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DEMA-CVN.

COM
GII THIU
CC TI BO CO TI HI NGH
TIM MCH MIN TRUNG- TY
NGUYN M RNG LN TH VI TI
BUN MA THUT THNG 8 NM 2011
TAC DUNG NHIEU MAT CUA STATIN
TRONG IEU TR RL LIPID MAU
(PLEIOTROPIC EFFECTS OF STATIN IN LIPID MANAGEMENT)
8 T8 ang Van Fhuor
h Y uor Tp. h6M
Slide 15. Gross photograph depicting multiple complicated
aortic atherosclerotic lesions characterised by ulceration or
rupture of their fibrous cap and subsequent thrombosis.
Slide 40. Photomicrograph of a ruptured plaque with thrombosis.
Libby P. Circulation 1995;91:2844-2850.
The Vulnerable Atherosclerotic Plaque
SMC smooth muscle cell
HDL-DR transplantation antigen indicating activation of SMCs
5
QUA TRNH TIEN TRIEN CUA QUAN IEM
VE VAI TRO CUA STATIN
6 nam Iruor 1 nam Iruor
hIan
IaI
Tuong IaI
Khang dinh rang
giam L0L se lam
giam nguy cJ BMv
Ta trung vao tinh
on dinh mang xJ
vua nhu la lJi ich
then chot ben tren
viec lam giam L0L
Ta trung lai vao lJi ich
chung tren mach mau
trong viec lam giam
hoac cham lai su tien
trien XvBM
YThC quan trong hJn?
Tinh doc la cua L0L?
Moi lien he mat thiet vJi
dien tien tren lam sang?
Moi muc do giam
giu mang lai lJi
ich
TIan IrIan quan dIam dua Iran LL
Cang tha cang tot Khong chi la giam
bao nhieu nhung la
lam giam nhu the
nao
L0L + CRF?
L0L + h0L?
G
VAI TRO CUA LDL OXY HOA TRONG X VA
ONG MACH
Endothelium
LDL
LDL
Lipid oxidation
MM-LDL
Smooth muscle cell
Foam cell
Fatty streak
M68F
IL1
Smooth muscle cell
proliferation ROS
Modified LDL uptake
Ox-LDL
Oxidation
Differentiation
X-LAM
+
Adhesion
Monocyte
M6F1
M68F
Macrophage
+
M6F1
+
Entry
7
Bang chng ve ng cong trong moi lien
quan gia LDL-C nguy c BMV (2001)
BuJng cong
nguy cJ BMv
100
L0LC (mg/dL)
?
Cac thu nghiem
lam sang
0ich te hoc
8
50
Secondary Prevention
Primary Prevention
CARE-Rx
4S-Rx
LIPID-Rx
CARE-PL
LIPID-PL
4S-PL
AFCAPS-Rx
AFCAPS-PL
WOSCOPS-Rx
WOSCOPS-PL
70 90 110 130 150 170 190 210
0
5
10
15
20
25
LDL-C Lowering With Statins:
Reduced CHD Events
Adapted from Illingworth DR. Med Clin North Am. 2000;84:23-42.
LDL Cholesterol (mg/dL)
O
MOI LIEN QUAN CO THE GIA LDL-C VA NGUY
C BENH MACH VANH (2001): Cac gia thuyet
hguy
cJ
BMv
100
L0LC (mg/dL)
hguJng:
Khong can thiet
hai ha qua tha
BuJng thang: Cang tha cang tot
BuJng cong:
Cang tha, cang tot,
vJi lJi ich giam dan
0
1
1O
Heart Protection Study
(Nghien cu keo dai 5 nam)
hguy
cJ
BMv
100
L0LC (mg/dL)
Simvastatin
4O mg
60
0iam 2G% nguy cJ
BMv
0iam 22% nguy cJ BMv
Simvastatin
4O mg
heart Frotection Study Collaborative 0rou. Lancet 2OO2;8GO:722.
11
PROVE ITTIMI 22
(Nghien cu trong 2 nam)
hguy
cJ
BMv
1OO
Muc L0LC
GO
Fravastatin
4O mg
0iam 1G% nguy cJ BMv
Atorvastatin
8O mg
Cannon CF et al. N Engl J Med 2OO4;85O:14O515O4.
12
Ket luan t cac nghien cu:
Vi muc tieu LDL Cang thap cang tot
hguy cJ BMv
(Log Scale)
8.7
2.O
2.2
1.7
1.8
1.O
L0LC (mg/dL)
4O 7O 1OO 18O 1GO 1OO
0
1
0rundy SM et al. Circulation 2OO4;11O:22728O.
18
LDL C Lower is Better
NCEP ATP III: LDL-C Goals
(2004 proposed modifications)
*Therapeutic option
70 mg/dL =1.8 mmol/L; 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160
mg/dL = 4.1 mmol/L
High Risk
CHD or CHD risk
equivalents
(10-yr risk
>20%)
L
D
L
-
C

