# Presentation: 749086

## Women’s  Health Initiative

**Women’s  Health Initiative**

## Components

- Preventive Clinical Trial
- Hormone Replacement Therapy
- Diet Modification
- Calcium+Vitamin D Supplementation
- Observational Study

## Risks and benefits of estrogen plus progestin in healthypostmenopausal women

**Risks and benefits of estrogen plus progestin in healthy****postmenopausal women**

**Principal results of the Women’s Health Initiative randomized controlled trial**

## WHI Estrogen+Progestin TrialBackground circa 1992

- Suspected benefits of hormones:
-  risk of CHD
-  risk of fracture
-  risk of colorectal cancer
- Suspected risks of hormones:
- Possible  risk of breast cancer
-  risk of VTE/PE

## WHI Estrogen+Progestin TrialPurpose

- To test the hypothesis that estrogen+progestin will reduce rates of CHD and osteoporosis-related fracture.
- To determine the balance of risks and benefits of estrogen+progestin on the overall health of postmenopausal women.

## WHI Estrogen+Progestin TrialSpecific Aims

- To test whether E+P reduces the incidence of CHD and other CVD
- To test whether E+P reduces the incidence of all osteoporosis-related fractures and hip fractures separately
- To assess whether E+P increases the risk of breast cancer

## WHI Estrogen+Progestin TrialSubgroups of Interest

- Women with and without previous CVD
- Obese and lean women
- Women at higher vs. lower risk of breast cancer
- Age groups
- Race/ethnicity groups

## WHI Hormone Program Design

**Hysterectomy**

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

**Placebo**

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

**N= 16,608**

**N= 10,739**

**YES**

**NO**

**Placebo**

## WHI Estrogen+Progestin Trial Global Index

- Defined to summarize important aspects of health benefits vs. risks
- Defined for each woman as the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture or death from other causes

## Evidence of increase breast cancer
OBF procedure using a 0.05-level one-sided test.  
OR
Evidence of increase 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)

- OBF procedure using a 0.05-level one-sided test.
- _OR_
- Evidence of increase 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 benefitEarly stopping considerations required:

**Notes:**
The monitoring plan did not require the same level of evidence for early stopping.  The plan was that significance at the one-sided 0.05 level would be appropriate.  This 0.05 level test was used without further adjustment for the primary, a priori specified safety outcome of breast cancer. 

 For the 7 other specifically monitored outcomes, a multiple comparisons (Bonferroni) correction was applied to the 0.05 level monitoring boundary.

For the global index to be considered supportive of harm, the Z statistic had to be below -1 (I.e., 1 standard deviation from the no effect). 

## Women’s Health Initiative Trial of Estrogen + Progestin

- Results

## Reports of Bleeding by Randomization Assignment

**Percent with bleeding**

**Visit**

## Mean Systolic Blood Pressure for Hormone Program

**Participants With Uterus**

## Mean Diastolic Blood Pressure for E+P Participants

## Blood Specimen Analysis for E+P Participants

**Triglycerides**

**Total****Cholesterol**

**Mean (mg/dl)**

## Blood Specimen Analysis for E+P Participants

**LDL-C**

**Mean (mg/dl)**

**HDL-C**

## Clinical Outcomes (Annualized Percentage) by

**Randomization Assignment**

**CHD **†** ****	****164****	****(0.37%)****	****122****	****(0.30%)****	****1.29****	****(1.02,1.63)****	****(0.85,1.97)**
- 	CHD Death	33	(0.07%)	26	(0.06%)	1.18	(0.70,1.97)	(0.47,2.98)
- 	Non-fatal MI	133	(0.30%)	96	(0.23%)	1.32	(1.02,1.72)	(0.82,2.13)
- CABG/PTCA	183	(0.42%)	171	(0.41%)	1.04	(0.84,1.28)	(0.71,1.51)

- * 	Adjusted for multiple comparisons across time (OBF procedures).  A  Bonferroni adjustment for 7 outcomes was applied to all outcomes other than CHD, Breast Cancer and the global Index.
- †	CHD includes acute MI requiring hospitalization, silent MI determined from serial electrocardiograms and coronary deaths.  There were 8 silent MIs.

