North American Menopause SocietyPresidential Plenary Symposium:

New Findings from the Kronos Early Estrogen Prevention Study (KEEPS) Randomized Trial

• Overview: KEEPS Rationale, Design, and Study PopulationJoAnn E. Manson, MD, DrPHBrigham and Women’s HospitalHarvard Medical School

• KEEPS Biomarker and Vascular Imaging FindingsS. Mitchell Harman, MD, PhDKronos Longevity Research InstitutePhoenix VA Health Care System

• KEEPS Cognitive Function and Mood/Affective OutcomesSanjay Asthana, MD, FACP, FCRPUniversity of WisconsinNIA/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 42-59 (mean age, 52.7, within 3 yrs of FMP)Trial Duration = 48 monthsMulti-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=0.0497

Mean SD

Age 52.7 2.6 Yrs since menopause 1.43 0.7BMI (kg/m2) 26.2 4.3Systolic BP (mm Hg) 119 15Diastolic BP (mm Hg) 75.0 9.2Total cholesterol (mg/dl) 208 34LDL cholesterol (mg/dl) 111 28HDL cholesterol (mg/dl)† 72.0 15 (p <0.05)

KEEPS Baseline Characteristics*

* Unless otherwise noted, there were no differences between treatment groups at baseline.

KEEPS Baseline Characteristics*

Race/EthnicityWhite 77%African-American 7%Hispanic 7%Asian 3%Other 6%

EducationNo college degree 28%Bachelor’s degree 40%>4 years college 32%

Prior Hormone UseNever 79%Current/Past 21%

SmokingNever 76%Current/Past 24%

* Unless otherwise noted, there were no differences between treatment groups at baseline.

Changes in Risk Factors, Blood Pressure

p=NS

p=NS

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

p=NS

Summary: Direction of Changes in Risk Factors*

* Relationship of some factors to CVD risk equivocal or subsidiary to related factors

Factor O-CEE T-E2Systolic BP Neutral NeutralDiastolic BP Neutral NeutralLDL Cholesterol Favorable NeutralTriglycerides Adverse NeutralHDL Cholesterol Favorable Neutral (?)Fasting Glucose Neutral FavorableHOMA-IR Neutral FavorableIL-6 Neutral NeutralCRP Adverse Neutral

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

p=NS

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

p=NS

Percent of Subjects with Increases in CAC Score ≥ 5 Agatston Units

o-CEE t-E2 Placebo o-CEE t-E2 Placebo o-CEE t-E2 Placebo

p=NS

p=NS

p=NS

Serious Adverse Events Probably or Possibly Related to HT

Event o-CEE t-E2 Placebo p Value*

Cardiovascular Disease (MI) 0 1 0 0.43Stroke 0 0 0 N/AVenous Thrombotic Disease 0 1 1 0.72Breast Cancer 3 3 2 0.70Endometrial Cancer 2 1 0 0.45Endometrial Hyperplasia 2 1 1 0.99Deaths (all cause) 1 0 0 0.44

*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

-7

-6

-5

-4

-3

-2

-1

0 o-CEE t-E2 Placebo

Month

Mea

n Ch

ange

Sco

re

18 36 48

* p < 0.05Better

Change from Baseline on POMS Depression-Dejection

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

1.5

*

o-CEE t-E2 Placebo

Month

Mea

n Ch

ange

Sco

re

18 36 48

* p < 0.05Better

Change from Baseline on POMS Tension-Anxiety

18 36 48

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