North American Menopause Society Presidential Plenary Symposium: New Findings from the Kronos Early Estrogen Prevention Study (KEEPS) Randomized Trial Overview: KEEPS Rationale, Design, and Study Population JoAnn E. Manson, MD, DrPH Brigham and Women’s Hospital Harvard Medical School KEEPS Biomarker and Vascular Imaging Findings S. Mitchell Harman, MD, PhD Kronos Longevity Research Institute Phoenix VA Health Care System KEEPS Cognitive Function and Mood/Affective Outcomes Sanjay Asthana, MD, FACP, FCRP University of Wisconsin NIA/NIH Wisconsin Alzheimer’s Dis. Research Ctr

The core KEEPS was funded by the Phoenix-based Kronos Longevity Research Institute, which is supported by the not-for-profit Aurora Foundation, and was conducted at 9 U.S. academic medical centers. The KEEPS Cognitive Ancillary Study was supported by a grant from the National Institute on Aging, NIH. Support

Principal Investigators S. Mitchell Harman (KEEPS Director, KLRI) Frederick Naftolin (KEEPS Co-Director, NYU) Eliot A. Brinton/Paul Hopkins (U. of Utah) Marcelle I. Cedars (UCSF) Rogerio A. Lobo (Columbia) JoAnn E. Manson (Harvard) George R. Merriam (VA Puget Sound/U. of Washington) Virginia M. Miller (Mayo Clinic) Nanette Santoro (U. of Colorado)/Genevieve Neal-Perry (Einstein) Hugh S. Taylor (Yale) Core Investigators and Ancillary Study Centers Sanjay Asthana (Cognitive Study PI, U. of Wisconsin) Dennis M. Black (Biostatistical Center, UCSF) Matthew J. Budoff (CAC Reading Center, UCLA) Howard N. Hodis (CIMT Reading Center, USC) Kronos Early Estrogen Prevention Study (KEEPS)

N = 727 women aged (mean age, 52.7, within 3 yrs of FMP) Trial Duration = 48 months Multi-center double-blinded placebo-controlled RCT Treatment Arms: Oral conjugated equine estrogens (o-CEE) given as Premarin®, 0.45 mg/d (lower dose than WHI) Transdermal Estradiol (t-E2) given by Climara® patch, 50 µg/d Placebo (active arms received cyclical micronized progesterone [Prometrium®], 200 mg/d x 12 days/month; placebo arm received placebo Prometrium) KEEPS Study Design

KEEPS: Specific Aims To compare effects of oral vs transdermal estrogen vs placebo on: 1)Atherosclerosis progression as assessed by Carotid IMT 2)Development/progression of coronary artery calcium (CAC) Other CVD risk factors/biomarkers (BP, lipids, HOMA-IR) Cognition and mood/depression (Ancillary Study) Vasomotor symptoms, sexual function, QOL Bone mineral density Mammographic breast density/breast outcomes (Ancillary Study )

42-59 years of age at randomization Final menses <3 years earlier Good general health Plasma FSH ≥ 35 mIU/ml and/or E2 levels <40 pg/ml Normal mammogram within one year before randomization Inclusion Criteria

† p= MeanSD Age Yrs since menopause BMI (kg/m 2 ) Systolic BP (mm Hg)11915 Diastolic BP (mm Hg) Total cholesterol (mg/dl)20834 LDL cholesterol (mg/dl)11128 HDL cholesterol (mg/dl) † (p <0.05) KEEPS Baseline Characteristics* *Unless otherwise noted, there were no differences between treatment groups at baseline.

KEEPS Baseline Characteristics* Race/Ethnicity White77% African-American7% Hispanic7% Asian3% Other6% Education No college degree28% Bachelor’s degree40% >4 years college32% Prior Hormone Use Never79% Current/Past21% Smoking Never76% Current/Past24% *Unless otherwise noted, there were no differences between treatment groups at baseline.

Changes in Risk Factors, Blood Pressure

Changes in Risk Factors, LDL Cholesterol & Triglycerides

Changes in Risk Factors, HDL Cholesterol Levels * * * * * Month

Changes in Risk Factors, Fasting Blood Sugar & Insulin Resistance

Changes in Risk Factors, CRP & IL-6

Summary: Direction of Changes in Risk Factors* * Relationship of some factors to CVD risk equivocal or subsidiary to related factors FactorO-CEET-E2 Systolic BPNeutral Diastolic BPNeutral LDL CholesterolFavorableNeutral TriglyceridesAdverseNeutral HDL CholesterolFavorableNeutral (?) Fasting GlucoseNeutralFavorable HOMA-IRNeutralFavorable IL-6Neutral CRPAdverseNeutral

Ultrasound Measurement of CIMT Thickness of the common carotid artery intima-media layers measured by ultrasound (CIMT). Hodis HN, et al. Distal Far Wall CCA Gray ’ s Anatomy, 1918, fig. 507 Arterial Lumen

Changes in Imaging Endpoints, CIMT

Coronary Artery Calcium (CAC) by CAT Scan Linear calcification in the left coronary artery in a KEEPS participant, Mayo Clinic

CAC Agatston Scores at Baseline O- T- o-CEE t-E2 Placebo

Percent of Subjects with Increases in CAC Score ≥ 5 Agatston Units o-CEE t-E2 Placebo

Serious Adverse Events Probably or Possibly Related to HT Evento-CEEt-E2Placebop Value* Cardiovascular Disease (MI) Stroke000N/A Venous Thrombotic Disease Breast Cancer Endometrial Cancer Endometrial Hyperplasia Deaths (all cause) *Calculated by Chi Square (with Yates’ correction) for both estrogen groups pooled vs. placebo (2 x 2 table)

Significant o-CEE by Risk interaction for the Verbal Learning and Memory Factor Women at “low” CVD risk receiving the o- CEE drug therapy were significantly more likely than the Placebo group to improve on Verbal learning and memory ability across time. Results: Cognition and Cardiovascular Risk Profile

Results: Tests of Mood and Affect Profile of Mood States (POMS) Total Score Depression-Dejection Tension-Anxiety

Change from Baseline on Total POMS * p < 0.05 Better

Change from Baseline on POMS Depression-Dejection * p < 0.05 Better

Change from Baseline on POMS Tension-Anxiety Better * p < 0.05

Both o-CEE and t-E2 had favorable effects on vasomotor sx, sexual function, QOL, bone density (presented elsewhere). Both had neutral effects on BP (adverse effect in WHI). Both had generally favorable or neutral effects on CVD biomarkers (but differences related to first-pass liver metabolism). Both had neutral effects on CIMT and CAC (but ns trend for latter). Both had neutral effects on cognition (adverse effect in WHI, age >65). Differences: o-CEE improved mood, t-E2 improved HOMA-IR and some advantages for sexual function. KEEPS highlights the need for individualized decision making about HT, given different treatment priorities and risk factor status of women. Additional research on HT in newly menopausal women, including different formulations/doses/routes of delivery, is needed. Overall Summary and Conclusions