The Importance of Potential Statin in High Risk Patient Masrul Syafri Bagian Kardiologi & Kedokteran Vaskular FKUA/RS M Djamil Padang CRE/006/FEB14-FEB15/BR

The Importance of Potential Statin in High Risk Patient

Masrul Syafri

Bagian Kardiologi & Kedokteran Vaskular

FKUA/RS M Djamil

Padang

CR

E/0

06/F

EB

14-F

EB

15/B

R

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.”

CVD: Cardiovascular disease

1. http://www.who.int/cardiovascular_diseases/en/

2. De Backer GG. Medicographia. 2009;31:343348.

CHD remains the main cause of global mortality and a major cause of morbidity and loss of quality of life.2

Multiple independentrisk factors (silo

approach)

Integrated identification and management of risk factors contributing to CVD risk

(global approach)

HT

N

Hyp

erch

ole

ster

ole

mia

Dia

bet

es

Traditional CVD perspective

New CVD risk perspective

AgeGenderDM

Hyper-cholesterol-

emia

HTN

New targets andgoals for therapy

Reduction oftotal CVD risk is the primary

goal

Smoking

Organdamage

New Paradigm: Multi-Risk Factor Approach

CVD: Cardiovascular disease;

DM: Diabetes mellitus; HTN: Hypertension

Volpe M, et al. J Human Hypertens. 2008;22:154–157.

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

LDL-C achieved mg/dL (mmol/L)

WOSCOPS – Placebo

AFCAPS - Placebo

ASCOT - PlaceboAFCAPS - Rx WOSCOPS - Rx

ASCOT - Rx

4S - Rx

HPS - Placebo

LIPID - Rx

4S - Placebo

CARE - Rx

LIPID - Placebo

CARE - Placebo

HPS - Rx

0

5

10

15

20

25

30

40(1.0)

60(1.6)

80(2.1)

100(2.6)

120(3.1)

140(3.6)

160(4.1)

180(4.7)

Even

t ra

te (

%)

6

Secondary Prevention

Primary Prevention

Rx - Statin therapyPRA – pravastatinATV - atorvastatin

200(5.2)

PROVE-IT - PRA

PROVE-IT – ATV

TNT – ATV10

TNT – ATV80

On-Treatment LDL-C is Closely Related to CHD Events in Statin Trials – Lower is Better

CORONA - RxCORONA - Placebo

Relationship between protection from stroke events and LDL-C reduction

0.2

0.4

0.6

0.8

1.0

1.2

-10 -20 -30 -40 -50

GISSIPROSPER

WOSCOPS

AFCAPS/TexCAPS

ALLHAT-LLT

LIPIDHPS ASCOT-LLA

4SCARE

GREACE MIRACL

Od

ds

rati

o f

or

stro

ke

red

uct

ion

Reduction in LDL-C (%)

On-Treatment LDL-C is Closely Related to Stroke Events in Statin Trials – Lower is Better

Amarenco P, et al. Stroke 2004;35:2902-2909

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

rop

ort

ion

al

red

uc

tio

n i

n

ev

en

t ra

te (

%S

E)

Pro

po

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na

l re

du

cti

on

in

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ve

nt

rate

(%

SE

)CTT Collaborators. Lancet 2005;366:1267–1278.

Relationship Between Proportional Reduction in Events and Mean LDL-C Reduction at 1 Year

50

40

30

20

10

0

0.5(19)

1.0(38)

1.5(58)

2.0(77)

-10Reduction in

LDL-C mmol/L (mg/dL)

50

40

30

20

10

-10

0

0.5(19)

1.0(38)

1.5(58)

2.0(77)

Reduction in LDL-C mmol/L (mg/dL)

A prospective meta-analysis of data from 90,056 individuals from 14 statin trials

…. 23% reduction in major coronary events

…. 21% reduction in major vascular events

ATP I1

• Exclusive focus on LDL-C

ATP II2

• Risk assessment guides therapy

ATP III3

• Lower LDL-C threshold for therapy initiation in high risk patients

ATP III Update4

• Lower LDL-C threshold for therapy initiation in very high risk patients

ACC/AHA Guidelines5

• Use of moderate- or high-intensity statin therapy for patients across 4 major groups at risk for ASCVD*

1988 1993 2001 2004 2013

History of U.S. Dyslipidemia Guideline Development

*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.