l
e
v
e
l
100 -
160 -
130 -
190 -
Lower
Risk
< 2 risk
factors
Moderately
High Risk
2 risk
factors
(10-yr risk
10-20%)
goal
160
mg/dL
goal
130
mg/dL
70 -
goal
100
mg/dL
or
optional
70
mg/dL*
Moderate
Risk
2 risk
factors
(10-yr risk
<10%)
goal
130
mg/dL
or
optional
100
mg/dL*
Grundy SM et al. Circulation 2004;110:227-239.
Existing LDL-C goals
Proposed LDL-C goals
15
Continuum of Patients at Risk for a
CHD Event
Post MI/Angina
Other Atherosclerotic
Manifestations
Subclinical Atherosclerosis
Multiple Risk Factors
Low Risk
Secondary
Prevention
Primary
Prevention
Courtesy of CD Furberg.
1G
Potential Time Course of Statin Effects
* Time course established
Days Years
LDL-C
lowered*
Inflammation
reduced
Vulnerable
plaques
stabilized
Endothelial
function
restored
Ischemic
episodes
reduced
Cardiac
events
reduced*
17
Bile acids
8TkTIh
Cholesterol
Acetate
L0L
recetor
Chylomicron
LIpoproIaIn IIpasa
vL0L
0L
L0L
8TkTIh. ME6hkhI8M 0F k6TI0h
0ietary cholesterol
and triglyceride
18
8quaIana
6hoIasIaroI
6hoIasIaroI
8ynIhasIs
6hoIasIaroI daposIIs
HMG-CoA
Reductase
8IaIIns
S O C CHE TAC ONG CUA STATIN
TREN NHIEU MAT
hM6ok
MavaIonaIa
IFF
FFF
DAVIGNON 03
FF
as
IarnasyIaIIon
ho, ar, ab
garanyIgaranyIaIIon
VasruIopaIhy, IhrombosIs
+ IFF
krIIvaIIon
0I 8IgnaIIng
MoIaruIas
Isoprana
8ynIhasIs
FroIIIaraIIon
MIgraIIon
hyparIrophy
VasoronsIrIrIIon
0xIdaIIon
InIIammaIIon
6oaguIaIIon
19
Effects of statins on
atherosclerotic plaque stability
Statin
therapy
Lipid-
lowering
Plaque
stability
Other
biological
Effects
Pleiotropic Effects?
Class effect
Drug-specific effects
Weissberg, 1999
Main Effects of Statins
Effects on lipids:
Reduce LDL-C, TC and TG
Increase HDL-C
Pleiotropic effects:
Improve or restore endothelial function
Enhance the stability of atherosclerotic plaques
Decrease oxidative stress
Decrease vascular inflammation
Anti-thrombotic effects
Takemoto M, Liao JK. Arterioscler Thromb Vasc Biol 2001;21:1712-1719.
21
KIM SOT TCH CC CC THNG S LDL, HDL
S GIP Y LI X VA NG MCH
V CI THIN KT CC LM SNG
LDL-C
Atherosclerosis
CVD
1,2
1. Amarenco P, et al. Stroke 2004;35:29022909; 2. Ballantyne CM, et al. Curr Opin Lipidol 1997;8:354361;
3. Whitney EJ et al. Ann Intern Med 2005;142:95104; 4. Waters D, et al. Circulation 1993;87:106775; 5.
OLeary DH, et al. N Engl J Med 1999;340:1422
4,5
HDL-C
3
22
Nicholls SJ et al. JAMA 2007;297:499508.
HDL-C |
>7.5%
LDL-C +
< 87.5
mg/dL
Th tch
mng x
va gim
>5%
Figure adapted from Nicholls et al. (2007)
Statin therapy is associated with regression of
coronary atherosclerosis when LDL-C is substantially
reduced and HDL-C is increased by more than 7.5%
23
Endpoint Events (%) RR (CI)
Treatment
(45,054)
Control
(45,002)
Year 01
Major coronary event 805 (1.8%) 980 (2.2%) 0.86 (0.770.95)
Coronary revascularisation 795 (1.8%) 841 (1.9%) 0.95 (0.841.08)
Stroke 297 (0.7%) 311 (0.7%) 0.96 (0.791.17)
Major vascular event 1747 (3.9%) 1951 (4.3%) 0.90 (0.850.96)
Year 12
Major coronary event 653 (1.5%) 856 (2.0%) 0.78 (0.700.87)
Coronary revascularisation 488 (1.1%) 653 (1.5%) 0.76 (0.660.87)
Stroke 264 (0.6%) 363 (0.8%) 0.75 (0.620.90)
Major vascular event 1231 (2.9%) 1603 (3.8%) 0.78 (0.730.83)
Year 5+
Major coronary event 274 (1.5%) 380 (2.2%) 0.71 (0.590.84)
Coronary revascularisation 203 (1.2%) 272 (1.6%) 0.73 (0.590.90)
Stroke 99 (0.5%) 119 (0.7%) 0.79 (0.571.10)
Major vascular event 468 (2.8%) 598 (3.8%) 0.74 (0.670.82)
Timing of Benefit in Statin Trials
Meta-analysis of 14 Studies (90,056 Subjects)
