JUPITER Primary Trial End Point: MI, Stroke, UA/Revascularization, CV Death

JUPITER Primary Trial End Point: MI, Stroke, UA/Revascularization, CV Death

Placebo 251/8901

Rosuvastatin 142 / 8901

HR 0.56, 95% CI 0.46-0.69P<0.00001

- 44 %

0 1 2 3 4

0.0

00

.02

0.0

40

.06

0.0

8

Cu

mu

lati

ve In

cid

ence

Number at Risk Follow-up (years)

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

Adapted from Ridker et al. NEJM 2008.

A Randomized Trial of Rosuvastatin in the Preventionof Cardiovascular Events Among 17,802 Apparently Healthy

Men and Women With Elevated Levels of C-Reactive Protein (hsCRP):

The JUPITER Trial

Paul Ridker, Eleanor Danielson, Francisco Fonseca, Jacques Genest,Antonio Gotto, John Kastelein, Wolfgang Koenig, Peter Libby,

Alberto Lorenzatti, Jean MacFadyen, Borge Nordestgaard, James Shepherd, James Willerson, and Robert Glynn

on behalf of the JUPITER Trial Study Group

JUPITER Trial Presented during AHA 2008 Scientific Sessions

Independent Steering Committee :P Ridker (Chair), F Fonseca, J Genest, A Gotto, J Kastelein, W Koenig, P Libby, A Lorenzatti, B Nordestgaard, J Shepherd, J Willerson

Independent Academic Clinical Coordinating Center: P Ridker, E Danielson, R Glynn, J MacFadyen, S Mora (Boston)

Independent Academic Study Statistician: R Glynn (Boston)

Independent Data Monitoring Board: R Collins (Chair), K Bailey, B Gersh, G Lamas, S Smith, D Vaughan

Independent Academic Clinical Endpoint Committee: K Mahaffey (Chair), P Brown,D Montgomery, M Wilson, F Wood (Durham)

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 in individuals potentially at increased cardiovascular risk due to elevated CRP levels who do not qualify for lipid-lowering treatment according to current guidelines

Adapted from Ridker et al. N Eng J Med 2008;359: 2195-207.

JUPITER - 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

Adapted from: Ridker PM. Circulation 2003; 108: 2292-97.Ridker PM. Am J Cardiol 2007; 100: 1659-64.Ridker PM. New Engl J Med 2002; 347: 1557-65.Ridker PM. Am J Cardiol 2003;92(suppl):17K-22K.

JUPITER: Background and Prior Work

Current guidelines for the prevention of myocardial infarctionstroke, and cardiovascular death endorse statin therapy among patients with established vascular disease, diabetes, and among those with hyperlidemia.

However, these screening and treatment strategies are insufficient as half of all heart attack and stroke events occur among apparently healthy men and women with average or even low levels of cholesterol.

Adapted from Ridker et al .NEJM 2008.

JUPITER: Background and Prior Work

To improve detection of individuals at increased risk forcardiovascular disease, physicians often measure high sensitivity C-reactive protein (hsCRP), an inflammatory biomarker that reproducibly and independently predicts future vascular events and improves global risk classification, even when cholesterol levels are low.

Prior work has shown that statin therapy reduces hsCRP, and that among stable coronary disease patients as well as those with acute ischemia, the benefit associated with statin therapy relates not only to achieving low levels of LDL, but also to achieving low levels of hsCRP.


Efficacy of lovastatin in AFCAPS/TexCAPS subgroups by baseline 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

Adapted from Ridker et al. N Engl J Med 2001;344:1959-65.

