Do Women Benefit From Statins for Primary Prevention?: Controversy, Challenges and Consensus C. Noel Bairey Merz MD, FACC, FAHA Professor and Women s Guild Endowed Chair Director, Barbra Streisand Women s Heart Center Director, Preventive Cardiac Center Cedars-Sinai Heart Institute Los Angeles, California, USA merz@cshs.org
Presenter Disclosure Information DISCLOSURE INFORMATION: The following relationships exist related to this presentation (*paid to CSMC): Grant support*: NHLBI, SWHR, Gilead Consulting*: Interquest, Dannemiller, Navvis, Voxmedia, BMS, Springer, Italian NIH Honorarium*: Gilead, Novant Health, Huntworth Health, Pri-Med, NAMS Stocks: None
CONTROVERSY PRIMARY PREVENTION 2004 Statins for secondary prevention is established Similar benefit in women, men Relative risk reduction ~20-30% Statins for primary prevention in women is controversial Prior meta-analyses: non-significant RR CHD events 0.87 (0.22-1.68), P=0.17 N = 11, 435 women Absence of data is not the same as negative data Walsh and Pignone, JAMA 2004;2243
Meta-analysis of Exclusively Primary Prevention Statin Trials in Women 2010 13 154 Women, 240 CVD events Year RR 95% CI Placebo Statin AFCAPS/TexCAPS 1998 0.67 (0.34-1.31) 21/498 14/499 MEGA 2006 0.73 (0.49-1.10) 56/2718 40/2638 JUPITER 2008 0.54 (0.37-0.80) 70/3375 39/3426 ALL P for heterogeneity 0.56 0.63 (0.49-0.82) P<0.001.1.5 1 5 10 Mora S et al Circulation 2010; 1069 Favors Statin Favors Placebo
Ongoing Controversy Statin Debate- JAMA April 2012
Evidence for benefit of primary prevention in women? No Statistically significant benefit for: Non fatal MI Coronary Heart Disease death All Cause Mortality Statistically Significant improvement in: hospitalization for unstable angina coronary revascularization
JUPITER Women vs Men Components 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 0.04 0.45 1.58 0.17 0.63 MI, Stroke, CVD Death 0.73 0.44 0.06 0.48 1.13 0.31 0.61 Revasc/Unstable Angina 0.24 0.63 0.01 0.11 0.51 0.46 0.85 All-cause Death 0.77 0.82 0.74 Mora S et al Circulation 2010; 1069 0.55 1.06 0.66 1.03
JUPITER Women (and Non-White) are Subgroups Trial Design Ridker PM et al NEJM 2008;2195 6,801 women > 60 years 11,001 men > 50 years Half as many women as men; 40% all subjects non-white CHALLENGES - SUBGROUP ANALYSIS Low Sample Size - wide confidence intervals and low precision Low Event Rates - reduce sensitivity to detect effect accurately Limited Trial Duration - lower relevance to lifetime risk
Men Sample Size, Confidence Intervals and Precision Sh Age <65 > 65 Race or ethnic group White Nonwhite Smoker Yes No Hypertension Yes No BMI <25.0 25.0-29.9 > 30.0 Family Hx of CHD Yes No Metabolic Syndrome Yes No ATP-III Risk Factors 0 > 1 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 # of Events 118 166 233 51 75 209 173 111 81 120 82 48 235 110 172 70 213 Incidence Rates (Placebo) 1.15 2.13 1.57 1.41 2.19 1.39 1.78 1.25 1.97 1.61 1.20 2.36 1.43 1.46 1.59 1.11 1.74 Should we withhold treatment for non-white men (who are our highest risk men) due to low precision? LDL < 100 >100 4,053 6,943 104 180 1.44 1.59 HDL <40 40 Triglycerides <150 > 150 hscrp <5 > 5 Time of Event < 24 Months >24 Months All Participants 3,238 7,762 7,275 3,725 6,771 4,230 11,001 5,228 11,001 84 200 189 95 150 134 208 76 284 1.61 1.51 1.55 1.52 1.38 1.79 1.36 2.32 1.54 Mora S et al Circulation 2010; 1069 0.20 0.5 1.0 2.0 4
Women: Sample Size, Confidence Intervals and Precision Age <65 > 65 Race/ethnicity White Nonwhite Smoker Yes No Hypertension Yes No BMI <25.0 25.0-29.9 > 30.0 Family Hx Yes No Metabolic Syndrome Yes No ATP-III Risk Factors 0 > 1 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 3,157 3,605 3,072 3,716 # of Events 14 95 79 30 19 90 82 27 30 41 38 17 92 58 51 47 62 Incidence Rates (Placebo) 0.49 1.22 1.16 0.81 2.58 0.92 1.28 0.66 1.31 1.25 0.76 1.57 0.96 1.06 1.04 0.93 1.14 Should we withhold treatment for women (the majority of victims) due to low precision? LDL < 100 >100 2,216 4,585 36 73 1.14 1.00 HDL < 50 > 50 Triglycerides <150 > 150 2,451 4,350 4,690 2,111 48 61 69 40 1.25 0.93 1.03 1.08 hscrp <5 > 5 Time of Event < 24 Months >24 Months All Participants 3,687 3,114 6,801 2,537 6,801 61 48 87 22 109 1.12 0.95 1.01 1.20 1.04 Mora S et al Circulation 2010; 1069 0.20 0.5 1.0 2.0 Rosuvastatin Superior Rosuvastatin Inferior