0.5 1.0 1.5
Treatment better Control better
Trend test for major vascular events: _ =13.9; P=0002
2
1
CTTC. Baigent C et al; Lancet 2005
VkI T0 8k0 VE Mk6h
+ Tao sang Ihuong,
| sua rhua
Fhur hoI rhur nang noI mar
| Iao h0
Tar dung rhong oxy hoa
+ Inh Iham rua noI mar
+ Ion Ihuong rar yau Io bao va
| dI Iru Ib noI mar
+TIan IrIan sang Ihuong
| 0n d}nh mang xo vua
+ IoI LIpId
+ oxy hoa
+ vIam
+ hnh Ihanh Ib boI
+ Ton Ihuong mIan d}rh
ImmunosupprassIon
+ 6raarIIva proIaIn
+ InIIammaIory ryIokInas
+ ong mau
+ kaI dnh IIau rau
| FIbrInoIysIs
+ TIssua FarIor
+ LL va Ts
| hL
ImmunosupprassIon
+ vIam
Z6
Xo vua dong marh. MoI banh dIan IIan IIan Iur
CRF=Creactive rotein; L0LC=lowdensity liorotein cholesterol.
Libby F. Circulation. 2OO1;1O4:8G5872; Ross R. N Engl J Med. 1OOO;84O:11512G.
MonoryIa
LL6
kdhasIon
moIaruIa
Marrophaga
Foam raII
0xIdItad
LL6
FIaqua rupIura
8mooIh musrIa
raIIs
6F
Tnh on d}nh rua
mang xo vua
0xy hoa VIam L rhur nang noI mar
Z7
L rhur nang noI mar. 8uor dau IIan Irong
IIan Irnh XVM
hoI mar bnh Ihuong hoI mar b} roI Ioan
0moigui h, 0/au vJ. J Vasc Med Biol.1OO1;8:8828O1; Ross R. N Engl J Med. 1OOO;84O:11512G; Kathir K, Adams MR.
Semin Vasc Med. 2OO8;8:8558G1; 0avignon J, 0an/ F. Circulation. 2OO4;1OO(sul ):2782.
vascular tone Related
latelet &
leukocyte
adhesion
|Flatelet/
leukocyte
adhesion
nhibit SMC
migration/
rolieration
Barrier to
lioroteins and
other lasma
comonents
vasoconstriction SMC
migration
& growth
|Liid
deosition &
clearance
ysIunrIIon
hyertension L0LC 0iabetes Smoking
SMC=smooth muscle cell.
Z8
L rhur nang noI mar. 8u maI ran bang rua
rhur nang noI mar
Kathir K, Adams MR. Semin Vasc Med. 2OO8;8:8558G1; 0moigui h, 0/au vJ. J Vasc Med Biol.1OO1;8:8828O1.
Co bang chung lam sang nao cho thay rang cac yeu to
danh dau viem giu du bao bien co mach vanh trong
tuJng lai va cung ca them thong tin tien luJng so vJi
cac yeu to nguy cJ kinh dien truJc day?
Is there clinical evidence that inflammatory markers predict future coronary events
and provide additional predictive information beyond traditional risk factors?
LDL VA TAC DUNG GAY VIEM
hormaI
LL
kIharoma
avaIopmanI
EndoIhaIIaI dysIunrIIon
Foam raII IormaIIon
| 6oIIagan synIhasIs
| 640 & 640L
LaukoryIa adhasIon
EndoIhaIIaI parmaabIIIIy
ModIIIad
LL
| EIarIro
nagaIIvIIy
8Z
LL
C04OL=C04O ligand; ThF=tumor necrosis actoralha; L=interleukin; vCAM=vascular cell adhesion molecule; CAM=intercellular
adhesion molecule.
Cockerill 0w et al. Arterioscler Thromb Vasc Biol. 1OO5;15:1O871OO4; Andre F et al. Circulation. 2OO2;1OG:8OG8OO; Libby F.
Circulation. 2OO1;1O4:8G5872; Libby F et al. Circulation. 2OO2;1O5:11851148; Ross R. N Engl J Med. 1OOO;84O:11512G.
VassaI Iuman
MonoryIa
Marrophaga
kdhasIon
moIaruIas
(V6kM1, I6kM1)
InIIammaIory madIaIors
(6F, 640l640L,
ThF, IL1, IL6)
InIIma
Foam
raII
VIam Iam Ihur day su IIan IrIan rua XVM
Endothelium
LL
0xLL
88
Parietal vascular inflammation
The activated macrophage produces inflammatory cytokines
activated
endothelium
CELLULAR
ADHESION
MOLECULES
induces cell
proliferation and
a prothrombic
state
attracts monocytes and T
lymphocytes
which adhere to
endothelial cells
cytokines (eg. IL-1, TNF-o)
chemokines (eg.MCP-1, IL-8)
growth factors (eg. PDGF, FGF)
Koenig W. Eur Heart J Suppl 1999;1(Suppl T);T19-26.
The Activated Endothelium
Ia Ir} IIan Iuong rua 6F va rar yau Io rh dIam
vIam khar. LL <180 mgldL
Ridker FM et al. N Engl J Med 2OOO;842:88G848.
4
8
2
1
1
h
g
u
y

