1. No category

H
How
tto A
Achieve
hi
B
Better
tt C
Cardiovascular
di
l
O t
Outcome
i H
in
Hypertensive
t
i P
Patients
ti t
Yong-Jin
Yong
Jin Kim,
Kim MD
Seoul National University Hospital
Global Burden of CV Disease
1990
Cause
Millions
2020
(%)
Millions
(%)
CHD
6.2
12.4
11.1
16.2
Stroke
4.3
8.5
7.7
11.3
Oth CVD
Other
26
2.6
51
5.1
60
6.0
88
8.8
TOTAL CVD
13.1
26.0
24.8
36.3
All Cause Death
50.4
100
68.3
100
WHO:WHF
Rank Order of Disability
y ((DALYs))
1999 Disease or Injury
2020 Disease or Injury
1.Acute lower respiratory infections
1. Ischemic heart disease
2.HIV/AIDS
2. Unipolar major depression
3.Perinatal conditions
3. Road traffic accidents
4.Diarrhoeal diseases
4. Cerebrovascular disease
5.Unipolar major depression
5. Chron obstruc pulmonary dis
6. Ischemic heart disease
6. Lower respiratory infections
7 Cerebrovascular disease
7.Cerebrovascular
7 Tuberculosis
7.
8.Malaria
8. War
9 Road traffic accidents
9.Road
9 Diarrhoeal diseases
9.
10.Chron obstruc pulmonary dis
10. HIV
Evolution of Atherosclerosis
G
Genetic
ti
E i
Environmental
t l
Cli i l Events
Clinical
E
t
0
20
40
60
Age (yrs)
Atherosclerosis in Korean War Casualties
300 autopsies (mean 22.1 yrs)
‰
‰
77 % Coronary atherosclerosis
39% Occlusive
O l i plaques
l
ENOS JAMA 1953
Individual Risk vs
P
Proportional
ti
l Attributable
Att ib t bl Risk
Ri k
5%
70%
25%
People with
l
low
risk
i k level
l
l
People with
average risk
i k llevell
People with
hi h risk
high
i k level
l
l
Individual
risk of CHD
Di t ib ti off cases
Distribution
Primary Risk Factors for CVD
Hypertension
yp
Diabetes mellitus
Age
g
CHD
Cigarette
g
smoking
g
Modifiable
Non modifiable
Non-modifiable
Family history of CHD
Dyslipidemia
y p
NCEP. Circulation 1994;89:1329–1445. Eur Heart J 1994;15:1300–1331.
Wood D et al. Eur Heart J 1998;19:1434–1503.
HT: A Risk Factor for CV Disease
Coronary
disease
50
Stroke
45.4
Peripheral
artery
disease
Heart
failure
40
Biennial
AgeAdjusted
Rate per
1000
P ti t
Patients
30
22 7
22.7
21.3
20
10
0
Risk ratio
95
9.5
12.4
3.3
Men Women
2.0
2.2
2.4
6.2
Men Women
3.8
2.6
99
9.9
5.0
7.3
2.0
Men Women
2.0
3.7
N
Normotensive
i
Kannel WB. JAMA. 1996;275:1571-1576.
13.9
3.5
2.1
6.3
Men Women
4.0
3.0
H
Hypertensive
i
CV Mortalityy Risk with BP Increment
8x
8
7
CV
Mortality
Risk
6
4x
5
4
3
2
2x
1
0
115/75
135/85
155/95
SBP/DBP (mm Hg)
175/105
*Individuals aged 40 to 69 years, starting at blood pressure 115/75 mm Hg
Chobanian AV et al. JAMA. 2003;289:2560-2572. Lewington S et al. Lancet. 2002;360:1903-1913.
Small Difference Produces Big
g Impact
p
• Meta-analysis of 61 observational studies
• 1 million adults
For every
2 mm Hg
d
decrease
in
i
mean SBP
Lewington S et al. Lancet. 2002;360:1903-1913.
• 7% reduction in
CHD mortality
•10% reduction in
stroke mortality
Evolution of Management
g
of HT
“ HT is an important compensatory
mechanism and BP should not be
tampered with ”
Dr. White PD. Heart disease. 1937
Headlines of the St. Louis Post-Dispatch, April 13, 1945
FDR’s Final Picture ((April
p 11, 1945))
226/118 in
1944
136/78 in
1935
260/150
in 1944
188/105
in 1941
1882 1945
1882-1945
Thirty-Second President
(1933-1945)
Franklin D.
