the importance of potential statin in high risk patient
DESCRIPTION
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. CVD is a leading cause of death worldwide. According to the WHO, 1 “An estimated 17.3 million people died from CVDs in 2008.” - PowerPoint PPT PresentationTRANSCRIPT
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
rtio
na
l re
du
cti
on
in
e
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
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
Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.
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
Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.
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
Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.
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
Lablanche JM, et al. Arch Cardiovasc Dis. 2010;103:160-169.
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%)
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 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
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
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
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
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
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
VariableRosuvastatin
20 mg/day(n=246)
Rosuvastatin40 mg/day(n=251)
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
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
-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 (%)
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
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
******
***
**
**
***
†
††
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
LUNARSafety & Tolerability
VariableRosuvastatin
20 mg/day(n=267)
Rosuvastatin40 mg/day(n=263)
Atorvastatin80 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 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
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
VariableRosuvastatin
20 mg/day(n=249)
Rosuvastatin40 mg/day(n=249)
Atorvastatin80 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; 109:1239-1246
VariableRosuvastatin
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)
LUNARSafety & Tolerability
SD = standard deviation
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
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
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
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
Pitt B, et al. Am J Cardiol 2012; 109:1239-1246
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 .