1. Should hsCRP be Included in the New Cardiovascular Guidelines?
Controversy and Consensus in the JUPITER Trial
Paul M Ridker, MD, MPH
Eugene Braunwald Professor of Medicine
Director, Center for Cardiovascular Disease Prevention
Brigham and Women’s Hospital
Harvard Medical School, Boston, MA USA
Dr Ridker is listed as a co-inventor on patents held by the Brigham and Women’s Hospital
that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes.

2. Paul M. Ridker, MD, MPH DISCLOSURES Consulting Fees
Siemens USA, AstraZeneca, VBL Therapeutics, Schering-Plough Corp. / Merck & Co., Inc., and Novartis AG
Grants/Contracted Research
NHLBI, National Cancer Institute, American Heart Association, Donald W. Reynolds Foundation, Leduc Foundation, Doris Duke Charitable Foundation, AstraZeneca, Novartis AG, and sanofi-aventis U.S. LLC
Dr. Ridker is listed as a co-inventor on patents held by the Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to Siemens and AstraZeneca.

3. LDLC Levels in 136,905 Patients Hospitalized With CAD: 2000- 2006
LDLC (mg/dL)
< 130 mg/dL
> 160 mg/dL
< 3.4 mmol/L
>4.1 mmol/L
Sachdeva et al, Am Heart J 2009;157:111-7.e2.

5. hsCRP and Risk of Future MI and CVA in Apparently Healthy Men
P Trend <0.001
Relative Risk of MI 1 2 3 4
P Trend <0.01 2
Relative Risk of Stroke 1 1 2 3 4
Quartile of hs-CRP
Quartile of hs-CRP
N Engl J Med 1997;336:973–979.

6. A Direct Comparison of LDL-C and hsCRP in the Prediction of First Ever Cardiovascular Events Among 27,939 Women
Total Cardiovascular Events
MI, CABG, PTCA
Relative Risk
Relative Risk
Ischemic Stroke
Cardiovascular Death
Relative Risk
Relative Risk
N Engl J Med 2002;347:

7. hsCRP Adds Prognostic Information Beyond Traditional Risk Factors in All Major Cohorts Evaluated
PHS 1997
WHS 2000
UK 2000
MONICA 2004
ARIC 2004
Iceland 2004
NHS 2004
HPFUS 2004
EPIC-N 2005
Strong 2005
Kuopio 2005
FHS 2008
CHS 2005
PIMA 2005
Fully Adjusted Relative Risk
< 1 mg/L
1 to 3 mg/L
> 3 mg/L

8. Coronary Heart Disease hsCRP concentration (mg/L)
C-reactive protein concentration and risk of cardiovascular events : 2010
Coronary Heart Disease
Ischaemic Stroke
All Vascular Deaths
3.0
2.5
2.0
1.5
1.0
hsCRP concentration (mg/L)
Risk ratio (95% CI)
0.5
4.0
8.0
Age, gender adjusted
Fully adjusted
Emerging Risk Factor Collaborators, Lancet 2010

9. Risk Ratio (95%CI) per 1-SD higher usual values
C-reactive protein concentration and risk of cardiovascular events : 2010
Direct comparison of hsCRP, systolic blood pressure, total cholesterol, and non-HDLC
Risk Ratio (95%CI)
hsCRP
Systolic BP
Total cholesterol
Non-HDLC
1.37 ( )
1.35 ( )
1.16 ( )
1.28 ( )
Risk Ratio (95%CI) per 1-SD higher usual values
Adjusted for age, gender, smoking, diabetes, BMI, triglycerides, alcohol, lipid levels, and hsCRP
Emerging Risk Factor Collaborators, Lancet 2010

11. Reynolds Risk Score – Example II
Clinical Example:
72 year old non-diabetic woman, smoker, systolic BP 145 mm Hg, TC 216 mg/dL, HDLC 82 mg/dL, hsCRP 7.7 mg/L, and a positive family history for MI.
Predicted 10-year risk
Framingham Covariates: percent
Reynolds Covariates: percent

12. Should our guidelines for vascular disease prevention change?
Inflammation, hsCRP, and Vascular Prevention
Is there evidence that individuals with elevated levels of the inflammatory biomarker hsCRP are at high vascular risk even when other risk factors are acceptable?
Is there evidence that individuals identified at increased risk due to inflammation benefit from a therapy they otherwise would not have received?
Should our guidelines for vascular disease prevention change?