c
J

t
u
J
n
g

d
o
i

c
a
c

b
i
e
n

c
o

m
a
c
h

v
a
n
h
Muc cua cac yeu to chi diem viem
hsCRF
2 8 4
SAA
LG
sCAM1
37
Hs-CRP and risk of future Acute MI
P<0.001
P<0.001
P=0.03
Quartile of hs-CRP
P < 0.001
R
e
l
a
t
i
v
e

r
i
s
k


R
R
Ref: Ridker et al, N Engl J Med. 1997;336:973979.
0
1
2
3
1 2 3 4
38
CRP and fatal incident
in Acute coronary syndrome
Ref: FRISC (2000), NEJM,343:1139
months
Death(%)
hs6F Ia YTh6 IIm marh
1.O 2.O 8.O 4.O 5.O G.O
Relative Risk (uer vs lower quartile)
Ch0 0eath
M
Stroke
Ch0
Fv0
Cv0
Ch0
Ch0
Ch0
Ch0
O
MRFT (Kuller 1996)
FhS (Ridker 1997)
FhS (Ridker 1997)
ChS/RhFF (Tracy 1997)
FhS (Ridker 1998)
whS (Ridker 1998, 2000)
M0hCA (Koenig 1999)
helsinki (Roivainen 2000)
Caerhilly(Mendall 2000)
Britain (Danesh 2000)
0
1
2
3
4
5
6
hs6F bo sung vao gIa Ir} du bao rua mur rhoIasIaroI
Ioan phan Irong vIar xar d}nh nguy ro hM6T
Ridker FM et al. Circulation 1OO8;O7:2OO72O11.
1OO8 Liincott williams & wilkins.
h
g
u
y

c
J

t
u
J
n
g

d
o
i
CRF >75
th
ercentile
TC >75
th
ercentile
+ +
+ +
P = O.O2
P = O.OO1
P = O.OO2
0.0
1.0
2.0
3.0
4.0
5.0
High Medium Low
Low
Medium
High
hs6F bo sung vao gIa Ir} du bao rua Iy so rhoIasIaroI Ioan
phan. hL Irong vIar xar d}nh nguy ro hM6T
Ridker FM et al. Circulation 1OO8;O7:2OO72O11.
1OO8 Liincott williams & wilkins.
Ty so Cholesterol TF :h0L
hsCRF
Yau Io nguy ro rua rar bIan ro IIm marh Irong Iuong IaI.
nghien cu WHS
Relative Risk o Future Cardiovascular Events
O
Ridker FM et al. N Engl J Med 2OOO;842:88G848.
Liorotein(a)
homocysteine
LG
TC
L0LC
sCAM1
SAA
Ao B
TC:h0LC
hsCRF
hsCRF + TC:h0LC
1.O 2.O 4.O G.O
48
CAC TAC ONG CUA STATIN
Iam IIpId mau
+
Iam krh Ihuor IoI IIpId va gIup on
d}nh mang xo vua
Tar dung rhong vIam
6aI IhIan rhur nang noI
mar
Tar dung rhong oxy hoa
NGHIEN CU ASAP:
HIEU QUA TREN CRP
kIorvasIaIIn varsus sImvasIaIIn
`PO.OO1 or dierence between grous; `` P=O.O2 or dierence between grous
`
``
5O
45
4O
85
8O
25
2O
15
1O
5
O
1 Year 2 Years
Atorvastatin
Simvastatin
F
e
r
c
e
n
t

