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The Importance of Potential Statin in

High Risk Patient


CRE/006/FEB14-FEB15/BR

Masrul Syafri
Bagian Kardiologi & Kedokteran
Vaskular
FKUA/RS M Djamil
Padang
CVD is a leading cause of death
worldwide
According to the WHO,1
An estimated 17.3 million people died from CVDs in 2008.
By 2030, almost 23.6 million people will die from CVDs.

CHD remains the main cause of global mortality and a major


cause of morbidity and loss of quality of life.2

CVD: Cardiovascular disease


1. http://www.who.int/cardiovascular_diseases/en/
2. De Backer GG. Medicographia. 2009;31:343348.
New Paradigm: Multi-Risk Factor Approach
Traditional CVD New CVD risk New targets and
perspective perspective goals for therapy

Hypercholesterolemia
DM
Gender
Age Reduction of
Diabetes
total CVD risk
HTN

Hyper- HTN
cholesterol- is the primary
emia
goal
Organ
damage

Smoking

Multiple independent
Integrated identification and management of
risk factors (silo
risk factors contributing to CVD risk
approach)
CVD: Cardiovascular disease;
(global approach)
DM: Diabetes mellitus; HTN: Hypertension
Volpe M, et al. J Human Hypertens. 2008;22:154157.
On-Treatment LDL-C is Closely Related to
CHD Events in Statin Trials Lower is Better
30
4S - Placebo

25 Rx - Statin therapy
PRA pravastatin Secondary Prevention
ATV - atorvastatin
4S - Rx
20

LIPID - Placebo
15
LIPID - Rx CARE - Placebo
CARE - Rx CORONA - Placebo
CORONA - Rx HPS - Placebo Primary Prevention
HPS - Rx TNT ATV10
10 PROVE-IT - PRA
TNT ATV80 WOSCOPS Placebo
PROVE-IT ATV AFCAPS - Placebo
6
5 AFCAPS - Rx WOSCOPS - Rx
ASCOT - Placebo
ASCOT - Rx
0
40 60 80 100 120 140 160 180 200
(1.0) (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2)
LDL-C achieved mg/dL (mmol/L)

Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004; 9(2): 269-279
LaRosa JC et al. N Engl J Med 2005; 352: 1425-1435
On-Treatment LDL-C is Closely Related to Stroke Events
in Statin Trials Lower is Better
Relationship between protection from stroke events and LDL-C reduction

1.2
GISSI
1.0 PROSPER
ALLHAT-LLT WOSCOPS

0.8 LIPID AFCAPS/TexCAPS


HPS ASCOT-LLA
4S
0.6 CARE

GREACE MIRACL
0.4

0.2
-10 -20 -30 -40 -50
Reduction in LDL-C (%)
Amarenco P, et al. Stroke 2004;35:2902-2909
Relationship Between Proportional Reduction in
Events and Mean LDL-C Reduction at 1 Year
A prospective meta-analysis of data from 90,056 individuals from 14 statin trials

A 1 mmol/L (39 mg/dL) reduction in LDL-C was associated with a ..


. 23% reduction in . 21% reduction in
50 major coronary events 50 major vascular events

40 40
Proportional reduction in

Proportional reduction in
30
event rate (%SE)

30

event rate (%SE)


20 20

10 10

0 0
0.5 1.0 1.5 2.0 0.5 1.0 1.5 2.0
(19) (38) (58) (77) (19) (38) (58) (77)
-10 -10
Reduction in Reduction in
LDL-C mmol/L (mg/dL) LDL-C mmol/L (mg/dL)

CTT Collaborators. Lancet 2005;366:12671278.


