ueda2013 primary prevention-d.lobna

Primary prevention : From Theory to real clinical evidence (insights from Jupiter trial)

Lobna Farag Eltoony Head of diabetes and Endocrinology Unit

Department Of Internal Medicine Asst University

Dyslipidemia (35.6%)

Diabetes Mellitus (8.7%) None (53.2%)

Hypertension (27.6%)

NHANES III = The Third National Health and Nutrition Examination Survey.

* Estimates based on application of age- and sex-specific prevalence estimates for each condition from the NHANES III data to the Kaiser Permanente

membership to simulate full ascertainment.

Selby JV et al. Am J Manag Care. 2004;10:163–170.

Overlap of Diabetes

and Hypertension

~70% of Diabetes

~22% of Hypertension

Prevalence of Vascular Disease Risk Factors Among Adults Aged >20 Years*

Inflammation drives many stages of the atherosclerotic process and

the major mechanisms are illustrated here.

Oh J et al. Dia Care 2011;34:S155-S160

Copyright © 2011 American Diabetes Association, Inc.

Atherosclerosis: An Inflammatory Disease

III.2

© 2002 PPS®

C

The Function of HDL

Diabetes Vasc Dis Res 2007;4(suppl 3):S5–S8

Antiatherogenic actions of HDL

Note: Risk estimates were derived from the experience of the Framingham Heart Study,

a predominantly Caucasian population in Massachusetts, USA.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in

Adults.

JAMA. 2001;285:2486-2497.

Assessing CHD Risk in Men Step 1: Age

Years Points

20-34 -9

35-39 -4

40-44 0

45-49 3

50-54 6

55-59 8

60-64 10

65-69 11

70-74 12

75-79 13

Step 2: Total Cholesterol

TC Points at Points at Points at Points

at Points at

(mg/dL) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age

70-79

<160 0 0 0 0 0

160-199 4 3 2 1 0

200-239 7 5 3 1 0

240-279 9 6 4 2 1

280 11 8 5 3 1

HDL-C

(mg/dL) Points

60 -1

50-59 0

40-49 1

<40 2

Step 3: HDL-Cholesterol

Systolic BP Points Points

(mm Hg) if Untreated if Treated

<120 0 0

120-129 0 1

130-139 1 2

140-159 1 2

160 2 3

Step 4: Systolic Blood Pressure

Step 5: Smoking Status

Points at Points at Points at Points

at Points at

Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age

70-79

Nonsmoker 0 0 0 0 0

Smoker 8 5 3 1 1

Age

Total cholesterol

HDL-cholesterol

Systolic blood pressure

Smoking status

Point total

Step 6: Adding Up the Points

Point Total 10-Year Risk Point Total 10-Year

Risk

<0 <1% 11 8%

0 1% 12 10%

1 1% 13 12%

2 1% 14 16%

3 1% 15 20%

4 1% 16 25%

5 2% 17 30%

6 2%

7 3%

8 4%

9 5%

10 6%

Step 7: CHD Risk

ATP III Framingham Risk Scoring

http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm

© 2001, Professional Postgraduate Services® www.lipidhealth.org

Risk Categorization

• Typical 10 year risk of stroke or myocardial infarction

• Low risk = < 15 percent

• Medium risk = 15-20 percent

• High risk = 20-30 percent

• Very high risk > 30 percent

LDL-C Treatment Goals

• Markedly elevated single risk factors such as familial

dyslipidaemias and severe hypertension.

• Calculated SCORE ≥5% and <10%.

115

mg/dl

100

mg/dl

70

mg/dl

Moderate

Risk

High

Risk

Very

High

Risk

• Documented CVD (CAD, stroke & PVD)

• Type 2 or type 1 diabetes with target organ damage

(such as microalbuminuria).

• Moderate to severe CKD (GFR <60 mL/min/1.73 m2).

• Calculated SCORE ≥10%.

Calculated SCORE ≥1% and <5%.

ESC/EAS

2011

Guidelines

ESC/EAS GUIDELINES. Zˇ eljko Reiner et al. European Heart Journal (2011) 32, 1769–1818

Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk

Pederson TR et al. Circulation 1998;97:1453-1460

Fitchett DH, Leiter LA, et al. Can J Cardiol 2005;21:85-90

LDL-C Lowering and the associated reduction of CV outcomes

Sachdeva et al, Am Heart J 2009;157:111-7.e2.

