Michal Vrablík Centre for Preventive Cardiology 3 rd Department of Internal Medicine, 1st Faculty of Medicine, Charles University in Prague Czech Republic

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 ?







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)

*

*# ‡

#

*#‡

*

* *#

# ‡

*#


Titration need

One and First step







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


Log scale


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


Log scale (mg)








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?







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


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


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







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








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







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

Documents

Michal Vrablík Centre for Preventive Cardiology 3 rd Department of Internal Medicine, 1st Faculty of Medicine, Charles University in Prague Czech Republic