History of U.S. Dyslipidemia Guideline
Development

1988 1993 2001 2004 2013

ATP III ACC/AHA


ATP I1 ATP II2 ATP III3
Update4 Guidelines5
Exclusive Risk Lower LDL- Lower LDL- Use of
focus on assessment C threshold C threshold moderate-
LDL-C guides for therapy for therapy or high-
therapy initiation in initiation in intensity
high risk very high statin
patients risk patients therapy for
patients
across 4
major
groups at
risk for
ASCVD*

*ASCVD, Atherosclerotic Cardiovascular Disease

1. NCEP. Arch Intern Med .1988;148:36-69. 2. NCEP ATP II. Circulation .1994;89:1333-445. 3. NCEP ATP III. Circulation.
2002;106:3143.
4. Grundy SM, et al. Circulation. 2004;110:227-239.. 5. Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002.
Available at: http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.
Target of LDL-C: NCEP-ATP III

Risk Category LDL-C

0-1 < 160 mg/dl

2 (10-year risk <10%) < 130 mg/dl

2 (10-year risk 10-20%) < 130 mg/dl

(Optional goal: < 100 mg/dl)

< 100 mg/dl


CHD and CHD risk equivalent
(optional goal: 70 mg/dl)

Grundy SM, et al. NCEP Report. Circulation 2004;110:227-239


Recommendation for treatment target LDL-C
(ESC/EAS 2011)
Recommendation Class Level
VERY HIGH CV risk I A
(established CVD, DM type
1 &2 with target organ
damage, severe CKD or
SCORE level > 10%) the
LDL-C goal is < 70 mg/dl
and or > 50% reduction
when target level cannot be
reached
HIGH CV risk (markedly II a A
elevated single risk
factor, a SCORE level >
5 to < 10%), an LDL-C
goal < 100 mg/dl
MODERATE risk II a C
(SCORE level >1 to< 5),
an LDL-C goal < 115
mg/dl
2013 ACC/AHA Guideline Recommendations for
Statin Therapy

ASCVD Statin Benefit Groups


Heart healthy lifestyle habits are the foundation of ASCVD prevention

Estimated 10-yr
LDL-C 190 Diabetes; ASCVD risk
Clinical ASCVD
mg/dL age 40-75 years* 7.5%; age 40-75
years*
High-Intensity High-intensity Moderate-intensity Moderate- to high-
statin (age 75 statin statin intensity statin
years)
Moderate-intensity High-intensity statin
Moderate-intensity statin if not a if estimated 10 year
statin if >75 years candidate for high- ASCVD risk 7.5%
or not a candidate intensity statin
for high-intensity
statin

ASCVD prevention benefit of statin therapy may be less clear in other groups . Consider additional factors
influencing ASCVD risk , potential ASCVD risk benefits and adverse effects, drug-drug interactions, and patient
preferences for statin treatment.

* With LDL-C of 70-189 mg/dL


Estimated using the Pooled Cohort Risk Assessment Equations

Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at:


http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.
Intensity of Statin Therapy

High-Intensity Statin Moderate-Intensity Low-Intensity Statin


Therapy Stain Therapy Therapy

LDLC 50% LDLC 30% to <50% LDLC <30%

Atorvastatin (40)80 mg Atorvastatin 10 (20) mg Simvastatin 10 mg


Rosuvastatin 20 (40) mg Rosuvastatin (5) 10 mg Pravastatin 1020 mg
Simvastatin 2040 mg Lovastatin 20 mg
Pravastatin 40 (80) mg Fluvastatin 2040 mg
Lovastatin 40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 24 mg

Lifestyle modification remains a critical component of ASCVD risk reduction, both prior to and in concert with the use
of cholesterol lowering drug therapies.

Statins/doses that were not tested in randomized controlled trials (RCTs) reviewed are listed in italics
Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL
Initiation of or titration to simvastatin 80 mg not recommended by the FDA due to the increased risk of myopathy, including
rhabdomyolysis.
Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at:
http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.
LDL Cholesterol
is
The Primary Target