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)

CHD and CHD risk

equivalent

< 100 mg/dl

(optional goal: 70 mg/dl)

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

Target of LDL-C: NCEP-ATP III

Recommendation for treatment target LDL-C (ESC/EAS 2011)

Recommendation Class Level

VERY HIGH CV risk (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

I A

HIGH CV risk (markedly elevated single risk factor, a SCORE level > 5 to < 10%), an LDL-C goal < 100 mg/dl

II a A

MODERATE risk (SCORE level >1 to< 5), an LDL-C goal < 115 mg/dl

II a C

Clinical ASCVD

• High-Intensity statin (age ≤75 years)

• Moderate-intensity statin if >75 years or not a candidate for high-intensity statin

LDL-C ≥190 mg/dL

• High-intensity statin

• Moderate-intensity statin if not a candidate for high-intensity statin

Diabetes; age 40-75 years*

• Moderate-intensity statin

• High-intensity statin if estimated 10 year ASCVD risk ≥7.5%

Estimated 10-yr ASCVD risk

≥7.5%†; age 40-75 years*

• Moderate- to high-intensity statin

ASCVD Statin Benefit GroupsHeart healthy lifestyle habits are the foundation of ASCVD prevention

2013 ACC/AHA Guideline Recommendations for Statin Therapy

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.

High-Intensity Statin Therapy

Moderate-Intensity Stain Therapy

Low-Intensity Statin Therapy

LDL–C ↓ ≥50% LDL–C ↓ 30% to <50% LDL–C ↓ <30%

Atorvastatin (40†)–80 mg Rosuvastatin 20 (40) mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20–40 mg‡ Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2–4 mg

Simvastatin 10 mg Pravastatin 10–20 mg Lovastatin 20 mg Fluvastatin 20–40 mg Pitavastatin 1 mg

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.

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.

Intensity of Statin Therapy

http://content.onlinejacc.org/article.aspx?articleid=1770217

LDL Cholesterolis

The Primary Target

in Dyslipedmia Treatment

NCEP ATP III 2003/ NCEP ATP III Update 2004ADA/ACC Guideline Update for Secondary Prevention 2006

ESC/EAS Guidelines for the management of Dyslipidemias 20112013 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:10.1186/1475-2840-7-312. Park et al, European Journal of Cardiovascular Prevention & Rehabilitation published online 7 March 2011 DOI:10.1177/17418267103971003. Pearson TA, et al The Lipid Treatment Assessment Project (L-TAP) Arch Intern Med 2000;160:459–467.

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

49.134.9

55.4

75.4 76

0

20

40

60

80

100

Pati

en

ts (

%)

at

LD

L-C

goal

Park JE et al. Eur J Cardiovasc Prevent Rehabil 2011; epub ahead of print.

Overall Very-high<70 mg/dL

High<100 mg/dL)

Moderate<130 mg/dL

Lower<160 mg/dL

Risk category and NCEP ATP III goal

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

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

Same medication (n=871)

Dose increased (n=618)

Switched to another therapy (n=407)

Dose increased+additional medication (n=156)

Lifestyle modification (n=332)

Other follow-up treatment (n=40)

0 5 10 15 20 25 30 35 40

35.9

25.5

16.8

6.4

13.7

1.7

No. of patients (%)

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

Type 2 diabetes

Hyperlipidaemic VTE patients

Women with CVD

Atherosclerosis

Acute coronary syndromes

TIA/stroke patients

Third report of the NCEP expert panel on detection, evaluation and treatment of high blood cholesterol on adults (ATP III). May 2001

Intensive treatment is needed1

• Target LDL-C <100mg/dL and optionally <70mg/dL

Patients need >50% LDL-C

reduction and optimize HDL-C

Rosuvastatin in Acute Coronary Syndrome

Acute coronary syndromes

Acute Coronary Syndrome

No ST Elevation ST Elevation

Unstable Angina Myocardial InfarctionNon Qw MI Qw MI

Non ST Elevation MI

Braunwald E et al. J Am Coll Cardiol 2000;36:970–1062.

Outcomes in primary prevention, stable and unstable coronary disease

Dea

th/n

onfa

tal M

I (%

)

Months of follow-up

Unstable angina/non-Q-wave MI (FRISC II)

16

12

8

4

0

0 2 4 6 8 10 12

Stable angina (SAPAT)

Wallentin L et al. Lancet 2000;356:9–16.Juul-Moller S et al. Lancet 1992;340:1421–1425.Shepherd J et al. N Engl J Med 1995;333:1301–1307.

Primary prevention (WOSCOPS)

Unstable angina: prognosis

Patients with unstable angina have a far worseshort-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;36:970–1062.Wallentin L et al. Lancet 2000;356:9–16.Juul-Moller S et al. Lancet 1992;340:1421–1425.