JUPITER population compared with previous trials in patients without established CHD

AFCAPS WOSCOPS JUPITER

Patients, n 6605 6595 17 802

% male 85 100 62

Duration, years 5.2 4.9 1.9

Diabetes, % 6 1 0

Baseline lipids, mmol/L*

total cholesterol 5.72 7.03 4.73

LDL-C 3.88 4.97 2.69

HDL-C 0.93–1.03 1.14 1.32

triglycerides 1.78 1.85 1.56

hsCRP, mg/L 0.2 NA 4.3

StatinLovastatin

20–40 mg

Pravastatin

40 mg

Rosuvastatin

20 mg

CVD=cardiovascular disease; CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; hsCRP=high sensitivity C-reactive protein; AFCAPS=Airforce/Texas Coronary Atherosclerosis Prevention Study; WOSCOPS=West of Scotland Coronary Prevention Study; *Baseline lipid levels are mean values.

Adapted from: Ridker et al. Am J Cardiol 2007;100:1659-64. Ridker et al. N Engl J Med. 2001;344:1959-65.

JUPITER WOSCOPS AFCAPS

Sample size (n) 17,802 6,595 6,605

Women (n) 6,801 0 997

Minority (n) 5,118 0 350

Duration (yrs) 1.9 (max 5) 4.9 5.2

Diabetes (%) 0 1 6

Baseline LDL-C (mg/dL) 108 192 150

Baseline HDL-C (mg/dL) 49 44 36-40

Baseline TG (mg/dL) 118 164 158

Baseline hsCRP (mg/L) > 2 NA NA

Intervention Rosuvastatin Pravastatin Lovastatin20 mg 40 mg 10-40 mg

Adapted from JUPITER Trial Study Group, Am J Cardiol 2007.

Comparison of the JUPITER Trial Population to Previous Statin Trials of Primary Prevention

JUPITER: Why Consider Statins for Low LDL, high hsCRP Patients?

In 2001, in an hypothesis generating analysis of apparently healthy individuals in the AFCAPS / TexCAPS trial*, we observed that those with low levels of both LDL and hsCRP had extremely low vascular event rates and that statin therapy did not reduce events in this subgroup (N=1,448, HR 1.1, 95% CI 0.56-2.08). Thus, a trial of statin therapy in patients with low cholesterol and low hsCRP would not only be infeasible in terms of power and sample size, but would be highly unlikely to show clinical benefit.

In contrast, we also observed within AFCAPS/TexCAPS that among those with low LDL but high hsCRP, vascular event rates were just as high as rates among those with overt hyperlipidemia, and that statin therapy significantly reduced events in this subgroup (N=1,428, HR 0.6, 95% CI 0.34-0.98).

Adapted from *Ridker et al. N Engl J Med 2001;344:1959-65.

JUPITER: Why Consider Statins for Low LDL, High hsCRP Patients?

However, while intriguing and of potential public health importance, the observation in AFCAPS/TexCAPS that statin therapy might be effective among those with elevated hsCRP but low cholesterol was made on a post hoc basis. Thus, a large-scale randomized trial of statin therapy was needed to directly test this hypotheses.

Adapted from Ridker et al. New Engl J Med 2001;344:1959-65.

Low LDL, Low hsCRP

Low LDL, High hsCRP

Statin Effective Statin Not Effective

1.0 2.00.5

[A]

[B]

Low LDL, Low hsCRP

Low LDL, High hsCRP

Statin Effective Statin Not Effective

1.0 2.00.5

AFCAPS/TexCAPS Low LDL Subgroups

RR

JUPITER - 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.

Adapted from Ridker et al. Circulation 2003;108:2292-97.

Rosuvastatin 20 mg (N=8901) MIMIStrokeStroke

UnstableUnstable AnginaAngina

CVD DeathCVD DeathCABG/PTCACABG/PTCA

JUPITERMulti-National Randomized Double Blind Placebo Controlled Trial of

Rosuvastatin in the Prevention of Cardiovascular EventsAmong Individuals With Low LDL and Elevated hsCRP

4-week 4-week run-inrun-in


No Prior CVD or DMMen >50, Women >60 LDL <130 mg/dL hsCRP >2 mg/L

JUPITER: Trial Design

Placebo (N=8901)

Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,

United Kingdom, Uruguay, United States, Venezuela

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; HbA1c=glycated haemoglobin

Median follow-up 1.9 years

Adapted from Ridker et al. N Eng J Med 2008;359:2195-207.