in Dyslipedmia Treatment

NCEP ATP III 2003/ NCEP ATP III Update 2004


ADA/ACC Guideline Update for Secondary Prevention 2006
ESC/EAS Guidelines for the management of Dyslipidemias 2011
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adults
Common dislipidemia patient in
Primary practice
In Germany dyslipidemia was highly frequent in
primary care (76% overall)1.
Life style intervention only control 10% dyslipidemia
of the patients1
After using pharmacotherapy, still many patient do
not achieve LDL-C1, same thing happens in Asia2,3
Starting doses is important, because commonly used
in clinical practice, and most of clinicians often fail to
titrate doses after initiating therapy to reach LDL
cholesterol goals1
1. Steinhagen-Thiessen, Cardiovascular Diabetology 2008, 7:31 doi:10.1186/1475-2840-7-31
2. Park et al, European Journal of Cardiovascular Prevention & Rehabilitation published online 7 March 2011 DOI:10.1177/1741826710397100
3. Pearson TA, et al The Lipid Treatment Assessment Project (L-TAP) Arch Intern Med 2000;160:459467.
Management of Hypercholesterolaemia remains
Sub-optimal: Pan-Asian CEPHEUS
Survey conducted in eight Asian countries of 7281 patients on lipid-
lowering therapy for 3 months
Only 34.9% of very high risk patients reached NCEP ATP III
goal and it was below from overall result
65.1% of very high risk patients did not reach NCEP ATP III
goal
100
Patients (%) at

75.4 76
80
LDL-C goal

55.4
60 49.1
40 34.9

20
0
Overall Very-high High Moderate Lower
<70 mg/dL <100 mg/dL) <130 mg/dL <160 mg/dL
Risk category and NCEP ATP III goal

Park JE et al. Eur J Cardiovasc Prevent Rehabil 2011; epub ahead of print.
Percentage of Patients at LDL-C goals recommended by the 2004 updated
NCEP ATP III* guidelines
% of Patients at LDL-C goals recommended by 2004 updated NCEP ATP III* guidelines

For patients in Hong Kong the treatment goal attainment rate was 82.9% while patients in other
countries had very low LDL-C attainment rate (31.3 52.7%).

Park JE et al. Eur J Cardiovasc Prevent Rehabil 2011; epub ahead of print.
PAN-ASIAN CEPHEUS Study:
Follow-up of Patients not achieving LDL-C goals

Follow-up of patients not achieving LDL-C goals

Other follow-up treatment (n=40) 1.7

Lifestyle modification (n=332) 13.7

Dose increased+additional medication


6.4
(n=156)
Switched to another therapy (n=407) 16.8

Dose increased (n=618) 25.5

Same medication (n=871) 35.9

0 5 10 15 20 25 30 35 40
No. of patients (%)

Park JE, et al. Eur J Prev Cardiol. 2012;19(4):781-794..


Treatment Gap

31.3% of patients had attained their therapeutic


LDL-C goals.
This result was below that of the overall Asian
rate (49.1%)
Patients compliance with drug treatment
appeared to be very poor in the Indonesian
population.
Examples of higher risk patients who
may benefit from intensive treatment

TIA/stroke patients

Type 2 diabetes Atherosclerosis


Intensive treatment is
needed1

Target LDL-C <100mg/dL and


optionally <70mg/dL

Acute coronary Hyperlipidaemic


syndromes VTE patients

Patients need
>50% LDL-C
Women with CVD
reduction and
optimize HDL-C

Third report of the NCEP expert panel on detection, evaluation and treatment of high blood cholesterol on adults (ATP III). May 2001
Rosuvastatin in Acute Coronary Syndrome
Acute coronary syndromes
Acute Coronary Syndrome

No ST Elevation ST Elevation

Non ST Elevation MI

Unstable Angina Myocardial Infarction


Non Qw MI Qw MI

Braunwald E et al. J Am Coll Cardiol 2000;36:9701062.


Outcomes in primary prevention, stable and unstable
coronary disease
16

12
Death/nonfatal MI (%)

Unstable angina/non-Q-wave MI (FRISC


8 II)
Stable angina (SAPAT)
Primary prevention (WOSCOPS)

0
0 2 4 6 8 10 12
Months of follow-up
Wallentin L et al. Lancet 2000;356:916.
Juul-Moller S et al. Lancet 1992;340:14211425.
Shepherd J et al. N Engl J Med 1995;333:13011307.
Unstable angina: prognosis

Patients with unstable angina have a far worse


short-term prognosis than do patients with stable angina

Despite recent advances in therapy, the relative risk of death or


nonfatal MI in patients with unstable angina versus those with
stable disease is higher over the first year

Braunwald E et al. J Am Coll Cardiol 2000;36:9701062.


