??????S? ??? ???

1
Y?????S? ??? ?GG????? ?G??F????? ????S????
??????S ???????S MD
2
Stroke the Medical Impact of the Problem
5 millions of deaths/year third cause of
mortality 15 millions/year of non-fatal strokes
first cause of disability Second cause of
dementia 1 out of 6 patients with non-fatal
stroke has a recurrence in 5 years
3
Stroke Mortality vs Usual BP by Age
Age at risk
Age at risk
Systolic Blood Pressure
Diastolic Blood Pressure
80-89 ys
80-89 ys
70-79 ys
70-79 ys
60-69 ys
60-69 ys
50-59 ys
50-59 ys
Stroke Mortality(Floating Absolute Risk and 95
CI)
70
80
90
110
100
Usual Systolic BP (mm Hg)
Usual Diastolic BP (mm Hg)
Prospective Studies Collaboration. Lancet.
20023601903-1913
4
Hypertension and Stroke Agenda
1. Primary prevention of stroke 2. Secondary
prevention of stroke 3. Blood pressure in acute
stroke
5
Effects of BP Reduction on CV Events
C
C
T
C
T
Total numbers of individuals affected
C
T
T
C
T
Stroke
CHD
Remaining vascular deaths
All vascular deaths
All other deaths
Reduction in odds () Number of SD 2p value
38 SD 4 8.7 lt 0.00001
16 SD 4 3.8 0.0001
4.8 lt 0.00001
6
Total number of individuals affected
7
Benefit of Antihypertensive Drug Treatment in
Older Patients with Isolated Systolic Hypertension
Trial SHEP SYST-EUR SYST-CHINA All Heterogenei
ty P 0.94 SHEP SYST-EUR SYST-CHINA All Heterog
eneity P 0.83 SHEP SYST-EUR SYST-CHINA All He
terogeneity P 0.96
Number of end-points Treat Control All CV
endpoints 199 289 137 186 74 94 410
569 Fatal and non-fatal stroke 103 159 47
77 45 59 195 295 Fatal and non-fatal
MI (including sudden death) 103 141 58
72 20 23 182 236
Odds ratios and confidence limits
Reduction and SD
Treatment better
Treatment worse
32 SD 5 2P lt 0.0001
37 SD 6 2P lt 0.0001
25 SD 8 2P 0.004
1.0
0.5
1.5
Staessen JA Eur Heart J 1999 (Suppl P) 3-8
8
Is it Possible to Improve Stroke Protection ?
More aggressive blood pressure reduction New
antihypertensive agents (ancillary
properties) Global risk approach
9
BPLT Trialist Collaboration Group - Prospective
Meta-Analysis Comparison of More and Less
Intensive Blood Pressure Lowering
ABCD-H, ABCD-N, HOT, UKPDS ? BP 4.2 / 3.5 mmHg
More vs Less
Stroke -23
CHD -15
Major CV events -15
CV death -7
CHF -6
Total death -4
Statistically significant
From Lancet 2003 362 1527
10
Meta-Analysis of Antihypertensive Treatment
Trials Effects on Stroke
Placebo-controlled studies ACEI vs
placebo CA vs placebo More vs less Active
vs active regimen studies ACEI vs D/BB CA vs
D/BB ACEI vs CA
Trials 5 4 4 5 9 5
BP difference -5 / -2 -8 / -4 -4 / -3 2 /
0 1 / 0 1 / 1
Relative risk 0.72 (0.64-0.81) 0.62
(0.47-0.82) 0.77 (0.63-0.95) 1.09
(1.00-1.18) 0.93 (0.86-1.00) 1.12 (1.01-1.25)
0.5
1.0
2.0
Relative risk
Favours 2nd listed
Favours 1st listed
Lancet 2003 362 1527
11
Primary end points among all subjects enrolled in
the Second Australian National Blood Pressure
Study Group
ACEi superior Diuretic superior
0.2 1.0 5.0
End Point Hazard Ratio (95 CI)
P value All CV events or death 0.89
(0.79-1.00) 0.02 from any cause All
Coronary events 0.68 (0.47-0.98)
0.16 Myocardial infarction 0.90
(0.75-1.09) 0.04 Stroke
1.02 (0.78-1.33) 0.91
Wing LMH et al, NEJM 2003
12
ALLHAT Relative Risks and 95 Confidence
Intervals (CIs) for Lisinopril/Chlorthalidone