LDLC Levels in 136,905 Patients Hospitalized With CAD: 2000- 2006

LDLC (mg/dL) 130-160 > 160 < 130

Majority of patients hospitalised with CAD had Normal LDL-C

Prevalence of conventional risk factors† in male patients with CHD

None

One

Two

Three

Four (0.9%)

Total male patients=87 869 CHD=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.

More than 90% of CHD Male patients had ≤2 risk factors

Mohamed A. Wahab EL AHLY Club player

Died in a match

No One is immune

Is it just Another Angle ?

Or

Are we looking in the wrong direction ?

Circulation 108: 250-252

A Multimarker Approach Should Focus

on Multiple Mechanisms / Pathologies

Hs-CRP

Inflammatory Markers: From Concept to Clinical Practice to Clinical Benefits:

Why the JUPITER Trial? , Presented by Paul M. Ridker, MD, MPH

Have trials really tested this direction?

4S

CARE

WOSCOPS

AFCAPS/TexCAPS

LIPID

No history of CHD or MI,low LDL-C,

HsCRP2mg/dl

JUPITER

The Pyramid of Recent Trials Relative Size of the Various Segments of the Population

Very high cholesterol with CHD or MI

Moderately high cholesterol in high risk CHD or MI

Normal cholesterol with CHD or MI

High cholesterol without CHD or MI

No history of CHD or MI Stat

in t

he

rap

y fr

om

On

e s

ucc

ess

to

an

oth

er

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

Ridker et al NEJM 2008

Is it LDL or inflammation or both?

PREVENTING THE FIRST MYOCARDIAL INFARCTION: PRIMARY

ENDPOINTS

At different LDL levels in these trials …. Placebo showed high no. of

events …. It seems it is not LDL alone

WOSCOPS AFCAPS MEGA JUPITER N = 6595 N = 6605 N = 7832 N = 17802

Fatal and nonfatal

MI

Fatal and nonfatal MI, unstable angina,

sudden cardiac death

Fatal and nonfatal

MI

15.4 10.9 5.0 14.8 Events per 1000 pt.yrs in placebo group

Prava 40 Lova 20 – 40 Prava 10 – 20 Rosuva 20

MI, stroke, unstable angina,

revascularisation, CV death.

1.00

0.99

0.98

0.97

0.96

0.00 0 2 4 6 8

Years of Follow-up

Primary Prevention : Whom Should We Treat ?

Ridker et al, N Engl J Med. 2002;347:1557-1565.

Pro

bab

ility

of

Eve

nt-

fre

e S

urv

ival

hsCRP < 2, LDL < 130

hsCRP > 2, LDL > 130

hsCRP < 2, LDL > 130

hsCRP > 2, LDL < 130

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

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 2.0 0.5

[A]

[B]

Low LDL, Low hsCRP

Low LDL, High hsCRP

Statin Effective Statin Not Effective

1.0 2.0 0.5

AFCAPS/TexCAPS Low LDL Subgroups

RR

AFCAPS/TEXCAPS showed statins to be effective in

lowering risk in the setting of normal LDL-C, but only when

inflammation was present

Jupiter : A different approach

JUPITER Trial Study Group, Am J Cardiol 2007; 100: 1659-1664.

Comparison of the Population in Statin trials Previous to Jupiter Trial Primary Prevention

WOSCOPS AFCAPS

Sample size (n) Small No. 6,595 6,605

Women (n) Not

represented 0 997

Non-Caucasian (n)

Not

represented

0 350

Duration (yrs) 4.9 5.2

Diabetes (%) 1 6

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

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

Baseline TG (mg/dL) 164 158

Baseline hsCRP (mg/L) Not Tested NA NA

Intervention Pravastatin

40 mg

Lovastatin

10-40 mg

JUPITER Trial Study Group, Am J Cardiol 2007; 100: 1659-1664.

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

JUPITER WOSCOPS AFCAPS

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

Women (n) 6,801 0 997

Non-Caucasian (n) 5,118 0 350

Duration (yrs) 1.9 (max 5) 4.9 5.2

Diabetes (%) 0 1 6

Baseline LDL-C (mg/dL) 104 192 150

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

20 mg Pravastatin

40 mg

Lovastatin

10-40 mg

4021

2873

2497

2020

987 804

741 487

345 336 327 273 270 253 222 209 204 202 197 162 143 85 83 32 15 14 0

5

10

15

20

25

Ran

do

miz

atio

ns

(% T

ota

l.)

