in a patient with low risk vascular profile,
without significant comorbidities: ASA or ER-Dipiridamole+ASA
- TIA / stroke in a patient WITH VASCULAR CO-MORBIDITIES / HIGH RISK:
CLOPIDOGREL
- New vascular event in a patient treated with ASA:
CLOPIDOGREL or ER-Dipiridamole+ASA
- New event in a patient with CLOPIDOGREL / peri-stenting / particular
group of pathology ( CURE, CARESS, CLAIR ): CLOPIDOGREL+ASA
( at least for a limited delay of 9 months )
Antithrombotic Therapy
ESO guidelines ischaemic stroke 2008
Recommendations The combination of aspirin and clopidogrel is not recommended
in patients with recent ischaemic stroke, EXCEPT IN PATIENTS
WITH SPECIFIC INDICATIONS (e.g. UNSTABLE ANGINA or NON-
Q-WAVE MI DURING THE LAST 12 MONTHS, or RECENT
STENTING); treatment should be given for up to 9 months after
the event (Class I, Level A)
Patients who have a stroke on antiplatelet therapy should be re-
evaluated for pathophysiology and risk factors (Class IV, GCP)
1. For patients with ischemic stroke or TIA and extracranial carotid or vertebral
ARTERIAL DISSECTION, antithrombotic treatment for at least 3 to 6 months
is reasonable (Class IIa; Level of Evidence B).
2. The relative efficacy of antiplatelet therapy compared with anticoagulation is
unknown for patients with ischemic stroke or TIA and extracranial carotid or
vertebral arterial dissection (Class IIb; Level of Evidence B). (New
recommendation)
3. For patients with stroke or TIA and extracranial carotid or vertebral arterial
dissection who have definite recurrent cerebral ischemic events despite
optimal medical therapy, endovascular therapy (stenting) may be considered
(Class IIb; Level of Evidence C).
4. Patients with stroke or TIA and extracranial carotid or vertebral arterial
dissection who fail or are not candidates for endovascular therapy may be
considered for surgical treatment (Class IIb; Level of Evidence C)
Recommendations
The observational data suggest that antiplatelet therapy and
anticoagulation are associated with similar risk of
subsequent stroke but that the former is likely safer
Ischemic stroke risk vs. bleeding risk
Guidelines for the management of atrial Fibrillation European Heart Journal 2010
AF and reccurent stroke
Recommendations • For patients with ischemic stroke or TIA with paroxysmal (intermittent) or
permanent AF, anticoagulation with a vitamin K antagonist (target INR 2.5;
range, 2.0 to 3.0) is recommended (Class I; Level of Evidence A).
• For patients unable to take oral anticoagulants, aspirin alone (Class I;
Level of Evidence A) is recommended.
• For patients with AF at high risk for stroke (stroke or TIA within 3 months,
CHADS2 score of 5 or 6, mechanical or rheumatic valve disease) who
require temporary interruption of oral anticoagulation, bridging therapy
with an LMWH administered subcutaneously is reasonable (Class IIa;
Level of Evidence C). (New recommendation )
2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial
Fibrillation (Updating the 2006 Guideline): A Report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice
Guidelines
The ACTIVE Investigators.N Engl J Med 2009;360:2066-78.
Circulation. 2011;123:104-123.