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

O’Sullivan, TSMJ 2007 (8): 52-56

Statin in dyslipidemia with ACS

PROVE-ITMIRACL

Statin effect on inflammation

A to Z PROVE-IT

CENTAURUS and statins in ACS

CR

E/0

21

/Ju

n1

2-J

un

13

/MF

CENTAURUS1 MIRACL2 PROVE-IT3 A to Z4

N 1108 3086 4162 4497

Inclusion Anticipated PCINo StatinsNo STEMI

No PCINo StatinNo QW MI

After PCI25% Statin35% STEMI

After PCI

40% STEMI

PCIAgeSex Male

63%6074%

None 6565%

69%5878%

44%6176%

End Point ApoB/ApoA1 Clinical Clinical Clinical

TT /Follow up

rosuvastatin 20 mg vs atorvastatin 80 mg, 3 months

atorvastatin 80 mg vs placebo, 4 months

pravastatin 40 mg vs atorvastatin 80 mg, 2 years

Simvastatin 40/80 mg vs placebo 4 month/ simvastatin 20 mg 2 years

1. Lablanche JM et al, Archives of Cardiovascular Diseases, 2010, 103 (3) :160-1692. Schwartz GG, et al , JAMA 2001; 285:1711-17183. Cannon CP, et al. N Engl J Med 2004;350:1495-504.4. De Lemos JA, et al JAMA 2004; 292:1307-1316

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

Comparison of the Effects Noted in The ApoB/ApoA-I ratio Using Rosuvastatin and atorvastatin in patients with Acute Coronary Syndrome

CENTAURUSStudy DesignCENTAURUSStudy Design

Rosuvastatin 20 mg n=437

Atorvastatin 80 mg n=450

Placebo n=887

Day -4PCI

3 months Day 0Day -6

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

PCI=percutaneous coronary intervention *Results of this group not reported

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

Rosuvastatin 20 mg n=221*

CENTAURUSPatient Population

CENTAURUSPatient 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


CENTAURUSPrimary End point

Percent Change in ApoB/Apo A-1 After 1 and 3 Months versus Baseline

CENTAURUSPrimary End point

Percent Change in ApoB/Apo A-1 After 1 and 3 Months versus Baseline

RSV 20 mg (n = 369)

ATV 80 mg (n = 384)

Estimated Difference*RSV 20 mg vs. ATV 80

mg

P value†

At 1 month −44.4(−43.1±16.5)

−42.9(−40.5±16.

3)−2.6 [−4.5; −0.0] 0.02

At 3 months

−44.4(−41.2±20.1)

−44.4(−41.7±17.

1)0.0 [−2.5; +1.7] 0.87

Data are median (mean ± standard deviation) or median (95% confidence interval)Intention to treat population*Hodges-Lehman estimate†Wilcoxon Rank Sum test


CENTAURUSChanges in Lipid Parameters

CENTAURUSChanges in Lipid Parameters

Baseline 1 month 3 months

RSV 20 mg (n=369)

ATV 80 mg (n=384)

RSV 20 mg (n=369)

ATV 80 mg (n=384)

RSV 20 mg (n=369)

ATV 80 mg (n=384)

ApoA-1, mg/dL

136 137 152 143 156 150

ApoB, mg/dL

130 129 81 78 86 80

ApoB/ApoA-1

0.99 0.98 0.55 0.57 0.57 0.55

LDL-C, mg/dL

129 128 68 68 74 71

HDL-C, mg/dL

40 40 45 43 47 46

Total-C, mg/dL

203 201 141 134 149 142

TG, mg/dL 170 166 134 116 139 125


CENTAURUSMajor Adverse Clinical Events

CENTAURUSMajor 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

CENTAURUSSafety

CENTAURUSSafety

RSV 20 mg (n=406)

ATV 80 mg (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 baseline at 1 month

0 (0.0%) 1 (0.2%)

Increase in SCr >100% from baseline at 3 months

1 (0.2%) 1 (0.2%)


Data are number of patients (%)ALT=alanine aminotransferase; CK=creatine kinase; SCr=serum creatinine; ULN=upper limit of normal

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

LipidsSafety

LipidsCRP

Safety

LipidsCRP

Safety

Patients (n=825)

18–75 years

Hospitalised for ACS (STEMI, NSTEMI, UA) within 48hrs of ischaemic symptoms

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

TGs <500 mg/dL (~5.6 mmol/L)

Rosuvastatin 40 mg (n=270)

Atorvastatin 80 mg (n=278)

Rosuvastatin 20 mg (n=277)

Visit:Week:

1 46

512

20

32

Screening / baseline blood analysis

LUNARStudy Design

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

Prospective, multi-centre, randomised, open-label, parallel-group phase IIIb study

Symptom Onset

Average time from symptom onset to study drug treatment = 3.9 days


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

LUNARPrimary & Secondary Endpoints


LUNARBaseline Characteristics

VariableRosuvastatin

20 mg/day(n=277)

Rosuvastatin40 mg/day(n=270)

Atorvastatin80 mg/day

(n=278)

