Aggressive Lipid Lowering Treatment
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Aggressive Lipid Lowering Treatment
Richard CESKACentre of Preventive Cardiology
University Hospital, Prague, Czech Republic
International Atherosclerosis Society
Chair: Federation for EUROPE
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Dyslipidemia Management
Part of the complex approach to decrease CV RISK
Influence all lipid parameters
LDL-C – The first target HDL-C,TGs, apoB…
To lower MACROvascular risk
To lower MICROvascular risk
To lower CV morbidity and mortality
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What does it mean? „Agressive Lipid
Lowering“ .
1. LDL-C
2. Residual Risk (DLP risk)
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LDL-C
• Killer No 1
• The most important risk factor for CVD
• The first target for lipid lowering treatment
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What is an appropriate What is an appropriate therapeutic target for therapeutic target for
LDL-C?LDL-C?
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The human evolutionWhat was the LDL-C of our
ancestry?
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What is desirable LDL- C ?•Hunter-Gatherer humans•Newborn•Primates•Domestic animals
•Adult Euro/American•(probable physiologic level)
•1,3-1,9 50-75 •0,8-1,8 30-70•1,0-2,1 40-80• > 2,1 >80
•1,3-1,8 50-70•Desirable
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LDL-Receptor PathwaySREBP Pathway
Michael BROWN Joseph GOLDSTEIN
LDL-receptor
Nobel Prize 1985SREBP
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Familial hypercholesterolemia, positive family history, LDL-C 8,2mmol/l (W
27years)
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MERCURY: LDL-C
-31,0
-35,4
-43,7
-37,2
-47,0
-50
-40
-30
-20
-10
0
pp<0.0001<0.0001pp<0.0001<0.0001
% c
han
ge f
rom
base
line
RosuvastatinAtorvastatinSimvastatinPravastatin
10R 10A 20A 20S 40P
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MERCURY: TG
-10,5
-13,5
-18,3
-15,9
-18,9
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
pp=0.0682=0.0682(NS)(NS)pp=0.6891 (NS)=0.6891 (NS)
pp=0.0011=0.0011pp<0.0001<0.0001
% c
han
ge f
rom
base
line
RosuvastatinAtorvastatinSimvastatinPravastatin
10R 10A 20A 20S 40P
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*p<0,01 ezetimibe + sdružené dávky statinů vs. sdružené dávky statinů samotné
Ballantyne CM et al Circulation 2003;107:2409–2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125–2134; Melani L et al Eur Heart J 2003;24:717–728,1381; Kerzner B et al Am J Cardiol 2003;91:418–424.
Ezetimibe + statins LDL-C
–60
–50
–40
–20
0
ezetimibe10 mg +
atorvastatin(n=255)
ezetimibe10 mg +
simvastatin(n=274))
ezetimibe10 mg +
lovastatin(n=192)l)
ezetimibe10 mg +
pravastatin(n=204))
–56*–51*
–40*–39*–30
–10
Stř
edn
í ho
dn
ota
% z
měn
y u
vyp
očí
tan
ého
LD
L-C
z v
ých
ozí
hla
din
y p
o 1
2-ti
týd
nec
h
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Treatment of Hyperlipidemia
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
LDL-CLDL-C LDL-CLDL-C
Therapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeTherapeutic Lifestyle Change
Drug TherapyDrug TherapyDrug TherapyDrug Therapy
Therapy of Choice: StatinTherapy of Choice: StatinTherapy of Choice: StatinTherapy of Choice: Statin
AlternativeAlternative/combo/combo:: Ezetimibe,r Ezetimibe,resin or niacinesin or niacin
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The The Lower Lower = = The The BetterBetter
for LDL-C loweringfor LDL-C lowering
For clinical outcomes reductionFor clinical outcomes reduction
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Scandinavian Simvastatin Survival
Study (4S)
Scandinavian Simvastatin Survival
Study (4S)
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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Primary Endpoint: Overall Survival
Primary Endpoint: Overall Survival
80828486889092949698
100
0 1 2 3 4 5 6
Simvastatin
Placebo
Years since randomizationYears since randomization
% S
urv
ivin
g%
Su
rviv
ing
30% risk reduction
p = 0.0003
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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Coronary MortalityCoronary Mortality
111
189
0
50
100
150
200
Placebo imvastatin
42% Risk Reduction42% Risk Reductionp<0.00001p<0.00001
Nu
mb
er
of
de
ath
sN
um
be
r o
f d
ea
ths
The Lancet, Vol 344, November 19, 1994The Lancet, Vol 344, November 19, 1994
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Atorvastatin 80 mg n=4,995
Atorvastatin 80 mg n=4,995
Primary Endpoint: Major cardiovascular event defined as coronary heart death (CHD) , nonfatal M, resuscitated cardiac arrest, and fatal or nonfatal stroke at a mean follow-up of 4.9 years.