Comparisons in Prespecified Subgroups
Stroke
Relative Risk(95 CI)
FavorsLisinopril
FavorsChlorthalidone
Relative Risk
Total
1.15 (1.02-1.30)
Age lt65 y
1.21 (0.97-1.52)
Age ?65 y
1.13 (0.98-1.30)
Men
1.10 (0.94-1.29)
Women
1.22 (1.01-1.46)
Black
1.40 (1.17-1.68)
Nonblack
1.00 (0.85-1.17)
Diabetic
1.07 (0.90-1.28)
Nondiabetic
1.23 (1.05-1.44)
1
0.5
2.0
Scales are shown in natural logarithm
JAMA 2002 Vol.288, No.23
13
HOPE Study Primary Endpoints
Plt0.001
20
ACE I Placebo
17.7
16
P0.001
Plt0.001
14.1
12.2
12.2
Plt0.001
12
10.4
9.9
Incidence ()
8.1
8
Plt0.001
6.1
4.9
3.4
4
0
Composite Endpoint
Death from CV causes
Myocardial infarction
Stroke
Death any cause
Hope Study Group N Engl J Med 342 2000
14
LIFE Fatal / Nonfatal Stroke
Intention-to-Treat
Proportion of patients with first event,
Atenolol
Losartan
Adjusted Risk Reduction 24.9,
p0.001 Unadjusted Risk Reduction 25.8, p0.0006
0
6
12
18
24
30
36
42
48
54
60
66
Study Month
Dahlöf B et al., Lancet 2002 359 995-1003
15
Summary of Reduction in Risk of Stroke
No Evident
AF
Diabetes
ISH
Total
Vascular
Subgroup
Mellitus
Subgroup
Patient
4
2
Disease
Subgroup
3
Population1
Subgroup
5
NNT
54
11
51
28
59
Percent
reduction
34
49
21
40
25
in risk of
stroke
lt0.001
0.018
0.204
0.020
0.001
p-value
1. Dahlöf B et al. Lancet 2002359995-1003. 2.
Kjeldsen SE et al. JAMA 20022881491-1498. 3.
Lindholm LH. et al., Lancet 20023591004-1010.
4. Dahlöf B et al. Presented at the European
Society of Cardiology Congress Berlin, Germany
August 31September 4, 2002. Poster 2163. 5.
Devereux RB et al. American Heart Association
Scientific Sessions Chicago, IL, USA November
1720, 2002. Oral presentation.
16
SCOPE
Candesartan n 2477
Control n 2460
Favours Candesartan
Favours Control
Major CV events CV deaths Non-fatal
MI Non-fatal stroke All MI Fatal MI All
stroke Fatal stroke Total mortality
n 242 145 54 68 70 18 89 24 259
rate 26.2 15.2 5.9 7.4 7.6 1.9 9.7
2.6 27.5
n 268 152 47 93 63 18 115 26 266
rate 29.8 16.3 5.2 10.3 6.9 2.0 12.7
2.8 28.8
0.5
1.0
2.0
Relative Risk
17
The VALUE Trial Secondary Endpoints and
All-Cause Death
7
9


Valsartan-based regimen Amlodipine-based regimen
8
6
7
5
6
All myocardial infarction
All heart failure
4
5
4
3
3
2
HR 1.19 95 CI 1.02-1.38 p 0.02
HR 0.89 95 CI 0.77-1.03 p 0.12
2
1
1
0
0
0
12
24
48
36
60
72
0
12
24
48
36
60
72
No. at risk Valsartan Amlodipine
No. at risk Valsartan Amlodipine
7649 7596
7458 7458
7177 7205
6853 6905
6504 6562
3864 3840
1520 1532
7649 7596
7444 7444
7169 7176
6852 6874
6498 6534
6072 6100
1513 1511
16
6


14
5
12
4
All stroke
All -cause death
10
8
3
6
2
4
HR 1.04 95 CI 0.94-1.14 p 0.45
HR 1.15 95 CI 0.98-1.35 p 0.08
1
2
0
0
0
12
24
48
36
60
72
0
12
24
48
36
60
72
Time (months)
Time (months)
No. at risk Valsartan Amlodipine
No. at risk Valsartan Amlodipine
7649 7596
7448 7455
7170 7195
6877 6918
6515 6587
3859 3846
1516 1532
7649 7596
7496 7484
7267 7276
6994 7025
6682 6729
3981 3961
1563 1582
From Julius. Lancet June 14 2004
18
Study Dihydropyridine CCBs ABCD ALLHAT CCB vs
Diuretic CCB vs ACEI ELSA FACET INSIGHT
MIDAS NICS SHELL STOP2 CCB vs
Conv. CCB vs ACEI Heterogeneity ?2
9.32 df 10 p 0.502 Non-dihydropyridin
e CCBs CONVINCE INVEST NORDIL VHAS Heterogene
ity ?2 4.64 df 3 p
