dyslipidemia vascular disease statin · 2015-07-07 · reduces cv risk: prove-it n number recurrent...
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Lipid is evolving
DyslipidemiaVascular disease
Statin Beyond
관동의대제일병원
내과박정배
&A
Dyslipidemia 와혈관질환,
그연결고리는?
약80%가
체내에서생성
약20%가
음식물에서흡수
Quantity of cholesterol
in the body
Bile
acid
s
배설
동맥경화증의위험요인
Coronary Heart Disease
Other
High blood
cholesterol
Smoking
Aging
Obesity
Hypertension
Diabetes
mellitus
Heredity
흡연이고혈압의위험요인인것처럼, 혈액중에콜레스테롤의양이많으면심장질환과동맥경화의위험요인이된다.
Compliant
Systole Diastole
Arterio and Atherosclerosis
Systole Diastole
Constant Stroke Volume
Aorta
Pulse pressure
compliant stiffened
죽상경화증(atherosclerosis) 과동맥경화증(arteriosclerosis)
O’Leary DH et al. N Engl J Med.1999;340(1):14-22
Vascular event (MI or Stroke) rate and IMT
Birgelen C et al. Circulation 2004;110:1579
Vascular event and Plaque
Pulse wave change (eg,augmentation index)
Evolving of Dyslipid Vascular disease
Vascular imagingEndothelial function test
Markers of Atherosclerosis and arteriosclerosis
are risk factors for adverse CV outcomes
Risk of CHD by Multiple Risks & Cholesterol
Kannel J. Am Coll Cardiol. 1990
8-y
ea
r p
rob
ab
ilit
y
(pe
r 1
00
0)
Cholesterol mg/dL 185↔335 185↔335 185↔335 185↔335
(mmol/L) (4.8↔8.7) (4.8↔8.7) (4.8↔8.7) (4.8↔8.7)
Glucose Intolerance 0 + + +
Systolic BP (mmHg) 105 195 195 195
Cigarettes 0 0 + +
LVH on ECG 0 0 0 +
60
50
40
30
20
10
0
60.2
34.6
23.2
3.9
&Q
ADyslipidemia, 혈관질환과의연결고리를어떻게끊을것인가?
Dyslipidemia Vascular disease
Statin & beyond
Meta-analysis of 38 1o & 2o prevention trials, with 98,000 patients
Mortality in CHD, p=0.012
Total mortality, p=0.04
Benefit of Lowering Cholesterol
Gould AL et al. Circulation 1998;97:946–952
Cholesterol reduction (%)
Mortalitylog oddsratio
0 4 8 12 16 20 24 28 32–1.0
–0.8
–0.6
–0.4
–0.2
0.0
적정한감량수치는기존체중의 5~7% 감량
음식: 포화지방 7% ↓ · 트랜스불포화지방산 1% ↓
·콜레스테롤 200mg/d ↓ /전체칼로리
염분섭취량 : 1200~2300mg/일
운동: 심혈관계질환예방 - 중등도 150분/강력한운동 90분 /주체중감량및유지: 중등도/강력한운동 7시간/주
금연: 금연권고+ 담배를끊고자하는의지평가필요.
생활습관개선요법이최대 3개월까지
2007 AHA·ADA
"당뇨병환자심혈관질환예방" 생활습관
지혈이상증의치료
고지혈증치료의기본원칙1) 고지혈증의종류에따라식이요법과운동처방을약 3개월동안시행한다.
2) 식이요법과운동요법이효과가없을때약물치료를시작한다.
3) 약물치료를시작한뒤에도식이요법과운동요법을병행한다.
운동식이요법
약물투여
Other major risk factors (beyond dyslipoproteinemia) include smoking, hypertension, and family history of premature CAD
Highest-risk patients, including those with 1) known CVD or 2)
diabetes plus one or more additional major CVD risk factor
High-risk patients, including those with 1) no diabetes or
known clinical CVD but two or more additional major CVD risk factors or 2) diabetes but no other major CVD risk factors
LDLcholesterol
(mg/dl)
<70
<100
Goals
Non-HDL cholesterol
(mg/dl)
<100
<130
ApoB
(mg/dl)
<80
<90
ADA. Diabetes Care 2008;31:811-822
ADA and NCEP ATP IIIRecommendations for Lipid Goals in Patients
first-line therapy
for reducing LDL levels
in patients at high risk for
atherosclerotic cardiovascular disease (ASCVD).
