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JUPITER: the Greatest but Not the Only In the Galaxy of
Rosuvastatin Data
Michal VrablíkMichal Vrablík
Centre for Preventive CardiologyCentre for Preventive Cardiology33rdrd Department of Internal Medicine, 1st Faculty of Department of Internal Medicine, 1st Faculty of
Medicine, Charles University in PragueMedicine, Charles University in PragueCzech RepublicCzech Republic
CARDIONALE, November 26, 2010, Prague
Aggressive DLP Management Reduces Risk…the Lower the Better
Adapted from Ballantyne CM et al. Am J Cardiol 1998;82:3Q–12Q.
LDL-C achieved mg/dL (mmol/L)LDL-C achieved mg/dL (mmol/L)
WOSCOPS - PlWOSCOPS - Pl
AFCAPS/TexCAPS - PlAFCAPS/TexCAPS - Pl
ASCOT - PlASCOT - PlAFCAPS/TexCAPSAFCAPS/TexCAPS - Rx- Rx
WOSCOPS - RxWOSCOPS - Rx
ASCOT - RxASCOT - Rx
ALLHAT - RxALLHAT - Rx ALLHAT - PlALLHAT - Pl
4S - Rx4S - Rx
HPS - PlHPS - Pl
LIPID - RxLIPID - Rx
4S - Pl4S - Pl
CARE - RxCARE - Rx
LIPID - PlLIPID - Pl
PROSPER - PlPROSPER - PlCARE - PlCARE - Pl
HPS - RxHPS - Rx
PROSPER - RxPROSPER - Rx
00
55
1010
1515
2020
2525
3030
70 (1.8)70 (1.8) 90 (2.3)90 (2.3) 110 (2.8)110 (2.8) 130 (3.4)130 (3.4) 150 (3.9)150 (3.9) 170 (4.4)170 (4.4) 190 (5.0)190 (5.0) 210 (5.4)210 (5.4)
Event
rate
(%
)Event
rate
(%
)
- Secondary prevention- Secondary prevention
- Primary prevention- Primary prevention
Rx - Statin therapyRx - Statin therapy
Pl - PlaceboPl - Placebo
Can you recognize them ?
Statins lower LDL-c and CVD risk across all high risk population groups
7 Properties of a Statin for the 21st Century
1. Significant TC and LDL-c lowering efficacy
2. Positive impact on other lipoprotein classes
3. Slowing progression/regression of atherosclerosis
4. Reduction in CVD events/mortality
5. Good safety profile
6. Added value
7. Acceptable cost
Does
rosuvastatin
fulfill these
requirements ?
7 Properties of a Statin for the 21st Century
1. Significant TC and LDL-c lowering efficacy
2. Positive impact on other lipoprotein classes
3. Slowing progression/regression of atherosclerosis
4. Reduction in CVD events/mortality
5. Good safety profile
6. Added value
7. Acceptable cost
Stellar study: LDL-C: Percentage Change from Baseline at Week 6
Change from baseline (%)0 -10 20 -30 -40 -50 -60
10mg
-5 -15 -25 -35 -45 -55
20mg
40mg
10mg
20mg
40mg
80mg
10mg
20mg
40mg
80mg
10mg
20mg
40mg
*** ^^^ ^^^
*** *** ^^^***
*** *** ***
rosuvastatin
atorvastatin
simvastatin
pravastatin
Rosuva 10mg (-46%)
Rosuva 20mg (-52%)***p<0.001 vs rosuv 10mg
^^^p<0.002 vs rosuva 20mg
Jones PH, Am J Cardiol. 2003 Jul 15;92(2):152-60
Stellar Study: Percentage of Patients Achieving Joint European Recommendations LDL-C Goal at
Week 6
0
20
40
60
80
100
79
52
68
80
26
46
63
5 15
93
81
27
91
77
10 10 20 40 10 20 40 10 20 40
rosuvastatin atorvastatin simvastatin pravastatin
Pati
en
ts a
ch
ievin
g L
DL-C
