Statins for the Primary Prevention of CVD in Women with Elevated hsCRP or Dyslipidemia: Results from JUPITER and Meta-Analysis of Women from Primary Prevention.

Statins for the Primary Prevention of CVD in Women with Elevated hsCRP or Dyslipidemia:

Results from JUPITER and Meta-Analysis of Women from Primary Prevention Statin Trials

Samia Mora, Robert J Glynn, Judith Hsia, Jean G MacFadyen,Jacques Genest, and Paul M Ridker

Brigham and Women’s HospitalHarvard Medical School

Boston, MA

on behalf of the JUPITER Trial Study Group

Circulation 2010; 121:1069-1077

Sources of FundingSources of Funding

The JUPITER Trial is an investigator-initiated study sponsored by AstraZeneca; The JUPITER Trial is an investigator-initiated study sponsored by AstraZeneca; The sponsor played no role in the conduct of the analyses or drafting of the paper.The sponsor played no role in the conduct of the analyses or drafting of the paper.

Author Disclosures Related to this PresentationAuthor Disclosures Related to this PresentationS Mora:S Mora: NHLBI (K08 HL094375),NHLBI (K08 HL094375), Merck, AstraZeneca (Research Grant, Merck, AstraZeneca (Research Grant,

Significant)Significant)

RJ Glynn:RJ Glynn: AstraZeneca, Bristol-Myers Squibb (Research Grant, Significant)AstraZeneca, Bristol-Myers Squibb (Research Grant, Significant)

J Hsia:J Hsia: Employed by AstraZeneca Employed by AstraZeneca

J Genest: J Genest: Merck, AstraZeneca,Resverlogix (Research Grant, Significant); Merck, Merck, AstraZeneca,Resverlogix (Research Grant, Significant); Merck, AstraZeneca, GlaxoSmithKline (Speaker’s Fees)AstraZeneca, GlaxoSmithKline (Speaker’s Fees)

PM Ridker:PM Ridker: Dr. Ridker is listed as a co-inventor on patents held by the Dr. Ridker is listed as a co-inventor on patents held by the Brigham and Women’s Hospital that relate to the use of Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to Siemens and AstraZeneca. diabetes that have been licensed to Siemens and AstraZeneca. Dr. Ridker also receives research grant support Dr. Ridker also receives research grant support (Significant) from AstraZeneca, Novartis, Merck, Roche, Sanofi-Aventis, (Significant) from AstraZeneca, Novartis, Merck, Roche, Sanofi-Aventis, non-financial support from Amgen,non-financial support from Amgen, and serves as consultant for AstraZeneca, Isis, Merck, Novartis, Sanofi-Aventis, Schering-Plough, Siemens, Novartis, Merck, Isis, and Vascular Biogenics

Background

Statins for patients with CVD is established• Similar benefit in women, men• Relative risk reduction ~20-30%

Statins for women with no CVD is controversial• Prior meta-analyses: non-significant • RR CHD events 0.87 (0.22-1.68), P=0.17

N = 11, 435 women

Walsh and Pignone, JAMA 2004;2243

Objectives

1. Pre-specified analysis in JUPITER for efficacy and safety of rosuvastatin in women and men with elevated hsCRP and non-elevated LDL cholesterol

2. Updated meta-analysis of statin therapy for primary prevention of CVD in women

JUPITERTrial Objective

To investigate whether rosuvastatin 20 mg vs placebo decreases major CVD eventsin apparently healthy men and women with LDL < 130 mg/dL (3.36 mmol/L) who are at increased vascular risk due to enhanced inflammatory response, with hsCRP > 2 mg/L

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

Ridker PM et al NEJM 2008;2195

Rosuvastatin 20 mg (N=8901)Rosuvastatin 20 mg (N=8901) MIMIStrokeStroke

UnstableUnstable AnginaAngina

CVD DeathCVD DeathCABG/PTCACABG/PTCA

6,801 women >> 60 60 years11,001 men >> 50 50 years

1,315 sites, 26 countries

4-week 4-week run-inrun-in

No Prior CVD or DMNo Prior CVD or DMMen Men >>50, Women 50, Women >>6060

LDL <130 mg/dL hsCRP >2 mg/L

JUPITERTrial Design

Placebo (N=8901)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

Ridker PM et al NEJM 2008;2195

JUPITERInclusion 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




Ridker et al NEJM 2008

Statistical Methods

1. JUPITERIntention to treat sex-specific Cox regression,pre-specified in trial protocol

P values from Wilcoxon 2 sample, chi2,heterogeneity (likelihood ratio tests)