D Roosevelt
Messerli FH,
FH N Engl J Med.
Med 1995
Treatment of Hypertension
yp
β-blocker
1957
1962
Chlorothiazide
JNC 1
1970
α-blocker
CCB
1976
JNC 7
1980
1990 2003
ACEI
ARB
Outcome in Treated HT After >20 Yrs
“Normotensive”
Treated BP
( N = 6810 )
145/93
–
10.3
1.8
10.8
29.2
( N = 686 )
185/114
145/89
20.1*
4.5*
4.5
8.9
37.4*
37.4
Screening BP (mm Hg)
g)
Final BP ((mm Hg)
CHD (%)
Stroke ((%))
Cancer (%)
All-cause
All
cause death (%)
*P < .002.
Andersson OK et al. BMJ. 1998;317:167-171.
CVD Survival in Treated HT
Untreated BP <140/90 mm Hg
Untreated BP ≥140/90
/ mm Hg
Treated BP at goal <140/90 mm Hg
T t d BP nott att goall ≥140/90 mm H
Treated
Hg
Su
urvival (%
%)
1
0.96
P=.03
0.92
P<.0001
0.88
P=.001
0.84
0.8
1
3 5
7
9 11 13 15 17 19 21 23 25
Follow--up (Years)
Follow
Benetos et al. J Hypertens.
Hypertens. 2003;21:16352003;21:1635-1640.
Better Outcome in HT
z
Agents with beyond BP lowering ?
HOPE: Events p
per Patient Group
p
Events
s per Patient Gro
oup (%)
20
15
RR=22%
P<.001
Placebo
17 8
17.8
14
RR=26%
P<.001
10
RR=20%
P<.001
RR=16%
P=.005
12.3
12.2
9.9
RR=32%
RR
32%
P<.001
8.1
6.1
4.9
5
0
Primary
Outcome
CV
Death
*MI, stroke, or CV death.
Yusuf et al. N Engl J Med.
Med. 2000;342:1452000;342:145-153.
Ramipril
MI
34
3.4
Stroke
RR=0%
P=NS
4.1
10.4
4.3
Non
Non-CV
Death
Total
Mortality
Ambulatory
y BP in HOPE Trial
SBP baseline
SBP year 1
DBP baseline
b
li
DBP year 1
Ramipril Group (n=20)
180
BP (mm Hg)
B
160
140
Night Δ=17/8 mm Hg (P
(P<.001)
24--h Δ=10/4 mm Hg (P
24
(P<.03)
120
100
80
60
40
1
3
2
5
4
7
6
9
8
11
10
13 15 17 19 21 23
12 14 16 18 20 22 24
Time (hours)
Svensson et al. Hypertension. 2001;38:e28
2001;38:e28--e32.
CAD Mortality
y and Usual BP by
y Age
g
IH
HD Mortaliity
(Floa
ating Absolute Risk and 95%
% CI)
Systolic BP
Diastolic BP
256
80--89 years
80
256
80--89 years
80
128
70--79 years
70
128
70--79 yyears
70
64
60--69 years
60
64
60--69 years
60
32
50--59 yyears
50
32
50--59 yyears
50
16
40--49 years
40
16
8
8
4
4
2
2
1
1
0
0
120
140
160
180
Usual Systolic BP (mm Hg)
Prospective Studies Collaboration. Lancet
Lancet.. 2002;360:19032002;360:1903-1913.