Secondary Endpoint: Major coronary events, cerebrovascular events, hospitalization for congestive heart failure (CHF), all-cause mortality, peripheral artery disease, any cardiovascular event, any coronary event
Primary Endpoint: Major cardiovascular event defined as coronary heart death (CHD) , nonfatal M, resuscitated cardiac arrest, and fatal or nonfatal stroke at a mean follow-up of 4.9 years.
Secondary Endpoint: Major coronary events, cerebrovascular events, hospitalization for congestive heart failure (CHF), all-cause mortality, peripheral artery disease, any cardiovascular event, any coronary event
TNT Trial
Presented at ACC 2005Presented at ACC 2005
Atorvastatin 10 mg n=5,006
Atorvastatin 10 mg n=5,006
10,003 patients with stable coronary heart disease Age 35-75 years, LDL between 130 and 250 mg/dL, triglyceride ≤ 600 mg/dL
19% female, mean age 60.3 yearsAll received atorvastatin 10 mg during 8 week open-label run-in period
10,003 patients with stable coronary heart disease Age 35-75 years, LDL between 130 and 250 mg/dL, triglyceride ≤ 600 mg/dL
19% female, mean age 60.3 yearsAll received atorvastatin 10 mg during 8 week open-label run-in period
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TNT: The Lower the Better
-22%
J. C. LaRosa et al. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease. // N Engl J Med 2005;352:1425-35.
Intensive lipid-lowering therapy with atorvastatin 80 mg/day in patients with stable
CHD provides significant clinical benefit beyond that provided by atorvastatin 10 mg/day
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TNT pts after CABG n = 4,654MACE -27%
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High-dose High-dose atorvastatinatorvastatin
80 mg/day80 mg/dayIf LDL was <40 mg/dL at 24 wks If LDL was <40 mg/dL at 24 wks
dose could be reduced to 40 dose could be reduced to 40 mg/daymg/day
n=4,439n=4,439
High-dose High-dose atorvastatinatorvastatin
80 mg/day80 mg/dayIf LDL was <40 mg/dL at 24 wks If LDL was <40 mg/dL at 24 wks
dose could be reduced to 40 dose could be reduced to 40 mg/daymg/day
n=4,439n=4,439
IDEAL Trial: Study Design
Presented at AHA 2005Presented at AHA 2005
Standard-dose Standard-dose simvastatinsimvastatin
20 mg/day20 mg/dayIf cholesterol >190 mg/dL at 24 wks If cholesterol >190 mg/dL at 24 wks
dose could be increased to 40 dose could be increased to 40 mg/daymg/day
n=4,449n=4,449
Standard-dose Standard-dose simvastatinsimvastatin
20 mg/day20 mg/dayIf cholesterol >190 mg/dL at 24 wks If cholesterol >190 mg/dL at 24 wks
dose could be increased to 40 dose could be increased to 40 mg/daymg/day
n=4,449n=4,449
8,888 patients 8,888 patients ≤80 years ≤80 years with definite history of with definite history of myocardial infarction and qualified for stain therapy at myocardial infarction and qualified for stain therapy at
time of recruitmenttime of recruitment RandomizedRandomized
8,888 patients 8,888 patients ≤80 years ≤80 years with definite history of with definite history of myocardial infarction and qualified for stain therapy at myocardial infarction and qualified for stain therapy at
time of recruitmenttime of recruitment RandomizedRandomized
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IDEAL Trial: Primary Endpoint
9,310,4
0
3
6
9
12
Atorvastatin Simvastatin
9,310,4
0
3
6
9
12
Atorvastatin Simvastatin
• The primary The primary composite endpoint composite endpoint of major coronary of major coronary event occurred in event occurred in 9.3% of the 9.3% of the atorvastatin group atorvastatin group and 10.4% of the and 10.4% of the simvastatin group.simvastatin group.
Primary Composite of major coronary event * Primary Composite of major coronary event * (%)(%)
p = 0.07p = 0.07
Presented at AHA 2005Presented at AHA 2005
%%
* Major coronary event defined as * Major coronary event defined as coronary death, hospitalization for coronary death, hospitalization for non-fatal acute MI or resuscitated non-fatal acute MI or resuscitated cardiac arrest.cardiac arrest.
