TARGET OF DYSLIPIDEMIA THERAPY IN

CARDIOVASCULAR RISK

DR. Dr. Eka Ginanjar, SpPD, K-KV, FINASIM, FACP, FICA


@Dr_EKG
Interest:
Interventional Cardiology
Peripheral & Endovascular
Intervention
Emergency Medicine
Acute Cardiovascular Care
Heart Failure and Stem Cell
Public Health and Health Economics
Hospital Management
CURRICULUM VITAE
• Education:
– Medical Doctor – FKUI 2003
– Spesialis Penyakit Dalam (SpPD) – FKUI/RSCM 2009
– Clinical and Interventional Cardiology – IJN, Malaysia 2012
– Konsultan Kardiovaskular (KKV), FKUI/RSCM 2014
– PhD in Medical Science – FKUI 2019
– Master in Hospital Administration (MARS) – FKMUI (candicate)
• Fellow/membership:
– Instructor for American Heart Association (AHA) BLS-ACLS 2010
– Fellow of Indonesian Society of Internal Medicine (FINASIM) 2012
– Fellow of American College of Physician (FACP) 2014
– Fellow of International College of Angiology (FICA) 2015
– Member of European Society of Cardiology (ESC) 2013
– Member of European Ass. of Percutaneous CV Interventions (EAPCI) 2013
– Member of Acute Cardiovascular Care Association (ACCA) 2013
• Position:
– Medical Staff and Lecturer at FKUI/RSCM
– Clinical and Interventional Cardiologist at PJT-RSCM
– Clinical and Interventional Cardiologist at RS MMC Jakarta
– HEAD OF INTEGREATED HEART CENTRE (PJT) – RSCM
– Head of Casemix Team RSCM
– National Casemix Center
– National Committee of Cardiocerebrovascular MOH
– Secretary General of PAPDI
 The Cardiovascular Continuum of
Events

ACS
Coronary
Secondary Arrhythmia and
prevention
Thrombosis Stroke Loss of Muscle

Myocardial Remodeling
Ischemia

Ventricular
CAD Dilatation

Atherosclerosi Congestive
s Heart
Primary Failure
prevention Risk Factors End-stage
( Dyslipidemia,  BP, DM, Heart Disease
Insulin Resistance,
Adapted from
Platelets, Fibrinogen, etc)
Dzau et al. Am Heart J. 1991;121:1244-1263
RISK FACTORS IN HARMONY
 Individuals with elevated Cholesterol are
at increased risk of CHD

Multiple Risk Factor Intervention Trial Framingham Study

(MRFIT) (n=361,662) (n=5209)
50 150
10-year CHD Death Rate

CHD Incidence per 1000

(Deaths per 1000)

125
40
100
30
75
20
50
10 25
0
0 150 200 250 300 204 205-234 235-264265-294 295
Serum cholesterol (mg/dL) Serum cholesterol (mg/dL)

Each 1% reduction in total cholesterol level Each 1% increase in total cholesterol level
resulted in a 2% decrease in CHD risk was associated with a 2% increase in CHD risk

Gotto AM Jr et al. Circulation. 1990;81:1721-1733.

Castelli WP. Am J Med. 1984;76:4-12.
 The Progression from CV Risk Factors to
Endothelial Injury and Clinical Events

LDL-C BP Risk factors Diabetes Smoking Heart failure

Oxidative stress

Endothelial dysfunction

NO Local mediators Tissue ACE-Ang II

Endothelium Growth factors Proteolysis

PAI-1 VCAM
matrix
ICAM cytokines

Vascular lesion and

Thrombosis Inflammation Vasoconstriction Plaque rupture
remodelling

Clinical endpoints

Atherothrombotic Manifestation (AMI, Stroke)

NO Nitric oxide
Modified from Gibbons GH, Dzau VJ. N Engl J Med 1994;330;1431-1438.
 Atherosclerosis
Endothelial Plaque instability
Inflammation Oxidation
dysfunction and thrombus

Plaque rupture

Adhesion Macrophage Oxidized

Monocyte LDL-C molecule LDL-C
Foam cell
CRP

Smooth muscle
cells

Libby P. Circulation. 2001;104:365-372; Ross R. N Engl J Med. 1999;340:115-126.

RISK FACTORS
 Multiple Studies Showed a Relationship Between LDL-C
Reduction & CHD Relative Risk

London WOSCOPS
100 Oslo CARE
Nonfatal MI and CHD death

MRC LIPID
Los Angeles
relative risk reduction, %
AF/TexCAPS
80 Upjohn HPS
LRC ALERT
NHLBI PROSPER
POSCH ASCOT-LLA
60 4S CARDS

40

20

–20

15 20 25 30 35 40
LDL-C reduction, %
MI = myocardial infarction.

Robinson JG et al. J Am Coll Cardiol. 2005;46:1855–1862.