0.201 Heterogeneity between subgroups ?2
0.06 df 1 p 0.804 All CCBs Heterogeneity
?2 14.02 df 14 p 0.448
Odds Ratio (95 CI) 1.60 (0.61-4.20) 0.94
(0.83-1.07) 0.82 (0.71-0.94) 0.63
(0.27-1.46) 2.56 (0.79-8.29) 0.91
(0.65-1.26) 2.01 (0.50-8.08) 1.03
(0.38-2.80) 0.97 (0.61-1.54) 0.87
(0.71-1.06) 0.96 (0.79-1.18) 0.90
(0.84-0.97) 0.90 (0.84-0.97) 1.15
(0.89-1.47) 0.88 (0.72-1.08) 0.81
(0.66-1.01) 1.25 (0.33-4.68) 0.92
(0.82-1.04) 0.93 (0.78-1.10) 0.90
(0.85-0.97) 0.90 (0.85-0.97)
2p value 0.006 0.006 0.184 0.390
0.002 0.002
Fixed effect Random
effect Fixed effect Random effect Fixed
effect Random effect
Calcium-Channel Blockade and Stroke Prevention
in Hypertension
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
2.4
2.6
From Angeli, Am J Hypertens 2004
Favours CCB
Favours other drugs
19
Agenda
1. Primary prevention of stroke 2. Secondary
prevention of stroke 3. Blood pressure in acute
stroke
20
(No Transcript)
21
Secondary Stroke Prevention
1. Is BP a risk factor for stroke
recurrence? 2. Does BP reduction decrease the
incidence of stroke recurrence? 3. Which
antihypertensive drugs should be used?
22
Relative risk of stroke
23
(No Transcript)
24
Secondary Stroke Prevention in a Population of
5665 Normotensive and Hypertensive Subjects PATS
RR 0.72
p lt 0.001
Active (n 2841)
Placebo (n 2824)
Events BP (mmHg)
159 144 / 87
217 149 / 89
Chin Med J 1995 108 710-717
25
(No Transcript)
26
PROGRESS Secondary Stroke Prevention
6.105 hypertensive and non-hypertensive patients
with a history of stroke or TIA BP reduction
with perindopril monotherapy or combined with
indapamide vs placebo on top of standard
treatment Total population Baseline BP
147/86 mmHg - 9.0/4.0 mmHg Hypertensive
patients Baseline BP 159/94 mmHg - 9.5/3.9
mmHg Normotensive patients Baseline BP 136/79
mmHg - 8.8/4.2 mmHg Combined therapy -
12.3/5.0 mmHg monotherapy - 4.9/2.8 mmHg
Lancet 2001 358 1033
27
Stroke Risk Reduction
0.20 0.15 0.10 0.05 0.00
Placebo
Proportion with event
Active
28 risk reduction 95 CI 17 - 38 Plt0.0001
0
1
2
3
4
Follow-up time (years)
Lancet 2001 358 1033-41
Active Perindopril 4 mg Indapamide
28
Monotherapy vs Combination Therapy
Stroke Combination Single drug Total
stroke Major vascular events Combination Single
drug Total events
Active 150/1770 157/1281 307/3051 231/1770 2
27/1281 458/3051
Placebo 255/1774 165/1280 420/3054 367/1774
237/1280 604/3054
Favours active
Favours placebo
Relative risk reduction (95 CI) 43 (30 to
54) 5 (-19 to 23) 28 (17 to 38) 40 (29 to
49) 4 (-15 to 20) 26 (16 to 34)
0.5
1.0
2.0
Hazard ratio
29
Combination Therapy Stroke by baseline BP
SBP 160 SBP 140-159 SBP lt 140 DBP 95 DBP
85-94 DBP lt 85 Total
active 57 54 39 27 65 58 150
placebo 106 87 62 68 99 88 255
Events
Favours active
Favours placebo
Risk reduction (95 CI) 47 (27 to 62) 41 (16
to 58) 39 ( 9 to 59) 62 (41 to 76) 36 (12
to 53) 37 (12 to 55) 43 (30 to 54)
0.4
1.0
2.0
Hazard ratio
30
Hypertension and Stroke
Primary prevention Reduced incidence of
stroke Secondary prevention Reduced incidence
of recurrent stroke Acute phase of stroke 80
have BP gt 140/90 mmHg 50 have a history
of hypertension Mortality 30 days 7.6
ischemic strokes 37.5 hemorrhagic
strokes To treat (Spencer, 1985) or not to treat
(Yatsu, 1985)?