c
h
a
n
g
e
i
n

h
s

C
R
F
44.O
14.O
4O.1
1O.7
Smilde TJ, et al. Lancet. 2OO1;857:577581.
46
hghIan ruu k8kF. kIorvasIaIIn Iam gIam 6F IoI hon
8ImvasIaIIn
hhung phaI hIan khar
Khong co moi lien quan giua muc giam CRF va L0LC
6o moI IIan quan rhaI rha gIua mur gIam 6F va
mur gIam IMT (r =.18; P=.08)
8anh nhan ro mur gIam 6F rao nhaI sa ro mur
gIam IMT rao nhaI
van wissen S et al. Atherosclerosis. 2OO2;1G5:8G18GG.
46
-50
-40
-30
-20
-10
0
C
h
a
n
g
e

f
r
o
m

b
a
s
e
l
i
n
e

(
%
)
Atorvastatin 80 mg Pravastatin 40 mg
hghIan ruu EVE8kL.
kIorvasIaIIn Iam gIam LL6 va 6F IoI hon FravasIaIIn
`P.OO1.
hissen SE et al. JAMA. 2OO4;2O1:1O711O8O.
*
*
LL6 6F
46.8
6.Z
86.4
Z6.Z
NGHIEN CU REVERSAL:
HIEU QUA TREN CRP
kIorvasIaIIn varsus pravasIaIIn
`PO.OOO1.
8G.4
`
Atorvastatin
5.2
Fravastatin
C
h
a
n
g
e

(
%
)
4O
8O
2O
1O
O
6F (mgldL)
Fravastatin Atorvastatin
Baseline 8.O 2.O
18 Months 2.O 1.O
hissen S. AhA 2OO8. 0rlando, Florida.
48
Hs-CRP Levels Significantly Reduced with
Statins
-30
-25
-20
-15
-10
-5
0
Atorvastatin 10 mg Simvastatin 20 mg Pravastatin 40 mg
%

c
h
a
n
g
e

i
n

h
s
-
C
R
P

a
f
t
e
r

6

w
e
e
k
s
Adapted from Jialal I, et al. Circulation. 2001;103:1933-1935.
49
hghIan ruu kLI. kIorvasIaIIn Iam gIam dang ka
6F o banh nhan T Iyp Z
-50
-40
-30
-20
-10
0
10
R
e
l
a
t
i
v
e

c
h
a
n
g
e

f
r
o
m

b
a
s
e
l
i
n
e

m
e
d
i
a
n

(
I
Q
R
)
`P.OO1.
0AL=diabetes atorvastatin liid intervention study.
0R=interquartile range
van de Ree MA et al. Atherosclerosis. 2OO8;1GG:12O185.
FIarabo kIorvasIaIIn
80 mg
kIorvasIaIIn
10 mg
`
6.6
14.6
46.7
60
hghIan ruu F0VE IT. 8anh nhan ro mur LL6 va 6F
Ihap nhaI sa ro I nguy ro IaI phaI rar bIan ro hon
Adated rom Ridker FM et al. N Engl J Med. 2OO5;852:2O28; Ridker FM et al. Fresented at AhA Scientiic Sessions; 2OO4.
LL6 >70 mgldL, 6F >Z mglL
LL6 <70 mgldL, 6F >Z mglL
FoIIoWup (yaars)
LL6 <70 mgldL, 6F <Z mglL
LL6 >70 mgldL, 6F <Z mglL
0.0 0.6 1.0 1.6 Z.0 Z.6 0.0 0.6 1.0 1.6 Z.0 Z.6 0.0 0.6 1.0 1.6 Z.0 Z.6
0.00
0.04
0.0Z
0.06
0.08
0.10
LDL-C <70 mg/dL, CRP <1 mg/L
AC TNH CHONG OXY HOA
Shishehbor MH, et al. Circulation. 2003;108:426-431.
Dityrosine Chlorotyrosine Nitrotyrosine Orthotyrosine
P<0.001
P<0.001
P=0.02
P=0.49
35
30
25
20
15
10
5
0
%

R
e
d
u
c
t
i
o
n

i
n

o
x
i
d
a
t
i
v
e

m
a
r
k
e
r
s
Reductions in plasma protein oxidation markers following 12 weeks of
treatment with atorvastatin 10 mg
SO SANH VAI TRO CHONG OXY HOA
Mason RP. J Am Coll Cardiol. 2000;35(Suppl A):317.
Walter MF, et al. ACC. 2004. New Orleans, LA.
45
40
35
30
25
20
15
10
0
5
-5
-10
-15
I
n
h
i
b
i
t
i
o
n

