# Presentation: 552942

## National Institutesof Health

**National Institutes****of Health**
**National Heart, Lung, and Blood Institute**
**Women’s Health Initiative (WHI) Clinical Trials ****and Observational Study**
**Presentations by **
**WHI Principal Investigators **

## WHI Clinical Centers (40)

**WHI**** ****Clinical**** ****Centers (40)**

**Seattle, WA**

**Portland, OR**

**Sacramento, CA**

**Reno, NV**

**Oakland, CA**

**Stanford, CA**

**Los Angeles, CA**

**Orange, CA**

**Torrance, CA**

**Honolulu, HI**

**San Diego, CA**

**Tucson, AZ**

**San Antonio, TX**

**Houston, TX**

**Gainesville, FL**

**Miami, FL**

**Birmingham, AL**

**Atlanta, GA**

**Memphis, TN**

**Chapel Hill, NC**

**Winston-Salem, NC**

**Washington, DC**

**Cincinnati, OH**

**Columbus, OH**

**Pittsburgh, PA**

**Newark, NJ**

**Stony Brook, NY**

**Pawtucket, RI**

**Boston, MA**

**Worcester, MA**

**Bronx, NY**

**Buffalo, NY**

**Detroit, MI**

**Minneapolis, MN**

**Milwaukee, WI**

**Madison, WI**

**Iowa City, IA**

**Chicago, IL**

**Clinical Center**

**Minority Clinical Center**

## WHI CT Sample Size, Outcomes, Follow-up Women, aged 50-79         Total CT = 68,133 

**WHI CT Sample Size, Outcomes, Follow-up** Women, aged 50-79         **Total**** CT = 68,133**

**Diet Modification (DM) Trial**
-    Primary Outcomes:
-    Breast & Colorectal Cancer
-    Secondary Outcome:
-    Coronary Heart Disease (CHD)
**Hormone Trials**
-    **Primary Outcome:**** ****CHD**
-    Secondary Outcomes:
-    Hip Fracture, Breast Cancer
-    Ancillary Study: Memory

**11.8% Overlap**

**Average 8.5 year**
**Follow-up**

**Average**
**8.5 year**
**Follow-up **

**DM**
**48,836**

**Hormone**
**27, 347**

## WHI CaD: Outcomes, Relationship to CT

**WHI CaD: Outcomes, Relationship to CT**

** ****Calcium + Vitamin D (CaD)**
-     Primary Outcome: Hip Fracture
-     Secondary Outcomes:
-      Other Fractures, Colorectal Cancer

**CaD**
**36,****282**** **

- at 1st (or 2nd)
- Annual Visit

- Total CT = **68,133**

- 53.3% of CT

**Hormone**
**27, 347**

**DM**
**48,836**

## WHI: Relationship of OS to CT

**WHI: Relationship of OS to CT**

**OS**
**93, 676**

- The Observational Study (OS) is a complement to the Clinical Trial

**Total WHI _x0008_Sample (CT+_x0008_OS) = 161,809**

- Women screened for the DM or HT trials could enroll in the OS, if they were ineligible for the CT, or chose not to join either DM or HT trials.

- Purpose of OS
-   To improve risk prediction of cardiovascular disease, cancers, fractures, and all-cause mortality (death) in postmenopausal women
-    To create a resource of data and biological samples which can be used to identify new risk factors and/or disease biomarkers
-   To examine impact of changes in lifestyle and risk factors on disease and mortality

## The Women’s Health Initiative (WHI) Postmenopausal Hormone Program: Background and Rationale 

**The Women’s Health Initiative (WHI) Postmenopausal Hormone Program: Background and Rationale**** **

**Marcia L. Stefanick, Ph.D.**** **
**Associate Professor of Medicine and of Gynecology and Obstetrics, Stanford University**
**PrincipaI Investigator, Stanford**
**Chair, WHI Steering Committee**

