Statin in High Risk Patient Masrul Syafri Bagian Kardiologi amp Kedokteran Vaskular FKUARS M Djamil Padang CRE006FEB14FEB15BR CVD is a leading cause of death worldwide According to the WHO ID: 739344
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Slide1
The Importance of Potential Statin in High Risk Patient
Masrul SyafriBagian Kardiologi & Kedokteran VaskularFKUA/RS M DjamilPadang
CRE/006/FEB14-FEB15/BRSlide2
CVD is a leading cause of death worldwideAccording 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.
2Slide3
Multiple independent
risk factors (silo approach)
Integrated identification and management of risk factors contributing to CVD risk
(global approach)
HTN
Hypercholesterolemia
Diabetes
Traditional CVD perspective
New CVD risk
perspective
Age
Gender
DM
Hyper-
cholesterol-
emia
HTN
New targets and
goals for therapy
Reduction of
total CVD risk
is the primary
goal
Smoking
Organ
damage
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. Slide4Slide5Slide6
Adapted from
Rosensen RS. Exp Opin
Emerg
Drugs
2004; 9(2): 269-279
LaRosa
JC et al.
N
Engl
J Med
2005; 352: 1425-1435LDL-C achieved mg/dL (mmol/L)
WOSCOPS – Placebo
AFCAPS - Placebo
ASCOT - Placebo
AFCAPS - 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)
Event rate (%)
6
Secondary Prevention
Primary Prevention
Rx -
Statin
therapy
PRA –
pravastatin
ATV -
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 - Rx
CORONA - PlaceboSlide7
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
GISSI
PROSPER
WOSCOPS
AFCAPS/TexCAPS
ALLHAT-LLT
LIPID
HPS
ASCOT-LLA
4S
CARE
GREACE
MIRACL
Odds ratio for stroke reduction
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
:2902-2909Slide8
A 1 mmol/L (39 mg/dL) reduction in LDL-C was associated with a …..
Proportional reduction in
event rate (%
SE)
Proportional reduction in
event 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
)
-10
Reduction 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 eventsSlide9
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.Slide10
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 Slide11
Recommendation for treatment target LDL-C (ESC/EAS 2011)
RecommendationClass
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 reachedI
AHIGH CV risk (markedly elevated single risk factor, a SCORE level > 5 to < 10%), an LDL-C goal < 100 mg/dl
II aA
MODERATE risk (SCORE level >1 to< 5), an LDL-C goal < 115 mg/dlII a
CSlide12
ASCVD Statin Benefit Groups
Heart 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.Slide13
High-Intensity Statin Therapy
Moderate-Intensity Stain TherapyLow-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 TherapySlide14
LDL Cholesterolis The Primary Targetin 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 2011
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in AdultsSlide15
Common dislipidemia patient in Primary practiceIn 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 Asia
2,3
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 goals
1
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:10.1177/1741826710397100
3. Pearson TA, et al The Lipid Treatment Assessment Project (L-TAP) Arch Intern Med 2000;160:459–467.Slide16Slide17
Management of Hypercholesterolaemia remains Sub-optimal: Pan-Asian CEPHEUS
Survey conducted in eight Asian countries of 7281 patients on lipid-lowering therapy for ≥3 monthsOnly 34.9% of very high risk patients reached NCEP ATP III goal and it was below from overall result65.1% of very high risk patients did not reach NCEP ATP III 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/dLLower
<160 mg/dL
Risk category and NCEP ATP III goal Slide18
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.Slide19
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..Slide20
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.Slide21
Examples of higher risk patients who may benefit from intensive treatment
Type 2 diabetesHyperlipidaemic 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 needed
1
Target LDL-C <100mg/dL and optionally <70mg/dL
Patients need >50% LDL-C reduction and optimize HDL-CSlide22
Rosuvastatin in Acute Coronary SyndromeSlide23
Acute coronary syndromes
Acute Coronary Syndrome
No ST Elevation
ST Elevation
Unstable Angina
Myocardial Infarction
Non Qw MI Qw MI
Non ST Elevation MI
Braunwald
E
et al
.