o
f

L
O
O
H

f
o
r
m
a
t
i
o
n

(
%
)
*
Atorvastatin
metabolite
Lovastatin Pravastatin Rosuvastatin Simvastatin
Treatment (500 nM)
*Ps 0.01 vs control
53
-80-60 -40-20
-0.1
Statins and Inflammation
Tahara et al. JACC 2006 48;1825
Baseline
43 subjects simvastatin 5-20 mg/d:
PET/CT of carotids, thoracic aorta
ASUV
0.2
0.1
-0.2
-0.3
-0.4
-20 -10 10 20 30
ALDL
simvastatin
r=0.520
P<0.01
0.2
0.1
-0.1
-0.2
-0.3
-0.4
-100 20 40 60
ASUV
AHDL
Post-treatment
FDG
PET
PET
PET/CT
D
i
e
t
S
i
m
v
a
s
t
a
t
i
n
54
CAC TAC ONG CUA STATIN
Iam IIpId mau
+
Iam krh Ihuor IoI
IIpId va gIup on d}nh
mang xo vua
Tar dung rhong vIam
6aI IhIan rhur nang noI mar
Tar dung rhong oxy hoa
55
Potential Time Course of Statin Effects
* Time course established
Days Years
LDL-C
lowered*
Inflammation
reduced
Vulnerable
plaques
stabilized
Endothelial
function
restored
Ischemic
episodes
reduced
Cardiac
events
reduced*
56
Angiography Does Not
Image Plaque
57
LDL Reduction and Angiography
M
L
D

d
e
c
r
e
a
s
e

(
m
m
/
y
e
a
r
)
Ballantyne et al. Current Opin Lipidology 1997;8:354361
r
2
= 0.71
P=0.0005
?
PLAC-1
LCAS
PLAC-1
CCAIT
REGRESS
MAAS MARS
MARS
LCAS
REGRESS
MAAS
CCAIT
-
0.01
0
0.01
0.02
0.03
0.04
0.05
70 80 90 100 110 120 130 140 150 160 170 180
LDL-C (mg/dL)
58
Far wall
Near
wall
Bifurcation
Internal External Skin
Ultrasound
pulse
B-Mode Ultrasound
59
Carotid Intima Medial Thickness
60
-4
-6
-2
6
4
2
0
LIPID
MARS
LDL-C Lowering Attenuates
Progression of IMT
REGRESS
CAIUS
ACAPS
CAIUS
ACAPS
REGRESS
ARBITER
MARS
ASAP
ASAP
ARBITER
KAPS
PLAC
PLAC
KAPS
LIPID
5 -5 -15 -35 -25 -55 -45
Percent reduction LDL-C (%)
A
n
n
u
a
l

p
e
r
c
e
n
t

c
h
a
n
g
e

I
M
T

(
%
)
Control
Active treatment
Amarenco. Stroke 2004;35:2902
61
ASAP: IMT Regression with
Intensive Lipid Lowering
Lancet 2001;357:577581
simvastatin
(N=139)
*
P=0.0001 for comparison between groups
-0.04
-0.02
0.00
0.02
0.04
*
C
h
a
n
g
e

I
M
T

(
m
m
)
atorvastatin
(N=141)
atorvastatin
(N=141)
*
simvastatin
(N=139)
0
-10
-20
-30
-40
-50
L
D
L
-
C

r
e
d
u
c
t
i
o
n

(
%
)
62
ARBITER: IMT Regression with
Intensive Lipid Lowering
Circulation 2002;106:20552060
*
P=0.03 and
**
P<0.001 for comparison between groups
pravastatin
(N=70)
0
L
D
L
-
C

r
e
d
u
c
t
i
o
n

(
%
)
**
-0.050
-0.025
0.000
0.025
*
C
h
a
n
g
e

I
M
T

(
m
m
)
atorvastatin
(N=72)
atorvastatin
(N=68)
pravastatin
(N=73)
-10
-20
-30
-40
-50
63
Patients (N=984)
Asymptomatic for CHD
Maximum IMT 1.2<3.5 mm
Modest hypercholesterolaemia
Men (aged 45-70)
Women (aged 55-70)
METEOR: Study Design
rosuvastatin 40 mg (N=702)
placebo (N=282)
Lipids
Safety
CIMT
Safety
Lipids
Safety
CIMT
Lipids
Safety
Lipids
Safety
CIMT
Safety
CIMT
Safety
Visit:
Week:
1
6
4
0
5
6
6
13
7
26
8
39
9
52
10
65
11
78
12
91
13
104
Run in / eligibility
2
4
3
2
Adapted from Crouse JR et al. Cardiovasc Drugs Ther 2004;18:231238
64
Time
(years)
C
h
a
n
g
e