31
Average SBP and DBP for First Ten Hospital for
Each Stroke Diagnostic Class, and Relative to
History of Hypertension and Hypertensive Treatment
Blood pressure (mmHg)
Blood pressure (mmHg)
ICH
HT, previous therapy
MHT
HTI
STM
HT, no previous therapy
EMB
TIA
No HT
Control
Control
HT, previous therapy
ICH
MHT
STM
HT, no previous therapy
HTI
Control
Control
EMB
No HT
TIA
Day
1
2
5
10
Day
1
2
5
10
From Wallace, JAMA 1981 246 2173
32
High Blood Pressure in Acute Phase of Stroke
Initially, elevated blood pressure may be
beneficial by increasing blood flow to ischemic
penumbra (physiological compensatory
mechanism) Sustained elevation in blood pressure
may be harmful by increasing cerebral edema and
the likelihood of the hemorrhagic transformation
of ischemic infarct
33
High Blood Pressure and Prognosis in Acute
Stroke Observational Studies
A) No prognostic impact - Miah (1983) 1 and 2
year mortality - Britton (1985) progression of
neurological symptoms at discharge - Dollber
g (1986) survival at discharge - Carlberg
(1993) 30-day mortality - Fiorelli (1995)
death or disability after 4 months
34
High Blood Pressure and Prognosis in Acute
Stroke Observational Studies
B) Negative impact high blood pressure worse
prognosis - Dunne (1987) severe disability or
death, neurological symptoms - Tuhrim
(1988) 30-day outcome - Sacco (1989) 30-day
stroke recurremce - Britton (1990) in-hospital
mortality - Davalos (1990) 3-month
deterioration - Dandapani (1995)mortality and
severe disability - Henon (1995) 3-month death
or disability - Leonardi-Bee (2002)early stroke
recurrency, late death or dependency
35
High Blood Pressure and Prognosis in Acute
Stroke Observational Studies
C)Positive impact high blood pressure better
prognosis
- Allen (1984) 2-month dependence or
death - Jorgensen (1996) early stroke
progression - Semplicini (2003) 7-day
neurological outcome
36
High Blood Pressure and Prognosis in Acute
Stroke Observational Studies
Possible hypotheses for conflicting
results - Only patients with cerebral
hemorrhage (4 studies) - Patients of stroke unit
(4 studies) - Patients investigated after one
week or more (6 studies) - Patients continuing
or starting antihypertensive therapy (4
studies) - Retrospective studies - Observer
bias or interobserver errors
37
Incidence of Ischemic Stroke Recurrency by
SBP The International Stroke Trial
Recurrent ischaemic stroke within 14 days ()
Baseline SBP (mmHg)
From Leonardi-Bee, Stroke 2002 33 1315
38
Baseline BP and Prognosis in Patients with Acute
Stroke
Neurological deterioration
Poor neurological outcome
Mortality



lt 120
121 - 140
141 - 160
161 - 180
181 - 200
gt 200
lt 120
121 - 140
141 - 160
161 - 180
181 - 200
gt 200
lt 120
121 - 140
141 - 160
161 - 180
181 - 200
gt 200
SBP on admission (mmHg)
SBP on admission (mmHg)
SBP on admission (mmHg)



lt 70
71 - 80
81 - 90
91 - 100
101 - 110
gt 110
lt 70
71 - 80
81 - 90
91 - 100
101 - 110
gt 110
lt 70
71 - 80
81 - 90
91 - 100
101 - 110
gt 110
DBP on admission (mmHg)
DBP on admission (mmHg)
DBP on admission (mmHg)
From Castillo, Stroke 2004 35 520
39
24-Hour ABPM and CV Prognosis in Acute Stroke
Correlation Goulene (2003) worse 146/
71 better 137/ 67 Sobrino (1999) dead
167/ 81 alive 134/ 78 Damasceno
(1999) dead 196/120 alive
165/101 Robinson (1997) worse 156/
88 better 140/ 80 No correlation Lip
(1997) no correlation between 24-hour ABPM and
middle-term prognosis
40
24-h Systolic Blood Pressure in Acute Stroke
Patients With and Without Brain Edema at CT Scan
Control after 5 Days
180
SBP (mmHg)
160
140
120
With brain edema Without brain edema
100
3h
5h
7h
9h
11h
13h
15h
17h
19h
21h
23h
25h
27h
Time from stroke onset
Statisticamente significativa
From Vemmos, J Hypertens 2003 21 2162
41
Independent Predictors of Early Complete Recovery
Baseline Mathew score gt 74 Lack of
hypertension No brain edema on CT scan 20 to
30 drop in MAP, day 2
Odds Ratio 331.3 1.9 4.2 2.9
95 CI 45.2-2426.2 1.1-3.1 2.1-2.8 1.3-6.3
From Chamorrd Stroke 1998 29 1890
42
Detrimental Effect of Blood Pressure Reduction
in the First 24 Hours of Acute Stroke Onset J.
