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