i
n

I
M
T

o
f

1
2

c
a
r
o
t
i
d

s
i
t
e
s

(
m
m
)
-0.01
+0.01
0.00
+0.02
2
1
+0.03
P=NS
(rosuvastatin vs. zero slope
placebo
+0.0131 mm/yr
(n=252)
rosuvastatin 40 mg
-0.0014 mm/yr
(n=624)
P<0.0001
(rosuvastatin vs. placebo)
Placebo; change in CIMT (95% CI) Rosuvastatin 40 mg; change in CIMT (95% CI)
Crouse JR III, et al. JAMA 2007;297 (12):13441353
METEOR: Results
G5
GG
67
Rotating transducer Coronary artery
Intravascular Ultrasound
68
Discord Between Lumen and
Atherosclerosis
Lumen
Area
EEM Area
Atheroma Area
Ultrasound Determination of Atheroma
Area
Frecise Flanimetry o EEM and Lumen Borders
with Calculation o Atheroma Crosssectional Area
7O
IVUS efficacy measures
Lumen
Area
(EEM Lumen)
EEM Area
E (EEM
CSA
- Lumen
CSA
)
number cross-sections
in patients pullback
Normalized*
Total
Atheroma
Volume
=
median number cross-
sections for all patients
x
Most diseased
contiguous
10 cross-sections
Change
in Percent
Atheroma
Volume
E n
EEM
CSA
=
E n
(EEM Lumen)
CSA
EEM
CSA

(Month 24) (baseline)


(EEM Lumen)
CSA
X 100 X 100
* Normalized = adjusting for pullbacks of differing lengths thereby resulting in an equal weighting of each
individual patient
71
CAC SIEU AM DUNG
SIEU AM TRONG LONG MACH (IVUS)
NGHIEN CU REVERSAL
Reversal of Atherosclerosis with aggressive lipid lowering
NGHIEN CU ASTEROID
A study to evaluate the effect of Rosuvastatin on Intravascular
ultrasound derived coronary atheroma burden
72
REVERSAL: Atheroma Volume
*
Wilcoxon signed rank test

ANCOVA of rank transformed results


P= 0.02

3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
-0.5
-1.0
2.7
-0.4
Progression (P=0.001*)
No change (P=0.98*)
%

c
h
a
n
g
e

i
n

t
o
t
a
l

a
t
h
e
r
o
m
a

v
o
l
u
m
e
pravastatin
atorvastatin
Nissen SE et al. JAMA 2004; 291(9)10711080
Percent Change in Total Atheroma Volume
Intensive Statin Therapy Halts the Progression
of Atherosclerosis: REVERSAL
*p<0.05, **ps0.001, ns non significant vs. baseline
PAV percent atheroma volume, TAV total atheroma volume
Nissen S et al. JAMA 2004;291:1071-1080.
prava 40 mg
atorva 80 mg
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
M
e
d
i
a
n

c
h
a
n
g
e

i
n

p
e
r
c
e
n
t

a
t
h
e
r
o
m
a

v
o
l
u
m
e

(
%
)
-1.2
-4.2
**
*
p<0.01
0
0.5
1
1.5
2
0.2
1.6
ns
**
p<0.001
Median change in PAV
-1
-0.5
0
0.5
1
1.5
2
2.5
3
M
e
d
i
a
n

c
h
a
n
g
e

i
n

a
t
h
e
r
o
m
a

v
o
l
u
m
e

(
%
)
-0.4
2.7
**
ns
p=0.02
Median change in
TAV
M
e
d
i
a
n

c
h
a
n
g
e

i
n

a
t
h
e
r
o
m
a

v
o
l
u
m
e

i
n

t
h
e

1
0

m
m

s
e
g
m
e
n
t

w
i
t
h

m
o
s
t

d
i
s
e
a
s
e

(
%
)
Median change in TAV in
most diseased subsegment
NEW
74
ASTEROID
A Study To evaluate the Effect of
Rosuvastatin On Intravascular
ultrasound-Derived coronary
atheroma burden
Reference: Nissen S et al. Effect of very high-intensity statin therapy on regression of coronary
atherosclerosis. The ASTEROID trial. JAMA 2006;295 (13):1556-1565.
75
ASTEROID
ASTER00 used intravascular ultrasound (vuS) to e
valuate the effect of rosuvastatin (CRESTOR) on a
therosclerotic disease in atients with coronary arte
ry disease (CA0)
t investigated whether rosuvastatin can induce regr
ession o the volume o coronary artery atheroma
7G
Endpoint analysis: Change in med
ian percentage atheroma volume
`O.OO1 or dierence rom baseline values. wilcoxon signed rank test
O.O
O.8
O.7
O.G
O.5
O.4
O.8
O.2
O.1
O
Median Fercent Atheroma volume
C
h
a
n
g
e

r
o
m

b
a
s
e
l
i
n
e

(
%
)
0.79%
*
Re: hissen S et al. JAMA 2OOG;2O5 (18):155G15G5.
rosuvastatin 40 mg
*p<0.001 vs. baseline,
PAV percent atheroma volume, TAV total atheroma
volume
-8
-7
-6
-5
-4
-3
-2
-1
0
M
e
d
i
a
n