Oliveira-Filho, S.C.S. Silva, C.C. Trabuco, B.B.
Pedreira, E.U. Sousa, and A. Bacellar Neurology
2003 61 1047
Conclusion Blood pressure reduction in the
first 24 hours of stroke onset is independently
associated with poor outcome after 3 months.
43
Antihypertensive Therapy for Acute Stroke
American Heart Association / American Academy of
Neurology Ischemic stroke systolic blood
pressure gt 220 mmHg or diastolic
blood pressure gt 120 mmHg Hemorrhagic stroke
systolic blood pressure gt 180 mmHg or
diastolic blood pressure gt 105 mmHg JNC 7
Guidelines (2003) in acute stroke control of
blood pressure at intermediate levels (of
approximately 160/100 mmHg) is appropriate Stateme
nt of ISH Modest (5-10) reductions in blood
pressure produce minimal or no measurable changes
in cerebral blood flow. By contrast, large (gt
15) reductions in blood pressure can reduce
perfusion Comment Based on pathophysiological
consideration or individual case-report. No
systematic review or large intervention trials on
blood pressure manipulation in acute stroke.
44
The ACCESS Study Evaluation of Acute Candesartan
Cilexetil Therapy in Stroke Survivors Joachim
Schrader, MD Stephan Lüders, MD Anke
Kulschewski, MD Jürgen Berger, PhD Walter
Zidek, MD Johannes Treib, MD Karl Einhäupl, MD
Hans Christoph Diener, MD Peter Dominiak, MD
on behalf of the ACCESS Study Group Stroke
2003 34 1699-1703
45
ACCESS Study Design
Candesartan
Cerebral Ischaemia Hypertension 500 PT, 55
centri
Candesartan if hypertensive
Placebo
No treatment if normotensive
gt 72 hours from stroke
Day 1
7
1 year
4-16 mg/d according to baseline BP combination
treatment allowed
Stroke 2003 34 1699-1703
46
ACCESS Study Principal Inclusion and Exclusion
Criteria
Inclusion Motor deficit Negative TAC for
hemorrhagic stroke Hypertension to be
treated a) SBP gt 200 mmHg and/or DBP gt 110
mmHg within 6-12 hours b) SBP gt 180 mmHg
and/or DBP gt 105 mmHg within 24-36 hours
Exclusion Age gt 85 years Patient not
conscious Occlusion or stenosis gt 70 of
internal carotid artery Malignant
hypertension III-IV NYHA cardiac failure Unstable
angina
Stroke 2003 34 1699-1703
47
ACCESS Study Endpoint of the Trial
Primary endpoint Death and disability (at 3
months) Combined secondary endpoint Total
mortality Cerebrovascular events Cardiac
events
Stroke 2003 34 1699-1703
48
ACCESS Study Time Course of Blood Pressure
250
Candesartan SBP Placebo SBP Candesartan
DBP Placebo DBP
mmHg
200
150
100
50
0
3 Mo
6 Mo
Day 1
Day 3
Day 5
Day 7
Day 2
Day 4
Day 6
12 Mo
Study start
Recruitment
Stroke 2003 34 1699-1703
49
ACCESS Study Cumulative Mortality at 12 Months
and CV Events
0.3
0.2
RR 0.47 (CI 0.25-0.86) p 0.026
Cumulative event rate
Placebo Placebo-censored Candesartan Candesa
rtan-censored
0.1
0.0
0
100
200
300
400
Days under observation
Stroke 2003 34 1699-1703
50
ACCESS Study Conclusions
Although the mechanisms by which angiotensin type
1 (AT1) receptor blockade affects cardiovascular
morbidity and mortality are still unresolved, the
present study shows that early neurohumoral
inhibition has similar beneficial effects in
cerebral and in myocardial ischemia. The fact
that no cardiovascular or cerebrovascular event
occurred as a result of hypotension is of
significant clinical importance. When there is
need for or no contraindication against early
antihypertensive therapy, candesartan cilexetil
is a safe therapeutic option according to the
ACCESS results.
Stroke 2003 34 1699-1703