Total Randomized = 17,802

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

8,155 fully complete

8,864 Vital status known

22 % d/c study med

8.0 % withdrew

4.4 % non-trial statin

JUPITER: Inclusion/Exclusion Criteria, Study Flow

89,890 screened

Inclusion criteria Men >50 years Women >60 years No CVD, No DM LDL <130 mg/dL hsCRP >2 mg/dL

4 week Placebo Run-in

Reason for Exclusion % LDL>130 mg/dL 52 hsCRP<2 mg/L 36 Withdrew consent 5 Diabetes 1 Hypothyroid <1 Liver disease <1 TG >600 mg/dL <1 Age out of range <1 Current use of HRT <1 Cancer <1 Poor compliance/Other <1 17,802 Randomized

8901 assigned to Rosuvastatin 20 mg

8901 assigned to Placebo

8,901 Included in Efficacy

and Safety Analyses

8,901 Included in Efficacy

and Safety Analyses

8,169 fully complete

8,857 Vital status known

19 % d/c study med

7.8 % withdrew

2.0 % non-trial statin

JUPITER – study design- started 2006 and scheduled to close in June 2011

Ridker PM. Circulation 2003; 108: 2292–2297

Lipids CRP

Tolerability

Lipids CRP

Tolerability HbA1C

Placebo

run-in

1 –6

2 –4

3 0

4 13

Final 3–4 y 6-monthly

Visit: Week:

Randomisation

Lipids CRP

Tolerability

Rosuvastatin 20 mg (n~7500)

Placebo (n~7500)

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

The Jupiter Patients

- Av. Age = 66 y - 16 % Smokers - Av S.B.P = 134-145 - 41 % Metabolic Syndrome - 11% F. history of CV problems

Nizzar Qabbani .... Died with MI in 1998

CRESTOR OUTCOMES STUDY JUPITER CLOSES EARLY DUE TO UNEQUIVOCAL

EVIDENCE OF BENEFIT

JUPITER- Trial Stopped March 31st, 2008

Why stopped early?

Why stopped early?

Ridker said : It's okay with me if these physicians want to ignore the data. I just don't want them taking care of my patients or my family."

For physicians who thought it was better not to stop :

Rosuvastatin

Placebo 8901 8353 3872 1333 534 173

8901 8412 3892 1352 543 156

Number at risk Years

0

1

2

4

6

7

8

9

0 1 2 3 4

HR 0.56 (95% CI 0.46-0.69) P=<0.00001

Rosuvastatin Placebo

3

5

44%

JUPITER:

Primary Endpoint (composite end point) C

um

ula

tive

inci

de

nce

, %

Number of events 142 (1.6%) 252 (2.8%)

Who will benefit ?

0.25 0.5 1.0 2.0 4.0

Rosuvastatin Superior Rosuvastatin Inferior

Men

Women

Age ≤ 65 Age > 65

Smoker Non-Smoker

Caucasian

Non-Caucasian

USA/Canada

Rest of World

Hypertension

No Hypertension

All Participants

N P for Interaction

11,001 0.80

6,801

8,541 0.32

9,261

2,820 0.63

14,975

12,683 0.57

5,117

6,041 0.51

11,761

10,208 0.53

7,586

17,802

JUPITER:

Primary Endpoint – Subgroup Analysis I

HR 0.63 (95% CI 0.41-0.98) P = 0.04

Black, Hispanic, Other (N = 5,019)

HR 0.55 (95% CI 0.43-0.69) P < 0.0001

Caucasian (N = 12,683)

0 1 2 3 4

0.0

0

0.0

2

0.0

4

0.0

6

0.0

8

0.1

0

Cu

mu

lati

ve In

cid

en

ce

Follow-up (years)

Placebo

Rosuvastatin

0 1 2 3 4

Follow-up (years)

Placebo

Rosuvastatin

JUPITER:

Primary Endpoint By Ethnicity

JUPITER

Primary Endpoint According to Baseline Glucose Levels

HR 0.51, 95% CI 0.40-0.67

P < 0.0001

Normal Fasting Glucose

HR 0.69, 95% CI 0.49-0.98

P= 0.04

Impaired Fasting Glucose

0 1 2 3 4

Follow-up Years

0.0

0

0.0

2

0.0

4

0.0

6

0.0

8

0.1

0

Cu

mu

lati

ve In

cid

ence

0 1 2 3 4

Follow-up Years

Rosuvastatin

Rosuvastatin

Placebo Placebo

Jupiter Benefits

- 54 %

0 1 2 3 4

Follow-up Years

0.5

1

1.5

2

2.5

3

Cu

mu

lati

ve In

cid

ence

JUPITER:

Fatal or Nonfatal Myocardial Infarction

HR 0.46 (95% CI 0.30-0.70) P<0.0002

Rosuvastatin Placebo

Number of events 31 68

Talaat El Sadaat Died 2012

MI Famous Politician

0 1 2 3 4

0.5

1

1.5

2

2.5

3

JUPITER:

Fatal or Nonfatal Stroke

Rosuvastatin Placebo

HR 0.52 (95% CI 0.34-0.79) P=0.002

- 48 %

Follow-up Years

Cu

mu

lati

ve In

cid

en

ce,

%

Number of events 33 64

Baseball historians consider Gibson to be among the very best

and power hitters and catchers in the history

of any league

Josh Gibson Died 35 y old

Stroke

0 1 2 3 4

1

2

3

4

5

6

Number at Risk

Rosuvastatin

Placebo

8,901 8,640 8,426 6,550 3,905 1,966 1,359 989 547 158

8,901 8,641 8,390 6,542 3,895 1,977 1,346 963 538 176

JUPITER:

Bypass Surgery or PTCA / Hospitalization for UA

Follow-up Years

Cu

mu

lati

ve In

cid

en

ce,

%

Rosuvastatin Placebo

HR 0.53 (95% CI 0.40-0.70) P<0.00001

- 47 %

Number of events 76 143

Bill Clinton Former USA President Bypass surgery and 2 stints At the age of 50’s

Mohamed Hamaki Egyptian Singer 2 coronaryt stints At the age of 30’s

JUPITER

Myocardial Infarction, Stroke, Cardiovascular Death

Placebo (N = 157)

Rosuvastatin (N = 83)

HR 0.53, 95%CI 0.40-0.69

P < 0.00001

- 47 %

0 1 2 3 4

0.0

0

0.0

1

0.0

2

0.0

3

0.0

4

0.0

5

Cu

mu

lati

ve In

cid

en

ce

Number at Risk Follow-up (years)

Rosuvastatin

Placebo

8,901 8,643 8,437 6,571 3,921 1,979 1,370 998 551 159

8,901 8,633 8,381 6,542 3,918 1,992 1,365 979 550 181

Sheikh Sayed Tantawy SHEIKH EL AZHAR Died in KSA Heart Attack - 2011

Galal Amer writer Died in a demonstration Heart Attack - 2012

JUPITER:

Death from Any Cause

Rosuvastatin

Placebo 8901 8782 4323 1613 683

8901 8787 4313 1601 682

Number at risk Years

0

1

2

3

4

5

6

7

0 1 2 3 4 6

Cu

mu

lati

ve In

cid

ence

, %

HR 0.80 (95% CI 0.67−0.97) P=0.021

Rosuvastatin Placebo

Number of events 198 247

- 20 %

VENOUS THROMBOSIS IN JUPITER

JUPITER

Total Venous Thromboembolism

0 1 2 3 4

0.0

00

0

.00

5

0.0

10

0

.01

5

0.0

20

0

.02

5

Cu

mu

lati

ve In

cid

en

ce

Number at Risk Follow-up (years)

Rosuvastatin

Placebo

8,901 8,648 8,447 6,575 3,927 1,986 1,376 1,003 548 161

8,901 8,652 8,417 6,574 3,943 2,012 1,381 993 556 182

HR 0.57, 95%CI 0.37-0.86

P= 0.007

Placebo 60 / 8901

Rosuvastatin 34 / 8901

- 43 %

Glynn et al NEJM 2009

It isn’t LDL alone, Not inflammation alone , it is both

0

1

2

3

4

5

hsC

RP

(m

g/L

)

0

20

40

60

80

100

120

140

LDL

(m

g/d

L)

Months 0 12 24 36 48

0

10

20

30

40

50

60

0

20

40

60

80

100

120

140

0 12 24 36 48

TG (

mg/

dL)

H

DL

(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

Ridker et al NEJM 2008

JUPITER LDL reduction, hsCRP reduction, or both?