Wallentin L et al. Lancet 2000;356:916.
Juul-Moller S et al. Lancet 1992;340:14211425.
Benefits assigned to statins

Improve cholesterol parameters


To achieve target LDL-C < 70 mg/dL

Pleiotropic effects
Plaque stabilization
Anti-inflammation
Anti-thrombogenicity
Arterial compliance
Modulation of endothelial function

OSullivan, TSMJ 2007 (8): 52-56


Statin in dyslipidemia with ACS

MIRACL PROVE-IT
Statin effect on inflammation

A to Z PROVE-IT
CENTAURUS and statins in ACS
CENTAURUS1 MIRACL2 PROVE-IT3 A to Z4
N 1108 3086 4162 4497
Inclusion Anticipated PCI No PCI After PCI After PCI
No Statins No Statin 25% Statin
No STEMI No QW MI 35% STEMI 40% STEMI
PCI 63% None 69% 44%
Age 60 65 58 61
Sex Male 74% 65% 78% 76%
End Point ApoB/ApoA1 Clinical Clinical Clinical
TT rosuvastatin 20 mg atorvastatin 80 pravastatin 40 Simvastatin

CRE/021/Jun12-Jun13/MF
/Follow vs atorvastatin 80 mg vs mg vs 40/80 mg vs
up mg, 3 months placebo, 4 atorvastatin 80 placebo 4
months mg, 2 years month/
simvastatin 20
mg 2 years
1. Lablanche JM et al, Archives of Cardiovascular Diseases, 2010, 103 (3) :160-169
2. Schwartz GG, et al , JAMA 2001; 285:1711-1718
3. Cannon CP, et al. N Engl J Med 2004;350:1495-504.
4. De Lemos JA, et al JAMA 2004; 292:1307-1316
Comparison of the Effects Noted in The ApoB/ApoA-I ratio Using Rosuvastatin and
atorvastatin in patients with Acute Coronary Syndrome

Lablanche JM et al, Archives of Cardiovascular Diseases, 2010, 103 (3) :160-169


CENTAURUS
Study Design
Patients 18 years with non-ST-elevation-ACS hospitalized <48 hours after symptom
onset and for whom a PCI was planned/anticipated within 4 days for treatment of the
index event

Two double-blind periods


1st study period: admission to hospital discharge, max 6 days
2nd study period: hospital discharge (day 0) to 3 months
1108 subjects randomized and received at least 1 dose of study drug
Rosuvastatin 20 mg n=221*

Rosuvastatin 20 mg n=437
Placebo n=887
Atorvastatin 80 mg n=450

Day -6 Day -4 Day 0 3 months


PCI
PCI=percutaneous coronary intervention *Results of this group not reported
Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.
CENTAURUS
Patient Population
Baseline Characteristics
Approximately 75% were male
Mean age approximately 60 years
35% had dyslipidemia
Treatment of ACS
PCI completed:
68% in the RSV group
64% in the ATV group
Time to PCI after admission: 1.2 days in both groups
Mean time to start of drug treatment after onset of ACS:
4.5 days in the RSV 20 mg group
4.6 days in the ATV 80 mg group

Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.


CENTAURUS
Primary End point
Percent Change in ApoB/Apo A-1
After 1 and 3 Months versus Baseline

RSV 20 mg ATV 80 mg Estimated Difference* P


(n = 369) (n = 384) RSV 20 mg vs. ATV 80 mg value

44.4 42.9
At 1 month 2.6 [4.5; 0.0] 0.02
(43.116.5) (40.516.3)
44.4 44.4
At 3 months 0.0 [2.5; +1.7] 0.87
(41.220.1) (41.717.1)
Data are median (mean standard deviation) or median (95% confidence interval)
Intention to treat population
*Hodges-Lehman estimate
Wilcoxon Rank Sum test

Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.