Statins:
* P<0.001 vs atorvastatin 10 mg; simvastatin 10 mg, 20 mg, 40 mg; pravastatin 10 mg, 20 mg, 40 mg
†P<0.002 vs atorvastatin 20 mg, 40 mg; simvastatin 20 mg, 40 mg, 80 mg; pravastatin 20 mg, 40 mg
‡P<0.001 vs atorvastatin 40 mg,80mg; simvastatin 40 mg, 80 mg; pravastatin 40 mg
LD
L-C
(S
E)
Re
du
cti
on
(%
)
Rosuvastatin(mg)
10
-45.8*
Pravastatin(mg)
10 20 40
-29.7
-24.4
-20.1
–60
–50
–40
–30
–20
–10
0
–52.4†
–55.0‡
20 40
Atorvastatin(mg)
10 20 40
-36.8
-47.8
-42.6
–51.1
80
Simvastatin(mg)
10 20 40
-28.3
-35.0
-38.8
–45.8
80
Percentage Change in LDL-C: Pairwise Comparisons with Rosuvastatin
Primary
prevention trials
Secondary
prevention trials
50 70 110 130 150 170 19090 210
% P
ati
en
ts w
ith
CH
D E
ven
t
LDL cholesterol
CARE-Rx
4S-Rx
LIPID-PL
4S-PL
CARE-PL
LIPID-Rx
AFCAPS-Rx
WOSCOPS-Rx
WOSCOPS-PL
AFCAPS-PL
25
20
15
10
5
0
ASCOT-PL
ASCOT-Rx
HPS-Rx
HPS-PL
HPS
LRC-PLLRC-Rx
POSCH-PL
POSCH-Rx
non statin trials
Statin trials
(mg/dL)
1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L)
TNT-80A
TNT-10A
Clear Cardiovascular Benefits of Intensive Lipid-Lowering Therapy
얼마나낮출것인가?
Stephen J Nicholls et al., JAMA 2007:297:499-508
Modified from Kannel WB et al., Am Heart J 1985:110:1100-1107
Modified from Paul Muntner et al., Presented at ACC in 2007
0.01
0.02
0.03
0.04
0.05
≧190160-189
130-159100-129
<100≧60 50-59 40-49 <40
HDL-C(mg/dL)
(mm/5year) ARIC Study
Inc
rea
se
of
IMT
0
0.5
1.5
2
3
220
160
10085 55 25
HDL-C(mg/dL)
2.5
1
Framingham Study
Re
lati
ve
ris
k f
or
CV
D
Not only LDL-C but also HDL-C are the key factor for the regression of
atherosclerosis and prevention of CVD
Relationship Between Changes in LDL-C and HDL-C Levels and CHD
Risk
Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm
1% decrease
in LDL-C reduces
CHD risk by
1%
1% increase
in HDL-C reduces
CHD risk by
3%
* P<0.002 vs pravastatin 10 mg
† P<0.002 vs atorvastatin 20 mg, 40 mg, 80 mg; simvastatin 40 mg; pravastatin 20 mg, 40 mg
‡ P<0.002 vs atorvastatin 40 mg, 80 mg; simvastatin 40 mg; pravastatin 40 mg
Rosuvastatin(mg)
Atorvastatin(mg)
Simvastatin(mg)
Pravastatin(mg)
10 20 40
3.2
4.4
5.6
10 20 40 80 10 20 40 0
2
4
6
8
10
12
5.7
4.84.4
2.1
7.7*
9.5†9.6‡
10 20 40 80
5.3
6.0
5.2
6.8
ITT = intention-to-treat
Jones PH, et al. Am J Cardiol. 2003;92:152-160
Percentage Change from Baseline in HDL-C at Week 6 by DoseH
DL
-C I
ncr
ease
(%
)
To Study the Disease you Need to Image the Vessel Wall
Carotid Intima Medial Thickness
Placebo; change in CIMT (95% CI) Rosuvastatin 40 mg; change in CIMT (95% CI)
Crouse JR III et al. JAMA 2007;297 (12):1344–1353
Time (years)
Ch
an
ge i
n I
MT
of
12
caro
tid
sit
es (
mm
)
-0.01
+0.01
0.00
+0.02
21
+0.03
P=NS(rosuvastatin vs. zero slope)
placebo+0.0131 mm/yr (n=252)
rosuvastatin 40 mg-0.0014 mm/yr (n=624)
Pro
gressio
n
Reg
ressio
n
P<0.0001 (rosuvastatin vs. placebo)
METEOR studyA Rate of changes of max. IMT at 12 carotid sites
Rosuvastatin vs placebo