J Am
Coll
Cardiol
2000;36:970–1062.Slide24
Outcomes in primary prevention, stable and unstable coronary disease
Death/nonfatal MI (%)
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)Slide25
Unstable angina: prognosisPatients with unstable angina have a far worse
short-term prognosis than do patients with stable anginaDespite 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.Slide26
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): 52-56Slide27
Statin in
dyslipidemia with ACSPROVE-IT
MIRACLSlide28
Statin effect on inflammation
A to Z
PROVE-ITSlide29
CENTAURUS and statins in ACS
CRE/021/Jun12-Jun13/MF
CENTAURUS
1
MIRACL
2
PROVE-IT
3
A to Z
4
N
1108308641624497Inclusion Anticipated PCINo Statins
No STEMINo PCINo StatinNo QW MIAfter PCI
25% Statin35% STEMIAfter PCI40% STEMIPCIAgeSex Male63%6074%
None 6565%69%5878%44%
6176%End PointApoB/ApoA1ClinicalClinical
Clinical TT /Follow uprosuvastatin 20 mg vs atorvastatin 80 mg, 3 monthsatorvastatin
80 mg vs placebo, 4 monthspravastatin
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; 292:1307-1316Slide30
Lablanche JM et al, Archives of Cardiovascular Diseases
, 2010, 103 (3) :160-169
Comparison of the
E
ffects
N
oted
in
The ApoB/
ApoA-I ratio Using Rosuvastatin and atorvastatin in patients with Acute Coronary
SyndromeSlide31
CENTAURUSStudy Design
Rosuvastatin 20 mg n=437
Atorvastatin 80 mg n=450
Placebo n=887
Day -4
PCI
3 months
Day 0
Day -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*Slide32
CENTAURUSPatient PopulationBaseline Characteristics
Approximately 75% were maleMean age approximately 60 years35% had dyslipidemiaTreatment of ACSPCI completed: 68% in the RSV group64% 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.Slide33
CENTAURUSPrimary End pointPercent 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
Lablanche JM, et al.
Arch Cardiovasc Dis.
2010;103:160-169.Slide34
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
Lablanche JM, et al.
Arch Cardiovasc Dis.
2010;103:160-169.Slide35
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
Lablanche JM, et al.
Arch Cardiovasc Dis.
2010;103:160-169.
All events were confirmed by the independent clinical adjudicating committeeSlide36
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%)
Lablanche JM, et al.
Arch Cardiovasc Dis.
2010;103:160-169.
Data are number of patients (%)
ALT=alanine aminotransferase; CK=creatine kinase; SCr=serum creatinine; ULN=upper limit of normalSlide37
CENTAURUS ConclusionIn 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 monthsThe ApoB/ApoA1 ratio decreased more rapidly with Rosuvastatin 20mg than Atorvastatin 80mgRosuvastatin 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, 1
03 (3) :160-169Slide38
LUNAR Study L
imiting UNder
-treatment of lipids in
A
CS
with
R
osuvastatin
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 (
L
imiting 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; 109:1239-1246Slide39
Lipids
Safety
Lipids
CRP
Safety
Lipids
CRP
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
4
6
5
12
2
0
3
2
Screening / baseline blood analysis
LUNAR
Study 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
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide40
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 6
12 weeks and at 2, 6, and 12 weeks
% change from baseline in the inflammatory marker high- sensitivity C-reactive protein (hsCRP) averaged over 6
12 weeks
LUNAR
Primary & Secondary Endpoints
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide41
LUNAR
Baseline Characteristics
Variable
Rosuvastatin
20 mg/day
(n=277)
Rosuvastatin
40 mg/day
(n=270)
Atorvastatin
80 mg/day
(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 angina75 (27.1%)
69 (25.6%)
67 (24.1%)
Medical
historyMI/ACS
Coronary artery diseasePCI
Coronary bypass
HypertensionDiabetes
HyperlipidemiaaSmoker30 (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
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide42
Variable
Rosuvastatin
20 mg/day