2. Meta-analysis

Random-effects regression models, tests for heterogeneity

Mora S et al Circulation 2010; 1069

JUPITERBaseline Clinical Characteristics

Women Men(N = 6801) (N = 11001)

Age, years (IQR) 68.0 (65.0-73.0) 63.0 (58.0-70.0)

Ethnicity, % Caucasian 61.7 77.1 Black 15.9 10.4 Hispanic 18.9 8.8

BMI, kg/m2 (IQR) 29.2 (25.7-33.2) 27.9 (25.1-31.2)

Hypertension, % 62.7 54.1

Smoker, % 7.6 21.0

Family History, % 12.2 11.1

Metabolic Syndrome, % 46.7 38.7

All values are median (interquartile range) or %Mora S et al Circulation 2010; 1069

JUPITERBaseline Blood Levels (median, interquartile range)

Women Men(N = 6801) (N = 11001)

hsCRP, mg/L 4.6 (3.1 - 7.7) 4.1 (2.7 – 6.8) LDL, mg/dL 109 (96 - 120) 108 (93 - 119)

HDL, mg/dL 54 (46 – 66) 45 (38 – 55)

Triglycerides, mg/L 118 (88 - 163) 118 (84 - 174)

Total Cholesterol, mg/dL 192 (175 - 205) 182 (165 - 195)

Glucose, mg/dL 93 (87 – 101) 95 (88 – 102)

HbA1c, % 5.8 (5.5 – 6.0) 5.6 (5.4 – 5.9)

All values are median (interquartile range).


JUPITEREffects of rosuvastatin 20 mg on lipids and hsCRP at 12 months

Women Men Rosuva Placebo Rosuva Placebo

hsCRP, mg/L - 1.8 - 0.6 - 1.7 - 0.8 (- 3.6, - 0.6) (- 2.2, +0.8) (- 3.4, - 0.4) (- 2.5, +0.8)

LDL, mg/dL - 51 + 4 - 49 + 3 (- 65, - 27) (- 7, +17) (- 62, - 29) (- 9, +15)

HDL, mg/dL + 3 + 1 + 3 + 1 (- 2, + 8) (- 4, + 6) (- 2, + 8) (- 3, + 5)

Triglycerides, mg/L - 17 - 1 - 16 + 2 (- 44, + 3) (- 23, +21) (- 50, +7) (- 26, +27)

Total Cholesterol, mg/dL - 51 + 4 - 50 + 3 (- 68, - 27) (- 9, +19) (- 66, - 28) (- 9, +17)

All values are median (interquartile range) change from baseline to 12 months


JUPITERPrimary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

Rosuva Placebo

No. (Rate)* No. (Rate)* HR 95% CI P for heterogeneity

Women 39 (0.56) 70 (1.04) 0.54 0.37-0.80

P=0.002 0.80

Men 103 (0.88) 181 (1.54) 0.58 0.45-0.73

P<0.0001

* Rates are per 100 person-years


JUPITERPrimary Trial Endpoint : Number Needed to Treat (5-years)

Rosuva Placebo

No. (Rate) No. (Rate) NNT*

Women 39 (0.56) 70 (1.04) 36

Men 103 (0.88) 181 (1.54) 22

All142 (0.77) 251 (1.36)

25

* Calculated based on the method of Altman and Andersen


JUPITERComponents of the Primary Endpoint

Endpoint Women Men P for Heterogeneity

Primary Endpoint 0.54 0.58 0.80 0.37 - 0.80 0.45 - 0.73

Nonfatal MI 0.56 0.29 0.24 0.24 - 1.33 0.16 - 0.54

Nonfatal Stroke 0.84 0.33 0.040.45 – 1.58 0.17 – 0.63

MI, Stroke, CVD Death 0.73 0.44 0.060.48 – 1.13 0.31 – 0.61

Revasc/Unstable Angina 0.24 0.63 0.010.11 – 0.51 0.46 – 0.85

All-cause Death 0.77 0.82 0.740.55 – 1.06 0.66 – 1.03Mora S et al Circulation 2010; 1069

0.20 0.5 1.0 2.0

Rosuvastatin Superior Rosuvastatin Inferior

Women

Metabolic SyndromeYesNo

ATP-III Risk Factors0 > 1

LDL < 100>100

HDL< 50> 50

Triglycerides<150> 150

hsCRP<5> 5

Time of Event< 24 Months>24 Months

All Participants

3,157 3,605

3,072 3,716

2,216 4,585

2,451 4,350

4,690 2,111

3,687 3,114

6,801 2,537

6,801

58 51

47 62

36 73

48 61

69 40

61 48

87 22

109

Age<65 > 65

Race/ethnicityWhiteNonwhite

SmokerYesNo

HypertensionYesNo

BMI<25.025.0-29.9> 30.0

Family Hx YesNo

N

1,942 4,859

4,197 2,604

515 6,283

4,263 2,536

1,412 2,335 3,043

829 5,949

# ofEvents

14 95

79 30

19 90

82 27

30 41 38

17 92

Incidence Rates(Placebo)

