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dr. Dasdo Antonius Sinaga, SpJP, FIHA. 3rd Pekanbaru Cardiology Update, August 25th 2013. Pangeran Hotel Pekanbaru. Learn more at PerkiPekanbaru.com
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Dasdo A Sinaga
Cardiologist
SECONDARY PREVENTION
� PRIMARY PREVENTION:
� To prevent cardiovascular event in patients without evidence of cardiovascular disease
� RISK FACTORS
� SECONDARY PREVENTION
� To prevent further events in patients with clinical evidence of cardiovascular disease
� RISK FACTORS
Guidelines target
modifiable risk factorsBEHAVIOR
Poor diet
Physical inactivity
Cigarette smoking
Excessive alcohol
NONMODIFIABLE
RISK FACTORS
Age
Sex
Genetic
predisposition
MODIFIABLE
RISK FACTORS
Elevated LDL-C
Hypertension
Reduced HDL-C
Diabetes
Obesity
Smoking
Socio-economic, cultural
and environmental
conditions and
modernization,
mechanization,
urbanization,
globalization
Adapted from Shao R. Presentation at the Global Forum on NCD Prevention and Control, 9-12 November 2003, Rio de Janeiro.
EXTERNAL FACTORS
CV
EVENTS
Coronary
heart disease
Myocardial
infarction
Congestive
heart
failure
Stroke
Peripheral
arterial
disease
RISK FACTORS
Age, Gender
Family History
Smoking Habit
Dyslipidemia
Hypertension
Diabetes Mellitus
CARDIOVASCULAR
EVENT
ACUTE CORONARY SYNDOME:
Unstable Angina Pectoris
Acute NSTEMI
STEMI
STROKE
RE-INFARCTION
CARDIOVASCULAR DEATH
STROKE
HEART FAILURE
Primary Prevention Secondary Prevention
� Patients with UA/NSTEMI and STEMI require secondary prevention for CAD at discharge.
� The management of the patient is detailed in the
� ACC/AHA/ ACP Guidelines for the Management of Patients With Chronic Stable Angina,
� ACC/AHA Guidelines for the Management of Patients With ST- Elevation MI
� Secondary Prevention
Long-Term Medical Therapy and SecondaryPrevention
AFTER DISCHARGE
� LONG TERM Medical Therapy� HOW LONG?
� Non Medical Management:� Diet
� Physical Activity
� Complimentary Treatment ??
SECONDARY PREVENTION
Smoking Cessation
Blood Pressure Control
Lipid Management
Physical Activity
Weight Management
Diabetes Management
Antiplatelet Agent
Renin-Angiotensin Aldosterone Inhibitor
Beta-Blockers
Influenza Vaccination
LIPID MANAGEMENT� Dietary therapy that is
� low in saturated fat and cholesterol (< 7% of total calories as saturated fat and < 200 mg/d cholesterol)
� started on discharge after recovery from ACS.
� Increased consumption of the following:� omega–3 fatty acids,
� fruits, vegetables,
� soluble (viscous) fiber, and
� whole grains.
� Calorie intake should be balanced with energy output to achieve and maintain a healthy weight.
Lipid Profile Assessment
� A lipid profile should be obtained from past records, but if not available, it should be performed in all patients with Acute Coronary Syndrome
� Preferably after they have fasted
� Within 24 hours of admission.
LIPID MANAGEMENT
TARGETED Lipid Profile
� TOTAL CHOLESTEROL
� Low-Density-Lipoprotein CHOLESTEROL
� TRIGLISERIDE
� High-Density-Lipoprotein CHOLESTEROL
� LIPOPROTEIN a (Lpa)
Non-HDL Cholesterol = all bad Cholesterol
= Total Chol - HDL
� Total Cholesterol
� LDL Cholesterol
� Trigliseride
� HDL Cholesterol
1. LDL
100 mg/dl � 70 mg/dl
2. NON- HDL
130 mg/dl � 100 mg/dl
3. Trigliseride
> 500 � Pankreatitis
3. HDL Cholesterol
�Kolesterol Total 230
�LDL 150
�HDL 30
�Trigliserida 240
�Kolesterol Total 210
�LDL 120
�HDL 60
�Trigliserida 148
*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
LDL-
C le
vel
70 -
130 -
100 -
160 -
Lower Risk< 2 risk factors
High Risk
CHD or CHD risk equivalents(10-yr risk >20%)
Goal 160
mg/dL
Goal 130
mg/dL
40 -
Goal 70
mg/dL*
Moderate Risk
≥ 2 risk factors(10-yr risk <10%)
Goal 100
mg/dL*
Grundy SM et al. Circulation 2004;110:227-239.
Proposed LDL-C goals
NCEP ATP III Guidelines: LDL-C Goals
(Update 2004)
Very high risk
CVD + •Multiple major risk factors (Diabetes)•Smoking •Metab Synd•ACS
� LDL-Cholesterol >= 100 mg/dl
� � prescribed drug therapy on hospital discharge, preference: statins.
� LDL-C < 100 mg/dL or unknown
� prescribed statin therapy on hospital discharge.