CENTAURUS
Changes in Lipid Parameters
Baseline 1 month 3 months

RSV 20 mg ATV 80 mg RSV 20 mg ATV 80 mg RSV 20 mg ATV 80 mg


(n=369) (n=384) (n=369) (n=384) (n=369) (n=384)

ApoA-1, 136 137 152 143 156 150


mg/dL
ApoB, 130 129 81 78 86 80
mg/dL
ApoB/Apo 0.99 0.98 0.55 0.57 0.57 0.55
A-1
LDL-C, 129 128 68 68 74 71
mg/dL
HDL-C, 40 40 45 43 47 46
mg/dL
Total-C, 203 201 141 134 149 142
mg/dL
TG, mg/dL 170 166 134 116 139 125

Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.


CENTAURUS
Major Adverse Clinical Events
RSV 20 mg (n=406) ATV 80 mg (n=423)
Period: day 0 to 3 months* 18 (4.4%) 23 (5.4%)
MI 6 (1.5%) 7 (1.7%)
Stroke 3 (0.7%) 0 (0.0%)
CV death 2 (0.5%) 1 (0.2%)
Non-CV death 0 (0.0%) 2 (0.5%)
Sudden and unexpected death 0 (0.0%) 1 (0.2%)
Unstable angina 6 (1.5%) 9 (2.1%)
Repeat vascularization 6 (1.5%) 7 (1.7%)

*Number of patients (%) with at least one major adverse clinical event in the period/category

All events were confirmed by the independent clinical adjudicating committee

Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.


CENTAURUS
Safety
RSV 20 mg ATV 80 mg
(n=406) (n=423)
ALT >3x ULN at 1 month 2 (0.5%) 6 (1.4%)
ALT >3x ULN at 3 months 1 (0.2%) 4 (0.9%)
CK >10x ULN at 1 month 0 (0.0%) 0 (0.0%)
CK >10X ULN at 3 months 0 (0.0%) 0 (0.0%)
Increase in SCr >100% from 0 (0.0%) 1 (0.2%)
baseline at 1 month
Increase in SCr >100% from 1 (0.2%) 1 (0.2%)
baseline at 3 months
Data are number of patients (%)
ALT=alanine aminotransferase; CK=creatine kinase; SCr=serum creatinine; ULN=upper limit of normal

Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.


CENTAURUS Conclusion
In the CENTAURUS trial, after an ACS:
Rosuvastatin 20 mg was superior to Atorvastatin 80 mg to decrease the ApoB/ApoA1
ratio at 1 month whereas no difference was shown at 3 months
The ApoB/ApoA1 ratio decreased more rapidly with Rosuvastatin 20mg than Atorvastatin
80mg
Rosuvastatin 20 mg and Atorvastatin 80 mg induced a similar reduction in LDL-
cholesterol
No meaningful differences were shown whenRosuvastatin 20mg was started at
admission or at discharge
Both treatments were well tolerated

Lablanche JM et al, Archives of Cardiovascular Diseases, 2010, 103 (3) :160-169


LUNAR Study
Limiting UNder-treatment of lipids in ACS
with Rosuvastatin

Objective :
A number of studies have compared the effectiveness of high-dose
atorvastatin (ATV80) to rosuvastatin 20 mg (RSV20) and
rosuvastatin 40 mg daily (RSV40), but none to date in patients with
acute coronary syndromes (ACS)

The objective of LUNAR (Limiting UNder-treatment of lipids in ACS


with Rosuvastatin) was therefore to compare the efficacy of once-
daily regimens of RSV20 and RSV40 with ATV80 in reducing low-
density lipoprotein cholesterol (LDL-C) levels in patients with ACS

Pitt B, et al. Am J Cardiol 2012; 109:1239-1246


LUNAR
Study Design

Rosuvastatin 20 mg (n=277)
Patients (n=825)
1875 years
Hospitalised for ACS (STEMI, NSTEMI,
UA) within 48hrs of ischaemic symptoms Rosuvastatin 40 mg (n=270)

LDL-C >70mg/dL (~1.8 mmol/L)


TGs <500 mg/dL (~5.6 mmol/L)
Atorvastatin 80 mg (n=278)
Prospective, multi-centre, randomised, open-label,
parallel-group phase IIIb study