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IDEAL Trial: Secondary Endpoints
12,0
26,5
13,7
30,8
0
8
16
24
32
Major CV events Any CV event
Atorvastatin Simvastatin
12,0
26,5
13,7
30,8
0
8
16
24
32
Major CV events Any CV event
Atorvastatin Simvastatin
• Major Major cardiovascular cardiovascular events, defined as events, defined as any primary event any primary event plus stroke, occurred plus stroke, occurred less often in the less often in the atorvastatin group.atorvastatin group.
•Any cardiovascular Any cardiovascular event, defined as event, defined as major CV event plus major CV event plus hospitalization for hospitalization for CHF and peripheral CHF and peripheral artery disease, also artery disease, also occurred less often in occurred less often in the atorvastatin the atorvastatin group.group.
Major cardiovascular events and Major cardiovascular events and any cardiovascular event (%)any cardiovascular event (%)
Presented at AHA 2005Presented at AHA 2005
%%
p=0.02
p<0.001
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UK Switching Study: Impact of Switching From Atorvastatin to Simvastatin
Patients Switched from Atorvastatin to
Simvastatin (n=2511)
Atorvastatin(n=9009)D
ea
th o
r C
V E
ven
t (%
)
Years after Index Date
12
10
8
6
4
2
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0
33%Increase in death
or CV events with switch to
Simvastatin (P=0.007)
PHILLIPS B, et al. Poster accepted for presentation at the European Society of Cardiology Congress, Sep 1-5, 2007
Primary end point: Primary end point: time to death or first time to death or first major CV event (MI, major CV event (MI,
stroke, and stroke, and revascularization)revascularization)
Primary end point: Primary end point: time to death or first time to death or first major CV event (MI, major CV event (MI,
stroke, and stroke, and revascularization)revascularization)
PHILLIPS B, et al. Poster accepted for presentation at the European Society of Cardiology Congress, Sep 1-5, 2007
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LDL-C lowering with statins: reduced CHD events
Events
(%
)
50
Secondary PreventionPrimary Prevention
CARE-Rx
4S-Rx
LIPID-Rx
CARE-PL
LIPID-PL
4S-PL
AFCAPS-RxAFCAPS-PL
WOSCOPS-RxWOSCOPS-PL
70 90 110 130 150 170 190 2100
5
10
15
20
25
LDL Cholesterol (mg/dL)The Lower The Better
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AVERT
Aggressive lipid-lowering therapy isas effective as angioplasty
Treatment with atorvastatin, as compared with angioplasty, was associated with a significantly longer time to a first ischemic
event and with a reduction in risk of 36%Pitt B.et al. AGGRESSIVE LIPID-LOWERING THERAPY COMPARED WITH ANGIOPLASTY IN STABLE CORONARY ARTERY DISEASE. // New Engl. J. Med. 1999;341:70-76.
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PROVE IT–TIMI 22(2-Year Trial)
0
1
LogCHDRisk
100 LDL-C Level60
Pravastatin40 mg
16% Reduction in CVD
Atorvastatin80 mg
Cannon CP et al. N Engl J Med 2004;350:1495-1504.
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High dose atorvastatin after strokeor trasient ischemic attack (SPARCL)
SPARCL
-16%
P. Amarenco et al. High-Dose Atorvastatin after Stroke or Transient Ischemic Attack.// N Engl J Med 2006;355:549-59.
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CHD Event Rates in Secondary Prevention and ACS Trials
Updated from - O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.
y = 0.1629x · 4.6776R² = 0.9029p < 0.0001
LDL Cholesterol (mg/dl)
CH
D E
ven
ts (
%)
PROVE-IT-PR
PROVE-IT-AT CARE-S
LIPID-S
HPS-S4S-S
HPS-P
CARE-P
LIPID-P
4S-P
0
5
10
15
20
25
30
30 50 70 90 110 130 150 170 190 210
TNT 80TNT 10A2Z 80
A2Z 20
IDEAL S20/40IDEAL A80
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High-dose statin betterHigh-dose statin worse
Odds Reduction
Event Rates
No./Total (%)
High Dose Std Dose
-16%3972/13798
(28.8)4445/13750
(32.3)
-16%1097/13798
(8.0)1288/13750
(9.4)
-12%462/13798
(3.3)520/13750
(3.8)
+3%340/13798
(2.5)331/13750
(2.4)
-6%808/13798
(5.9)857/13750
(6.2)
-18%316/13798
(2.3)381/13750
(2.8)
Coronary Death or Any Cardiovascular Event
Coronary Death or MI
Cardiovascular Death
Non-Cardiovascular Death
Total Mortality
Stroke
0.5 1 2.5
OR 0.8295% CI, 0.71-0.96p=0.012
Odds Ratio (95% CI)
Meta-Analysis of Intensive Statin Therapy All Endpoints
Cannon CP, et al.