13. Inflammation, Statin Therapy, and hsCRP: Initial Observations
P Trend = 0.005
-21.6% (P=0.004) 3
0.25
Placebo
0.24 2
0.23
0.22
Relative Risk
Median hs-CRP (mg/dL)
0.21 1
Pravastatin
0.20
0.19
0.18
Pravastatin
Placebo
Pravastatin
Placebo
Baseline
5 Years
Inflammation Absent
Inflammation Present
Circulation. 1998;98:839–844.
Circulation. 1999;100:

14. Clinical Relevance of Achieved LDL and Achieved CRP
After Treatment with Statin Therapy
0.0
0.5
1.0
1.5
2.0
2.5
0.00
0.02
0.04
0.06
0.08
0.10
Recurrent Myocardial Infarction or Coronary Death
(percent)
Follow-Up (Years)
LDL > 70 mg/dL, CRP > 2 mg/L
LDL > 70 mg/dL, CRP < 2 mg/L
LDL < 70 mg/dL, CRP > 2 mg/L
LDL < 70 mg/dL, CRP < 2 mg/L
NEJM 2005;352:20-28.

15. Probability of Event-free Survival
Primary Prevention : Whom Should We Treat ?
1.00
hsCRP < 2, LDL < 130
0.99
hsCRP < 2, LDL > 130
0.98
Probability of Event-free Survival
hsCRP > 2, LDL < 130
0.97
hsCRP > 2, LDL > 130
0.96
0.00 2 4 6 8
Years of Follow-up
N Engl J Med. 2002;347:

16. JUPITER
Trial Design
JUPITER Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
Rosuvastatin 20 mg (N=8901)
No Prior CVD or DM
Men >50, Women >60
LDL <130 mg/dL
hsCRP >2 mg/L
Placebo (N=8901)
4-week run-in
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

17. JUPITER Why Consider Statins for Low LDL, high hsCRP Patients?
AFCAPS/TexCAPS Low LDL Subgroups
Low LDL, Low hsCRP
Low LDL, High hsCRP
Low LDL, Low hsCRP
Low LDL, High hsCRP
[A]
[B]
0.5
1.0
2.0
0.5
1.0
2.0 RR
Statin Effective
Statin Not Effective
Statin Effective
Statin Not Effective
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.
New Engl J Med 2001;344:

18. Comparison of the JUPITER trial population to previous statin trials
of primary prevention
JUPITER WOSCOPS AFCAPS
Sample size (n) 17, , ,605
Women (n) 6,
Minority (n) 5,
Duration (yrs) (max 5)
Diabetes (%)
Baseline LDL-C (mg/dL)
Baseline HDL-C (mg/dL)
Baseline TG (mg/dL)
Baseline hsCRP (mg/L) > NA NA
Intervention Rosuvastatin Pravastatin Lovastatin
20 mg 40 mg mg
JUPITER Trial Study Group, Am J Cardiol 2007; 100:

19. JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
NEJM 2008;359:
HR 0.56, 95% CI
P <
Placebo 251 / 8901
0.08
Number Needed to Treat (NNT5) = 25
- 44 %
0.06
Cumulative Incidence
0.04
Rosuvastatin 142 / 8901
0.02
0.00 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,631
8,412
6,540
3,893
1,958
1,353
983
544
157
Placebo
8,901
8,621
8,353
6,508
3,872
1,963
1,333
955
534
174

20. Fatal or Nonfatal Myocardial Infarction
JUPITER
Fatal or Nonfatal Myocardial Infarction
NEJM 2008;359:
Rosuvastatin
Placebo
- 55 % 1 2 3 4
Follow-up Years
0.000
0.005
0.010
0.015
0.020
0.025
0.030
Cumulative Incidence
HR 0.45, 95%CI
P <

21. Fatal or Nonfatal Stroke
JUPITER
Fatal or Nonfatal Stroke
NEJM 2008;359:
0.030
HR 0.52, 95%CI
P = 0.002
0.025
Placebo
0.020
Cumulative Incidence
0.015
- 48 %
0.010
0.005
Rosuvastatin
0.000 1 2 3 4
Follow-up Years

22. - 47 % JUPITER Arterial Revascularization / Unstable Angina
NEJM 2008;359:
HR 0.53, 95%CI
P <
0.06
Placebo (N = 143)
0.05
0.04
- 47 %
Cumulative Incidence
0.03
0.02
Rosuvastatin (N = 76)
0.01
0.00 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,640
8,426
6,550
3,905
1,966
1,359
989
547
158
Placebo
8,901
8,641
8,390
6,542
3,895
1,977
1,346
963
538
176

23. Total Venous Thromboembolism
JUPITER
Total Venous Thromboembolism
HR 0.57, 95%CI
P= 0.007
0.025
0.020
Placebo 60 / 8901
0.015
- 43 %
Cumulative Incidence
0.010
Rosuvastatin 34 / 8901
0.005
0.000 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,648
8,447
6,575
3,927
1,986
1,376
1,003
548
161
Placebo
8,901
8,652
8,417
6,574
3,943
2,012
1,381
993
556
182

