JUPITER Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin Ridker P et al. N Eng J Med 2008;359:

JUPITERJUPITER

Justification for the Use of statins in Primary prevention: an

Intervention Trial Evaluating Rosuvastatin

Ridker P et al. N Eng J Med 2008;359: 2195-2207

JUPITER JUPITER

JUPITER is the first large-scale, prospective study to examine the role of statin therapy in individuals with low to normal LDL-C levels, but with increased cardiovascular risk identified by elevated CRP

It assessed the long-term impact of rosuvastatin (CRESTOR™) in individuals potentially at increased cardiovascular (CV) risk due to elevated CRP levels who do not qualify for lipid-lowering treatment according to current guidelines


JUPITER - RationaleJUPITER - Rationale

Nearly half of all cardiovascular events occur in patients who are apparently healthy and who have low or normal levels of LDL-C

hsCRP predicts cardiovascular disease independent of LDL-C levels

Along with improved screening there is a need to examine the use of lipid-lowering agents as a method of reducing the risk of cardiovascular events

Ridker PM. New Engl J Med 2002; 347: 1557–1565

Prevalence of conventional risk factorsPrevalence of conventional risk factors†† in in patients with CHDpatients with CHD

None

One

Two

Three

Four (0.9%)

Total patients=87 869CHD=coronary heart disease†smoking, hypertension, hypercholesterolaemia and diabetes mellitus

19.4%

43.0%

27.8%

8.9%

Khot UN et al. JAMA 2003; 290: 898–904

CRP is a strong independent predictor of CRP is a strong independent predictor of CV events in womenCV events in women

Apo=apolipoprotein; CRP=C-reactive protein; CV=cardiovascular; HDL-C=high-density lipoprotein cholesterol; IL=interleukin; LDL-C=low-density lipoprotein cholesterol; Lp(a)=lipoprotein (a); SAA=serum amyloid A; sICAM-1=soluble intercellular adhesion molecule 1; TC=total cholesterol

0

Lp(a)HomocysteineIL-6TCLDL-CsICAM-1SAAApoBTC/HDL-CCRPCRP + TC/HDL-C

Relative risk of future CV events

1.0 2.0 4.0 6.0

Blake GJ, Ridker PM. Circ Res 2001; 89: 763–771

CRP predicts risk of MI and stroke in apparently CRP predicts risk of MI and stroke in apparently healthy menhealthy men

CRP=C-reactive protein; MI=myocardial infarction*p=0.02 versus quartile 1; ***p<0.001 versus quartile 1

Quartile of CRP

Relativerisk of ischaemicstroke

0

0.5

1.0

1.5

2.0

1 2 3 4

*

Quartile of CRP

Relative risk of MI

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

1 2 3 4

***

Ridker PM et al. N Engl J Med 1997; 336: 973–979

CV event-free survival in women using combined LDL-C CV event-free survival in women using combined LDL-C and hsCRP measuresand hsCRP measures

CV=cardiovascular; hsCRP=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol Median LDL-C=3.2 mmol/L (124 mg/dL)Median CRP=1.5 mg/L

1.00

0.99

0.98

0.97

0.96

0

Low LDL-C, low hsCRP

High LDL-C, high hsCRP

High LDL-C, low hsCRP

Low LDL-C, high hsCRP

Probability of event-free survival


Efficacy of lovastatin in AFCAPS/TexCAPS subgroups by Efficacy of lovastatin in AFCAPS/TexCAPS subgroups by baseline LDL-C and hsCRPbaseline LDL-C and hsCRP

Study group Rate of cardiovascular events

NNT

Lovastatin Placebo

Low LDL-C/low hsCRP 0.025 0.022 N/A

Low LDL-C/high hsCRP 0.029 0.051 48

High LDL-C/low hsCRP 0.020 0.050 33

High LDL-C/high hsCRP 0.038 0.055 58

Median LDL-C=3.9 mmol/L (149 mg/dL). Median hsCRP=1.6 mg/LAFCAPS/TexCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; hsCRP=high-sensitivity C-reactive protein; LDL-C=low-density lipoprotein cholesterol; N/A=not applicable; NNT=number needed to treat to prevent one coronary event


JUPITER - ObjectiveJUPITER - Objective

• The primary objective was to investigate whether long-term treatment with rosuvastatin 20 mg decreases the rate of first major cardiovascular events compared with placebo in patients with low to normal LDL-C but at increased cardiovascular risk as identified by elevated CRP levels

