ueda2013 primary prevention-d.lobna

1. 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

2. 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*

3. 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.

4. Atherosclerosis:
An Inflammatory Disease
III.2
© 2002 PPS®
C

5. The Function of HDL

6. Diabetes Vasc Dis Res 2007;4(suppl 3):S5–S8
Antiatherogenic actions of HDL

7. 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 MenStep 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 Service
www.lipidhealth.org

8. 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

9. 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

10. Relationship Between Changes in LDL-C
and HDL-C Levels and CHD Risk
Pederson TR et al. Circulation 1998;97:1453-1460

11. Fitchett DH, Leiter LA, et al. Can J Cardiol 2005;21:85-90
LDL-C Lowering and the associated
reduction of CV outcomes

12. 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

13. 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

14. Mohamed A. Wahab
EL AHLY Club player
Died in a match
No One is immune

15. Is it just Another
Angle ?
Or
Are we looking in the
wrong direction ?

16. Circulation 108: 250-252
A Multimarker Approach Should Focus
on Multiple Mechanisms / Pathologies

17. Hs-CRP

18. Inflammatory Markers: From Concept to Clinical Practice to Clinical Benefits:
Why the JUPITER Trial? , Presented by Paul M. Ridker, MD, MPH

19. Have trials really tested this
direction?

20. 4S
CARE
WOSCOPS
AFCAPS/TexCAPS
LIPID
No history of CHD or MI,low LDL-C,
HsCRP2mg/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
StatintherapyfromOnesuccesstoanother

21. 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

22. Is it LDL or inflammation or
both?

23. 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 14.8Events
per 1000
pt.yrs in
placebo
group
Prava 40 Lova 20 – 40 Prava 10 – 20 Rosuva 20
MI, stroke, unstable
angina,
revascularisation,
CV death.

24. 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.
ProbabilityofEvent-freeSurvival
hsCRP < 2, LDL < 130
hsCRP > 2, LDL > 130
hsCRP < 2, LDL > 130
hsCRP > 2, LDL < 130

25. 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 2.00.5
[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
AFCAPS/TEXCAPS showed statins to be effective in
lowering risk in the setting of normal LDL-C, but only when
inflammation was present

26. Jupiter : A different approach

27. 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

28. 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

29. 4021
2873
2497
2020
987
804
741
487
3453363272732702532222092042021971621438583321514
0
5
10
15
20
25
Randomizations(%Total.)
Total Randomized = 17,802
JUPITER:
17,802 Patients, 1,315 Sites, 26 Countries

30. 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

31. 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 y6-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

32. The Jupiter Patients

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

34. Nizzar Qabbani .... Died with MI in
1998

35. CRESTOR OUTCOMES STUDY JUPITER CLOSES EARLY DUE TO UNEQUIVOCAL
EVIDENCE OF BENEFIT
JUPITER- Trial Stopped
March 31st, 2008

36. Why stopped early?

37. Why stopped early?

38. 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 :

39. 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)
Cumulativeincidence,%
Number of events 142 (1.6%) 252 (2.8%)

40. Who will benefit ?

41. 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

42. 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
0.000.020.040.060.080.10
CumulativeIncidence
Follow-up (years)
Placebo
Rosuvastatin
0 1 2 3 4
Follow-up (years)
Placebo
Rosuvastatin
JUPITER:
Primary Endpoint By Ethnicity

43. 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
0.000.020.040.060.080.10
CumulativeIncidence
0 1 2 3 4
Follow-up Years
Rosuvastatin
Rosuvastatin
Placebo
Placebo

44. Jupiter Benefits

45. - 54 %
0 1 2 3 4
Follow-up Years
0.5
1
1.5
2
2.5
3
CumulativeIncidence
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

46. Talaat El Sadaat
Died 2012
MI
Famous Politician

48. 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
CumulativeIncidence,%
Number of events 33 64

49. 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

50. 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
CumulativeIncidence,%
Rosuvastatin Placebo
HR 0.53 (95% CI 0.40-0.70)
P<0.00001
- 47 %
Number of events 76 143

51. 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

52. 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
0.000.010.020.030.040.05
CumulativeIncidence
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

53. Sheikh Sayed Tantawy
SHEIKH EL AZHAR
Died in KSA
Heart Attack - 2011
Galal Amer
writer
Died in a demonstration
Heart Attack - 2012

54. 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
CumulativeIncidence,%
HR 0.80 (95% CI 0.67−0.97)
P=0.021
Rosuvastatin Placebo
Number of events 198 247
- 20 %

55. VENOUS THROMBOSIS IN JUPITER

56. JUPITER
Total Venous Thromboembolism
0 1 2 3 4
0.0000.0050.0100.0150.0200.025
CumulativeIncidence
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

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

58. 0
1
2
3
4
5
hsCRP(mg/L)
0
20
40
60
80
100
120
140
LDL(mg/dL)
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)HDL(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

59. 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
1.00.50.25 2.0 4.0
Rosuvastatin
Better
Rosuvastatin
Worse

60. 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
1.00.50.25 2.0 4.0
Rosuvastatin
Better
Rosuvastatin
Worse

61. 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
1.00.50.25 2.0 4.0
P < 0.001
Rosuvastatin
Better
Rosuvastatin
Worse

62. 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
1.00.50.25 2.0 4.0
P < 0.001
P < 0.001
Rosuvastatin
Better
Rosuvastatin
Worse

63. 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
1.00.50.25 2.0 4.0
Rosuvastatin
Better
Rosuvastatin
Worse

64. 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
1.00.50.25 2.0 4.0
P < 0.001
Rosuvastatin
Better
Rosuvastatin
Worse

65. 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
1.00.50.25 2.0 4.0
P < 0.001
Rosuvastatin
Better
Rosuvastatin
Worse
P < 0.001

66. Treating Average risk People : Is it cost
Effective ?

67. 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

68. 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

69. Rosuvastatin Vs other statins

70. 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

71. 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

72. 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
ChangeinHDL-Cfrom
baseline(%)

73. Jupiter confirms safety

75. 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 mg40 mg20 mg
simvastatin
80 mg40 mg20 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
Elevated
transaminases
(%ofpatients)%decreaseinLDL-C
-60
-50
-40
-30
-20
-10
0
-70
40 mg20 mg10 mg
rosuvastatin
40 mg20 mg10 mg
-52%
-55%
-63%
Risk Benefits
decrease in LDL-C

76. 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
OccurrenceofALT>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

77. 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 (%)
OccurrenceofCK>10×ULN(%)
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

78. Jupiter turning guidelines upside
down

79. 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

80. 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.
Relativeriskreduction(%)
% Reduction in LDL-C
0 10 20 30 40 50 60
0
10
20
30
40
50
60
AF/TEX
ASCOT JUPITER
CARDS
LIPSCARE
SPARCLALERT
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

81. 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)

82. 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

84. Male
Above 50
Smoker
Regardless to TC
Is High Risk

85. 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%

86. THANKS