## A Brief History of Hormone Therapy

**Progestins ****protect ****uterus**

**E** associated with **lower CHD**

**E** associated with **fewer fractures; ****higher BMD**

**E** associated with** **
**higher breast cancer**

**Observational Studies** suggest **Benefits > Risks**

**1942: FDA approved Estrogen ****for treatment of menopausal symptoms**

**CEE in men: blood clots, heart attacks**

**E** associated with** ****uterine cancer**

**“****Feminine forever”**

**Prescriptions (Millions)**

**1997**:** HERS-**** E+P**
**blood clots**
**1998: HERS **
**1****st**** yr **= **heart attacks; no 4yr benefit**
**2001: AHA **position

**OCs **associated with** blood clots, heart attacks**

**2000: Br CA  E+P > E only**

**1995**:** PEPI **
**E vs E+P**

**E+P ****lower CHD**

## Observational Studies are Biased

**Observational Studies are Biased**

**Women who use Hormones over an extended time differ from those who don’t, in many ways besides HT use. ****Compared to non-users,  estrogen users are generally:**
**Literature is based mostly on estrogen without progestin**

-    **less obese**
**   ****less likely to smoke**
**   ****more physically active**
**   ****more highly educated**
**   ****more likely to go to doctors regularly **
**    ****more likely to check cholesterol, BP, etc. ****	****(& have mammograms & other screening)**
**  ****less likely to consume high fat diet and salt**

**Differences could explain why hormone users have a lower CHD**

## WHI Hormone Trials: Specific Aims

- To test whether** Estrogen + Progestin**** ****(E+P)**** - or-  Estrogen Only (E-Alone)**
**reduce the incidence of Coronary Heart Disease and other Cardiovascular Disease**
**reduce the incidence of all osteoporosis-related fractures and hip fractures, separately**
**increase the risk of breast cancer**
- To determine the** balance of risks and benefits of menopausal hormones on the overall health** of postmenopausal women.

## WHI Hormone Program Study Population: Inclusion criteria

**Age 50-79 at baseline**
**Post menopausal**, defined as:
**No uterine bleeding for >6 months**
- 	(>12 mo, if aged 50-54)
**Current/prior use of menopausal hormones**
**Post hysterectomy with symptoms**
- Likely to reside in the clinic area for 3 years
**Willing to provide written informed consent**

## WHI Estrogen+Progestin TrialBackground circa 1992

**Suspected ****benefits**** of hormones:**
****** **risk of** Coronary Heart Disease (CHD)**
****** **risk of** Osteoporotic (hip/other) Fracture**
- ( risk of colorectal cancer, *suspected later)*
**Suspected ****risks**** of hormones:**
****** **risk of** Breast Cancer**
****** **risk of** Blood Clots: Pulmonary Emboli ****(lungs),**** Deep Vein Thromboses ****(legs)****     **
*	**(based on Oral Contraceptive literature, later, HERS)*

## *

**Hysterectomy**

**CEE (Conjugated equine estrogens) 0.625 mg/d**** **

**CEE 0.625 mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d**** **

**N= 16,608**

**N= 10,739**

**YES**

**NO**

**Placebo**

**Placebo**

*****

*** ****Initially: CEE only (N=331), CEE+_x0008_MPA, or Placebo_x0008__x0008_**

## WHI Hormone Sample Size, Outcomes, Follow-up Women, aged 50-79      Total HT trials = 27,347 

**E only**
**10,739**

- WHI Hormone Sample Size, Outcomes, Follow-up Women, aged 50-79      Total HT trials = 27,347

**Hormone Trials**
-    **Primary Outcome:**
-      Coronary Heart Disease
-    **Secondary Outcomes:**
-      Hip Fracture; Other Fractures
-      Breast & Endometrial Cancers
-    WHI Memory Study (WHIMS)
-       - *for women 65+* - Memory

**Average Follow-up 5.2 years**

**Average **
**8.5 years**

**E+P**
**16,608**

## WHI HRT:  Baseline Age DistributionMean ± SD: HystX-E only = 63.6 ± 7.3; Uterus-E+P = 63.3 ± 7.1

**WHI HRT:  Baseline Age Distribution**Mean ± SD: **HystX-E only = 63.6** ± 7.3; **Uterus-E+P = 63.3** ± 7.1

**60-69**
**E****=****45%; E+P****=****45%**

**70-79**
**E****=****24%; E+P****=****22%**

**50-59**
**E=31%; E+P=33%**

## WHI HRT: Minority Distribution    HystX: 2657/10,739 (24.7%)  Uterus: N = 2663/16,608 (16.0%)Total HRT: N = 5320/27,347 (19.5%)