40--49 years
40
70
80
90 100 110
Usual Diastolic BP (mm Hg)
Odds Ratio (Expe
O
erimenta
al/Refere
ence)
Odds Ratio for CV Events & SBP
1.50
1.25
Recent trials
Recent
Older
Older trials placebo
AASK L vs H
ABCD/NT L vs H
ALLHAT/Aml
ALLHAT/Lis
ALLHAT/Lis ≥65
ALLHAT/Lis Blcks
ANBP2
CONVINCE
DIABHYCAR
ELSA
IDNT2
LIFE/ALL
LIFE/DM
NICOLE
PREVENT
SCOPE
ALLHAT/Dox
ATMH
EWPHE
HEP
HOPE
HOT
HOT M vs H
INSIGHT
MIDAS/NICS/VHAS
L vs H
MRC
MRC2
PART2/SCAT
PATS
PROGRESS/Per
PROGRESSION/Com
RCT70--80
RCT70
RENAAL
SHEP
STONE
STOP 1
STOP2/CCBs
STOP2/ACEIs
Syst--China
Syst
Syst--Eur
Syst
UKPDS C vs A
UKPDS L vs H
Older trials active
P<.0001
< 0001
1.00
0.75
HOPE
0.50
0.25
-5
0
5
10
15
20
25
Difference (reference minus experimental)
in Systolic BP (mm Hg)
Staessen et al. J Hypertens.
Hypertens. 2003;21:10552003;21:1055-1076.
New-Onset DM With RAS Blockade
0
Lisinopril Ramipril
p
(ALLHAT) (HOPE)
Losartan Candesartan
(LIFE)
(SCOPE)
Valsartan
(VALUE)
Candesartan
(CHARM)
-10
% Reduction
in New-Onset
Diabetes -20
-19
-25
-30
-30
-23
23
-22
-33
33
-40
ALLHAT Officers and Collaborators. JAMA. 2002;288:2981-2997. Yusuf S et al. JAMA. 2001;286:18821885. Dählof B et al. Lancet. 2002;359:995-1003. Lithell H et al. J Hypertens. 2003;21:875-886. Julius S
et al. Lancet. 2004;363:2022-2031. Pfeffer MA et al. Lancet. 2003;362:759-766.
Better Outcome in HT
z
A
Agents
t with
ith beyond
b
d BP lowering
l
i ?
z
Rapid BP lowering in high-risk
high risk patients
VALUE: Primary
y Composite
p
Endpoint
p
Valsartan-based regimen
ValsartanA l di i -based
AmlodipineAmlodipine
b
d regimen
i
Pro
oportio
on of Patients
s
With Firs
st Eve
ent (%)
14
12
10
8
6
4
2
0
HR=1.03; 95% CI 0.940.94-1.14: P=0.49
0
6
Number at risk
Valsartan
Amlodipine besylate
12
18
24 30 36 42
Time (months)
48
54
7649 7459 7407 7250 7085 6906 6732 6536 6349 5911 3764 1474
7596 7469 7424 7267 7117 6955 6772 6576 6391 5959 3725 1474
Julius et al. Lancet
Lancet.. June 2004;363.
60
66
VALUE: Fatal and Non-Fatal MI
Pro
oportio
on of P
Patients
With First Event (%
W
%)
7
Valsartan-based regimen
ValsartanA l di i -based
AmlodipineAmlodipine
b
d regimen
i
6
5
4
3
2
1
HR=1.19; 95% CI 1.021.02-1.38; P=0.02
0
0
Number at risk
Valsartan
A l di i besylate
Amlodipine
b l t
19%
6
12
18
24 30 36 42
Time (months)
48
54
7649 7499 7458 7319 7177 7016 6853 6680 6504 6078 3864 1520
7596 7497 7458 7332 7205 7065 6905 6727 6562 6141 3840 1532
Julius S et al. Lancet
Lancet.. June 2004;363.
60
66
VALUE: Systolic
y
BP in Study
y
Sitting SBP by Time and Treatment Group
mmHg
155
V l
Valsartan
(N=7649)
150
145
Amlodipine
(N=7596)
140
m
mmHg
135
Baseline
5.0
4.0
3.0
2.0
1.0
0
–1.0
1
2
3
4
6
12 18 24 30 36
Months
42 48 54 60 66
(or final visit)
Difference in SBP Between Valsartan and Amlodipine
1
2
3
4
6
12
18
24
Months
Julius S et al. Lancet
Lancet.. June 2004;363.