JUPITER: 17,802 Patients, 1,315 Sites, 26 Countries

4021

2873

2497

2020

987804

741487

34533632727327025322220920420219716214385833215140%

5%

10%

15%

20%

25%

Urugu

ay

Switzer

land

Roman

ia

Chile

Eston

ia

Israe

l

El Salv

ador

Bulgar

ia

Panam

a

Norway

Venez

uela

Germ

any

Argen

tina

Costa

Rica

Russia

Brazil

Denm

ark

Colom

bia

Belgium

Mex

ico

Poland

The N

ethe

rland

s

Canad

a

South

Afri

ca

United

King

dom

United

Sta

tes

Ra

nd

om

iza

tio

ns

(%

To

tal.

) Total Randomized = 17,802


JUPITER - Patient Flow

89,890 subjects screened 17,802 randomised

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


JUPITER: Inclusion and Exclusion Criteria, Study Flow

89,863 Screened

17,802 Randomized

8,901 Assigned to Rosuvastatin 20 mg

8,901 Assigned toPlacebo

Reason for Exclusion (%)

LDL-C > 130 mg/dL 53hsCRP < 2.0 mg/L 37Withdrew Consent 4Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1Poor Compliance/Other 3

8,600 Completed Study120 Lost to follow-up


8,901 Included in Efficacy and Safety Analyses


89,890 Screened

Men > 50 yearsWomen > 60 yearsNo CVD, No DMLDL < 130 mg/dLhsCRP > 2 mg/L

17,802 Randomized

Reason for Exclusion (%)

LDL > 130 mg/dL 52hsCRP < 2.0 mg/L 36Withdrew Consent 5Diabetes 1Hypothyroid <1Liver Disease <1TG > 500 mg/dL <1Age out of range <1Current Use of HRT <1Cancer <1Poor Compliance/Other 3

4 weekPlaceboRun-In


8,901 Assigned to Rosuvastatin 20 mg

8,901 Assigned toPlacebo





JUPITER - Major Exclusion Criteria

Current use of statins or other lipid-lowering therapies

Current use of post menopausal hormone replacement therapy

Prior history of cardiovascular or cerebrovaascular 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

CHD = coronary heart disease; CK = creatinine kinase; ULN = upper limit of normal; SBP = systolic blood pressure; DBP = diastolic blood pressure

Adapted from: Ridker et al. N Eng J Med 2008;359:2195-207. Ridker PM. Circulation 2003;108:2292-97.

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 (%).


JUPITER:Baseline Blood Levels (median, interquartile range)

Rosuvastatin Placebo(N = 8901) (n = 8901)

hsCRP, mg/L 4.2 (2.8 - 7.1) 4.3 (2.8 - 7.2) LDL, mg/dL 108 (94 - 119) 108 (94 - 119)

HDL, mg/dL 49 (40 – 60) 49 (40 – 60)

Triglycerides, mg/L 118 (85 - 169) 118 (86 - 169)

Total Cholesterol, mg/dL 186 (168 - 200) 185 (169 - 199)

Glucose, mg/dL 94 (87 – 102) 94 (88 – 102)

HbA1c, % 5.7 (5.4 – 5.9) 5.7 (5.5 – 5.9)

All values are median (interquartile range). [ Mean LDL = 104 mg/dL ]


Total cholesterol (mmol/L) 4.81 (4.34-5.17) 4.78 (4.37-5.15)

LDL cholesterol (mmol/L) 2.79 (2.43-3.08) 2.79 (2.43-3.08)

HDL cholesterol (mmol/L) 1.27 (1.03-1.55) 1.27 (1.03-1.55)

Triglycerides (mmol/L) a1.33 (0.96-1.91) 1.33 (0.97-1.91)

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

Glucose (mmol/L) 5.2 (4.8-5.7) 5.2 (4.9-5.7)

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=a8901 n=8901

JUPITER - Baseline laboratory parameters*

For hsCRP, values are the average of the values obtained at two screening visits*All values are median (interquartile range) or N (%).