OR, 0.9495% CI, 0.85-1.04P=0.20
OR, 1.0395% CI, 0.88-1.20p=0.73
OR, 0.8895% CI, 0.78-1.00p=.054
OR, 0.8495% CI, 0.77-0.91p=0.00003
OR, 0.8495% CI, 0.80-0.89p<0.0001
Cannon CP, et al. JACC 2006; 48: 438 - 445.
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20
40
30
0
10
0 30 months 5 years
Summary: 5 Years Of Follow-Up In IDEAL Is The Longest Period Of Follow-Up Of ACS Patients On Statin TherapyC
ard
iac
Eve
nt
(%) 50
60
Atorvastatin 80 mgPravastatin 40 mg
Simvastatin 20-40 mg
16% RRRP=0.005
PROVE IT
MI or UA
18% RRRP=0.04
IDEAL
All MI
Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006
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PCSK9 (proprotein convertase subtilisin/kexin type 9) Enzyme - associated with plasma levels of LDL –C(expressed in the liver, intestine and kidney)
Overexpression of gene for PCSK9 more PCSK9 enzyme LDLreceptors reduction (LDL-Receptor enable removal of LDL-C from the plasma) increase in circulating LDL-C
High levels of PCSK9 = high LDL-C levels
Conversely, lacking Pcsk9 leads to increased levels of hepatic LDL receptors,and they remove LDL from the plasma at an accelerated rate)
Low levels of PCSK9 = low LDL- C levels
1.Brown, M.S.,Science, Vol 311, March 24, 2006
2. Cohen J.C. et al.,New England Journal of Medicine, Volume 354, 2006 Number 12
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Cohens et al. study
• Studied patients with lifelong low LDL-C levels, due to loss of- function mutations in the gene encoding PCSK9 = they have low level of PCSK9 = low level of LDL-C
• Severe mutation: LDL-C was reduced by 1 mmol/l (38 mg/dl)
prevalence of CHD declined by a remarkable 88%.
• Less severe mut.:LDL-C was reduced by only 0,52 mmol/l (21 mg/dl)
CHD incidence declined by 47%.
Cohen et al., N Engl J Med 2006;354:1264-72.
Brown, M.S.,Science, Vol 311, March 24, 2006
The Longer The Better
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Why does lowering of LDL-C concentration by 40 mg/dl
by a PCSK9 mutation reduce CHD incidence by 88%,
whereas a 40-mg/dl lowering with a statin reduces CHD
prevalence by only 23% on average ???
The Longer The Better
Cohen et al., N Engl J Med 2006;354:1264-72.
Brown, M.S.,Science, Vol 311, March 24, 2006
Cohen et al. study
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The most likely answer is
DURATION
The Longer The Better
Cohen et al., N Engl J Med 2006;354:1264-72.
Brown, M.S.,Science, Vol 311, March 24, 2006
Cohens et al. study
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• People with mutations in PCSK9 likely have
maintained relatively low LDL levels
throughout their lives.
• People in statin trials have had their LDL levels
lowered for only 5 years.
• Atherosclerosis is a chronic disease that
begins in the teenage years
The Longer The Better
Cohen et al., N Engl J Med 2006;354:1264-72.
Brown, M.S.,Science, Vol 311, March 24, 2006
Cohens et al. study
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Recent Coronary IVUS Progression Trials
-1.2
-0.6
0
0.6
1.2
1.8
50 60 70 80 90 100 110 120
MedianChange
In PercentAtheromaVolume
(%)
Mean Low-Density Lipoprotein Cholesterol (mg/dL)
REVERSALpravastatin
REVERSALatorvastatin
CAMELOTplacebo
A-Plusplacebo
ACTIVATEplacebo
Relationship between LDL-C and Progression Rate
ASTEROIDrosuvastatin
r2= 0.95p<0.001
Nissen S. JAMA 2006
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Rosuvastatin 40 mg (n=349 evaluated serial IVUS examinations)
Patients
CAD, undergoing coronary angiography
Target coronary artery: ≤50% reduction in lumen diameter of
≥40 mm segment
No cholesterol entry criteria
≥18 years
Visit:Week:
Lipids LipidsTolerability
IVUSLipids
Tolerability
LipidsTolerability
TolerabilityTolerability Tolerability
1–6
20
313
426
539
652
765
878
991
10104
Eligibilityassessment
CAD=coronary artery disease; PCI=percutaneous coronary intervention; IVUS=intravascular ultrasound
ASTEROID: study design
IVUSLipids
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IVUS Objem atero plátu
Precise Planimetry of EEM and Lumen Bordersallows calculation of Atheroma Cross-sectional Area
EEM = External Elastic Membrane
EEM Area
LumenArea
Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory
(EEM area — Lumen Area)
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ASTEROID Trial: Principal Findings
• LDL Levels were LDL Levels were reduced from reduced from 130.4 mg/dL at 130.4 mg/dL at baseline to a baseline to a mean of 60.8 mean of 60.8 mg/dL at 2 year mg/dL at 2 year follow-up follow-up (p<0.001), with (p<0.001), with 75% of patients 75% of patients achieving an LDL achieving an LDL <70 mg/dL. <70 mg/dL.