**	****	****	****	****	****95% CI****	****Estrogen+Progestin****	****Placebo****	****Hazard Ratio****	****Nominal****	****	****Adjusted ***

## Clinical Outcomes (Annualized Percentage) by

**Randomization Assignment**

- Stroke	127	(0.29%)	85	(0.21%)	1.41	(1.07,1.85)	(0.86,2.31)
- 	Fatal stoke	16	(0.04%)	13	(0.03%)	1.20	(0.58,2.50)	(0.32,4.49)
- 	Non-fatal stroke	94	(0.21%)	59	(0.14%)	1.50	(1.08,2.08)	(0.83,2.70)

**	****	****	****	****	****95% CI****	****Estrogen+Progestin****	****Placebo****	****Hazard Ratio****	****Nominal****	****	****Adjusted**

## Clinical Outcomes (Annualized Percentage) by

**Randomization Assignment**

- VTE† 	151	(0.34%)	67	(0.16%)	2.11	(1.58,2.82)	(1.26,3.55)
- 	DVT† 	115	(0.26%)	52	(0.13%)	2.07	(1.49,2.87)	(1.14,3.74)
- 	PE†	70	(0.16%)	31	(0.08%)	2.13	(1.39,3.25)	(0.99,4.56)

- † 	VTE, venous thromboembolic disease; DVT, deep vein thrombosis; PE, pulmonary embolism

**	****	****	****	****	****95% CI****	****Estrogen+Progestin****	****Placebo****	****Hazard Ratio****	****Nominal****	****	****Adjusted**

## Clinical Outcomes (Annualized Percentage) by

**Randomization Assignment**

- Total CVD	694	(1.57%)	546	(1.32%)	1.22	(1.09,1.36)	(1.00,1.49)

**	****	****	****	****	****95% CI****	****Estrogen+Progestin****	****Placebo****	****Hazard Ratio****	****Nominal****	****	****Adjusted**

## Clinical Outcomes (Annualized Percentage) by

**Randomization Assignment**

**Invasive breast****	****166****	****(0.38%)****	****124****	****(0.30%)****	****1.26****	****(1.00,1.59)****	****(0.83,1.92)****cancer**
- Endometrial cancer 	22	(0.05%)	25	(0.06%)	0.83	(0.47,1.47)	(0.29,2.32)
- Colorectal cancer	45	(0.10%)	67	(0.16%)	0.63	(0.43,0.92)	(0.32,1.24)
- Total cancer	502	(1.14%)	458	(1.11%)	1.03	(0.90,1.17)	(0.86,1.22)

**	****	****	****	****	****95% CI****	****Estrogen+Progestin****	****Placebo****	****Hazard Ratio****	****Nominal****	****	****Adjusted**

## Clinical Outcomes (Annualized Percentage) by

**Randomization Assignment**

- Hip fracture	44	(0.10%)	62	(0.15%)	0.66	(0.45,0.98)	(0.33,1.33)
- Vertebral fracture	41	(0.09%)	60	(0.15%)	0.66	(0.44,0.98)	(0.32,1.34)
- Other osteoporotic	579	(1.31%)	701	(1.70%)	0.77	(0.69,0.86)	(0.63,0.94)fracture†
- Total fracture	650	(1.47%)	788	(1.91%)	0.76	(0.69,0.85)	(0.63,0.92)

- †	Other osteoporotic fractures include all fractures other than chest/sternum, skull/face, fingers, toes and cervical vertebrae, and hip and vertebral fractures (reported separately).

**	****	****	****	****	****95% CI****	****Estrogen+Progestin****	****Placebo****	****Hazard Ratio****	****Nominal****	****	****Adjusted**

## Clinical Outcomes (Annualized Percentage) by

**Randomization Assignment**

- Death from other	165	(0.37%)	166	(0.40%)	0.92	(0.74,1.14)	(0.62,1.35)causes
- Total death	231	(0.52%)	218	(0.53%)	0.98	(0.82,1.18)	(0.70,1.37)

- † 	Global index is the first event for each participant from among the following types: CHD; stroke; PE; breast cancer; endometrial cancer; colorectal cancer; hip fracture; and death from other causes.

**Global index ****†**** ****	****751****	****(1.70%)****	****623****	****(1.51%)****	****1.15****	****(1.03,1.28)****	****(0.95,1.39)**

**	****	****	****	****	****95% CI****	****Estrogen+Progestin****	****Placebo****	****Hazard Ratio****	****Nominal****	****	****Adjusted**

## Slide 24

## Kaplan-Meier Estimates of Cumulative Hazards for CHD

- The number of women at risk are presented below the horizontal axis for each treatment arm.

## Kaplan-Meier Estimates of Cumulative Hazards for Stroke

- The number of women at risk are presented below the horizontal axis for each treatment arm.

## Kaplan-Meier Estimates of Cumulative Hazards for PE

- The number of women at risk are presented below the horizontal axis for each treatment arm.