Type of ACSSTEMI 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 historyMI/ACSCoronary artery diseasePCICoronary bypass HypertensionDiabetesHyperlipidemiaa

Smoker

30 (10.8%)46 (16.6%)65 (23.5%)5 (1.8%)

144 (52.0%)32 (11.6%)83 (30.0%)40 (14.4%)

39 (14.4%)55 (20.4%)55 (20.4%)

6 (2.2%)137 (50.7%)35 (13.0%)83 (30.7%)44 (16.3%)

29 (10.4%)37 (13.3%)50 (18.0%)9 (3.2%)

139 (50.0%)36 (16.5%)65 (23.4%)50 (18.0%)

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

a Reported by investigators as history of dyslipidemia, hyperlipidaemia, or elevated cholesterol



20 mg/day(n=246)


Atorvastatin80 mg/day(n=257)

LDL-C (mg/dL) 138.4 138.8 133.2

HDL-C (mg/dL) 39.5 38.8 39.9

Non–HDLC (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

Non–HDL-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

LUNARBaseline Characteristics

LDL-C = low density lipoprotein cholesterol, HDL-C = high density lipoprotein cholesterol, TC = total cholesterol, Apo=apolipoprotein, hs-CRP = high sensitivity C-reactive protein


-46.8-42.7-42.0

-50

-40

-30

-20

-10

0

*

Average change in LDL-C from baseline (%)

Rosuvastatin20 mg

Rosuvastatin40 mg

Atorvastatin80 mg

LUNARPrimary Endpoint

*p< 0.05 versus atorvastatin 80 mg

Similar results were achieved in all subcategories of ACS (unstable angina, non-STEMI, and STEMI)Pitt B, et al. Am J Cardiol 2012; 109:1239-1246

LUNARPrimary Endpoint

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

Time (weeks)

0 2 4 6 8 10 12

Rosuvastatin 20mgRosuvastatin 40mgAtorvastatin 80 mg

0

-10

-20

-30

-40

-50

-60

*

***

Mean Change in LDL-C from Baseline (%)


9.7

11.9

5.6

0

5

10

15

**

Mean change in

HDL-C from baseline (%)

Rosuvastatin20 mg

Rosuvastatin40 mg

Atorvastatin80 mg

***

LUNARSecondary Endpoint

**p< 0.01, *** p<0.001 versus atorvastatin 80 mgPitt B, et al. Am J Cardiol 2012; 109:1239-1246

LUNARSecondary Endpoints

** p<0.01, ***p<0.001 versus atorvastatin 80 mg †p< 0.05, †† p<0.01 versus rosuvastatin 20mg

Non–HDLC

Total cholesterol

Triglycerides

LDL-C / HDL-C

Non–HDL-C / HDL-C

TC / HDL-C

Apo BApo A-I

Apo B / Apo A-I hsCRP

-100

-80

-60

-40

-20

0

20

Mean Change in Parameter from Baseline (%)

Rosuvastatin 20mg

Rosuvastatin 40mg

Atorvastatin 80mg

******

***

**

**

***

†

††


LUNARSafety & Tolerability


20 mg/day(n=267)



(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 tissue disorders

5 (1.9%) 6 (2.3%) 17 (6.3%)

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

AE = adverse event

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



20 mg/day(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 ULN at maximum, n (%)

(n=234)

2 (0.9%)(n=229)

0(n=244)

3 (1.2%)


ULN = upper limit of normal



20 mg/dayRosuvastatin

40 mg/dayAtorvastatin80 mg/day

Serum creatinine, μmol/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


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

LUNARSummary


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

LUNARConclusion


Statin: Risk and Benefit Ratio

Therapeutic effect

Side effect

CV protection

Myotoxicity

Liver toxicity

Renal Toxicity

Drug Interaction

Benefit

Risk

• Intensive statin treatment produces more benefits

• Statins is well tolerated

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

Statin Pharmacophore

OO

N

N

S

N

OH

OHO

O

CH3

CH3

CH3

F

CH3

Ca(3R, 5S)

More lipophilic *

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

CRESTOR

CerivastatinSimvastatin

FluvastatinAtorvastatin

Pravastatin

* log D at pH 7.4

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

CRESTOR : New Hydrophyllic Statin

Disampaikan : Poster di di XII Simposium Internasional Aterosklerosis ( ISA ) , Stockholm , 25 Juni - 29 2000.Kutipan : Am J Cardiol 2001; 87 ( suppl ) : 28B - 32BAterosklerosis 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 lainnyaPopulasi : In vitronomor :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 .

Documents

The Importance of Potential Statin in High Risk Patient Masrul Syafri Bagian Kardiologi & Kedokteran Vaskular FKUA/RS M Djamil Padang CRE/006/FEB14-FEB15/BR