goal (%
)
Dose (mg)808020 40
n=156 n=158 n=154 n=156 n=165 n=162 n=158 n=159 n=164n=159 n=157 n=160n=163n=165
* p<0.001 vs rosuva 10mg# p<0.001 vs rosuva 20mg‡ p<0.001 vs rosuva 40mg
LDL-C goal: <116mg/dL (3.0 mmol/L)
*
*# ‡
#
*#‡
*
* *#
# ‡
*#
Jones PH, Am J Cardiol. 2003 Jul 15;92(2):152-60
Titration need
One and First step
7 Properties of a Statin for the 21st Century
1. Significant TC and LDL-c lowering efficacy
2. Positive impact on other lipoprotein classes
3. Slowing progression/regression of atherosclerosis
4. Reduction in CVD events/mortality
5. Good safety profile
6. Added value
7. Acceptable cost
Stellar Study: HDL-C: Percentage Change from Baseline at Week 6
0
2
4
6
8
10
12
10 20 40 80
Dose (mg)
LS
mean
% c
han
ge f
rom
baselin
e
rosuvastatin atorvastatin simvastatin pravastatin
Log scale
Jones PH, Am J Cardiol. 2003 Jul 15;92(2):152-60
Stellar Study: TG: Percentage Change from Baseline at Week 6
-35
-30
-25
-20
-15
-10
-5
0
10 20 40 80
Dose (mg)
LS
mean
% c
han
ge f
rom
baselin
e
rosuvastatin atorvastatin simvastatin pravastatin
Log scale (mg)
Jones PH, Am J Cardiol. 2003 Jul 15;92(2):152-60
7 Properties of a Statin for the 21st Century
1. Significant TC and LDL-c lowering efficacy
2. Positive impact on other lipoprotein classes
3. Slowing progression/regression of atherosclerosis
4. Reduction in CVD events/mortality
5. Good safety profile
6. Added value
7. Acceptable cost
Rosuvastatin: Imaging Studies
Rosuvasatin: Asteroid StudyLet Us Take a Look Inside
Rosuvastatin: Asteroid - Design
Rosuvastatin: Asteroid Lipid changes
TC TG LDL HDL apoB
mmol/L g/l3, 4 ± 0,66 1, 37 ± 0,64 1, 57 ± 0,52 1, 27 ± 0,33 0, 75 ± 0,22
EOS Lipid Levels
And What About Atherosclerosis?
7 Properties of a Statin for the 21st Century
1. Significant TC and LDL-c lowering efficacy
2. Positive impact on other lipoprotein classes
3. Slowing progression/regression of atherosclerosis
4. Reduction in CVD events/mortality
5. Good safety profile
6. Added value
7. Acceptable cost
JUPITER TRIAL
JUPITER – study design
LipidsCRP
Tolerability
LipidsCRP
TolerabilityHbA1C
Placebo
run-in
1–6
2–4
30
413 Final 6-monthly
Visit:Week:
Randomisation
LipidsCRP
Tolerability
Rosuvastatin 20 mg (n=8901)
Placebo (n=8901)
Lead-in/eligibility
No history of CAD
men ≥50 yrs
women ≥60 yrs
LDL-C <130 mg/dL
CRP ≥2.0 mg/L
CAD=coronary artery disease; LDL-C=low-density lipoprotein cholesterol; CRP=C-reactive protein; HbA 1c=glycated haemoglobin
Median follow-up 1.9 years
Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER - Study Endpoints Primary Endpoint
– Time to the first occurrence of a major cardiovascular event, composite of:
• cardiovascular death
• Stroke
• MI
• unstable angina
• arterial revascularisation
Secondary Endpoints:
– total mortality
– non-cardiovascular mortality
– development of diabetes mellitus