## Kaplan-Meier Estimates of Cumulative Hazards for Breast Cancer

- The number of women at risk are presented below the horizontal axis for each treatment arm.

## Kaplan-Meier Estimates of Cumulative Hazards for Colorectal Cancer

- The number of women at risk are presented below the horizontal axis for each treatment arm.

## Kaplan-Meier Estimates of Cumulative Hazards for Hip Fracture

- The number of women at risk are presented below the horizontal axis for each treatment arm.

- The number of women at risk are presented below the horizontal axis for each treatment arm.

## Total death

- Year 1	22	(0.26%)		17	(0.21%)	1.24
- Year 2	30	(0.36%)		30	(0.38%)	0.96
- Year 3	39	(0.47%)		35	(0.44%)	1.06
- Year 4	55	(0.69%)		48	(0.63%)	1.09
- Year 5	41	(0.69%)		44	(0.79%)	0.87
- Year 6	44	(0.86%)		44	(1.04%)	0.83
**	****	****Z-value for trend  -0.79**

**	****Estrogen+Progestin****	****Placebo****	****Ratio**

**Clinical Outcomes (Annualized Percentage) by**
**Randomization Assignment**

## Global index

- Year 1	123	(1.46%)		96	(1.19%)	1.22
- Year 2	134	(1.60%)		117	(1.47%)	1.09
- Year 3	127	(1.54%)		107	(1.36%)	1.13
- Year 4	155	(1.96%)		127	(1.68%)	1.16
- Year 5	112	(1.88%)		77	(1.38%)	1.36
- Year 6	100	(1.95%)		99	(2.33%)	0.84
**	****	****Z-value for ****trend****  -****0.87**

**	****Estrogen+Progestin****	****Placebo****	****Ratio**

**Clinical Outcomes (Annualized Percentage) by**
**Randomization Assignment**

## Attributable Risk Summary

- Excess risk per 10,000 person-years on E+P
- 7 more women with CHD
- 8 more women with stroke
- 8 more women with PE
- 8 more women with breast cancer
- Risk reduction per 10,000 person-years on E+P
- 6 fewer colorectal cancer
- 5 fewer hip fractures
- Summary: 19 additional monitored events per 10,000 person years on E+P

## Women’s Health Initiative Trial of Estrogen + Progestin

- Summary

## WHI Estrogen+Progestin TrialSummary

- Treatment with estrogen plus progestin for up to 5 years is not beneficial overall.
- There is early harm for CHD, continuing harm for stroke and VTE, and increasing harm for breast cancer.
- This risk-benefit profile is not consistent with a viable intervention for primary prevention of chronic diseases in postmenopausal women.

## WHI Estrogen+Progestin TrialSummary

- This trial did not address the use of estrogen plus progestin for short-term relief of menopausal symptoms.

## WHI Estrogen+Progestin TrialLimitations

- Still undetermined is:
- Effects of other doses, formulations or routes of administration
- Effects of progestin separate from estrogen
- Longer term assessment of risks and benefits
- Rates of discontinuation in the active treatment arm may have diluted the observed risks and benefits.
- Early stopping limits precision of the results.

## WHI Estrogen+Progestin TrialImplications

- Estrogen plus progestin should not be initiated or continued for the primary prevention of CHD.
- The risks for  CHD, stroke, PE and breast cancer must be weighed against the benefit for fracture in selecting from the available agents to prevent osteoporosis.

## AI/AN Mortality Rate, Colorectal Cancer,By Region, Females, 1994-1998

**Rate per 100,000 per year, adjusted to 1970 U.S. population**

## AI/AN Mortality Rate, Breast Cancer,By Region, Females, 1994-1998

**Rate per 100,000 per year, adjusted to 1970 U.S. population**

## Stroke Mortality for American Indians and Alaska Natives, 1992-96

**Rates per 100,000,  age-adjusted to 1940 US population**

**US All-Races rate (1994)**

**Rate significantly different from US rate**

## Number of Deaths from Stroke for all AI/AN, 1992-96

**Adjusted for miscoding of Indian race**

## Outcomes from HRT

| Outcome | # cases/yr* | Hazard Ratio |
| --- | --- | --- |
| Breast cancer | 300-600 | 1.26 |
| Colon cancer | 100-375 | 0.63 |
| Ovarian cancer | 90 | 1.8 (estrogen only) |
| Acute MI | 2,000 (?) | 1.3 |
| Stroke | ~500 deaths | 1.4 |

***Estimated current yearly cases among AI/AN women, all U.S.  Multiply by **
**  ****hazard ratio to estimate number of cases if all women were taking HRT.**