Ridker PM. Circulation 2003; 108: 2292–2297

JUPITER – study designJUPITER – 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


JUPITER - Study EndpointsJUPITER - 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 criteriaJUPITER - 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

JUPITER - Major exclusion criteria JUPITER - Major exclusion criteria Current use of statins or other lipid-lowering therapies

Current use of hormone replacement therapy

Prior history of cardiovascular or cerebrovascular events, such as MI, unstable angina, prior arterial revascularisation or stroke, or CHD-risk equivalents

Chronic inflammatory condition, such as severe arthritis, lupus or inflammatory bowel disease and/or treatment with immunosuppressants

Uncontrolled:

– hypertension: SBP > 190 mmHg or DBP > 100 mmHg

– hypothyroidism: TSH > 1.5 x ULN

CK 3 x ULN

Serum creatinine > 2.0 mg/dL

Evidence of hepatic dysfunction (ALT > 2 x ULN)

History of prior malignancy, alcohol or drug abuse

Ridker PM. Circulation 2003; 108: 2292–2297 CHD = coronary heart disease; CK = creatinine kinase; ULN = upper limit of normal; SBP = systolic blood pressure; DBP = diastolic blood pressure


JUPITER - Patient Flow

89,890 subjects screened 17,802 randomized

Rosuvastatin 20mgn=8,901

Placebon=8,901

Lost to follow upn=44

Completed studyn=8,857

Lost to follow upn=37

Completed studyn=8,864


Age (years) 66 (60-71) 66 (60-71)

Male sex (%) 61.5 62.1Race (%)

White 71.4 71.1Black 12.4 12.6Hispanic 12.6 12.8Other 3.6 3.5

BMI (kg/m2) 28.3 (25.3-32.0) 28.4 (25.3-32.0)

Systolic BP (mmHg) 134 (124-145) 134 (124-145)Diastolic BP (mmHg) 80 (75-87) 80 (75-87)

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

Total cholesterol (mg/dL) 186 (168-200) 185 (169-199) LDL cholesterol (mg/dL) 108 (94-119) 108 (94-119)

HDL cholesterol (mg/dL) 49 (40-60) 49 (40-60)

Triglycerides (mg/dL) 118 (85-169) 118 (86-169)

hsCRP (mg/L) 4.2 (2.8-7.1) 4.3 (2.8-7.2)

Glucose (mg/dL) 94 (87-102) 94 (88-102)

HbA1c(%) 5.7 (5.4-5.9) 5.7 (5.5-5.9)

Glomerular filtration rate,(ml/min/1.73m2) 73.3 (64.6-83.7) 73.6 (64.6-84.1)

Rosuvastatin Placebon=8901 n=8901

JUPITER - Baseline laboratory parameters*

For hsCRP, values are the average of the values obtained at two screening and visits

*All values are median (interquartile range) or N (%).Ridker P et al. N Eng J Med 2008;359: 2195-2207

Current smoker (%) 15.7 16.0 Family history CHD† (%) 11.2 11.8Metabolic syndrome‡ (%) 41.0 41.8Aspirin use (%) 16.6 16.6

Medical History Rosuvastatin Placebo n=8901 n=8901

JUPITER - Medical History

†Family history of premature CHD defined as first degree relative with CHD at age < 55 yrs (male), < 65 yrs

(female); ‡ Metabolic syndrome defined according to consensus criteria of AHA/NHLBIRidker P et al. N Eng J Med 2008;359: 2195-2207

JUPITER population compared with previous trials JUPITER population compared with previous trials in patients without established CHDin patients without established CHD

AFCAPS WOSCOPS JUPITER

Patients, n 6605 6595 17 802

% male, n 85 100 62

Duration, years 5.2 4.9 1.9

Diabetes, % 6 1 0

Baseline lipids, mg/dL*

total cholesterol

221 272 183

LDL-C 150 192 104

HDL-C 36–40 44 51

triglycerides 158 164 138

hsCRP, mg/L 0.2 NA 4.3

Statin Lovastatin 20–40 mg

Pravastatin 40 mg

Rosuvastatin 20 mgCVD=cardiovascular disease; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density

lipoprotein cholesterol; hsCRP=high sensitivity C-reactive protein; *Baseline lipid levels are mean values.