LumenArea
EEM Area
Atheroma Area
Ultrasound Determination of Atheroma Area
Precise Planimetry of EEM and Lumen Borders
with Calculation of Atheroma Cross-sectional Area
Atheroma Burden and Incident Clinical Events
Nicholls S. AHA Scientific Sessions 2007
Ch
an
ge P
AV
Yes No
P=0.04
Change Percent Atheroma Volume
PA
V
Baseline Percent Atheroma Volume
Yes No
P<0.001
Incidence of cardiovascular death, myocardial infarction, hospitalisation for unstable angina, stroke and coronary revascularisation
ILLUSTRATE (N=1180)
42.0
38.5
35.0
0.6
0.3
0.0
REVERSAL: Benefit of Intensive LDL-C Lowering on Plaque Progression
Percen
t ch
an
ge in
ath
ero
ma v
olu
me
Progression (P=0.001)
No change (P=0.98)
P=0.02 between treatment groups
pravastatin 40 mg
atorvastatin 80 mg
Nissen SE et al. JAMA 2004;291:1071–1080
3
2
1
0
-1
REVERSALComparison of % LDL Cholesterol Reduction and
Change in Atheroma Volume
% Change in LDL Cholesterol
Ch
an
ge i
n A
thero
ma V
olu
me,
mm
3
50% LDL-C reduction
-15
-10
-5
0
5
10
15
20
-80 -70 -60 -50 -40 -30 -20 -10 0 10 20
ASTEROID: Regression with High Dose Statin Therapy
%
349 patients treated with rosuvastatin 40 mg for 2 yearsLDL-C 60.8 mg/dL and increase HDL-C by 14.7%
Percent Atheroma Volume
Atheroma Volume Most Diseased 10 mm
Total Atheroma Volume
P<0.001P<0.001
mm
3
mm
3
-0.79 -5.6-12.5
0.0
-0.5
-1.0
P<0.001
0.0
-2.5
-7.5
-5.0
0
-5
-15
-10
Nissen SE, Nicholls S et al. JAMA 2006;295:1555–1565
A
ASTEROID rosuvastatin
50 60 80 90 100 110
0.6
1.2
1.8
Relationship Between LDL-C Levels and Change in Percent Atheroma Volume for
Several IVUS Trials
Med
ian
ch
an
ge i
n p
ercen
t ath
erom
a v
olu
me (
%)
Mean LDL-C (mg/dL)
0
-1.2
-0.6
70 120
A-Plus placebo
CAMELOT placebo
REVERSAL pravastatin
REVERSAL atorvastatin
R2 = 0.97 P<0.001
Progression
Regression
Nissen S et al. JAMA 2006
Cholesterol Treatment Trialists’ (CTT):
Relative Risk of Major Vascular Events
-20%
-10%
0%
10%
20%
30%
40%
50%
60%
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2
LDL cholesterol difference (mmol/L)
Relative
risk
reduction
22% reduction per 1 mmol/L
lower LDL-C14 statin trials
Baigent C. Lancet 2005 Oct 8; 366:1267-78
&A
Statin and beyond?
•Rosuvastatin 20 mg (N=8901) •MI•Stroke
•Unstable• Angina
•CVD Death•CABG/PTCA
JUPITER
Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events
Among Individuals With Low LDL and Elevated hsCRP
•4-week run-in
Ridker et al, Circulation 2003;108:2292-2297.
•No Prior CVD or DM•Men >50, Women >60
• LDL <130 mg/dL• hsCRP >2 mg/L
•Placebo (N=8901)
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Lowering CRP with Statin Therapy
Reduces CV Risk: PROVE-IT
n
Number
recurrent
events
Number of
events/
100 pt yr
Study group(levels after statin)
Low LDL-C/low CRP
Low LDL-C/high CRP
High LDL-C/low CRP
High LDL-C/high CRP
1018
899
742
1086
48
56
47
92
2.4
3.2
3.1
4.6
Ridker PM et al. N Engl J Med 2005;352:20-28.
hs-CRP?