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 coronary heart disease (CHD) defined as first degree relative with CHD at age < 55 yrs (male), < 65 yrs (female); ‡ Metabolic syndrome defined according to consensus criteria of American Heart Association and the National Heart, Lung, and Blood Institute


JUPITER - Study End Points

Primary End Point– Time to the first occurrence of a major cardiovascular event, composite of:

• cardiovascular death• Stroke• MI• unstable angina• arterial revascularisation

Secondary End Points:– total mortality– non-cardiovascular mortality– development of diabetes mellitus– development of venous thromboembolic events – bone fractures– discontinuation of study medication due to adverse effects.


JUPITER: Primary Objectives

To investigate whether rosuvastatin 20 mg compared to placebo would decrease the rate of first major cardiovascular events among apparently healthy men and women with LDL < 130 mg/dL (3.36 mmol/L) who are nonetheless at increased vascular risk on the basis of an enhanced inflammatory response, as determined by hsCRP > 2 mg/L.

To enroll large numbers of women and individuals of Black or Hispanic ethnicity, groups for whom little data on primary prevention with statin therapy exists.

Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin


hsC

RP

(m

g/L

)L

DL

(m

g/d

L)

Months0 12 24 36 48

TG

(m

g/d

L)

HD

L (

mg

/dL

)

Months

JUPITER: Effects of Rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP

LDL decrease 50 percent at 12 months

hsCRP decrease 37 percent at 12 months

HDL increase 4 percent at 12 months

TG decrease 17 percent at 12 months


JUPITER: Adverse Events and Measured Safety Parameters

Event Rosuvastatin Placebo P

Any SAE 1,352 (15.2) 1,337 (15.5) 0.60Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34Myopathy 10 (0.1) 9 (0.1) 0.82Rhabdomyolysis 1 (0.01)* 0 (0.0) --Incident Cancer 298 (3.4) 314 (3.5) 0.51Cancer Deaths 35 (0.4) 58 (0.7) 0.02Hemorrhagic stroke 6 (0.1) 9 (0.1) 0.44

GFR (ml/min/1.73m2 at 12 mth) 66.8 (59.1-76.5) 66.6 (58.8-76.2) 0.02ALT > 3xULN 23 (0.3) 17 (0.2) 0.34

Fasting glucose (24 mth) 98 (91-107) 98 (90-106) 0.12HbA1c (% at 24 mth) 5.9 (5.7-6.1) 5.8 (5.6-6.1) 0.01Glucosuria (12 mth) 36 (0.5) 32 (0.4) 0.64Incident Diabetes** 270 (3.0) 216 (2.4) 0.01

*Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%)**Physician reported


JUPITER: Grouped Components of the Primary End Point

HR 0.53, CI 0.40-0.70P<0.00001

Rosuvastatin

Placebo

Myocardial Infarction, Stroke, orCardiovascular Death

Arterial Revascularization orHospitalization for Unstable

Angina

HR 0.53, CI 0.40-0.69P<0.00001

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

ence

Follow-up (years)

0 1 2 3 4

0.00

0.01

0.02

0.03

0.04

0.05

Cu

mu

lati

ve In

cid

ence

Follow-up (years)