� Non HDL-C < 130 mg/dL
� HDL-C level < 40 mg/dL
� should receive special emphasis on nonpharmacologicaltherapy (eg, exercise, weight loss, and smoking cessation) to increase HDL-C.
� Elevated LDL-C (>= 100 mg per dL),
� further therapy to achieve an LDL-C < 100 mg/dL.
Further titration to < 70 mg/dL is reasonable.
If triglycerides are greater than or equal to 500 mg/dL, therapeutic options to prevent pancreatitis are fibrateor niacin before LDL-lowering therapy is recommended.
It is also recommended that LDL-C be treated to goal after triglyceride-lowering therapy.
� EARLY SECONDARY trials
� before the use of statin therapy VS STATIN therapy
� significant reductions of
� 25% in nonfatal Myocardial Infarctions and
� 14% in fatal Myocardial Infarction
� Subsequently, a growing body of evidence, mainly from large randomized clinical trials of statin therapy, has firmly established the desirability of lowering atherogenic serum lipids in patients who have recovered from a STEMI.
� Hydroxymethyl glutaryl-coenzyme A reductaseinhibitors (HMG CoA Reductase Inhibitor / statins), in the absence of contraindications, regardless of baseline LDL-C and diet modification, should be given to post-ACS patients, including post-revascularization patients.
� Lipid-lowering medications should be initiated before discharge.
STATIN
26
Statin Mechanism Of Action
Statin Liver
Peripheral cell
Vessel
LDL receptor
HMG-CoA
Mevalonic acid
Cholesterol
HMG-CoA reductase
Atherosclerosis: A
Progressive Disease
CRP=C-reactive protein; LDL-C=low-density lipoprotein cholesterol.
Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126.
Monocyte LDL-CAdhesion molecule
Macrophage
Foam cell
OxidizedLDL-C
Plaque rupture
Smooth muscle cells
CRP
Plaque instabilityand thrombus
OxidationInflammationEndothelial dysfunction
28
Statin’s Pleiotropic Effects in
Atherosclerotic Lesion
Inhibitory action Inhibitory action Inhibitory action Inhibitory action
on thrombosis on thrombosis on thrombosis on thrombosis
formationformationformationformation
Plaque stabilizationPlaque stabilizationPlaque stabilizationPlaque stabilization
LDLLDLLDLLDL MonocyteMonocyteMonocyteMonocyte
PlateletPlateletPlateletPlatelet
Endothelial cellEndothelial cellEndothelial cellEndothelial cell
Inhibitory action on Inhibitory action on Inhibitory action on Inhibitory action on
monocyte adhesion monocyte adhesion monocyte adhesion monocyte adhesion
Oxidized LDL Oxidized LDL Oxidized LDL Oxidized LDL
Improvement of Improvement of Improvement of Improvement of
endothelial functionsendothelial functionsendothelial functionsendothelial functions
Inhibitory action on migration and Inhibitory action on migration and Inhibitory action on migration and Inhibitory action on migration and
proliferation of smooth muscle cellsproliferation of smooth muscle cellsproliferation of smooth muscle cellsproliferation of smooth muscle cells
MacrophageMacrophageMacrophageMacrophage
Inhibitory action on Inhibitory action on Inhibitory action on Inhibitory action on
change from Mchange from Mchange from Mchange from MΦ into into into into
foam cellsfoam cellsfoam cellsfoam cells
Pleitropic Effects of StatinsStatins pleitropic effects are dissociated from their hypolipidemic effects. These effects include:
Wassmann S, et al Endothelium. 2003;10:23-33.
Endothelial functionNO bioactivity
EndothelinEndothelialprogenitor cells
Macrophages
InflammationImmunomodulation
Immune injury
Coagulation
Platelet activation
Thrombogenicity
Proliferation
LDL-CHDL-CTriglycerides (TG)
Plaque progression
MMPsCollagen
Plaque stability
AT1 receptorAntioxidant effect
Free radicals
Early intensive treatment with a statin is both safe and effective in the acute phase after MI or UA ( PROVE IT, MIRACLE, A to Z )
30
31
Cyclopropyl group
Hydrophilic areas
Hydrophobic areas
Hydrophobic areas
Hydrophobic areas
Mode of Action
pitavastatinsimvastatinatorvastatin
IC50(nM)
5.817.132.9
[ratio][1]
[2.9][5.7]
J. Atheroscler. Thromb 7(3): 138, 2000
Figure 5 - Pitavastatin in the complex with active site of human
HMG-CoA Reductase ( Adapted from Yamazaki et al )
Solubility (log P)
CYP Metabolism(in human)
Excreted asActive Metabolite
T1/2(hr)
BA (%)
Excretion into urine
(%)Drugs
PravastatinWater-soluble (-0.47)
Negligible Unchanged– 18 20 1-2
FluvastatinLipid-
soluble (1.73)
CYP2C9 MetaboliteNo 10 - 35 <6 1.2
AtorvastatinLipid-
soluble (1.53)
CYP3A4 No DataYes 12 2 14
PitavastatinPitavastatin
Lipid-
soluble (1.49)
Unchanged– 60* < 2 11Negligible
SimvastatinLipid-
soluble (4.40)
CYP3A4 Yes < 5 13 1-2Metabolite
Not
Met
abol
ized
by
CY
PM
etab
oliz
ed b
y C
YP
* Estimated from first pass metabolism model
RosuvastatinWater-soluble (-0.33)
Slightly metabolized
CYP2C9, 2C19Mainly
Unchanged– 20 10 19
Medical Consultation & New Remedies 2003; 40(5): 351J Clin Pharmacol.2002; 42(8): 835, J Clin Pharmacol.2003;43(9):1015
What STATIN ?