30
36 42
48
54
60 66
(or final visit)
VALUE: Outcome and SBP Differences
New ESC Guideline: Early
y Treatment
Better Outcome in HT
z
A
Agents
t with
ith beyond
b
d BP lowering
l
i ?
z
Rapid BP lowering in high-risk
high risk patients
z
Lower BP target in high-risk patients
Rate/1000 pe
erson--years
HOT - Rate of Major
j CV Events
p for trend
0.005
30
25
20
15
BP goal
mmHg
<90
<85
<80
p for trend 0.5
10
5
0
All n=18790
Diabetic n=1501
Hansson et al., Lancet 1998
UKPDS: Tight
g BP Control
Tight group 144/82 mmHG vs less tight 154/87 mmHG
0
Any DiabetesRelated
DiabetesEndpoint Related Death
Stroke
Microvascular Retinopathy Deterioration
Endpoints Progression
of Vision
Heart
Failure
10
20
30
40
50
60
24
P=0.0046
32
P=0.019
44
P=0.013
37
P=0.0092
34
P=0.0038
47
P=0.0036
56
P=0.0043
P 0.0043
*Compared with less tight control. Captopril and atenolol were equally effective in reducing risk and were equally safe in patients with diabetes.
UKPDS Group. BMJ. 1998;317:703-713.
CAMELOT Study
y Design
g
Comparison of Amlodipine versus Enalapril
to Limit Ischemic Occurrences of Thrombosis
Amlodipine 10 mg
PTCA &
Angiogram
2000
Patients
Enalapril 20 mg
Placebo
QCA
100 sites
24 Months
Prospective, Randomized, Double Blind, Multicenter
Endpoints:
E d i t : CHD D
Death,
th R
Resuscitated
it t d A
Arrest,
t N
Nonfatal
f t l MI
MI,
Stroke, TIA, CABG, Revascularization, Unstable Angina,
Hospitalized CHF
CAMELOT: Systolic
y
BP
S
Systoli
c Pres
ssure (m
mm Hg
g)
132
130
128
126
124
122
Placebo
Enalapril
Amlodipine
120
0
1
3
6
9
12
15
Months after randomization
18
21
24
CAMELOT: Time to Major
j CV Event
25%
23.1%
20.2%
Ev
vent Ra
ate (%
%)
20%
16.6%
15%
10%
A l di i
Amlodipine
Enalapril
5%
Pl
Placebo
b
0%
0
4
8
12
16
Time (months)
20
24
ESC Guidelines for Target
g BP
Evolution of JNC Guidelines
Better Outcome in HT
z
A
Agents
t with
ith beyond
b
d BP lowering
l
i ?
z
Rapid BP lowering in high-risk
high risk patients
z
Lower BP target in high-risk patients
z
Improve target BP lowering: adherence
Target
g BP Lowering
g
BP goal achieved
Patients (%)
100
60
79
BP goal not achieved
70
81
72
Germany
Spain
Italy
46
80
60
40
20
0
*Treated for hypertension
BP goal is <140/90 mmHg
England
Sweden
Korea
Source: Wolf-Maier et al. Hypertension 2004;43:10–17;
Korea National Health and Nutrition Survey 2005
Nonadherence With Antihypertensive
Medicati n
Medication
1-year retrospective study in new starters (N = 8643)
100
Patie
ents (%))
90
80
70
60
50
43
40
30
20
21
Achieved ≥80%
Adherence
Did Not Fill
Second Rx
20
10
0
Days With Drug
on Hand
Monane M et al. Am J Hypertens. 1997;10:697-704.
Medication Adherence Declines When a
S
Second
dD
Drug IIs P
Prescribed
ib d
Antihypertensive therapy
Lipid-lowering therapy
B th
Both
80
Pattients Witth
MPR ≥0.80 (%
%)
70
*
*
60
50
*
*
*
40
*
*
*
*
*
30
20
10
0
Month 1-2
Month 3-4
Month 5-6
*P < .05 vs both.
Schwartz JS et al. J Am Coll Cardiol. 2003;41(6 suppl A):526A. Abstract 1095-57.
Month 7-8
Month 9-10
Lower Pill Burden
better adherence to AHT and LLT
As the number of pre
pre-existing
existing Rx meds increased, the likelihood of
adequately refilling AHT and LLT decreased
Number of
pre-existing
Rx medications
≥6
Likelihood of achieving adherence
L
Lesser
G
Greater
t
0.0
0.5
1.0
1.5
2.0
2.5
Adjusted odds ratio for
adherence to both AHT
and LLT*
(PDC ≥80%) (95%
confidence interval)
1.00 (reference group)
3-5
1.23 (1.10-1.38)
2
1.30 (1.14-1.49)
1
1.61 (1.40-1.84)
0
1.96 (1.72-2.25)
*P<0.001 for all groups versus reference group.
