# Presentation: 045146

## Women’s Health Initiative (WHI) Estrogen plus Progestin Trial Design, Primary Results (JAMA 2002)  2003 Updates - Selected Outcomes

**Women’s Health Initiative (WHI) ****Estrogen plus Progestin Trial**** ****Design, Primary Results (JAMA 2002) **** 2003 Updates - Selected Outcomes**

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

## WHI Hormone Trials: Specific Aims

- To test whether** Estrogen + Progestin**** ****(E+P)**** ****- or-  Estrogen Only (E-Alone)**
**reduces the risk of CHD ****or other CVD, e.g. Stroke**
**increases the risk of Breast Cancer**
**reduces the risk of Hip and other Fractures**
- To determine the** overall balance of health risks and benefits of E+P and E-alone**

## *

**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_**

***= Premarin®***

***= Prempro®***

## Outcomes Monitored by DSMB

**Cardiovascular disease**
**Coronary Heart Disease (CHD)**
**Strokes**
**Pulmonary Emboli** **(PE)**
**Invasive Breast Cancer**
**Colorectal cancer**
**Endometrial cancer**
**Hip Fractures**
**Deaths from other causes**
- Global Index*: provides overall balance of benefits and risks *earliest occurrence of CHD, stroke, PE, breast cancer, colorectal cancer, endometrial cancer, hip fracture or death from other causes

## April 2000: WHI Data Safety Monitoring Board (DSMB) requested that HT Participants be informed that:

**There was a small increase in the number of heart attacks, strokes, and blood clots in the lungs **and legs** in women receiving active hormones, compared to women taking placebo.**
**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** **

**June 2001: ****WHI DSMB required that ****all HT **(E+P and
-     E alone)** Participants be informed that:**

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

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

## WHI: Preliminary Results With CEE/MPA

**CHD 1.29**
**Stroke 1.41**
**Breast Cancer 1.26**
**VTE 2.11**
**Colon Cancer 0.63**
**Hip Fracture 0.66**
**Total Fracture 0.76**
**Death 0.98**

**WHI: Preliminary Results With CEE/MPA**

**Hazard Ratio**

**Nominal 95% CI**
**Adjusted 95% CI**

_**Event nHR**_

*Writing Group for WHI Investigators:*** JAMA 2002; 288: 321-333**

## Kaplan-Meier Estimates of Cumulative Hazards for the Global Index

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

## WHI E+P Trial: Annualized Event Rates

**Placebo**

**E + P**

**Deaths**

**Neutral**

**Number of Cases****per 10,000 Women per Year**

- 60
- 50
- 40
- 30
- 20
- 10
- 0

**CHD*******

**Stroke*******

**Breast****Cancer*******

**PE*******

**Colorectal****Cancer*******

**Hip****Fracture*******

**Endometrial****Cancer**

- Risks*

**7**

**8**

**   ****8**

**      ****8**

**Additional Events**

**6**

**  ****5**

**  ****Reduced         Events**

***Statistically significant based on 95% nominal CI on Hazard Ratios **

**Adapted from: **Writing Group for the Women’s Health Initiative. **JAMA. 2002;288:321-333**

## Estrogen+Progestin Study Results Summary

**19 more health problems  per 10,000 women assigned to E+P **compared to placebo** **
**Over 5 years, a net 1 per 100 women in  E+P group had a harmful outcome.**
**Treatment with estrogen + progestin for up to 5 years is not beneficial to overall health.**

## Updated Results: WHI Estrogen + Progestin Randomized, Placebo-controlled Clinical Trial

- Manson J et al. **N Engl J Med 2003; 349**: **523-534**
**  ****Stroke**
- Wassertheil-Smoller S et al. **JAMA 2003; 289: 2673-2684**
**  ****Breast Cancer **(and Mammograms)
**Chlebowski, Rowan T** et al. **JAMA 2003; 289: 3243-3253**
**  ****Fractures and Bone Mineral Density**
**Cauley, Jane A**. et al. **JAMA 2003; 290: 1729-1738**

- Updated Results: WHI Estrogen + Progestin Randomized, Placebo-controlled Clinical Trial

## CHD Update: Manson JE, et al  N Engl J Med 2003; 349: 523-34

** ****CHD outcomes through July 7, 2002**** **
** ****mean 5.6 yr follow-up **(vs. 5.2 in 1st report)** **
** **335 CHD cases (vs. 286 in first report)
** ****centrally-adjudicated **by cardiologists
** ****Additional CHD**** ****endpoints:**** **
**	****     ****angina, acute coronary syndrome, and CHF**
** ****Analyses of subgroups**** ****defined by clinical ****	****    **
**       ****characteristics and biomarkers**