N Rate Placebo 7832 1.11 LDL Achieved > 70 mg/dL 2110 0.91 LDL Achieved < 70 mg/dL 5606 0.51 Placebo LDL Reduction < 50 % LDL Reduction > 50 % Placebo hsCRP Achieved > 2 mg/L hsCRP Achieved < 2 mg/L Placebo hsCRP Reduction < 50 % hsCRP Reduction > 50 %

P < 0.001

1.0 0.5 0.25 2.0 4.0

Rosuvastatin Better

Rosuvastatin Worse

JUPITER LDL reduction, hsCRP reduction, or both?

N Rate Placebo 7832 1.11 LDL Achieved > 70 mg/dL 2110 0.91 LDL Achieved < 70 mg/dL 5606 0.51 Placebo 7832 1.11 LDL Reduction < 50 % 4181 0.74 LDL Reduction > 50 % 3535 0.47 Placebo hsCRP Achieved > 2 mg/L hsCRP Achieved < 2 mg/L Placebo hsCRP Reduction < 50 % hsCRP Reduction > 50 %

P < 0.001

P < 0.001

1.0 0.5 0.25 2.0 4.0

Rosuvastatin Better

Rosuvastatin Worse

JUPITER LDL reduction, hsCRP reduction, or both? N Rate

Placebo 7832 1.11 LDL Achieved > 70 mg/dL 2110 0.91 LDL Achieved < 70 mg/dL 5606 0.51 Placebo 7832 1.11 LDL Reduction < 50 % 4181 0.74 LDL Reduction > 50 % 3535 0.47 Placebo 7832 1.11 hsCRP Achieved > 2 mg/L 4305 0.77 hsCRP Achieved < 2 mg/L 3411 0.42 Placebo hsCRP Reduction < 50 % hsCRP Reduction > 50 %

P < 0.001

P < 0.001

1.0 0.5 0.25 2.0 4.0

P < 0.001

Rosuvastatin Better

Rosuvastatin Worse

JUPITER LDL reduction, hsCRP reduction, or both? N Rate

Placebo 7832 1.11 LDL Achieved > 70 mg/dL 2110 0.91 LDL Achieved < 70 mg/dL 5606 0.51 Placebo 7832 1.11 LDL Reduction < 50 % 4181 0.74 LDL Reduction > 50 % 3535 0.47 Placebo 7832 1.11 hsCRP Achieved > 2 mg/L 4305 0.77 hsCRP Achieved < 2 mg/L 3411 0.42 Placebo 7832 1.11 hsCRP Reduction < 50 % 4143 0.70 hsCRP Reduction > 50 % 3573 0.51

P < 0.001

P < 0.001

1.0 0.5 0.25 2.0 4.0

P < 0.001

P < 0.001

Rosuvastatin Better

Rosuvastatin Worse

JUPITER LDL reduction, hsCRP reduction, or both?

N Rate Placebo LDL>70mg/dL,hsCRP>2 mg/L LDL<70mg/dL,hsCRP>2 mg/L LDL>70mg/dL,hsCRP<2 mg/L LDL<70mg/dL,hsCRP<2 mg/L Placebo LDL>70mg/dL,hsCRP>1 mg/L LDL<70mg/dL,hsCRP>1 mg/L LDL>70mg/dL,hsCRP<1 mg/L LDL<70mg/dL,hsCRP<1 mg/L

1.0 0.5 0.25 2.0 4.0

Rosuvastatin Better

Rosuvastatin Worse

JUPITER LDL reduction, hsCRP reduction, or both?

N Rate Placebo 7832 1.11 LDL>70mg/dL,hsCRP>2 mg/L 1384 1.11 LDL<70mg/dL,hsCRP>2 mg/L 2921 0.62 LDL>70mg/dL,hsCRP<2 mg/L 726 0.54 LDL<70mg/dL,hsCRP<2 mg/L 2685 0.38 Placebo LDL>70mg/dL,hsCRP>1 mg/L LDL<70mg/dL,hsCRP>1 mg/L LDL>70mg/dL,hsCRP<1 mg/L LDL<70mg/dL,hsCRP<1 mg/L

1.0 0.5 0.25 2.0 4.0

P < 0.001

Rosuvastatin Better

Rosuvastatin Worse

JUPITER LDL reduction, hsCRP reduction, or both?