• HDL levels were HDL levels were
increased from increased from 43.1 mg/dL at 43.1 mg/dL at baseline to a baseline to a mean of 49.0 mean of 49.0 mg/dL at follow-mg/dL at follow-up (p<0.001).up (p<0.001).
LDL/
HD
L LD
L/H
DL
mg/
dLm
g/dL
Mean LDL level decrement and HDL level increment
(mg/dL)
43,1
60,849,0
130,4
0
22
44
66
88
110
132
LDL Levels HDL Levels
Baseline Follow-up
43,1
60,849,0
130,4
0
22
44
66
88
110
132
LDL Levels HDL Levels
Baseline Follow-up
p<0.001p<0.001
p<0.001p<0.001
Presented at ACC 2006Presented at ACC 2006
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*p<0.001 for difference from baseline. Wilcoxon signed rank test
-10-9-8-7-6-5-4-3-2-10
Median Atheroma Volume in themost diseased 10mm
subsegmentMedian Normalised Total
Atheroma Volume
Chang
e f
rom
base
line (
%)
- 9.1%
*
*- 6.8%
Endpoint analysis: Change in key IVUS parameters
Ref: Nissen S et al. JAMA 2006;295 (13):1556-1565.
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Regression of atherosclerosis in ASTEROID
Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory
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ACS Patients: Major Coronary Events MI + CHD Death +
Resuscitated Cardiac Arrest
Years Since Randomization
Cu
mu
lati
ve H
azar
d (
%)
0 1 2 3 4 50
4
8
12
16
20
HR = .66 (95% CI = 0.46, 0.95), P=.02
34% RRR
SimvastatinAtorvastatin
Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006
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Odds ratio
0.5 1 3.0
Study (n)
Treatment Achieved LDL (mg/dl)
Odds ratio (95% CI)
0.74 (0.58,0.94) TNT (10,001) Atorvastatin 8077
0.72 (0.52,0.98) A to Z (4497) Simvastatin 8063
0.54 (0.34,0.85) PROVE-IT (4162) Atorvastatin 8062
0.80 (0.61,1.05) IDEAL (8888) Atorvastatin 8081
0.73 (0.63,0.84), p<0.001 Overall (95% CI)
Intensive statintherapy better
Moderate statintherapy better
Atorvastatin 10101
Simvastatin 2077
Pravastatin 4095
Simvastatin 20104
Intensive Moderate
Scirica BM, et al. AHA 2005
Meta-Analysis of Intensive Statin Therapy CHF
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Residual Cardiovascular Risk in Major Statin Trials: Standard Doses
Adapted from Libby PJ, et al. J Am Coll Cardiol, 2005:46:1225-1228.
62%69%73%75%
62%
75%
0
20
40
60
80
100
4S LIPID CARE HPS WOS AFCAPS /TexCAPS
LDL
N 4444 4159 20 536 6595 66059014
-35% -28% -29% -26% -25%-25%
Secondary High Risk Primary
Pat
ien
ts E
xper
ien
cin
g
Maj
or
Co
ron
ary
Eve
nts
, %
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Residual CVD Risk in Patients Treated With Intensive Statin Therapy
Pa
tie
nts
Ex
pe
rie
nc
ing
M
ajo
r C
VD
Ev
en
ts, % Standard statin therapy
Intensive high-dose statin therapy
PROVE IT-TIMI 222 IDEAL3 TNT4
N
LDL-C,*mg/dL
1Superko HR. Br J Cardiol. 2006;13:131-136. 2Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.3Pedersen TR, et al. JAMA. 2005;294:2437-2445. 4LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435.
4162 8888 10 001
95
*Mean or median LDL-C after treatment
62 104 81 101 77
Statistically significant, but clinically inadequate CVD reduction1
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Reduction in rate of first major coronary events
per each 39 mg/dL reduction in LDL-C*
ResidualRisk
Atherogenicdyslipidemia
Metabolicsyndrome
Diabetes
Hypertension
Smoking
It is time to treat the Residual CVD Risk in Patients With Dyslipidemia
23%23%
*Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet. 2005;366:1267-1278.