Placebo

Rosuvastatin

- 47 %- 47 %


JUPITER: Individual Components of the Primary End Point

*Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death

Endpoint Rosuvastatin Placebo HR 95%CI P

Primary Endpoint* 142 251 0.56 0.46-0.69 <0.00001

Non-fatal MI 22 62 0.35 0.22-0.58 <0.00001Any MI 31 68 0.46 0.30-0.70 <0.0002

Non-fatal Stroke 30 58 0.52 0.33-0.80 0.003Any Stroke 33 64 0.52 0.34-0.79 0.002

Revascularization or Unstable Angina 76 143 0.53 0.40-0.70 <0.00001

MI, Stroke, CV Death 83 157 0.53 0.40-0.69 <0.00001


JUPITER: Primary End Point – Subgroup Analysis I

0.25 0.5 1.0 2.0 4.0

Rosuvastatin Superior Rosuvastatin Inferior

MenWomen

Age < 65Age > 65

SmokerNon-Smoker

CaucasianNon-Caucasian

USA/CanadaRest of World

HypertensionNo Hypertension

All Participants

N P for Interaction

11,001 0.80 6,801

8,541 0.32 9,261

2,820 0.6314,975

12,683 0.57 5,117

6,041 0.5111,761

10,208 0.53 7,586

17,802


0.00

0.02

0.04

0.06

0.08

0 1 2 3 4 5Years

Placebo

Rosuvastatin 20 mg

JUPITER - Primary End PointTime to first occurrence of a CV death, non-fatal stroke, non-fatal

MI, unstable angina or arterial revascularisation C

um

ula

tive

Inci

den

ce

Number at riskRosuvastatin 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 2 yrs = 95 5 yrs* = 25

*Extrapolated figure based on Altman and Andersen method

JUPITER - Primary End Point 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 Interval

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


JUPITER: Primary Endpoint – Subgroup Analysis II

0.25 0.5 1.0 2.0 4.0

Rosuvastatin Superior Rosuvastatin Inferior

Family HX of CHDNo Family HX of CHD

BMI < 25 kg/m2

BMI 25-29.9 kg/mBMI > 30 kg/m

Metabolic SyndromeNo Metabolic Syndrome

Framingham Risk < 10%Framingham Risk > 10%

hsCRP > 2 mg/L Only

All Participants

N P for Interaction

2,045 0.0715,684

4,073 0.70 7,009 6,675

7,375 0.1410,296

8,882 0.99 8,895

6,375

17,802

2

2

hsCRP > 2 mg/L Only 6,375


JUPITER: Secondary End Point – All Cause Mortality

Placebo 247 / 8901

Rosuvastatin 198 / 8901

HR 0.80, 95%CI 0.67-0.97P= 0.02

- 20 %

0 1 2 3 4

0.00

0.01

0.02

0.03

0.04

0.05

0.06

Cu

mu

lati

ve I

nci

den

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: Statins and the Development of Diabetes

0.25 0.5 1.0 2 4

WOSCOPS Pravastatin

HPS Simvastatin

ASCOT-LLA Atorvastatin

JUPITER Rosuvastatin

PROVE-IT Atorvastatin VS

Pravastatin

0.70 (0.50–0.98)

1.20 (0.98–1.35)

1.20 (0.91–1.44)

1.11 (0.67–1.83)

1.25 (1.05–1.54)

Statin Better Statin Worse

HR (95% CI)

PROSPER Pravastatin 1.34 (1.06–1.68)


JUPITER: Predicted Benefit Based on LDL Reduction vs Observed Benefit


Pro

port

iona

l red

uctio

n in

va

scul

ar e

vent

rat

e (9

5% C

I)

Mean LDL cholesterol differencebetween treatment groups (mmol/L)

IDEAL

TNT

A-to-Z

CTT

PROVE-IT

JUPITER PREDICTED

JUPITER: Predicted Benefit Based on LDL Reduction vs Observed Benefit

Pro

po

rtio

na

l re

du

ctio

n in

va

scu

lar

eve

nt

rate

(9

5%

CI)

Mean LDL cholesterol differencebetween treatment groups (mmol/L)

IDEAL

TNT

A-to-Z

CTT

PROVE-IT

JUPITER PREDICTED

JUPITER OBSERVED


Prevalence of conventional risk factors† in male patients with CHD

None

One

Two

Three

Four (0.9%)

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

19.4%

43.0%

27.8%

8.9%

Adapted from Khot et al. JAMA 2003;290:898-904.

CRP is a strong independent predictorof CV 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)

Homocysteine

IL-6

TC

LDL-C

sICAM-1

SAA

ApoB

TC/HDL-C

CRP

CRP + TC/HDL-C

Relative risk of future CV events

1.0 2.0 4.0 6.0

Adapted from Blake GJ, Ridker PM. Circ Res 2001;89:763-71.