24. Secondary Endpoint – All Cause Mortality
JUPITER
Secondary Endpoint – All Cause Mortality
NEJM 2008;359:
HR 0.80, 95%CI
P= 0.02
Placebo 247 / 8901
0.06
- 20 %
0.05
0.04
Cumulative Incidence
0.03
Rosuvastatin 198 / 8901
0.02
0.01
0.00 1 2 3 4
Follow-up (years)
Number at Risk
Rosuvastatin
8,901
8,847
8,787
6,999
4,312
2,268
1,602
1,192
683
227
Placebo
8,901
8,852
8,775
6,987
4,319
2,295
1,614
1,196
684
246

25. JUPITER Primary Endpoint – Understudied or “Low Risk” Subgroups
NEJM 2008;359:
Understudied Subgroups N
HR (95%CI)
Women
6, ( )
Age > 70
5, ( )
Black, Hispanic, Other
5, ( )
“Low Risk” Subgroups
Framingham Risk < 10 %
8, ( )
4, ( )
BMI < 25 mg/m2
No Hypertension
7, ( )
No metabolic Syndrome
10, ( )
All Participants
17, ( )
0.25
0.5
1.0
2.0
4.0
Rosuvastatin Superior
Rosuvastatin Inferior

26. JUPITER: Primary Endpoint by Time Since Randomization
P value
6 months
0.029
12 months
<0.001
18 months
<0.001
2 years
<0.001
2.5 years
<0.001
3 years
<0.001
0.1 1
Hazard ratio (95% CI)

27. JUPITER Event Reduction at All Levels of Baseline LDLC < 130 mg/dL
0.20
0.5
1.0
2.0
4.0
Rosuvastatin Better
Rosuvastatin Worse
Baseline Levels
LDLC
<
100 mg/dL
LDLC <90 mg/dL
LDLC <80 mg/dL
LDLC <70 mg/dL
LDLC <60 mg/dL
All Participants N
6,269
3,687
2,033
1,022
511
17,802

28. JUPITER
Absolute Risk Reduction Increases With Increasing Levels of hsCRP
0.20
0.5
1.0
2.0
Better
Worse
Baseline hsCRP
>10 mg/L _
>9 mg/L
>8 mg/L
>7 mg/L
>6 mg/L
>5 mg/L
>4 mg/L
>3 mg/L
>2 mg/L N
2,503
3,071
3,839
4,723
5,897
7,425
9,726
12,939
17,802
3.0
4.0
5.0
Placebo Event Rate

29. JUPITER: Primary Endpoint According to Baseline Glucose Levels
Normal Fasting Glucose
Impaired Fasting Glucose
HR 0.52 (95% CI )
HR 0.66 (95% CI ) 10 10
Placebo
Placebo 8 8 6 6
Cumulative incidence, % 4 4
Rosuvastatin 2
Rosuvastatin 2 1 2 3 4 1 2 3 4
Years
Years
Of the 5572 individuals enrolled in JUPITER who were at high risk for developing diabetes due to impaired fasting glucose at study entry, the reduction in major CV events with rosuvastatin allocation was fully consistent with the trial as a whole. 29

30. Number Needed to Treat (5 year)
JUPITER
Number Needed to Treat (5 year)
Endpoint All FRS<10 FRS>10
Primary Endpoint
Primary Endpoint, Mortality
MI, Stroke, CABG/PTCA, Death
MI, Stroke, Death
Benchmarks:
Statins for hyperlipidemia 5-year NNT
Diuretics year NNT
Beta-blockers 5-year NNT
Aspirin Men year NNT
Aspirin Women year NNT

31. Full Adjusted Hazard Ratio
JUPITER
LDL reduction, hsCRP reduction, or both?
Lancet 2009;373:
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
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
P < 0.001
P < 0.001
0.25
0.5
1.0
2.0
4.0
Rosuvastatin
Better
Rosuvastatin
Worse
Full Adjusted Hazard Ratio
0.21, 95% CI , P <

32. Should our guidelines for vascular disease prevention change?
Inflammation, hsCRP, and Vascular Prevention
Is there evidence that individuals with elevated levels of the inflammatory biomarker hsCRP are at high vascular risk even when other risk factors are acceptable?
Is there evidence that individuals identified at increased risk due to inflammation benefit from a therapy they otherwise would not have received?
Should our guidelines for vascular disease prevention change?