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Residual Risk: Definitions
1. CVD incidence in patients on statin treatment
• Standard dose, e.g. simvastatin 20-40 mg• Intensive dose, e.g. atorva 80, rosuva 40
2. CVD incidence in patients treated to LDL goal
3. CVD incidence in patients on optimal treatments to prevent CVD, including anti-hypertensive, anti-platelet, LDL, smoking, nutrition, lifestyle
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30% of adults in CZ: Metabolic Syndrome
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RFs in abdominal obesity
Patients with abdominal
obesity (high waist
circumference) often
present with one or
more additional
CV risk factors
(104 cm)(1.8 mmol/L)
(0.9 mmol/L)
(6.0 mmol/L)
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HypertensionCentral obesity
Smoking , Depression
Cardiometabolic risk in MS patient
• Hypertriglyceridemia• Low HDL-C• Elevated apolipoprotein B• Small, dense LDL particles• Postprandial hyperlipidaemia
• Hyperinsulinemia• Glucose intolerance• Insulin resistance• Impaired fibrinolysis• Endothelial dysfunction
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Intra-abdominIntra-abdominalal (viscer (visceralal) ) fat fat examinationexamination
The dangerous inner fat!
BackBack
Visceral AT
Subcutaneous AT
FrontFront
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Intra-abdominal fat examination
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Atherogenity: The role of particle size
HDL
LDL
VLDL
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Atherogenic Nonatherogenic
HDL
25,5nm –A profil25,5nm – B profilLDL
Small dense Large
Large
VLDL
Large Small
Small
Particle size and CV risk
< >
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How to decrease residual risk?
• Treatment of HLP/ DLP• (part of the complex approach)
Focused on:
HDL-C
TGs•
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TGs, (HDL-C) Fibrates
Statin + Fibrate
COMBO
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-60
-50
-40
-30
-20
-10
0
Elevated TGs identify patients in whom fibrate therapy reduces CV risk (1)
• HHS1,2: Fibrates reduced the incidence of CV events by 56% in patients with TG levels >2.3 mmol/L (200 mg/dL) compared with a 34% reduction in the overall population
Rel
ativ
e ri
sk r
educ
tion
in t
ota
l C
VE
s/1
000
(%)
Overall(n=4,081)
TG >200 mg/dL(n=1,046)
1 Frick MH et al. N Engl J Med 1987;317:1237-45.2 Barter PH, Rye KA. Arterioscler Thromb Vasc Biol 2008;28:39-46.
p<0.02
p not available
-56%
-34%
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Elevated TGs identify patients in whom fibrate therapy reduces CV risk
• BIP1: Fibrate treatment significantly reduced the risk of CV events by 39.5% in patients with TG ≥2.3 mmol/L (200 mg/dL) vs. a 7.3% reduction in the overall population
*CV events: fatal or nonfatal MI or sudden death (primary endpoint)1 The BIP Study Group. Circulation 2000;102:21-7.
-40
-30
-20
-10
0
Rel
ativ
e ri
sk r
educ
tion
in C
V e
vent
s (%
)*
Overall(n=3,090)
TG 200 mg/dL(n=459)
p=0.24
p=0.02
-39.5%
-7.3%
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High TGs /low HDL-C identify patients in whom fibrate reduces