Visit: 1 2 3 4 5
Week: 0 2 6 12

Symptom
Onset Screening / baseline Lipids Lipids Lipids
blood analysis Safety CRP CRP
Average time from symptom onset to Safety Safety
study drug treatment = 3.9 days
ACS = acute coronary syndrome, STEMI = ST elevation myocardial infarction,
NSTEMI = non-ST elevation myocardial infarction, UA = unstable angina, LDL-C = low-
density lipoprotein cholesterol, TGs = triglycerides, CRP = C-reactive protein

Pitt B, et al. Am J Cardiol 2012; 109:1239-1246


LUNAR
Primary & Secondary Endpoints

Primary Endpoint
% change in LDL-C (direct measurement) from baseline, averaged over
measurements at 6 and 12 weeks

Secondary Endpoints
% change from baseline in LDL-C at 2, 6, and 12 weeks
% change from baseline in total cholesterol (TC), high-density lipoprotein
cholesterol (HDL-C), TG, non-HDL-C, apolipoprotein A-I (Apo A-I),
apolipoprotein B (Apo B), LDL-C/HDL-C, TC/HDL-C, non-HDL-C/HDL-C,
Apo B/Apo A-I, and LDL-C (Friedewald calculation) averaged over 612
weeks and at 2, 6, and 12 weeks
% change from baseline in the inflammatory marker high- sensitivity C-
reactive protein (hsCRP) averaged over 612 weeks

Pitt B, et al. Am J Cardiol 2012; 109:1239-1246


LUNAR
Baseline Characteristics

Rosuvastatin Rosuvastatin Atorvastatin


Variable 20 mg/day 40 mg/day 80 mg/day
(n=277) (n=270) (n=278)

Type of ACS
STEMI 113 (40.8%) 100 (37.0%) 107 (38.5%)
NSTEMI 89 (32.1%) 101 (37.4%) 104 (37.4%)
Unstable angina 75 (27.1%) 69 (25.6%) 67 (24.1%)

Medical history
MI/ACS 30 (10.8%) 39 (14.4%) 29 (10.4%)
Coronary artery disease 46 (16.6%) 55 (20.4%) 37 (13.3%)
PCI 65 (23.5%) 55 (20.4%) 50 (18.0%)
Coronary bypass 5 (1.8%) 6 (2.2%) 9 (3.2%)
Hypertension 144 (52.0%) 137 (50.7%) 139 (50.0%)
Diabetes 32 (11.6%) 35 (13.0%) 36 (16.5%)
Hyperlipidemiaa 83 (30.0%) 83 (30.7%) 65 (23.4%)
Smoker 40 (14.4%) 44 (16.3%) 50 (18.0%)
a Reported by investigators as history of dyslipidemia, hyperlipidaemia, or elevated cholesterol

ACS = acute coronary syndrome, STEMI = ST elevation myocardial infarction, NSTEMI = non-ST
elevation myocardial infarction, MI = myocardial infarction, PCI = percutaneous coronary intervention

Pitt B, et al. Am J Cardiol 2012; 109:1239-1246


LUNAR
Baseline Characteristics

Rosuvastatin Rosuvastatin Atorvastatin


Variable 20 mg/day 40 mg/day 80 mg/day
(n=246) (n=251) (n=257)

LDL-C (mg/dL) 138.4 138.8 133.2


HDL-C (mg/dL) 39.5 38.8 39.9
NonHDLC (mg/dL) 161.2 162.8 156.0
Total cholesterol (mg/dL) 200.7 201.7 195.9
Triglycerides, mg/dL 180.8 182.7 157.5 (n = 254)
LDL-C / HDL-C 3.68 3.77 3.59
NonHDL-C / HDL-C 4.32 4.46 4.25
TC / HDL-C 5.32 5.46 5.25
Apo B (mg/dL) 130.0 (n=223) 132.2 (n=224) 127.4 (n=231)
Apo A-I (mg/dL) 134.6 (n=223) 134.0 (n=224) 135.3 (n=231)
Apo B / Apo A-I 1.00 (n=223) 1.01 (n=224) 0.97 (n=231)
hs-CRP* 12.3 (n=238) 12.9 (n=241) 12.3 (n=249)
* Median value LDL-C = low density lipoprotein cholesterol, HDL-C = high density lipoprotein cholesterol,
TC = total cholesterol, Apo=apolipoprotein, hs-CRP = high sensitivity C-reactive protein