– development of venous thromboembolic events
– bone fractures
– discontinuation of study medication due to adverse effects.Ridker PM. Circulation 2003; 108: 2292–2297
JUPITER - Major inclusion criteria
Men aged ≥50 years; women aged ≥60 years
Fasting LDL-C levels 130 mg/dL (3.4 mmol/L) , CRP levels ≥2.0 mg/L and TG levels 500 mg/dL (5.7 mmol/L) on initial screening
Ridker PM. Circulation 2003; 108: 2292–2297
Age (years) 66 (60-71) 66 (60-71)
Male sex (%) 61.5 62.1BMI (kg/m2) 28.3 (25.3-32.0) 28.4 (25.3-32.0)
BP (mmHg) 134/80 134/80TC (mg/dL/mmol/L) 186 (4,8) 185 (4,8) LDL –c (mg/dL/mmol/L) 108 (2,8) 108 (2,8)
HDL – c (mg/dL/mmol/L) 49 (1,3) 49 (1,3)
Triglycerides (mg/dL/mmol/L) 118 (1,3) 118 (1,3)
hsCRP (mg/L) 4.2 (2.8-7.1) 4.3 (2.8-7.2)
Glucose (mg/dL/mmol/L) 94 (5,2) 94 (5,2)
HbA1c(%) 5.7 (5.4-5.9) 5.7 (5.5-5.9)
Rosuvastatin Placebon=8901 n=8901
JUPITER - Baseline characteristics*
*All values are median (interquartile range) or N (%).Ridker P et al. N Eng J Med 2008;359: 2195-2207
Placebo
Rosuvastatin 20 mg
JUPITER - Primary Endpoint Time to first occurrence of a CV death, non-fatal stroke, non-fatal
MI, unstable angina or arterial revascularization
Hazard Ratio 0.56 (95% CI 0.46-0.69)P<0.00001
Ridker P et al. N Eng J Med 2008;359: 2195-2207
NNT for 2y = 95 5y* = 25
*Extrapolated figure based on Altman and Andersen method
0 1 2 3 4
0.0
00
.02
0.0
40
.06
0.0
8
Cu
mu
lati
ve
In
cid
en
ce
Follow-up (years)Number at Risk
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
Placebo
Rosuvastatin 20mg
JUPITER - Total Mortality Death from any cause
Hazard Ratio 0.80 (95% CI 0.67-0.97)p=0.02
Ridker P et al. N Eng J Med 2008;359: 2195-2207
0 1 2 3 4
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Cu
mu
lati
ve
In
cid
en
ce
Number at Risk Follow-up (years)RosuvastatinPlacebo
8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 2278,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246
JUPITER - Dual Treatment Target
Placebo 7832 (1.11) 1.00
Rosuvastatin[Dual target: LDL-C < 70mg/dL, hsCRP < 2mg/L]Dual target achieved 2685 (0.38) 0.35 0.23-0.54Dual target not achieved 5031 (0.74) 0.64 0.49-0.84P-value (active treatment) 0.033P-value (trend across groups) <0.0001
LDLC ≥ 70mg/dL 2110 (0.91) 0.85 0.60-1.21LDLC < 70mg/dL 5606 (0.51) 0.45 0.33-0.59P-value (trend across hsCRP strata) <0.0001
hsCRP ≥ 2mg/L 4305 (0.77) 0.68 0.51-0.89hsCRP < 2mg/L 3411 (0.42) 0.36 0.24-0.54P-value (trend across LDL-C strata) <0.0001
Group N (Event rate*) HR** 95% CI P-value
Ridker PM et al. The Lancet 2009. DOI: 10.1016/S0140-6736(09)60447-5
* Rates are per 100 person years; **Fully adjusted model controlled for age (years), baseline LDL-C (mg/dL), baseline hsCRP (mg/L), baseline HDL-C (mg/dL, blood pressure, gender, body mass index (kg/m2), smoking status and parental history of premature coronary heart disease.