JUPITER Event Rates and Accuracy Primary Trial Endpoint : Number Needed to Treat (5-years) Mora S et al Circulation 2010; 1069 Women have lower event rates Rosuva Should we withhold treatment for women due to low accuracy? Placebo No. (Rate) No. (Rate) NNT* Women 39 (0.56) 70 (1.04) 36 Men 103 (0.88) 181 (1.54) 22 All 142 (0.77) 251 (1.36) 25 * Calculated based on the method of Altman and Andersen
JUPITER Pre-specified tests of heterogeneity** Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death CONCLUSION: Similar to secondary prevention, women and men in primary prevention have equivalent risk reduction 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 Men 103 (0.88) 181 (1.54) 0.58 0.45-0.73 P=0.002 0.80 P<0.0001 * Rates are per 100 person-years; ** Intention to treat sex-specific Cox regression, pre-specified in trial protocol, p values from Wilcoxon 2 sample, chi 2, heterogeneity (likelihood ratio tests) Mora S et al Circulation 2010; 1069
Limited Trial Duration and Lower Relevance to Lifetime Risk a clinically relevant question Do patients typically live longer than: 5 year trial duration? 10 year Risk Score estimates? Should we be using Lifetime Risk?
ASCVD Risk Calculator New Threshold of 7.5% 10 yr risk for women and men 40.0 35.0 10-Year and Lifetime ASCVD Risks Lifetime risk for lifestyle counseling and future treatment consideration 30.0 Predicted Risk (%) 25.0 20.0 15.0 10.0 No treatment at 4% risk; re-assess annually 5.0 0.0 Your 10-Year ASCVD Risk (%) 10-Year ASCVD Risk (%) for Someone Your Age with Optimal Risk Factor Levels (shown above in column E) Your Lifetime ASCVD Risk* (%) Lifetime ASCVD Risk (%) for Someone at Age 50 with Optimal Risk Factor Levels (shown above in column E) http://my.americanheart.org/professional/statementsguidelines/prevention-guidelines_ucm_457698_subhomepage.jsp
NNT to prevent 1 CVD event over 10 years 120 110 100 90 80 70 60 50 40 30 20 10 Moderate & high intensity statins 2.5% CVD reduction vs new DM Similar benefit (RRR) and harm (NNH) in women and men Moderate intensity statin assumptions 35% RRR & NNH=100 5.0% 7.5% 10.0% 15.0% 20.0% 25.0% 0 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 10-year CVD risk NNH= 100 NNT to prevent 1 CVD event over 10 years High intensity statin assumptions 45%RRR & NNH=33 120 110 100 90 80 2.5% 70 60 50 5.0% 40 NNH= 30 33 20 7.5% 10 10.0% 15.0% 0 20.0% 25.0% 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 10-year CVD risk Number needed to harm (NNH) is lower for moderate intensity statins (simva, prava, lovastatin; more research needed in low potency statins in primary prevention lower risk groups for longer term risk reduction vs harm of increased diabetes.
Do Women Benefit from Statins for Primary Prevention: Controversy, Challenge and Consensus Controversy Subgroup data in women (and non-whites) remains controversial due to lack of adequate data Challenges Inadequate sample size, event rates and trial duration limit precision, accuracy and relevance of trial subgroup analyses Consensus Women (and other subgroups) should be treated accordingly to trial evidence of risk and benefit
Remaining Questions Research Needed (How, What and Why) How confident are we that statins DO NOT save lives in primary but DO save lives in secondary prevention (for women and men)? What do we value - Is reduction in revascularization and angina hospitalization, e.g. morbidity and cost justification for use of statins for primary prevention? Why are underpowered data sufficient to make treatment decisions on the 51% of the population that now comprise the majority of CVD victims (e.g. women)? Is it time to stop comparing women to men and fund an adequately powered primary prevention women only trial?* (*note: NIH 2010: breast cancer funding $674m for 40K annual deaths women CVD funding $173m for 419K annual deaths