Retrospective cohort study of a managed care population. N=8406 patients with hypertension who added AHT and LLT to existing Rx meds within a 90-day period. Adherence to
concomitant therapy: sufficient AHT and LLT Rx meds to cover ≥80% of days per 91-day period.
Chapman RH, et al. Arch Intern Med. 2005;165:1147-1152.
ESC Guidelines on Combination Therapy
py
z
More than one agent is necessary to achieve
target BP in the majority of patients
z
Fixed combinations of two drugs simplify
treatment/favor compliance
Task Force of ESH/ESC. J Hypertens 2007;25:1105–87
Adherence is fundamental to better
cardiovascular (CV) health
“Drugs
g don't work in p
patients who don't take them.”
— C. Everett Koop, (Former US Surgeon General)
Better Outcome in HT
z
A
Agents
t with
ith beyond
b
d BP lowering
l
i ?
z
Rapid BP lowering in high-risk
high risk patients
z
Lower BP target in high-risk patients
z
Improve target BP lowering: adherence
z
Global risk management:
g
“Add statin”
Target
g BP lowering
g in ALLHAT
Global Risk Management
g
Millions of p
people,
p , WW*,, 2000
Dyslipidemia
(138 million)
Hypertension
(109 million)
Diabetes
(41MM)
Smoking
(164 million)
Obesity
(91 MM)
Metabolic Syndrome
(100MM)
*7 countries: U.S., U.K., Italy, Germany, France, Spain, and Japan; population 706 million
Source:Decision Resources; Cardiovascular Outlook; DataMonitor
Concurrent Hypertension and
D li id i Is
Dyslipidemia
I Very
V
Prevalent
P
l t
33%
24%
61M
44M
HTN
15%
27M
DYS
HTN/DYS
NHANES III. Phase 2. Fasting Sample, N=185M
15%
27 Million Patients
Patien
nts witth TC ≥ 250 m
mg/dL
Hypercholesterolemia Is Common
in Patients With Hypertension*
37
40
35
35
36
Normal BP
28
30
25
19
18
20
Antihypertensive
Rx
15
10
5
0
High BP
Men
MacMahon SW, et al. Arteriosclerosis. 1985;5:391-396.
Women
SBP and Cholesterol on CHD Death Rate
Age-adjusted
CHD death rates
per 10,000
10 000
person-years
33.7
21
22.6
17.1
17 7
17.7
12.3
16.7
10.9
13 7
13.7
79
7.9
5
79
7.9
5.6
9.6
8.3
8.5
6.3
6
3.4
3.1
12.2
5.9
55.55
4.3
SBP q
quintile (mm
(
Hg)
g)
Neaton JD et al. Arch Intern Med 1992;152:56-63.
12.7
≥245
221-244
203 220
203-220
182-202
<182
Cholesterol
quintile
( /dL)
(mg/dL)
Evolution of Management of
Hypercholesterolemia
Evolution of Management of
Hypercholesterolemia
The Pyramid
y
of Recent Trials
Very high chol
with CHD or MI
High chol
in high risk CHD or MI
4S
4S
LIPID
Normal chol
CARE
with CHD or MI
High cholesterol
without
ith t CHD or MI
WOSCOPS
No history of CHD or MI
Low to moderate cholesterol
without
ith t CHD or MI
AFCAPS/
TexCAPS
ASCOT
How About in Patients with Normal
Cholesterol ?
Heart Protection Studyy
20,000 pt with CHD or at high risk (TC >135 mg/dl)
40
-24%
24% RR
In
ncidence
e%
30
20
p<0.0001
Placebo (
(n=10,267)
)
Simvastatin (n=10,269)
-13% RR
P=0.0003
-25% RR
10
p<0.0001
0
All-cause
mortality
Major
j
vascular
events
All stroke
Adapted from HPS Collaborative Group, Lancet 2002;360:7–22
Heart Protection Study
y
ASCOT Study
y Design
g
R = Randomized
18,000 patients
R
9000 β-blocker ±
diuretic
5000 TC ≤6.5 mmol/L
(≤250 mg/dL)
500
open
p lipid
p
lowering
2250
statin
9000 CCB ± ACE
4000 TC >6.5 mmol/L
(>250 mg/dL)
g
+
4000 TC >6.5 mmol/L
(>250 mg/dL)
g
5000 TC ≤6.5 mmol/L
(≤250 mg/dL)
4500
4500
R
R
2250 placebo
8000
open lipid lowering
These are the target numbers of patients.