## CHD*: Overall HR and HR Year of Follow-Up

**CHD*: Overall HR and HR Year of Follow-Up**

**HR**=**1.81**

**1.34**

**1.27**

**1.25**

**1.45**

**0.70**

**CHD Update:*** Manson JE, et al*  **N Engl J Med 2003; 349: 523-34**

- CHD: N (Annualized %)**     *********acute MI + silent MI+ CHD death (stratified, adjusted)**
**E+P**: 188 (**0.39**%)  **Placebo**: 147 (**0.33**%)**   ****HR=1.24****	**(1.00-1.54)

## WHI E+P: Intermediate Outcomes at Year 1 (% change, E+P minus Placebo)

**CHD Update:*** Manson JE, et al*  **N Engl J Med 2003; 349: 523-34**

## WHI E+P CHD Update: Analyses by Subgroups

**Age**** **(yrs):**  ****50-59,** **60-69,** **70-79** **      ****	****	****	****      ****	**p = 0.36
- Years** **since Menopause:** ****< 10,**  **10-19,**   **≥ 20** 			p = 0.33
**Hot Flashes **(in women aged 50-59):**  ****Yes**,  **No****      ****	****	**p = 0.16
**Hot Flashes + Night Sweats **(50-59):** ****Yes**,  **No** 		p = 0.61
**BMI**** **(kg/m2):** ****< 25.0**,  **25-29.9**,  **≥ 30**   			p = 0.60
**Race/Ethnic Group:**** **non-Hsp **White**, non-Hsp **Black**, **Hispanic** 	p = 0.41
**Education Level:****      ****≤ H.S. or GED,     > H.S.****	****	**p = 0.86

**CHD Update:*** Manson JE, et al*  **N Engl J Med 2003; 349: 523-34**

## WHI E+P CHD Update: Analyses by Subgroups

**LDL-C (mg/dl): ****< 126,  126-155,   >155** ** ****	****	****	****p = 0.01**
**HDL-C;     Triglycerides;    Total Cholesterol **(p = 0.07)**	****   **NS
**Lp(a);   Fibrinogen;   Factor VIII:C;   C-reactive Protein****	****   **NS
**Cigarette Smoking:****  ****Never or former, Current** 		p = 0.64
**Hypertension **(140/90 or treated):**  **** No,  Yes ****	****	**p = 0.49
**Diabetes: ****No, Yes - treated, Yes - all cases ****	****	**p = 0.51** **
**Number of Risk Factors**** ****0, 1-2, 3 **(smoking, hypertension, 	p = 0.96
- 	 diabetes, high cholesterol, parental history-father<55 yrs; mother < 65 yrs)
**Aspirin Use:      ****Yes**,  **No** **	****	****	****	****	**p = 0.71
**Statin Use:        ****Yes**,  **No** **	****	****	****	****	**p = 0.44

**CHD Update:*** Manson JE, et al*  **N Engl J Med 2003; 349: 523-34**

## E + P and Risk of CHD:  Additional Analyses of Subgroups

**‡****	****includes history of MI, CABG, PTCA, stroke, or transient cerebral ischemia.**
**§****	****includes history of MI, CABG, or PTCA.**

**E + P and Risk of CHD:  Additional Analyses of Subgroups**

**CHD Update:*** Manson JE, et al*  **N Engl J Med 2003; 349: 523-34**

## Clinical Outcomes (Annualized Percentage) by

**Randomization Assignment**

**Stroke**	151	(**0.31%**)**	**107 (**0.24%**)**	****1.31****	****(1.02,1.08)****	**
- 	**Ischemic****	**125 	(**0.26%**)**	**81	(**0.18%**)**	****1.44****	****(1.09, 1.90)****	**
**	****He****morrhagic****	**18 	(0.04%)	20	(0.04%)	0.82	(0.43, 1.56)**	**

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

**Stroke Update**: Wassertheil-Smoller et al. **JAMA 2003; 289:2673-2684**

## Summary and Implications of Stroke Data

**Wassertheil-Smoller S et al.**** ****JAMA 2003; 289: 2673-2684**

** ****E+P increases risk of** **ischemic stroke**
**   ****Excess strokes:** **7 per 10,000 women per year**
**Excess risk is:**
**not explained by blood pressure increase**
**apparent in hypertensives and normotensives**
**apparent in all subgroups examined**
-  **No significant interaction with any biomarker studied**

## Updated Results: WHI Estrogen + Progestin Randomized, Placebo-controlled Clinical Trial

- Anderson GL S et al. **JAMA 2003; 290: 1739-1748****  **
** ****Colorectal Cancer**
- Chlebowski RT. (Submitted to NEJM)
** ****Diabetes**
- Margolis K et al. (Submitted to JAMA)
-  Venous Thromboembolism  (in preparation)

- Updated Results: WHI Estrogen + Progestin Randomized, Placebo-controlled Clinical Trial

## WHI E+P Trial Findings for Gynecological Cancers (Average 5.6 years of follow-up)

** ****Endometrial Cancer ****(58 cases)**
**	****	****HR = 0.81;   CI: 0.48-1.36**
**No appreciable differences in distributions of tumor histology, stage, or grade for either.**
** ****Cervical Cancer ****(13 cases)**
- 		Data too limited.