CV risk
1 Keech A et al. Lancet 2005;366:1849-61.2 Scott R et al. Diabetes Care 2009;31:493-98.
-30
-20
-10
0R
elat
ive
risk
red
uctio
n (%
)
p=0.035
Low HDL-C (<1.03 mmol/L or 40 mg/dL for men and <1.29 mmol/L or 50 mg/dL for women) and elevated TG (≥2.3 mmol/L or 200 mg/dL) defined according to ATP III criteria
p=0.030
p=0.010
p<0.005
Overall(n=9,795)
Low HDL-C(n=5,820)
Low HDL-C + elevated TG
(n=2,014)Elevated TG
(n=2,517)
Total CVD
-27%-23%
-14%-11%
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Small dense LDL reduction Small dense LDL reduction - 56%after statin + fenofibrate combo
Grundy SM, Vega GL, Yuan Z, et al. Effectiveness and Tolerability of Simvastatin Plus Fenofibrate for Combined Hyperlipidemia (The SAFARI Trial) Am J Cardiol 2005;95:462–468
0%
20%
40%
60%
80%
100%
simvastatin 20 mg+ fenofibrát 160 mg
simvastatin 20 mg simvastatin 20 mg+ fenofibrát 160 mg
simvastatin 20 mg
malé denzní střední velké lehké
n=61812 týdnů
Before Before afterafterLDL particlesLDL particles
-56%-56%
SAFARI
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Studies with fibrates: Comparison of general population and subgroups ith lo HDL and high Tgs
Trial(Drug)
Primary Endpoint: Entire Cohort (P-value)
Lipid Subgroup Criterion
Primary Endpoint: Subgroup
HHS (Gemfibrozil)
-34%
TG > 200 mg/dlLDL-C/HDL-C > 5.0 -71%
BIP (Bezafibrate)
-7.3%
TG > 200 mg/dl -39.5%
FIELD(Fenofibrate)
-11%
TG > 204 mg/dlHDL-C < 42 mg/dl
-27%
ACCORD(Fenofibrate)
-8% TG > 204 mg/dlHDL-C < 34 mg/dl -31%
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HDL-C (LDL,TG)
Niacin
Statin + Niacin (laropiprant)
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-50
-40
-30
-20
-10
0
10
20
30
Efficacy of Extended-Release NiacinEfficacy of Extended-Release NiacinC
han
ge f
rom
Base
line
2500 mg
3000 mg
Goldberg A et al. Am J Cardiol 2000;85:1100-1105.
2000 mg
1500 mg
1000 mg
500mg
HDL-C
LDL-CLp(a)
TG
–9%–14%
–22% –21%–17%
29.5%30%26%
22%15%
10%
–28%
–35% –44%–39%
–11%
–5%
–26%
–3%
–12%
–30%
–24%–17%
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0
5
10
15
20
25
30
35
Coronary Drug Project:Coronary Drug Project:Clinical Outcomes*Clinical Outcomes*
Even
t R
ate
(%
)
Coronary Drug Project Research Group. JAMA 1975;231:360–381.
CV SurgeryStroke/TIANonfatal MINonfatal MI/CHD Death
*Total follow-up, adjusted for baseline characteristics, †p<0.05, ‡5-year rate
MI=myocardial infarction; CHD=coronary heart disease; TIA=transient ischemic attack; CV=cardiovascular
Placebo
Niacin
−14†
−27†
−26†
−47†‡
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ARBITER 2: Secondary Efficacy Endpoint—Clinical Events
• Composite clinical event endpoint
– Unstable angina/MI hospitalization
– Stroke
– Sudden cardiac death
– Percutaneous coronary revascularization, CABG, or peripheral revascularization
Pati
en
ts w
ith
Even
t (%
)
P = .20
9.6
3.8
60%
0
2
4
6
8
10
12
Statin +Placebo
Statin +Niacin ER
Taylor AJ et al. Circulation 2004;110:3512-3517.
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HDL-CNew experimental approach
ApoA-I Milano
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Normal Apo A1 and Apo A1 Milano Dimer
A1m/A1m
A1
1 1
243243
173173ss
1
25
35
66 121 165209 220
243
18714399
Lipid Binding In Vivo Catabolism
LCAT Activation Cholesterol Efflux
“Receptor” Binding
Franceschini G. Eur J Clin Invest 1996;26:733–746.
A1=apolipoprotein A1A1m=apolipoprotein A1 MilanoLCAT=lecithin cholesterol acyl- transferase
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Evaluation of Plaque Changes in Rabbits by Apo A1 Milano
Infusion: Plaque Lipid ContentApo A1 Milano (1g)Apo A1 Milano (1g)SalineSaline
Unpublished data from Chiesa G et al. Circ Res 2002;90:974–980.
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HDL-CNew experimental approach
CETP inhibitors
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Background: CETP inhibition
HDLHDL
LDL / LDL / VLDLVLDL
LiverLiver
BileBile
CECE
LDL-RLDL-R
FCFC
FFCC
LCATLCAT
CETPCETP
CCEESR-B1SR-B1
X X inhibitioninhibition
Cholesteryl ester transfer protein (CETP) is a plasma protein that catalyzes the transfer of CE from HDL to apoB-containing lipoproteins (VLDL and LDL-C) in exchange for Trig.