(n=246)
Rosuvastatin
40 mg/day
(n=251)
Atorvastatin
80 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)
161.2162.8
156.0
Total cholesterol (mg/dL)200.7
201.7
195.9
Triglycerides, mg/dL180.8
182.7
157.5 (n = 254)
LDL-C / HDL-C
3.683.77
3.59
Non–HDL-C / HDL-C
4.32
4.464.25TC / HDL-C5.32
5.46
5.25Apo 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
LUNAR
Baseline 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
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide43
*
Average change in
LDL-C from baseline (%)
Rosuvastatin
20 mg
Rosuvastatin
40 mg
Atorvastatin
80 mg
LUNAR
Primary 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; 109:1239-1246Slide44
LUNAR
Primary Endpoint
*p
0.05;
**
p
0.01 versus atorvastatin 80 mg
Time (weeks)
0 2 4 6 8 10 12
Rosuvastatin 20mg
Rosuvastatin 40mg
Atorvastatin 80 mg0
-10-20
-30
-40-50
-60
*
**
*
Mean Change in LDL-C from Baseline (%)
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide45
**
Mean change in
HDL-C from baseline (%)
Rosuvastatin
20 mg
Rosuvastatin
40 mg
Atorvastatin
80 mg
***
LUNAR
Secondary Endpoint
**p< 0.01, *** p<0.001 versus atorvastatin 80 mg
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide46
LUNAR
Secondary Endpoints
** p<0.01, ***p<0.001 versus atorvastatin 80 mg †p< 0.05, †† p<0.01 versus rosuvastatin 20mg
Mean Change in Parameter from Baseline (%)
Rosuvastatin 20mg
Rosuvastatin 40mg
Atorvastatin 80mg
***
***
***
**
**
***
†
††
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide47
LUNAR
Safety & Tolerability
Variable
Rosuvastatin
20 mg/day
(
n=267
)
Rosuvastatin
40 mg/day
(
n=263)
Atorvastatin
80 mg/day
(
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
001 (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
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide48
Variable
Rosuvastatin
20 mg/day
(
n=249)
Rosuvastatin
40 mg/day
(
n=249)
Atorvastatin
80 mg/day
(
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%)
LUNARSafety & Tolerability
ULN = upper limit of normal
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide49
Variable
Rosuvastatin
20 mg/day
Rosuvastatin
40 mg/day
Atorvastatin
80 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 m
2
(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)
LUNAR
Safety & Tolerability
SD = standard deviation
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide50
RSV20 was as effective as ATV80 in reducing LDL-C, and had a significantly greater effect than ATV80 in raising HDL-CRSV40 was significantly more effective than ATV80 in reducing LDL-C and increasing HDL-CRSV40 was also significantly more effective than ATV80 in improving several other important lipid parameters Apo A-I , LDL-C/HDL-C, non
HDL-C/ HDL-C, TC/HDL-C, and Apo B/Apo A-IThe safety profile of RSV20, RSV40 and ATV80 were similar
LUNAR
Summary
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide51
RSV20 might be considered as an alternative to ATV80 in patients with ACSRSV40 may be preferable to ATV80 in patients with ACS, in particular in patientsin whom a target LDL-C <70 mg/dL has not been achieved by prior statin therapyin whom it would be unlikely to achieve a target LDL-C <70 mg/dL with ATV80, based upon their baseline LDL-C
LUNAR
Conclusion
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246Slide52
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
toleratedSlide53
ConclusionStatin is beneficial for ACS with dyslipidemiaRosuva 20 mg is equal to atorva 80 mg and rosuva 40 mg is better than atorva 80 mg, in lowering LDL-CRosuvastatin is well tolerated in ACS with DyslipidemiaSlide54
Thank YouSlide55
Statin Pharmacophore
O
O
N
N
S
N
O
H
O
H
O
O
C
H
3
C
H
3
C
H
3
F
C
H
3
Ca
(3R, 5S)
More lipophilic *
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
CRESTOR
Cerivastatin
Simvastatin
Fluvastatin
Atorvastatin
Pravastatin
* log D at pH 7.4
Buckett et al., ISA (2000); McTaggart et al., (2001)
CRESTOR
:
New Hydrophyllic StatinSlide56
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 .