33. 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 <2mmol/L or 50% reduction Class I
Most pts with Diabetes Level A
FRS > 20 %
RRS > 20 %
Moderate FRS % <2mmol/L or 50 % reduction Class IIA
RRS % Level A
LDL > 3.5 mmol/L
TC/HDLC > 5.0
hsCRP > 2 in
men >50 yr
women > 60 yr
Low FRS < 10 % <5mmol/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

34. FRS (%) Rosuvastatin Placebo HR (95%CI)
JUPITER
Primary Endpoint in “Intermediate Risk” Groups
FRS (%) Rosuvastatin Placebo HR (95%CI)
5 – 10 % 32 (0.50) 59 (0.92) ( )
10 – 20 % 74 (0.95) 145 (1.84) ( )
None of these patients are currently eligible to receive statin therapy because, using traditional risk factors alone and calculating Framingham 10-year risk, they are less than 20 % AND they already have untreated LDL-C levels below the treatment target in primary prevention (ie < 130 mg/dL). However, they ALL have hsCRP > 2 mg/L.

35. US FDA APPROVES NEW INDICATION FOR CRESTOR (ROSUVASTATIN CALCIUM)
Approval based on JUPITER study which evaluated CRESTOR in a previously unstudied population
For immediate release: 9 February 2009
The US Food and Drug Administration (FDA) has approved CRESTOR (rosuvastatin calcium) to reduce the risk of stroke, myocardial infarction (heart attack) and arterial revascularization procedures in individuals without clinically evident coronary heart disease but with an increased risk of cardiovascular disease (CVD) based on age (men ≥50 and women ≥60), high-sensitivity C-reactive protein (hsCRP) ≥ 2 mg/L, and the presence of at least one additional CVD risk factor, such as hypertension, low HDL-C, smoking, or a family history of premature coronary heart disease.

36. Clinical Implications of the JUPITER Trial:
Atherosclerotic Risk in Communities (ARIC)
Men > 50, Women > 60, No Prior CVD, No JUPITER Exclusion
LDL < LDL < 130
CRP < 2 CRP > 2 N
LDL (mg/dL)
FRS (%)
CRP (mg/L)
CV Event
Rate/100py
Wang et al, J Am Coll Cardiol 2009;54:2388–95)

37. Clinical Implications of the JUPITER Trial:
Atherosclerotic Risk in Communities (ARIC)
Men > 50, Women > 60, No Prior CVD, No JUPITER Exclusion
LDL < 130 LDL > 130 LDL < 130 LDL > 130
CRP < 2 CRP < 2 CRP > 2 CRP > 2 N
LDL (mg/dL)
FRS (%)
CRP (mg/L)
CV Event
Rate/100py
Wang et al, J Am Coll Cardiol 2009;54:2388–95)

38. Clinical Relevance of hsCRP in the CORONA Trial :
Identifying a High Risk CHF Population That Benefits From Statin Therapy
Primary Endpoint
hsCRP < 2 mgL
hsCRP > 2 mg/L
P-value
0.5
0.02
Total Mortality
hsCRP < 2 mgL
hsCRP > 2 mg/L
0.2
0.05
Coronary Endpoint
hsCRP < 2 mgL
hsCRP > 2 mg/L
0.3
0.017
Hosp. Worsening CHF
hsCRP < 2 mgL
hsCRP > 2 mg/L
0.4
0.009
Morality/HF Hosp.
hsCRP < 2 mgL
hsCRP > 2 mg/L
0.3
0.006
0.5
1.0
1.5
Rosuvastatin
Superior
Rosuvastatin
Inferior
McMurray JV et al, Circulation 2009;

39. Public Health Implications
JUPITER
Public Health Implications
Exercise, diet, and smoking cessation remain the first
interventions for those with elevated LDLC or hsCRP.
However, 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.
Simplified guidelines that advocate combined lifestyle and
pharmacologic therapy in those groups where trial evidence
clearly supports a net benefit have the potential to greatly
improve patient care and public health.
With thanks to the 17,802 patients and the >1,000 physicians worldwide for their effort and commitment to the JUPITER trial program.

40. Public Health Implications
JUPITER
Public Health Implications
Low LDL, Low hsCRP
Low LDL, High hsCRP
Low LDL, Low hsCRP
Low LDL, High hsCRP
[A]
[B]
0.5
1.0
2.0
New Engl J Med 2001;344:
0.5
1.0
2.0 RR
Statin Effective
Statin Not Effective
We must rely on hard clinical trial evidence to inform clinical
guidelines and compute cost-effectiveness. Making
assumptions about the net benefit to risk ratio for statins in
specific patient groups where contradicting data exist (such as
those with low LDLC and low hsCRP) is unwarranted
and will lead to claims that we are promoting pharmaceutical
use in the absence of evidence.