Ridker PM et al. Am J Cardiol 2007; 100: 1659–1664

Ridker PM et al. N Engl J Med. 2001 344: 1959-65

0

1

2

3

4

5

6

7

8

9

0 1 2 3 4 5Years

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 P

erc

en

t of

pati

en

ts w

ith

pri

mary

en

dp

oin

t

Number at risk RSV 8901 8412 3893 1353 538 157 Placebo 8901 8353 3872 1333 531 174

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

JUPITER - Primary Endpoint Components

Primary Endpoint 251 (1.36) 142 (0.77) 0.56 0.46-0.69 <0.001*

(Time to first occurrence of CV death, MI, stroke, unstable angina, arterial revascularisation)

Non-fatal MI 62 (0.33) 22 (0.12) 0.35 0.22-0.58 <0.001*

Fatal or non-fatal MI 68 (0.37) 31 (0.17) 0.46 0.30-0.70 0.0002

Non-fatal stroke 58 (0.31) 30 (0.16) 0.52 0.33-0.80 0.003Fatal or non-fatal stroke 64 (0.34) 33 (0.18) 0.52 0.34-0.79 0.002

Arterial Revascularization 131 (0.71) 71 (0.38) 0.54 0.41-0.72 <0.0001

Unstable angina† 27 (0.14) 16 (0.09) 0.59 0.32-1.10 0.09

CV death, stroke, MI 157 (0.85) 83 (0.45) 0.53 0.40-0.69 <0.001*

Revascularization or unstable angina 143 (0.77) 76 (0.41) 0.53 0.40-0.70 <0.001*

Placebo Rosuvastatin HR95% CI p-value

[n=8901] [n=8901]

n (rate**) n (rate**)

HR – Hazard Ratio; CI – Confidence Limit

** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual p-value was < 0.00001


JUPITER – Subgroup analysis

Rosuvastatin better Placebo better

N P- value*

Age 0.32≤ 65 years 8,541>65 yrs 9,261Gender 0.80Males 11,001Females 6,801Race 0.57White 12,683Non-white 5,117Hypertension 0.53Yes 10,208No 7,586Region 0.51US or Canada 6,041Other 11,761Metabolic syndrome 0.14Yes 7,375No 10,296

Family history of CHD 0.07Yes 2,045No 15,684

Framingham risk score 0.99≤10% 8,882>10% 8,895

0 0.2

0.4

0.6

0.8 1

1.2


Hazard ratio (95% CI)

0

1

2

3

4

5

6

7

0 1 2 3 4 5Years

Placebo

Rosuvastatin 20mg

JUPITER - Total Mortality Death from any cause

Perc

en

t to

tal m

ort

ality

Number at risk RSV 8901 8787 4312 1602 676 227 Placebo 8901 8775 4319 1614 681 246

Hazard Ratio 0.80 (95% CI 0.67-0.97)p=0.02


JUPITER JUPITER

Effects on LDL-C, HDL-C, TG and hsCRP at 12 months;

Percentage change between rosuvastatin and placebo

-60

-50

-40

-30

-20

-10

0

10 LDL-C HDL-C TG hsCRP

Perc

en

tag

e c

han

ge

from

baselin

e (

%)

50%

4%

17%

37%

p<0.001

p<0.001*

p<0.001

p<0.001

*P-value at study completion (48 months) = 0.34Ridker P et al. N Eng J Med 2008;359: 2195-2207

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


JUPITER – summary and perspectives The JUPITER study included patients with low to normal LDL-C who

were at increased CV risk as identified by elevated CRP levels and who did not require statin treatment based on current treatment guidelines

A 44% reduction in the primary endpoint of major cardiovascular events (composite of: CV death, MI, stroke, unstable angina, arterial revascularisation) was observed in patients who received rosuvastatin 20 mg compared with placebo (p< 0.00001)

A 20% reduction in total mortality was observed in patients who received rosuvastatin 20 mg compared with placebo (p=0.02), a unique finding for statins in a population without established CHD

In JUPITER, long-term treatment with rosuvastatin 20 mg was well tolerated in nearly 9000 study participants

There was no difference between treatment groups for muscle weakness, cancer, haematological disorders, gastrointestinal, hepatic or renal systems

The results from JUPITER highlight the importance of highly effective statin treatment for these patients with an increased risk of CV disease


AcknowledgementsAcknowledgements

The JUPITER Steering Committee

– P Ridker (Chairman), Boston, MA, USA

– A Gotto, New York, NY, USA

– P Libby, Boston, MA, USA

– J Willerson, Houston, TX, USA

– J Genest, Montreal, Canada

The JUPITER Independent Data Monitoring Board

The JUPITER investigators and participating patients

This study is supported by AstraZeneca

JUPITER Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin Ridker P et al. N Eng J Med 2008;359:

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