Pitt B, et al. Am J Cardiol 2012; 109:1239-1246


LUNAR
Primary Endpoint

Rosuvastatin Rosuvastatin Atorvastatin


20 mg 40 mg 80 mg
0

-10

Average change
in -20
LDL-C from
baseline (%)
-30

-40
-42.0 -42.7
-50 -46.8
*
*p< 0.05 versus atorvastatin 80 mg
Similar results were achieved in all subcategories of ACS (unstable
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246 angina, non-STEMI, and STEMI)
LUNAR
Primary Endpoint

0 Rosuvastatin 20mg
Rosuvastatin 40mg
Atorvastatin 80 mg
-10

Mean Change
-20
in LDL-C from
Baseline (%)
-30

-40 **
*

-50 *

-60
0 2 4 6 8 10 12
Time (weeks)

*p 0.05; **p 0.01 versus atorvastatin 80 mg


Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
LUNAR
Secondary Endpoint

15
***
11.9
**
9.7
Mean change in 10
HDL-C from
baseline (%)

5.6
5

0
Rosuvastatin Rosuvastatin Atorvastatin
20 mg 40 mg 80 mg

**p< 0.01, *** p<0.001 versus atorvastatin 80 mg


Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
LUNAR
Secondary Endpoints
20 ***
**

Mean
0
Change in
Parameter
from
-20
Baseline (%)


-40 ***
**
***
***
-60
Rosuvastatin 20mg
Rosuvastatin 40mg
-80 Atorvastatin 80mg

-100

** p<0.01, ***p<0.001 versus atorvastatin 80 mg p< 0.05,


Pitt B, et al. Am J Cardiol 2012; 109:1239-1246 p<0.01 versus rosuvastatin 20mg
LUNAR
Safety & Tolerability

Rosuvastatin Rosuvastatin Atorvastatin


Variable 20 mg/day 40 mg/day 80 mg/day
(n=267) (n=263) (n=269)

Any Serious AE* 28 (10.5%) 23 (8.7%) 38 (14.1%)

Serious Cardiovascular AE* 9 (3.4%) 5 (1.9%) 6 (2.2%)


Unstable angina 4 (1.5%) 3 (1.1%) 3 (1.1%)
Myocardial infarction 5 (1.9%) 2 (0.8%) 2 (0.7%)
Cerebrovascular accident 0 0 1 (0.4%)

Withdrawal due to AE 10 (3.7%) 16 (6.1%) 25 (9.3%)


Musculoskeletal and connective 5 (1.9%) 6 (2.3%) 17 (6.3%)
tissue disorders

Death* 0 2 (0.8%) 1 (0.4%)

*None of the serious AEs, serious cardiovascular AEs or deaths were considered by the investigators to be related to study treatment

AE = adverse event

Pitt B, et al. Am J Cardiol 2012; 109:1239-1246


LUNAR
Safety & Tolerability

Rosuvastatin Rosuvastatin Atorvastatin


Variable 20 mg/day 40 mg/day 80 mg/day
(n=249) (n=249) (n=257)

Alanine aminotransferase
3 ULN at 2 consecutive visits, n (%) 1 (0.4%) 0 1 (0.4%)

Creatine kinase
10 ULN, n (%) 0 1 (0.4%) 0

Serum creatinine
increased 30% from baseline and (n=234) (n=229) (n=244)
ULN at maximum, n (%) 2 (0.9%) 0 3 (1.2%)

ULN = upper limit of normal

Pitt B, et al. Am J Cardiol 2012; 109:1239-1246


LUNAR
Safety & Tolerability
Rosuvastatin Rosuvastatin Atorvastatin
Variable 20 mg/day 40 mg/day 80 mg/day

Serum creatinine, mol/L


(n=266) (n=263) (n=269)

Baseline, mean (SD) 88.5 (16.2) 87.0 (16.0) 90.1 (17.4)

(n=220) (n=202) (n=210)

Change at final visit, mean (SD) 6.3 (12.0) 4.9 (11.2) 5.8 (14.3)

eGFR, mL/min/1.73 m2
(n=266) (n=263) (n=269)