Sever PS, et al, for the ASCOT investigators. J Hypertens. 2001;19:1139-1147.
2250 placebo
500
open
p lipid
p
lowering
2250
statin
SBP
P (mm H
Hg)
ASCOT–LLA: BP changes
g
170
Atorvastatin 10 mg
160
Placebo
150
140
130
0
1
2
3
0
1
2
3
Close-out
DBP (mm Hg)
100
95
90
85
80
75
Years
Cl
Close-out
t
Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
ASCOT–LLA: cholesterol changes
g
Placebo
Atorvastatin 10 mg
200
1.3 mmol/L
1.0 mmol/L
4
150
(mg/dL
L)
Tottal choles
sterol
(mmol/L
L)
6
100
2
0
1
2
3
150
125
3
1.2 mmol/L
1.0 mmol/L
100
2
75
1
0
1
2
Years
3
Close-out
(mg
g/dL)
LDL chole
L
esterol
(mmo
ol/L)
4
ASCOT–LLA: nonfatal MI & fatal CHD
Cumulative incidence (%)
4
HR=0.64 (0.50-0.83)
3
P=0 0005
P=0.0005
36%
reduction
2
Atorvastatin 10mg
1
0
0.0
Placebo
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Sever PS et al. Lancet 2003;361:1149-1158
ASCOT–LLA
“Benefits
Benefits are Independent of Baseline Cholesterol
Cholesterol”
B
Baseline
li TC (mg/dl)
(
/dl)
RR
p
< 5,0
5 0 (193)
0 63
0.63
0 098
0.098
5 0 – 5,99
5,0
5 99 (193-231)
0 62
0.62
0 011
0.011
> 6,0
6 0 (231)
0 69
0.69
0 084
0.084
ASCOT BPLA and LLA Combined
Rates/1000 Patient-Years
Amlodipine ±
Perindopril +
At
Atorvastatin
t ti
Atenolol ±
Thiazide +
Pl
Placebo
b
Relative Risk
Reduction
Nonfatal MI and fatal
CHD
4.6
9.0
48%
Fatal and nonfatal stroke
42
4.2
86
8.6
44%
End Point
Sever P et al. Eur Heart J. 2006;27:2982-2988;
http://www.ascotstudy.org/healthcare_professionals/slides_and_resources.htm.
Global Risk Management:
g
“Add statin”
z If perfect control of a risk factor is difficult (eg,
blood
bl
d pressure control
t l in
i the
th elderly),
ld l ) total
t t l risk
i k
can still be reduced by reducing other risk factors
such as smoking or blood cholesterol
10%
Reduction
in BP
+
10%
Reduction
in TC
=
45%
Reduction
i CVD
in
Emberson J et al. Eur Heart J. 2004;25:484-491.
Graham et al. Eur Heart J. 2007. Advance Access Published Online August 28, 2007 Accessed at
http://eurheartj.oxfordjournals.org/cgi/content/full/ehm316v1
Effect of Cholesterol and BP on CHD Risk
Deaths/10,000
patient-years
N = 316,099
316 099
34
23
21
18
17
17
12
13
11
12
10
0
9
6
6
245+
4
221-244
8
8
6
6
3
203-220
6
3
182-202
<182
BP = blood pressure; CHD = coronary heart disease.
Neaton JD et al. Arch Intern Med. 1992;152:56-64.
14
<118
5
142+
132-141
125-131
118-124
ESH Guidelines. Eur Heart J. 2007. http://eurheartj.oxfordjournals.org/cgi/content/full/ehm236v1#SEC10
Evolution in Understanding
g CVD
Global CV Risk
Perspective
Total risk
Diabete
es
Hyperlip
H
pidemia
a
Hyperte
ension
Traditional
CVD Perspective
Independent risk
risk-factors
factors
treated individually
DM
age
sex
LIPID
HTN
smoking
g
Vascular Disease Is an
Interplay of risk-factors
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