c
h
a
n
g
e

i
n

n
o
r
m
a
l
i
s
e
d

t
o
t
a
l

a
t
h
e
r
o
m
a

v
o
l
u
m
e

(
%
)
-6.8
*
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
M
e
d
i
a
n

c
h
a
n
g
e

i
n

a
t
h
e
r
o
m
a

v
o
l
u
m
e

i
n

t
h
e

1
0

m
m

s
e
g
m
e
n
t

w
i
t
h

m
o
s
t

d
i
s
e
a
s
e

(
%
)
-9.1
*
Nissen S et al. JAMA 2006;295 (13):1556-1565.
Very Intensive Statin Therapy Significantly
Regresses Atherosclerosis: ASTEROID
-1
-0.5
0
M
e
d
i
a
n

c
h
a
n
g
e

i
n

p
e
r
c
e
n
t

a
t
h
e
r
o
m
a

v
o
l
u
m
e

(
%
)
-0.79
*
Median change in PAV
Median change in TAV in
most diseased subsegment
NEW
Median change in
normalised TAV
Please consult local Prescribing Information for
guidance on the use of CRESTOR.
IVUS
parameter
measured
Number (%) of patients showing regression
measured by each IVUS parameter: ASTEROID
0 10 20 30 40 50 60 70 80 90 100
Patients showing regression (%)
Percent atheroma volume (PAV)
Atheroma volume in the most diseased 10 mm subsegment
Normalised total atheroma volume (TAV)
78 %
78 %
64 %
IVUS
parameter
measured
Patients showing regression (%)
63.6%
78.1%
77.9%
rosuvastatin 40 mg
NEW
Nissen S et al. JAMA 2006;295 (13):1556-1565.
Please consult local Prescribing Information for
guidance on the use of CRESTOR.
7O
1
O.5
O
O.5
1
1.5
2
5O GO 7O 8O OO 1OO 11O 12O
ASTER00
8
rosuvastatin
AFlus
2
lacebo
ACTvATE
1
lacebo
CAMEL0T
4
lacebo
REvERSAL
5
ravastatin
REvERSAL
5
atorvastatin
Mean L0LC (mg/dL)
The relationship between mean LDL-C and change in
percent atheroma volume (PAV) in IVUS studies

Change in
Fercent
Atheroma
volume`
(%)
ASTEROID and REVERSAL investigated active statin treatment; AFLuS, ACTvATE Ah0 CAMEL0T investigated nonstatin theraies but included lacebo arms who received
background statin theray (G2%, 8O% and 84% resectively).
`Median change in FAv rom ASTER00 and REvERSAL; LS mean change in FAv rom AFLuS, ACTvATE Ah0 CAMEL0T
Progression
Regression
1 hissen S et al. h Engl J Med 2OOG;854:125812G8. Z Tardi J et al. Circulation 2OO4;11O:88728877. 8 hissen S et al. JAMA 2OOG;2O5 (18):155G15G5
4 hissen S et al. JAMA 2OO4;2O2: 22172225. 6 hissen S et al. JAMA 2OO4; 2O1.1O711O8O
80
ApoB/AI
CRP
New Paradigms for Lipid
Lowering Therapy
Role of atherosclerosis imaging in CHD prevention
Acute coronary event
Diabetes
High global risk score (>3%/yr)
Aggressive statin
or statin plus
treatment
Low risk (<1%/yr), asymptomatic Diet, lifestyle
Medium risk (1-3%/yr) Scan
Sub-clinical
atherosclerosis
yes
no
LDL <70 mg/dL
(2.0 mmol/L)
HDL >40 mg/dL
(1.1 mmol/L)
CRP <1.0mg/L
Targets
hi
lo
81
Horizons in Lipid Regulation
New modalities
ACAT inhibition
CETP inhibition
MTP inhibition
PPAR agonist
PPAR o, agonist
LXR o,| agonist
New statin indications
CVD in renal disease
Heart failure
Inflammatory
conditions (RA)
Stroke
Metabolic syndrome
KET LUAN
Statin la nhom thuoc giu lam giam L0LC tot nhat hien nay
Ben canh tac dung lam giam liid mau, statin con co nhieu tac
dung co lJi khac, nhu:
tac dung chong viem
Tac dung chong oxy hoa
Fhuc hoi chuc nang noi mac
Tac dung chong ong mau
Cac statin khac nhau co nhieu qua khac nhau tren cac tac dung
cong them nay. Trong do atorvastatin,rosuvastatin cho thay co
nhieu nghien cuu chung minh duJc vai tro on dinh va lam giam
su tien trien XvBM
Cam n s theo doi cua qu v

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