Conversion: LDL-C < 70 mg/dL = 1.8 mmol/L
HR – Hazard Ratio; CI – Confidence Interval
Hazard Ratios for Incident CV Events According to Achieved Concentrations of LDL-C and hsCRP
7 Properties of a Statin for the 21st Century
1. Significant TC and LDL-c lowering efficacy
2. Positive impact on other lipoprotein classes
3. Slowing progression/regression of atherosclerosis
4. Reduction in CVD events/mortality
5. Good safety profile
6. Added value
7. Acceptable cost
JUPITERTolerability and safety data
Adverse Events, (%) Any serious adverse event 15.5 15.2 0.60Muscle weakness, stiffness, pain 15.4 16.0 0.34Myopathy 0.1 0.1 0.82Rhabdomyolysis 0.0 <0.1* ----Newly diagnosed cancer 3.5 3.4
0.51Death from cancer 0.7 0.4
0.02Gastrointestinal disorders 19.2 19.7
0.43Renal disorders 5.4 6.0
0.08Bleeding 3.1 2.9
0.45Hepatic disorders 2.1 2.4
0.13
Other events, (%)Newly diagnosed diabetes** 2.4 3.0
0.01Haemorrhagic stroke 0.1 0.1
0.44
Placebo Rosuvastatin p-value [n=8901] [n=8901]
*Occurred after trial completion; **physician reported newly diagnosed diabetes Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITERLaboratory Safety Data
Laboratory Values, N (%) Serum creatinine‡ 10 (0.10) 16 (0.20) 0.24ALT > 3 x ULN# 17 (0.20) 23 (0.30) 0.34Glycosuria† 32 (0.40) 36 (0.50) 0.64
Laboratory Values, median values (IQR) GFR*, (mL/min/1.73m2) 66.6 (58.8-76.2) 66.8 (59.1-76.5)0.02% HbA1c** 5.8 (5.6-6.1) 5.9 (5.7-6.1)0.001Fasting plasma glucose**, (mg/dL) 98 (90-106) 98 (91-107) 0.12
Placebo Rosuvastatin p-value[n=8901] [n=8901]
GFR = Glomerular filtration rate, HbA1c = Haemoglobin A1c
# on consecutive visits, ‡ >100% increase from baseline, *at 12 months, **at 24 months, †>trace at 12 months
Ridker P et al. N Eng J Med 2008;359: 2195-2207
7 Properties of a Statin for the 21st Century
1. Significant TC and LDL-c lowering efficacy
2. Positive impact on other lipoprotein classes
3. Slowing progression/regression of atherosclerosis
4. Reduction in CVD events/mortality
5. Good safety profile
6. Added value
7. Acceptable cost
JUPITER – Venous Thromboembolic Events
Glynn RJ et al. NEJM 2009; 360: (10.1056/NEJMoa0900241)
Primary efficacy analysis, 94 cases
All cases of VTE 60 (0.32) 34 (0.18) 0.57 0.37-0.86 0.007
Unprovoked VTE 31 (0.17) 19 (0.10) 0.61 0.35-1.09 0.09
Provoked VTE 29 (0.16) 15 (0.08) 0.52 0.28-0.96 0.03
Pulmonary embolism 22 (0.12) 17 (0.09) 0.77 0.41-1.45 0.42
Deep vein thrombosis 38 (0.20) 17 (0.09) 0.45 0.25-0.79 0.004
Endpoint Placebo Rosuvastatin HR 95% CI p-value
[n=8901] [n=8901]
n (rate*) n (rate*)
* Rates are per 100 person years
HR – Hazard Ratio; CI – Confidence Interval
VTE – venous thromboembolism
Unprovoked VTE = occurred in absence of malignancy, trauma, hospitalization or surgery within 3 months before event. Provoked VTE = includes events that occurred in patients with cancer or during or shortly after trauma or surgery
Occurrence of Venous Thromboembolism by Study Group
7 Properties of a Statin for the 21st Century
1. Significant TC and LDL-c lowering efficacy
2. Positive impact on other lipoprotein classes
3. Slowing progression/regression of atherosclerosis
4. Reduction in CVD events/mortality
5. Good safety profile
6. Added value
7. Acceptable cost
Development of Statin Prices
Comparison of Prices after First Introduction to Market and Current Situation
Rosuvastatin: a Galaxy of Evidence
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