 Per 1.0 mmol/L (40 mg/dL) LDL-C reduction:

➢ 10% proportional reduction in all-cause mortality

➢ 20% proportional reduction in CAD death
➢ The risk for major coronary events was reduced by 23%
➢ The risk for stroke was reduced by 17%
Primary targets of therapy : LDL-C
Secondary targets : non-HDL-C and apo B
Recommendation for pharmacological treatment of
hypercholesterolemia (ESC - 2016)

• Prescribe statin up to the

highest recommended dose
or highest tolerable dose to
reach the target level
New ACC/AHA cholesterol treatment guideline
published November 2018

AHA, American Heart Association

ACC, American College of Cardiology
17
 Guidelines specify statin doses
High-intensity Moderate-intensity Low-intensity
↓ LDL-C by ≥50% ↓ LDL-C by 30–50% ↓ LDL-C by <30%*
Atorvastatin (40)–80 mg 10–20 mg –
Rosuvastatin 20–40 mg 5–10 mg –
Simvastatin – 20–40 mg 10 mg
Pravastatin – 40–80 mg 10–20 mg
Lovastatin – 40 mg 20 mg

Fluvastatin XL – 80 mg –
Fluvastatin – 40 mg bid 20–40 mg
Pitavastatin – 2–4 mg 1 mg
Bold: Statins and doses evaluated in RCTs
Italics: Statins and doses approved by US FDA but not tested in RCTs reviewed
*Should be used in patients unable to tolerate moderate-to high-intensity therapy
Asian ancestry may modify the statin dose prescribed

Stone NJ, et al. J Am Coll Cardiol 2018. Epub ahead of print

20 Reproduced with kind permission from American College of Cardiology
 The Changing Concept
Short Term treatment
Efficacy: Surrogate end point:
- Lowering LDL - CRP
- Lowering TG - Plaque
- Increasing HDL - Pleiotrophic effect
- Lowering OxLDL

Long Term treatment

Clinical end point:

- Mortality
- Morbidity (CV events, stroke, MI etc)
Statins Stabilize The Plaque In Vivo
Unstable plaque Stable plaque
Fibrous cap Fibrous cap

Statin

Fewer
inflammatory
Inflammatory cells
cells Lipid core Lipid core

▪ Reduce expression of metalloproteinase (MMP)

Statin
▪
pleiotropic effect:
Reduce disruption of collagen

Control
▪
instability plaque
Decrease lipid content of the plaque
Statin treated

MMP = extracellular enzymes that have the ability to degrade the collagen matrix of the
fibrous cap of atherosclerotic plaque, increasing the likelihood of rupture
Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995;91:2844-2850
. Toschi V et al. Circulation. 1997;95:594-599; Libby P. Circulation. 1995;91:2844-2850.
CLINICAL STUDY

From Short Term Therapy

Until
Long Term Therapy
With Atorvastatin
PURSUIT : Retrospective analysis shows early
mortality reduction with lipid-lowering therapy

Survival (%)
100
Lipid-lowering agents (n=2141)
99
98

97

96

95 No lipid-lowering agents (n=6374)

94

93
Log rank  2=87, p<0.001
92
0 30 60 90 120 150 180
Days
Aronow et al (2000)
GUSTO IIb/PRISM : Early reduction in death/MI in
patients on lipid-lowering therapy

• GUSTO IIb – Retrospective analysis of 12,630 ACS

patients (±ST elevation)
• Mortality at 30 days and 6 months was significantly
reduced in patients receiving lipid-lowering agent
• 52% reduction in 6-month mortality (RR 0.48, 95% CI
0.28-0.83) after adjusting for other variables

• PRISM – Retrospective analysis of 1616 patients

• 302 patients were continued on background statin
therapy
• Death/MI rate at 30 days was significantly lower in
these patients (p<0.01)
Aronow et al, Hamm et al (AHA 2000)
CARDS : Primary End Point – Major CV Events*
Acute CAD Events, Coronary Revascularization, or Stroke
15 End of
# of Placebo
n Events Treatment
Median LDL Atorvastatin 10 mg
Cumulative Hazard (%)

Atorva 10
83 77 mg/dL
mg 1,428 37%
10
Placebo 1,410 127 120 mg/dL Relative Risk
Reduction
(P=0.001)
(95% CI: 17–52)
5

Trial Stopped Early

0
% Years
0.0 1.0 2.0 3.0 3.9 4.75

▪ N = 2,838 ; Inclusions: 1. Type 2 DM with no clinically evident CAD, 2.≥1 other CAD risk factor
(smoking, HT, albuminuria, retinopathy) + LDL-C ≤ 160 mg/dL & TG ≤ 600 mg/dL, 3. Aged 40–75 yrs
▪ The study was stopped 2 yrs earlier than anticipated after a median f. up of 3.9 yrs, due to beneficial
effect of atorvastatin
▪ The results were similar in pts with LDL-C <120 mg/dL & ≥120 mg/dL
Colhoun HM, et al. Lancet. 2004;364:685-696.
 CARDS : Secondary Endpoint
- Stroke
≥65 years
10.00
Relative risk -48% (95% CI-74 to 0), P=0.051
Cumulative hazard (%)