0.491.22

1.160.81

2.580.92

1.280.66

1.311.250.76

1.570.96

1.061.04

0.931.14

1.141.00

1.250.93

1.031.08

1.120.95

1.011.20

1.04


0.20 0.5 1.0 2.0

Rosuvastatin Superior Rosuvastatin Inferior

Incidence Rates

Men

Age<65 > 65

Race or ethnic groupWhiteNonwhite

SmokerYesNo

HypertensionYesNo

BMI<25.025.0-29.9> 30.0

Family Hx of CHDYesNo

Metabolic SyndromeYesNo

ATP-III Risk Factors0 > 1

LDL < 100>100

HDL <40≥40

Triglycerides<150> 150

hsCRP<5> 5

Time of Event< 24 Months>24 Months

All Participants

N

6,599 4,402

8,486 2,513

2,305 8,692

5,945 5,050

2,661 4,674 3,631

1,216 9,735

4,218 6,691

3,303 7,683

4,053 6,943

3,238 7,762

7,275 3,725

6,771 4,230

11,001 5,228

11,001

# ofEvents

118166

233 51

75209

173111

81120 82

48235

110172

70213

104180

84200

189 95

150134

208 76

284

(Placebo)

1.152.13

1.571.41

2.191.39

1.781.25

1.971.611.20

2.361.43

1.461.59

1.111.74

1.441.59

1.611.51

1.551.52

1.381.79

1.362.32

1.54


JUPITERAdverse Events and Measured Safety Parameters

Event Women Men Rosuva Placebo Rosuva Placebo

Any SAE 7.7 7.4 7.6 7.9Muscle weakness 8.9 8.3 8.1 7.9Myopathy 0.07 0.06 0.04 0.04Rhabdomyolysis 0 0 0.01 0Incident Cancer 1.4 1.4 0.2 0.2Cancer Deaths 0.2 0.2 0.2 0.3Hemorrhagic stroke 0.04 0.04 0.02 0.05

GFR (ml/min/1.73m2 at 12 mth) 64.1 64.2 71.0 70.5ALT > 3xULN 0.04 0.07 0.16 0.10

Fasting glucose (24 mth) 96 95 99 99HbA1c (% at 24 mth) 5.9 5.9 5.9 5.8Incident Diabetes* 1.5 1.0 1.4 1.2

All values are medians or rates per 100 person-years*Physician reported, P for heterogeneity by sex = 0.16 Mora S et al Circulation 2010; 1069

Meta-analysis of Exclusively Primary Prevention Statin Trials in Women

.1 .5 1 5 10

AFCAPS/TexCAPS 1998

MEGA 2006

JUPITER 2008

0.63 (0.49-0.82) P<0.001P for heterogeneity 0.56ALL

Favors Statin Favors Placebo

(0.34-1.31)

(0.49-1.10)

(0.37-0.80)

21/498

56/2718

70/3375

14/499

40/2638

39/3426

RR 95% CI Placebo Statin

0.67

0.73

0.54

Year

13 154 Women, 240 CVD events


Study Limitations

JUPITER median follow-up 1.9 years (max 5)

Limited long-term safety data for rosuvastatin

Low absolute event rates in women <65 years

Meta-analysis: degree of LDL cholesterol lowering differed


Conclusions – JUPITER sex-specific analysis

Among apparently healthy women with elevated hsCRP and non-elevated LDL cholesterol, rosuvastatin resulted in similar and significant relative risk reduction in CVD compared with men

Women had lower absolute event rates, especially <65 years old

Women had more benefit for revascularization / unstable angina, men had more benefit for stroke

Subgroup analysis suggested women with family history of premature CHD benefit more than those without family history

Higher physician-reported diabetes in women compared with men,but test for heterogeneity by sex non-significant

Overall safety in women similar to men Mora S et al Circulation 2010; 1069

JUPITERConclusions – Meta-Analysis

For primary prevention of CVD in women, statin allocation yielded significant relative risk reduction by one third

This relative risk reduction is similar to prior results in men for primary prevention and men or women for secondary prevention

These findings may have guideline implications for statin therapy in apparently healthy women meeting JUPITER entry criteria, even without high risk Framingham scores


Statins for the Primary Prevention of CVD in Women with Elevated hsCRP or Dyslipidemia: Results from JUPITER and Meta-Analysis of Women from Primary Prevention.

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