Baseline, mean (SD) 81.9 (15.7) 83.5 (17.0) 81.7 (17.1)

(n=220) (n=202) (n=210)

Change at final visit, mean (SD) 6.6 (12.6) 5.3 (11.5) 6.5 (13.4)

SD = standard deviation

Pitt B, et al. Am J Cardiol 2012; 109:1239-1246


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Summary

RSV20 was as effective as ATV80 in reducing LDL-C, and had a


significantly greater effect than ATV80 in raising HDL-C
RSV40 was significantly more effective than ATV80 in reducing LDL-C and
increasing HDL-C
RSV40 was also significantly more effective than ATV80 in improving
several other important lipid parameters
Apo A-I , LDL-C/HDL-C, nonHDL-C/ HDL-C, TC/HDL-C, and Apo
B/Apo A-I
The safety profile of RSV20, RSV40 and ATV80 were similar

Pitt B, et al. Am J Cardiol 2012; 109:1239-1246


LUNAR
Conclusion

RSV20 might be considered as an alternative to ATV80 in patients with ACS


RSV40 may be preferable to ATV80 in patients with ACS, in particular in
patients
in whom a target LDL-C <70 mg/dL has not been achieved by prior statin
therapy
in whom it would be unlikely to achieve a target LDL-C <70 mg/dL with
ATV80, based upon their baseline LDL-C

Pitt B, et al. Am J Cardiol 2012; 109:1239-1246


Statin: Risk and Benefit Ratio

Intensive statin treatment produces more benefits


Statins is well tolerated Side effect
Therapeutic effect

Myotoxicity
Liver toxicity
Renal Toxicity
CV protection
Drug Interaction
Conclusion
Statin is beneficial for ACS with dyslipidemia
Rosuva 20 mg is equal to atorva 80 mg and rosuva 40 mg
is better than atorva 80 mg, in lowering LDL-C
Rosuvastatin is well tolerated in ACS with Dyslipidemia
Thank You
CRESTOR : New Hydrophyllic Statin

Statin Pharmacophore
More lipophilic *

O Ca 2.0
(3R, 5S) HO Cerivastatin
O Simvastatin
1.5
OH Fluvastatin
1.0 Atorvastatin

F
CH3 0.5

CH3 0.0

N N CRESTOR
-0.5

H3C N
Pravastatin
-1.0
S CH3
O O * log D at pH 7.4

Buckett et al., ISA (2000); McTaggart et al., (2001)


Disampaikan : Poster di di XII Simposium Internasional Aterosklerosis ( ISA ) , Stockholm , 25
Juni - 29 2000.
Kutipan : Am J Cardiol 2001; 87 ( suppl ) : 28B - 32B
Aterosklerosis 2000; 151:41 abs MoP29 : W6

Latar Belakang : Ada variabilitas luas dalam lipophilicity statin yang tersedia dan telah hipotesis
bahwa hal ini dapat menjadi faktor yang berkontribusi terhadap kemampuan statin untuk
bertindak di luar sel dari organ target ( hati) seperti otot .

Desain Studi :
Tujuan: Untuk mengukur lipophilicity ( logD ) dari CRESTOR dan statin lainnya
Populasi : In vitro
nomor :
Metodologi : . LogD dari statin antara ) ) dapar fosfat 1M , pH 7,4 dan oktanol ( 1:100 v / v )
ditentukan dengan menggunakan metode labu micro - shake dengan konsentrasi obat ditentukan
oleh HPLC .
CRESTOR adalah enatiomer tunggal ( 3R , 5S ) dirumuskan dan diberikan sebagai garam kalsium
dari asam hidroksi aktif .

Hasil Key :
CRESTOR relatif hidrofilik , penengah antara pravastatin dan statin lainnya .

kesimpulan :
CRESTOR , seperti pravastatin , kurang kemungkinan untuk menyeberangi membran sel
dibandingkan dengan statin lipofilik lainnya . Hal ini dapat menyebabkan sebagian, dengan
tingkat selektivitas efek pada sintesis kolesterol antara sel-sel hati dan non - hati .