Free Cholesterol (FC) Free Cholesterol (FC) in Extrahepatic in Extrahepatic tissuestissues
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Effects on LDL-C and HDL-C
HDL-C
Study Week
BaselineWk 6Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76
HD
L-C
(m
g/d
L) (
SE
)
0
20
40
60
80
100
120
AnacetrapibPlacebo
Anacetrapib n =Anacetrapib n =776 757 718 687 647 607 572 543
Placebo n =Placebo n =766 761 741 744 736 711 691 666
LDL-C
Study Week
BaselineWk 6Wk 12Wk 18Wk 24Wk 30 Wk 46 Wk 62 Wk 76
LDL-
C (
mg/
dL)
(SE
)
0
20
40
60
80
100
AnacetrapibPlacebo
Anacetrapib n = 804 771 716 687 646 604 568 540
Placebo n = 803 759 741 743 735 711 691 666
-39.8% (p<0.001) +138.1% (p<0.001)
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Lipid Parameters
Parameter
LS Mean Percent (95% CI) Placebo-Adjusted
Change from Baseline
Week 24 Week 76
Non-HDL-C -31.7* (-33.6, -29.8) -29.4* (-31.6, -27.3)
Apo B -21.0* (-22.7, -19.3) -18.3* (-20.2, -16.4)
Apo A-1 44.7* (42.8, 46.5) 42.3* (40.5, 44.1)
TC 13.7* (12.0, 15.3) 15.6* (13.8, 17.3)
TG -6.8 (-9.9, -3.9) -5.3 (-8.9, -1.7)
Lp(a) -36.4 (-40.7, -32.3) -38.8 (-44.5, -33.9)
ApoE 29.2* (24.7, 33.7)35.3* (30.6, 40.1)
*p<0.001; means for all variables except for triglycerides, lipoprotein(a), for which medians are shown
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Pioglitazone
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No. of ObservationsGlimepiridePioglitazone
-2
0
2
4
6
8
Week
Glimepiride Pioglitazone
206201
203198
206201
206201
724824Baseline
Mazzone T et al. JAMA 2006;296:2572−2581.
HDL Cholesterol ChangesLS
Mean
Ch
an
ge f
rom
Baselin
e,
HD
L-C
(m
g/d
L)
−1.1%
12.8%
*p<0.0001
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PROactive Trial: Significant Reduction in Secondary
Outcome
0
5
10
15
20
25
Even
ts,
%
0 6 18 24 3612 30Time from randomization (months)
*Excluding silent myocardial infarction (MI)
All-cause mortality, nonfatal MI*, stroke
Dormandy JA et al. Lancet 2005;366:1279–1289.
Pioglitazone301 events
Placebo358 events16% RRR
HR 0.84 (0.72–0.98) P = 0.027
16% RRRHR 0.84 (0.72–0.98)
P = 0.027
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CHICAGO: Mean Change in CIMT
-0,010
-0,005
0,000
0,005
0,010
0,015
0,020
Glimepiride
Pioglitazone
LS M
ean C
hange f
rom
Base
line
Post
eri
or
Wall
CIM
T (
mm
)
Treatment group difference, Final Visit
−0.013 (95% CI: −0.024,−0.002)
Baseline CIMTLS Mean (SE)
GLM (N=186)0.779 (0.0085) mm
PIO (N=175)0.771 (0.0085) mm
p=0.017
0.012
−0.001
Adapted from Mazzone T et al. JAMA 2006;296:2572–2581.
CIMT=carotid intima-media thickness
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Telmisartan Improves cholesterol and
lipids
-35
-30
-25
-20
-15
-10
-5
0Total cholesterol LDL-cholesterol Triglycerides
Change f
rom
baseline (
mg/d
L)
Eprosartan
Telmisartan
* P<0.05 vs Eprosartan
*
Derosa et al. Hypertens Res 2004;27:457–464
*
*
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How to influence Residual Risk???
What is the priority
???
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Lifestyle changes,
Lifestyle changes, Lifestyle changes, Lifestyle changes, Lifestyle changes, Lifestyle
changes, Lifestyle changes , Lifestyle changes, lifestyle changes,
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BUT!!!???
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![Page 90: Aggressive Lipid Lowering Treatment](https://reader033.fdocuments.in/reader033/viewer/2022061516/568148e0550346895db5fb84/html5/thumbnails/90.jpg)
Complex treatment of the patient with „CARDIOMETABOLIC RISK“
CMRDiet &
Physical Activity
ACE-IARBsCCBs
Anti-ThromboticAgents
???
NiacinFenofibrate
StatinsResins,eze,niacin
SulfonylureaInzulin
Metformin
GlitazonesGliptines
…..
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Dyslipidemia Managementas a part of complex approach
Use therapy which is effective, safe, well tolerated, supported by EBM data in appropriate dose.
Decrease of CV RISK
Hypolipidemic treatment
LDL-C - main targetof treatment, than RR
„The Lower The Better“
„The Earlier The Better“
„The Longer The Better“
Highers doses(higher prices)
More patients(not at desired goal)
Longer treatment
Longer treatment
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Thank you!!!