CRP predicts risk of MI and strokein apparently healthy men

CRP=C-reactive protein; MI=myocardial infarctionQuartile 1: ≤ 0.55 ; Quartile 2: ≤ 0.56-1.14;Quartile 3: 1.15-2.10 ; Quartile 4: 2.11.*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

***


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


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)

0.00

0.02

0.04

0.06

0 1 2 3 4 5Years

Placebo

Rosuvastatin 20 mg

JUPITER - Total Mortality Death from any cause

Cu

mu

lati

ve In

cid

ence

Number at riskRosuvastatin 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 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

Per

cen

tag

e ch

ang

e fr

om

bas

elin

e (%

)

50%

4%

17%

37%

P<0.001

P<0.001*

P<0.001

P<0.001

*P-value at study completion (48 months) = 0.34


JUPITER - Tolerability 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


JUPITER - Laboratory 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) 0.001

Fasting plasma glucose** (mmol/L) 5.4 (5.0-5.9) 5.4 (5.1-5.9)0.12

Placebo Rosuvastatin P value[n=8901] [n=8901]

GFR = Glomerular filtration rate, HbA1c = Haemoglobin A1c; IQR = interquartile range

‡ >100% increase from baseline;# on consecutive visits; † >trace at 12 months; *at 12 months, **at 24 months


JUPITER: Conclusions – Efficacy I

Among apparently healthy men and women with elevatedhsCRP but low LDL, rosuvastatin reduced by 47 percent incident myocardial infarction, stroke, and cardiovascular death.

Despite evaluating a population with lipid levels widely considered to be “optimal” in almost all current prevention algorithms, the relative benefit observed in JUPITER was greater than in almost all prior statin trials.

In this trial of low LDL/high hsCRP individuals who do notcurrently qualify for statin therapy, rosuvastatin significantlyreduced all-cause mortality by 20 percent.


JUPITER: Conclusions – Efficacy II

Benefits of rosuvastatin were consistent in all sub-groups evaluated regardless of age, sex, ethnicity, or other baseline clinical characteristic, including those with elevated hsCRP and no other major risk factor.

Rates of hospitalization and revascularization were reducedby 47 percent within a two-year period suggesting that the screening and treatment strategy tested in JUPITER is likely to be cost-effective, benefiting both patients and payers.

The Number Needed to Treat in JUPITER was 25 for the primary endpoint, a value if anything smaller than that associated with treating hyperlipidemia in primary prevention.


JUPITER: Conclusions - Safety

With regard to safety , the JUPITER results show no increase in serious adverse events among thoseallocated to rosuvastatin 20 mg as compared to placeboin a setting where half of the treated patients achievedlevels of LDL< 55 mg/dL (and 25 percent had LDL < 44mg/dL).

show no increase in myopathy, cancer, hepaticdisorders, renal disorders, or hemorrhagic stroke with treatment duration of up to 5 years.

show no increase in systematically monitored glucose orglucosuria during follow-up, but small increases inHbA1c and physician reported diabetes similar to thatseen in other major statin trials.


JUPITER – Summary

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.


JUPITER: Public Health Implications

Application of the simple screening and treatment strategy tested in the JUPITER trial over a five-year period could conservatively prevent more than 250,000 heart attacks, strokes, revascularization procedures, and cardiovascular deaths in the United States alone.

We thank the 17,802 patients and the >1,000 investigatorsworldwide for their personal time, effort, and commitmentto the JUPITER trial.

www.brighamandwomens.org/jupitertrial


JUPITER: Implications for Primary Prevention

Among men and women age 50 or over :

If diabetic, treatIf LDLC > 160 mg/dL, treat

If hsCRP > 2 mg/L, treat

A simple evidence based approach to statin therapyfor primary prevention.


Acknowledgements

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 slide presentation may include evolving scientific information that has not been reviewed and approved by Health Canada.

These slides are intended for educational purposes only.

DISCLAIMER

Documents

JUPITER Primary Trial End Point: MI, Stroke, UA/Revascularization, CV Death