Source :
Saito Y, Teramoto T, Yamada N, et al. Clinical efficacy of NK-104 (Pitavastatin), a new synthetic HMG-CoA
reductase inhibitor, in the dose finding, double –blind, three-group comparative study. J Clin Ther Med. 2001;
17: 829-55. Japanese.
Mean % Change of Lipid Profiles
with Pitavastatin
( LDL-C lowering effect until 47% within 12 weeks )
( Dose Finding Study )
Over 12 weeks Pitavastatin was non-inferior to
Atorvastatin in reducing LDL-C and increasing
HDL-C
Budinsky, Clin.Lipidol, 4/3,291-302, 2009
Pitavastatin was non-inferior compared
to simvastatin in reducing LDL-C and
increasing HDL-C
Ose L et al. 2009;25(11):2755-64
Change in LDL-C
4,530 3,499 3,550 4,228 4,987 5,115 5,339 5,464
162.4±34.6
108.5±27.2
0 3 months 6 months 1 year 2 years 3 years 4 years 5 years
-30.5%
Mean±S.D.p<0.001 (repeated measures ANOVA)
(mg/dL)
80
100
120
140
160
180
200
0
60
No. of patients
LDL-
C
Teramoto T, et al. Jpn Pharmacol Ther 2011;39:789–803
Time Course of HDL-C Level (Subgroup with baseline HDL-C <40 mg/dL)
Percent change 14.0±±±±20.1 16.1±±±±21.5 20.3±±±±22.0 24.9±±±±27.5
(mg/dL)
30
35
40
45
50
55
0 12 28 52 1040
Mean±S.D. (n=86)p<0.001 by ANOVA and linear regression model
(weeks)
35.4±3.2
40.4±7.6
41.0±7.5
42.5±7.8
44.1±9.3
HDL-C target*
*Recommended by JAS Guideline 2007
Teramoto T et al. J Atheroscler Thromb. 2009;16(5):654
Impact of Statin Therapy on Plaque
Characteristics
To evaluate the effect of statin treatment on coronary Plaque composition and Morphology
by optical coherence tomography (OCT), grayscale and integrated backscatter (IB) intravascular ultrasound (IVUS) imaging
The result of this study was published in JACC in 2012
Hattori K et al. J Am Coll Cardiol 2012; 5: 169-177
Inclusion Criteria : Stable Angina Patients who have been undergoing elective PCI to
evaluate the effect of statin therapy on nontarget lession
Exclusion Criteria : Patients already established on lipid-lowering therapy and those with
contraindications to repeat coronary angiography and intra-coronary
imaging
Study Design : non-randomized, case-control study
Methods : 42 patients with stable angina undergoing elective PCI ( 26 received
pitavastatin 4 mg/day and 16 who declined any form of lipid-lowering
pharmacotherapy received dietary intervention alone
Post PCI :Serial OCT, Grayscale and IB-IVUS 9 months
Serial OCT, Grayscale and IB-IVUS
Pitavastatin 4mg/dayPitavastatin 4mg/day
Diet Only
Non-
RandomizedStable
Angina
Protocol
Non-
Randomized
Case control
study
Hattori K et al. J Am Coll Cardiol 2012; 5: 169-177
Result of Pitavastatin Group
Result of Dietary Group
Treatment with Pitavastatin in patients with stableangina post PCI induces
� Significant plaque regression and,
� By decreasing plaque lipid content and
� Increasing plaque fibrous cap thickness, and inducesplaque stabilization
Conclusion of the research
Hattori K et al. J Am Coll Cardiol 2012; 5: 169-177
% Change in Plaque Volume
ALL(n=252)
Atorvastatin20mg(n=127)
Pitavastatin4mg(n=125)
-30
-20
-10
0
-17.5%n.s.
*** *** ***
:p<0.001***
Hiro T et al. J Am Coll Cardiol 2009
MonocyteLDL-CAdhesion molecule
Macrophage
Foam cell
OxidizedLDL-C
Plaque rupture
Smooth muscle cells
CRP
SUMMARY� Lipid Management is crucial as a part of secondary prevention
in patients with Acute Coronary Syndrome� Lifestyle Modification and Medical Therapy
� Early Intensive Statin in all ACS patients, REGARDLESS of the cholesterol levelsBeyond lowering cholesterol level, PLEIOTROPIC effect of statin is beneficial for all CAD patients.
� Tailored targeted cholesterol level is encouragedIn high risk patients, LDL < 70 mg/dl should be reached.
� Pitavastatin proven as a potent statin in reducing LDL and enhancing HDL-cholesterol level.
THANK YOU