JUPITER Primary Trial Endpoint: MI, Stroke, UA/Revascularization, CV Death
Ridker et al. NEJM 2008;359(21):2280-2
Cu
mu
lati
ve In
cid
ence
Number Needed to Treat (NNT5) = 25
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
JUPITER Effects on LDL-C, HDL-C, TG and hsCRP at 12 months;
Percentage change between rosuvastatin and placebo
-60
-50
-40
-30
-20
-10
0
10 LDL-C HDL-C TG hsCRPP
ercen
tag
e c
han
ge
from
baselin
e (
%)
50%
4%
17%
37%
p<0.001
p<0.001*
p<0.001
p<0.001
*P-value at study completion (48 months) = 0.34Ridker P et al. N Eng J Med 2008;359: 2195-2207
0 1 2 3 4
0.0
00
0.0
05
0.0
10
0.0
15
0.0
20
0.0
25
Cu
mu
lati
ve I
ncid
en
ce
Number at RiskFollow-up (years)
Rosuvastatin
Placebo
8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161
8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182
HR 0.57, 95%CI 0.37-0.86
P= 0.007
Placebo 60 / 8901
Rosuvastatin 34 / 8901
- 43 %
JUPITERTotal Venous Thromboembolism
Artery or vein?
Rosuvastatin in Older Patients with Systolic Heart Failure (CORONA)
NEJM 2007. 357:2248-2261
일차종말점(심혈관계사망, 비치명적심근경색, 비치명적뇌졸중의첫발생까지의시간)
Hazard ratio
= 0.84 (0.7-1.0)
Heart failure?
Williams, B. et al. Circulation 2009;119:53-61
CAFE-LLA: Statin therapy does not influence
central aortic pressure or hemodynamics
Arteriosclerosis?
CAFÉ -BLA: Lower central aortic BP with
newer vs older antihypertensive regimen
despite similar brachial BP
140
135
130
125
120
115
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6
Time (years)
mm Hg
Brachial SBP
Central aortic SBP
CAFE Investigators. Circulation. 2006;113:1213-25.
Amlodipine
± perindopril
Atenolol
± thiazide
A
&A
Statin 안전한가?
http://www.circ.ahajournals.org/cgi/content/full/111/23/3016
The Issue of Statin Safety
Where do We Stand?
Scott M. Grundy, MD, PhD
Circulation. 2005;111:3016-3019.
higher risk for severe myopathy
advanced age (especially >80 years) (women > men)
small body frame and frailty
multisystem disease (eg, CRF, especially if caused by diabetes)
perioperative periods
multiple medications (especially gemfibrozil, cyclosporine, azole
antifungals, itraconazole and ketoconazole, macrolide antibiotics,
erythromycin and clarithromycin, HIV protease inhibitors, the
antidepressant nefazodone, and verapamil)
consumption of large quantities of grapefruit juice (>1 quart/day)
alcohol abuse (which independently predisposes to myopathy)
Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C; American College of
Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/AHA/NHLBI Clinical
Advisory on the Use and Safety of Statins. Circulation. 2002; 106: 1024–1028
Deaths Due to Suicide, Cancer, and Hemorrhagic Stroke
Number (%) of patients
Quintile 1
<64 mg/dL
(114/1722)*
Quintile 2
64–<77 mg/dL
(529/1403)*
Quintile 3
77–<90 mg/dL
(1019/968)*
Quintile 4
90–<106 mg/dL
(1515/515)*
Quintile 5
106 mg/dL
(1718/266)*
Suicide 1 (0.1) 0 (0.0) 1 (0.1) 1 (0.0) 1 (0.1)
Cancer 21 (1.1) 37 (1.9) 34 (1.7) 32 (1.6) 30 (1.5)
Hemorrhagic stroke† 6 (0.3) 5 (0.3) 6 (0.3) 8 (0.4) 7 (0.4)
*Number of patients: atorvastatin 10 mg/atorvastatin 80 mg†Fatal and non-fatal
Number needed to treat for 1 year to:
Cause a GI Bleed1 Cause a Fatal GI Bleed1
Aspirin
Cause Severe Myositis2 Cause Fatal Myositis2
Statins
1Derry S, Loke YK. 20002Thompson PD, et al. 2003
Statin Safety in Perspective
248 2066
100,000 1,000,000
Evolving of Dyslipid Vascular disease
Target: LDL, … HDL-chol
Statins: dyslipidemia and vascular disease
and so athersclerotic CV disease
Statins and beyond:
useful in high inflammatory condition, VTE
not useful in systolic HF and arteriosclerosis
Statins and safety: quite safe
The Future of Best Practice
“Normal” plasma cholesterol
-
-
-
-
-
-700(18.0)
300(7.7)
200(5.2)
150(3.9)
100(2.6)
50(1.3)
0
Rat
Guinea pig
Sheep
Rabbit
Pig
Newborns
Normal adults
FH homozygotes
FH heterozygotes
Physiologic level forplasma LDL-chol
as predicted from receptorStudies 25 mg/dL
Cow
Camel
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