## Estrogen+Progestin Study Participants

**16,608 women joined this part of the study**.
- The E + P trial was **for women who still had a uterus when they joined**** **WHI Hormone Study**  **
- Participants were **assigned by chance **to take active E+P or inactive (placebo) pills.
- The **estrogen plus progestin combination we studied is identical to Prempro® **
- 	***(The estrogen is identical to the most common dose of Premarin®)***

## Outcomes Monitored by DSMB

**Cardiovascular disease**
**Heart attacks ****(Coronary Heart Disease, CHD)**
**Strokes**
**Blood Clots in the Lungs** (Pulmonary Emboli)
**Breast Cancer**
**Colorectal cancer**
**Endometrial (uterine) cancer**
**Hip Fractures**
**Deaths from other causes**
- Global Index (includes all of the above) - Defined to provide index of overall balance of benefits and risks

## Trial monitoring for benefitEarly stopping considerations required:

- Statistical rules based on O’Brien-Fleming (OBF) procedures using a 0.025-level, one-sided test
- AND
**Global index supportive of benefit**
- Statistical rules based on OBF procedures using a 0.05-level, one-sided test

**OBF = O’Brien PC, Fleming TR.  Biometrics. 1979;35:549-556.**

- Trial monitoring **for benefit****Early stopping considerations required:**

## Trial monitoring for riskEarly stopping considerations required:

- OBF procedure using a 0.05-level one-sided test.
- _OR_
**Evidence of increases in CHD, stroke, PE, hip fracture, colorectal cancer, endometrial cancer, or death from other causes**** **
- OBF procedure using a 0.05-level one-sided test, with Bonferroni correction.
- AND
**Global index supportive of overall harm (Z < -1.0)**

**Freedman, et al.  Control Clin Trials.  1996;17:509-525.****  **

- Trial monitoring **for risk****Early stopping considerations required:**

## At the request of WHI Data Safety Monitoring Board, HT Participants were informed (April 2000) that:

**There was a small increase in the number of heart attacks, strokes, and blood clots in the legs and lungs, in women receiving active hormones, compared to women taking placebo. **
***It was believed that this difference was reduced and may disappear after 2 years (as in HERS).***

## WHI Data Safety Monitoring Board required that HT Participants be informed (June 2001) that:

**After an average of 4 years of follow-up, **there were** more heart attacks, more strokes, and more PE and DVT, **in **active hormone group **(E+P + E-Alone combined)** **vs placebo** **
**Fewer than 1% of women had any one of these events per year in either active or placebo group**
**Case-Control Biomarker Study was Initiated**:
**Factor V Leiden, Prothrombin (G20210A) mutation, Selected Coagulation & Inflammation factors, etc.**

## NHLBI accepted DSMB recommendation to stop WHI Estrogen + Progestin Trial  (May 2002)

- After an average of **5.2 years**:
- Women in **Estrogen + Progestin trial told to stop **study pills: **risks of E+P exceed the benefits**.
**Participants in the E+P trial continue to be monitored, to determine how long risks or benefits persist, over time**
**Women in Estrogen-Alone study asked to continue **study pills:  **balance of benefits and risks is unclear.**
- At this time, **no increased risk of breast cancer** has been seen in women taking **estrogen only, vs placebo**.
- E-Alone participants will continue to be closely monitored.

## Results of Estrogen plus Progestin Use in Health Postmenopausal Women: Implications for Clinical Practice 

**Results of Estrogen plus Progestin Use in Health Postmenopausal Women: Implications for Clinical Practice**** **

**Risk of Cardiovascular Disease and Stroke**
** ****Marian C. Limacher, M.D. (Gainesville)**
**Risk of Fracture**
** ****Rebecca D. Jackson, M.D. (Columbus)**
**Risk of Cancer**
** ****Rowan T. Chlebowski, M.D., Ph.D. ****(Harbor-UCLA)**