dr. Dasdo Antonius Sinaga, SpJP, FIHA. 3rd Pekanbaru Cardiology Update, August 25th 2013. Pangeran Hotel Pekanbaru. Learn more at PerkiPekanbaru.com

1. Dasdo A Sinaga
Cardiologist

2. 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

3. Guidelines target
modifiable risk factors
BEHAVIOR
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

4. 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

5. 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 Secondary
Prevention

6. AFTER DISCHARGE
LONG TERM Medical Therapy
HOW LONG?
Non Medical Management:
Diet
Physical Activity
Complimentary Treatment ??

8. 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

10. 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.

12. 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.

13. LIPID MANAGEMENT
TARGETED Lipid Profile
TOTAL CHOLESTEROL
Low-Density-Lipoprotein CHOLESTEROL
TRIGLISERIDE
High-Density-Lipoprotein CHOLESTEROL
LIPOPROTEIN a (Lpa)

14. 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

15. Kolesterol Total 230
LDL 150
HDL 30
Trigliserida 240
Kolesterol Total 210
LDL 120
HDL 60
Trigliserida 148

16. *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-Clevel
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

17. 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 nonpharmacological
therapy (eg, exercise, weight loss, and smoking cessation)
to increase HDL-C.

18. 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 fibrate
or niacin before LDL-lowering therapy is
recommended.
It is also recommended that LDL-C be treated to goal
after triglyceride-lowering therapy.

22. 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.

24. Hydroxymethyl glutaryl-coenzyme A reductase
inhibitors (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. 26
Statin Mechanism Of Action
Statin Liver
Peripheral cell
Vessel
LDL receptor
HMG-CoA
Mevalonic acid
Cholesterol
HMG-CoA reductase

27. 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-C
Adhesion
molecule
Macrophage
Foam cell
Oxidized
LDL-C
Plaque rupture
Smooth muscle
cells
CRP
Plaque instability
and thrombusOxidationInflammation
Endothelial
dysfunction

28. 28
Statin’s Pleiotropic Effects in
Atherosclerotic Lesion
Inhibitory actionInhibitory actionInhibitory actionInhibitory action
on thrombosison thrombosison thrombosison thrombosis
formationformationformationformation
Plaque stabilizationPlaque stabilizationPlaque stabilizationPlaque stabilization
LDLLDLLDLLDL MonocyteMonocyteMonocyteMonocyte
PlateletPlateletPlateletPlatelet
Endothelial cellEndothelial cellEndothelial cellEndothelial cell
Inhibitory action onInhibitory action onInhibitory action onInhibitory action on
monocyte adhesionmonocyte adhesionmonocyte adhesionmonocyte adhesion
Oxidized LDLOxidized LDLOxidized LDLOxidized LDL
Improvement ofImprovement ofImprovement ofImprovement of
endothelial functionsendothelial functionsendothelial functionsendothelial functions
Inhibitory action on migration andInhibitory action on migration andInhibitory action on migration andInhibitory action on migration and
proliferation of smooth muscle cellsproliferation of smooth muscle cellsproliferation of smooth muscle cellsproliferation of smooth muscle cells
MacrophageMacrophageMacrophageMacrophage
Inhibitory action onInhibitory action onInhibitory action onInhibitory action on
change from Mchange from Mchange from Mchange from MΦ intointointointo
foam cellsfoam cellsfoam cellsfoam cells

29. Pleitropic Effects of Statins
Statins pleitropic effects are dissociated from their hypolipidemic effects.
These effects include:
Wassmann S, et al Endothelium. 2003;10:23-33.
Endothelial function
NO bioactivity
Endothelin
Endothelial
progenitor cells
Macrophages
Inflammation
Immunomodulation
Immune injury
Coagulation
Platelet activation
Thrombogenicity
Proliferation
LDL-C
HDL-C
Triglycerides (TG)
Plaque progression
MMPs
Collagen
Plaque stability
AT1 receptor
Antioxidant 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. 30

31. 31
Cyclopropyl group
Hydrophilic areas
Hydrophobic areas
Hydrophobic areas
Hydrophobic areas
Mode of Action
pitavastatin
simvastatin
atorvastatin
IC50
（nM）
5.8
17.1
32.9
[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 )

32. Solubility
(log P)
CYP
Metabolism
(in human)
Excreted asActive
Metabolite
T1/2
(hr)
BA
(%)
Excretion
into urine
(%)
Drugs
Pravastatin
Water-
soluble
(-0.47)
Negligible Unchanged– 18 20 1-2
Fluvastatin
Lipid-
soluble
(1.73)
CYP2C9 MetaboliteNo 10 - 35 <6 1.2
Atorvastatin
Lipid-
soluble
(1.53)
CYP3A4 No DataYes 12 2 14
PitavastatinPitavastatin
Lipid-
soluble
(1.49)
Unchanged– 60* < 2 11Negligible
Simvastatin
Lipid-
soluble
(4.40)
CYP3A4 Yes < 5 13 1-2Metabolite
NotMetabolized
byCYP
Metabolizedby
CYP
* Estimated from first pass metabolism model
Rosuvastatin
Water-
soluble
(-0.33)
Slightly
metabolized
CYP2C9, 2C19
Mainly
Unchanged– 20 10 19
Medical Consultation & New Remedies 2003; 40(5): 351
J Clin Pharmacol.2002; 42(8): 835, J Clin Pharmacol.2003;43(9):1015
What STATIN ?

33. 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 )

34. 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

35. Pitavastatin was non-inferior compared
to simvastatin in reducing LDL-C and
increasing HDL-C
Ose L et al. 2009;25(11):2755-64

36. 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

37. 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 52 104
0
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

38. 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

39. 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

40. Result of Pitavastatin Group

41. Result of Dietary Group

42. Treatment with Pitavastatin in patients with stable
angina post PCI induces
Significant plaque regression and,
By decreasing plaque lipid content and
Increasing plaque fibrous cap thickness, and induces
plaque stabilization
Conclusion of the research
Hattori K et al. J Am Coll Cardiol 2012; 5: 169-177

43. % Change in Plaque Volume
ALL
(n=252)
Atorvastatin
20mg
(n=127)
Pitavastatin
4mg
(n=125)
-30
-20
-10
0
-17.5%
n.s.
*** *** ***
:p<0.001***
Hiro T et al. J Am Coll Cardiol 2009
MonocyteLDL-C
Adhesion
molecule
Macrophage
Foam cell
Oxidized
LDL-C
Plaque rupture
Smooth muscle
cells
CRP

44. 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 levels
Beyond lowering cholesterol level, PLEIOTROPIC effect of
statin is beneficial for all CAD patients.
Tailored targeted cholesterol level is encouraged
In high risk patients, LDL < 70 mg/dl should be reached.
Pitavastatin proven as a potent statin in reducing LDL and
enhancing HDL-cholesterol level.

45. THANK YOU