statins for the primary prevention of cvd in women with elevated hscrp or dyslipidemia: results from...
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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
8,600 Completed Study120 Lost to follow-up
8,901 Included in Efficacy and Safety Analyses
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
8,857 Completed Study44 Lost to follow-up
8,901 Assigned to Rosuvastatin 20 mg
8,901 Assigned toPlacebo
8,864 Completed Study37 Lost to follow-up
8,901 Included in Efficacy and Safety Analyses
8,901 Included in Efficacy and Safety Analyses
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).
Mora S et al Circulation 2010; 1069
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
Mora S et al Circulation 2010; 1069
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
Mora S et al Circulation 2010; 1069
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
Mora S et al Circulation 2010; 1069
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
Mora S et al Circulation 2010; 1069
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
Mora S et al Circulation 2010; 1069
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
Mora S et al Circulation 2010; 1069
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
Mora S et al Circulation 2010; 1069
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
Mora S et al Circulation 2010; 1069