5.00
48%

0.00
0.00 1.00 2.00 3.00 4.00 4.75
Years
Atv 572 555 541 438 273 64
Pbo 557 537 520 396 244 62

Diabetes Care 29:2378-2384, 2006

 Atorvastatin Reduced Hs-CRP
Across a Broad Range of Pts
Athyros PROVE-
DALI2 ARBITER5 ASAP4
et al 3 IT 8
80 mg 80 mg 20 mg 80 mg
80 mg
(n=64) (n=79) (n=100) (n=135)
(n=2099)
Statin-
Type 2 eligible§ Metabolic Heterozygous
ACS
diabetes syndrome FH

CRP at CRP at CRP at CRP at CRP at

baseline = baseline = baseline = baseline = baseline =
3.0 mg/L‡ 4.3 mg/L† 4.4 mg/L 2.1 mg/L‡ 12.3 mg/L‡

30 weeks 12 months 12 months 2 years 2 years

47% 51% 65% 40% 89%

(P<0.001) (P=0.005) (P<0.05) (P<0.001) (P<0.001)

% reductions are from baseline; study variance from 30 weeks until 2 years of
Treatments. ( ASAP : the smallest Baseline CRP )

1. Gomez-Gerique JA, et al. Atherosclerosis. 2002;162:245-51; 2. van de Ree MA, et al. Atherosclerosis. 2003 Jan;166:129-35; 3. Athyros VG, et al. Metabolism.
2005;54:1065-74; 4. van Wissen S, et al. Atherosclerosis. 2002;165: 361-6; 5. Taylor AJ, et al. Circulation. 2002;106:2055-60; 6. Nissen SE et al. JAMA.
2004;291:1071-80; 7. Kinlay S et al. Circulation. 2003;108:1560-6; 8. Cannon CP, et al. N Engl J Med. 2004;350:1495-504
Atorvastatin Shows Early & Rapid Effects in
Hard & Surrogate End Point Trials
16 1 1.5 2 3.3 4
Weeks Year Years Years Years Years

MIRACL ARBITER REVERSAL PROVE IT ASCOT-LLA ALLIANCE

• Regression • Reductions
of carotid IMT • Stopped • Reductions
•Reductions in the • Reduction in nonfatal
with progression s in MI,
composite MI and CV
in recurrent atorvastatin, of
primary fatal CHD, outcomes
but was atheroscler
ischemic stable with end point fatal and compared
osis vs with usual
events, pravastatin
continued of mortality nonfatal
care
over and major stroke vs
including 12 months progression
ASAP CV events placebo CARDS
stroke, • Over 2 years, with
compared
after ACS regression of pravastatin • Reduction in
carotid IMT with with CV events
vs placebo atorvastatin, pravastatin and stroke in
whereas
simvastatin patients with
showed growth diabetes
of lesions

Schwartz GG et al for the Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) Study Investigators. JAMA.
2001;285:1711-1718. Taylor AJ et al. Circulation. 2002;106:2055-2060. Smilde TJ et al. Lancet. 2001;357:577-581. Nissen SE et al for the
REVERSAL Investigators. JAMA. 2004;291:1071-1080. Cannon CP et al for the Pravastatin or Atorvastatin Evaluation and Infection
Therapy—Thrombolysis in Myocardial Infarction 22 Investigators. N Engl J Med. 2004;350:1495-1504. Sever PS et al for the ASCOT
Investigators. Lancet. 2003;361:1149-1158. Koren MJ et al on behalf of the ALLIANCE Investigators. J Am Coll Cardiol. 2004;44:1772-
1779. Colhoun HM et al on behalf of the CARDS Investigators. Lancet. 2004;364:685-696.
 Safety Across The Dose Range
Proven Safety Profile
Across The Dosage Range & Over Long Term Treatment

Atorvastatin Atorvastatin Atorvastatin Atorvastatin

Placebo
10mg 20mg 40mg 80mg
n=1949
n=6343 n=242 n=186 n=2345

Myalgia 2% 3% 2% 3% 3%
Arthralgia 1% 2% 0% 3% 1%
Arthritis 1% 1% 2% 0% <1%
Joint disorder <1% <1% 0% 1% <1%
Myopathy* 0% 0% 0% 0% 0%

* In post-marketing surveillance, rare cases of myopathy & rhabdomyolysis

have
Data been reported
on file, with atorvastatin & other statins
Pfizer Inc.
YOUR CLINICAL JUDGMENT IS VERY
IMPORTANT
 Summary

▪ Atorvastatin has been shown to reduce CV events in pts with other

risk factors (many studies)
▪ Accumulating evidence suggests that atorvastatin may have
vasculoprotective effects beyond lipid lowering, including:
▪ Improving endothelial function
▪ Reducing CRP & other markers of inflammation
▪ Increasing plaque stability by reducing plaque volume & oxidative stress
▪ Enhanced cholesterol-independent benefits with intensive statin
therapy may contribute to greater reductions in CV outcomes
▪ Statin Long-term treatment has Greater Benefits than only short term
treatment
▪ Atorvastatin has well established safety profile
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