N Rate Placebo 7832 1.11 LDL>70mg/dL,hsCRP>2 mg/L 1384 1.11 LDL<70mg/dL,hsCRP>2 mg/L 2921 0.62 LDL>70mg/dL,hsCRP<2 mg/L 726 0.54 LDL<70mg/dL,hsCRP<2 mg/L 2685 0.38 Placebo 7832 1.11 LDL>70mg/dL,hsCRP>1 mg/L 1874 0.95 LDL<70mg/dL,hsCRP>1 mg/L 4662 0.56 LDL>70mg/dL,hsCRP<1 mg/L 236 0.64 LDL<70mg/dL,hsCRP<1 mg/L 944 0.24

1.0 0.5 0.25 2.0 4.0

P < 0.001

Rosuvastatin Better

Rosuvastatin Worse

P < 0.001

Treating Average risk People : Is it cost Effective ?

Ridker et al. Circulation CV Qual Outcomes 2009;2: 616-23.

Benchmarks: Statins for hyperlipidemia 5-year NNT 40-60 Diuretics 5-year NNT 80-100 Beta-blockers 5-year NNT 120-160 Aspirin Men 5-year NNT 220-270 Aspirin Women 5-year NNT 280-330

JUPITER: Number Needed to Treat (5 year)

Endpoint All FRS≤10 FRS>10

Primary Endpoint 25 47 17

Primary Endpoint, Mortality 20 34 14

MI, Stroke, CABG/PTCA, Death 20 37 14

MI, Stroke, Death 29 60 20

0

50

100

150

200

250

300

350

400

450

Estimated 5-Year NNT Values for the Primary Prevention of Cardiovascular Disease In Middle-Aged Populations

Rosuvastatin Vs other statins

CRESTOR® versus Comparators: LDL-C Efficacy at 10mg Dose

The STELLAR Study

Change in LDL-C from baseline (%)

0 –10 –20 –30 –40 –50 –60

10 mg *

–5 –15 –25 –35 –45 –55

20 mg †

40 mg ‡

10 mg

20 mg

80 mg

10 mg

20 mg

40 mg

80 mg

10 mg

20 mg

40 mg Rosuvastatin 10 mg (–46%)

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

40 mg

*p<0.002 vs atorvastatin 10 mg; simvastatin 10, 20, 40 mg; pravastatin 10, 20, 40 mg †p<0.002 vs atorvastatin 20, 40 mg; simvastatin 20, 40, 80 mg; pravastatin 20, 40 mg ‡p<0.002 vs atorvastatin 40 mg; simvastatin 40, 80 mg; pravastatin 40 mg Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Statins: TC/HDL-C Ratio Efficacy Across the Dose Range

Jones PH, et al. for the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) Study Group. Effects of rosuvastatin versus atorvastatin, simvastatin, and pravastatin on non-high-density lipoprotein cholesterol, apolipoproteins, and lipid ratios in patients with hypercholesterolemia: Additional results from the STELLAR trial. Clinical Therapeutics 2004;26(9):1388-1399.

*p<0.002 vs equivalent parts of the authorized doses of comparators

CRESTOR® versus atorvastatin - change in HDL-C across the dose range

The STELLAR Study

*p<0.002 vs atorvastatin 20, 40 and 80 mg †p<0.002 vs atorvastatin 40 and 80 mg Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

0

2

4

6

8

10

12

10

Atorvastatin

Rosuvastatin

20 40 80

ns

*

†

n=473

n=634

Dose (mg); log scale

Ch

ange

in H

DL-

C f

rom

b

ase

line

(%

)

Jupiter confirms safety

Data from prescribing information for atorvastatin, simvastatin, and rosuvastatin. Clinical Advisory on Statins.

This does not represent data from a comparative study.

LDL vs Incidence of Elevated Transaminases

80 mg 40 mg 20 mg

simvastatin 80 mg 40 mg 20 mg

-48%

-34% -29%

10 mg 20 mg 40 mg 80 mg

atorvastatin 10 mg 20 mg 40 mg 80 mg

-55% -51%

-46%

-38%

0.0

0.5

1.0

1.5

2.0

2.5

Elev

ated

tr

ansa

min

ase

s (%

of

pat

ien

ts)

% d

ecre

ase

in L

DL-

C

-60

-50

-40

-30

-20

-10

0

-70

40 mg 20 mg 10 mg

rosuvastatin 40 mg 20 mg 10 mg

-52%

-55%

-63%

Risk Benefits

decrease in LDL-C

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

LDL-C reduction (%)