- WHI E+P Trial Findings for Gynecological Cancers (Average 5.6 years of follow-up)

- Anderson GL S et al. **JAMA 2003; 290: 1739-1748**

## Discontinuation and “Drop-in” Rates by Randomization Assignment and Follow-up Time

**Percent**

*Writing Group for WHI Investigators**:*** JAMA 2002; 288: 321-333**

## WHI E+P Trial: Primary EndpointsPercent Event Rates Based on Analysis TypeFinal centrally-adjudicated outcomes - 2003 (average 5.6 yrs of follow-up)

- 0

- 20

- 40

- 60

- 80

**CHD****1**

**Stroke****2**

**Breast Cancer****3**

- % Increase Over Placebo

- Intention to treat

- 24%

- 31%

- 24%

**WHI E+P Trial: Primary Endpoints****Percent Event Rates Based on Analysis Type****Final centrally-adjudicated outcomes - 2003**** (average 5.6 yrs of follow-up)**

**1**   Manson JE et al **N Engl J Med  2003; 349: 523-534 **
**2**   Wassertheil-Smoller S et al **JAMA 2003; 289: 2673-2684**
**3**   Chlebowski RT et al. **JAMA 2003; 289: 3243-3253 **

## WHI E+P Trial: Primary EndpointsPercent Event Rates Based on Analysis TypeFinal centrally-adjudicated outcomes - 2003 (average 5.6 yrs of follow-up)

- 0

- 20

- 40

- 60

- 80

**CHD****1**

**Stroke****2**

**Breast Cancer****3**

- % Increase Over Placebo

- Intention to treat

- 24%

- 31%

- 24%

**Compliant:**
**taking ****≥80% study pills;**** censored 6 mo. after becoming non adherent**

**WHI E+P Trial: Primary Endpoints****Percent Event Rates Based on Analysis Type****Final centrally-adjudicated outcomes - 2003**** (average 5.6 yrs of follow-up)**

**1**   Manson JE et al **N Engl J Med  2003; 349: 523-534 ****	****  ****HR: 1.50  (1.14-1.97)**** **
**2**   Wassertheil-Smoller S et al **JAMA 2003; 289: 2673-2684****	****  ****HR: 1.50  (1.08-2.08)**
**3**   Chlebowski RT et al. **JAMA 2003; 289: 3243-3253 ****	****  ****HR: 1.49  (1.13-1.96)**** **

## Updated Results: WHI E + P Trial

- Hays J et al. **N Engl J Med 2003; 348:1839-1854**
-   Gynecological Symptoms  (in preparation)
** **
**  ****Dementia**
- Shumaker S et al **JAMA 2003: 289: 2651-2662**
** ****Global Cognitive Function**
- Rapp S et al **JAMA 2003: 289: 2663-2672**

**- - - - - - - - - -  ****WHI** **Memory Study (WHIMS)****  - - - - - - - - - **
**E+P Trial Participants (n=4532) aged ≥ 65 yrs **(baseline)

- Updated Results: WHI E + P Trial

## WHIMS: Frequencies of Probable Dementia and Mild Cognitive Impairment Over 4.1 Years

- _ __Dementia_ - **23** excess cases per 10,000 person-yrs
- _ __MCI _- No differences

*Shumaker et al* **JAMA 2003; 289:2651-2662**

## Attributable Risk Summary

**Excess risk per 10,000 women per year on E+P**
** ****8******* more women with **breast cancer**
-  **6******* more women with **CHD**
** ****7******* more women with **strokes**
** ****8 ** more women with **PE**
**Risk reduction per 10,000 women per year**** **
** ****6****  **fewer **colorectal cancer**** **
** ****5******* fewer **hip fractures**

*Writing Group for WHI Investigators**:*** JAMA 2002; 288: 321-333 **
*******2003**** ****UPDATES:  CHD **(Manson);** Stroke **(Wassertheil-Smoller);** ****	****Breast Cancer **(Chlebowski);** Hip Fractures **(Cauley)

## WHI Estrogen+Progestin TrialImplications

- The overall **risks of estrogen+progestin outweigh the benefits** when taken to prevent chronic diseases in postmenopausal women.
**Estrogen + progestin should not be initiated or continued for the primary prevention of CHD.**
- Risk for  CHD, stroke, PE and breast cancer must be weighed against benefit for fracture in selecting from available agents to prevent osteoporosis.