Fluvastatin (20, 40, 80 mg)

Rosuvastatin (5, 10, 20, 40 mg)

Lovastatin (20, 40, 80 mg)

Atorvastatin (10, 20, 40, 80 mg) Simvastatin (40, 80 mg)

ALT >3 × ULN: Frequency by LDL-C reduction1,2

Occ

urr

en

ce o

f A

LT >

3×

ULN

(%

)

Persistent elevation is elevation to >3 x ULN on 2 successive occasions 1. Brewer H Am J Cardiol 2003;92(Suppl):23K–29K 2. Davidson M Exp Opin Drug Saf 2004;3 (6):547-557

CRESTOR® safety;

Liver effects - Benefit:Risk

CRESTOR® safety;

Muscle effects - Benefit:Risk

CK >10 x ULN: Frequency by LDL-C Reduction1,2

0.0

0.5

1.0

1.5

2.0

2.5

3.0

20 30 40 50 60 70

LDL-C reduction (%)

Occ

urr

en

ce o

f C

K >

10

× U

LN (

%)

Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)

Rosuvastatin (5, 10, 20, 40 mg)

Pravastatin (20, 40 mg)

Atorvastatin (10, 20, 40, 80 mg) Simvastatin (40, 80 mg)

1.Brewer H Am J Cardiol 2003;92(Suppl):23K–29K 2.Davidson M Exp Opin Drug Saf 2004;3 (6):547-557

Jupiter turning guidelines upside down

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.

Ridker et al NEJM 2008

Primary endpoint* data from major placebo-controlled statin outcomes studies correlating risk reduction with LDL-C

reduction

Fabbri G, Maggioni AP. Adv Ther. 2009; 26: 469–487 Copyright 2009. With kind permission from Springer Science and Business Media.

Rela

tive r

isk r

ed

ucti

on

(%

)

% Reduction in LDL-C

0 10 20 30 40 50 60

0

10

20

30

40

50

60

AF/TEX ASCOT JUPITER

CARDS

LIPS CARE

SPARCL ALERT

ASPEN PROSPER

WOSCOPS

LIPID

HPS

Regression line through the origin

95% confidence limits

4S

*is proportional to the number of paPrimary endpoint used for all studies, with the exception of 4S (major coronary events), HPS (major vascular event), LIPID (CHD death or nonfatal MI), SPARCL (major CV event. ) The area of the plotted symbol tients in the study

None of these patients are currently recommended to receive statin therapy because they have Framingham 10-year risk <20% AND LDL-C levels below the treatment target (ie < 130 mg/dL). All have hsCRP > 2 mg/L.

JUPITER: Public Health Implications: Primary Endpoint at “Intermediate Risk”

FRS (%) Rosuvastatin Placebo HR 95% CI

5–10%

(N=6091) 32 (0.50) 59 (0.92) 0.55 (0.36-0.84)

10–20%

(N=7340) 74 (0.95) 145 (1.84) 0.51 (0.39-0.68)

2009 Canadian Cardiovascular Society (CCS) Guidelines for the Diagnosis and Treatment of Dyslipidemia and

Prevention of Cardiovascular Disease in the Adult

Primary Goal: LDLC

High CAD, CVA, PVD

Most pts with Diabetes

FRS >20%

RRS >20%

<2 mmol/L or 50%

reduction

Class I

Level A

Moderate FRS 10-19%

RRS 10-19%

LDL >3.5 mmol/L

TC/HDLC >5.0

hsCRP >2 in

men >50 yr

women >60 yr

<2 mmol/L or 50%

reduction

Class IIA

Level A

Low FRS <10% <5 mmol/L Class IIA

Level A

Secondary Targets TC/HDLC <4, non HDLC <3.5 mol/L

hsCRP <2 mg/L, TG <1.7 mol/L, ApoB/A <0.8

Male Above 50 Smoker Regardless to TC Is High Risk

Take Home Messages

• We should start assessing patients at increased risk

• Treat to target LDL-C or 50% reduction in LDL-C

• Based on Jupiter , FDA approved CRESTOR 20 mg for patients who are at increased risk of heart disease but have not been diagnosed with it.

• Jupiter showed a significant reduction in the first occurrence of any major cardiovascular event by 44%

• Jupiter showed a significant reduction in non fatal MI by 65%

THANKS