# Presentation: 209849

## WHI: E + P  Trial Cardiovascular Findings

- Marian Limacher, MD
- Professor of Medicine
- Division of Cardiovascular Medicine
- University of Florida

## Mortality in Women, 1999

- Deaths per 100,000

## HRT and CVD – Sources of Evidenceprior to 1990’s

- Biological effects
- Animal models
- Epidemiological studies:
- Strong consistent association
- Repeated in different populations
- Plausible biological mechanisms
- Dose-response
- Duration-response
*But: no adequate clinical trials*

## Heart and Estrogen/Progestin Replacement Study (HERS)

- First randomized, blinded, placebo-controlled secondary prevention trial of HRT and CAD
- 2763 women < 80, mean 66.7yrs
- .625 mg CEE plus 2.5 mg MPA vs. placebo
- Mean F/U 4.1 yrs

- Hulley JAMA 1998;280:605-613

## HERS Primary Outcomes

- All: p = NS

## HERS Secondary Outcomes

- All: p = NS

## HERS Primary CHD Outcomes

**Cumulative # events**

## HERS II

- At end of randomized study, ppts asked to continue on treatment assignment
- 93% agreed to continue
- Additional 2.7 yrs follow-up (6.8 years total)
*No difference in MI or CHD death*
*No difference in other cardiovascular outcomes*

- Grady D, et al. HERS-II.  JAMA 2002;288:49-57.

## WHI Estrogen+Progestin TrialSpecific Aims

- Primary Endpoint: To test whether E+P reduces the incidence of CHD and other CVD
- Secondary Endpoints:
- 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

## Severely underweight (recommended lower limit of 18 kg/m2)
Hematocrit < 32%; Platelets < 75,000 cells/ml
Lipemic serum leading to a diagnosis of hypertriglyceridemia
History of bleeding disorder serious enough to require transfusion
Severe hypertension (>200/105)
History of pulmonary embolism or deep vein thrombosis (added as criteria in 1997)

- Hematocrit < 32%; Platelets < 75,000 cells/ml
***Lipemic serum leading to a diagnosis of hypertriglyceridemia***
- History of bleeding disorder serious enough to require transfusion
***Severe hypertension (>200/105)***
***History of pulmonary embolism or deep vein thrombosis (added as criteria in 1997)***

- Study Population:Safety exclusions

## Development of breast cancer
Endometrial cancer, atypia or hyperplasia not responsive to treatment
Deep vein thrombosis or PE
Malignant melanoma
Meningioma
Triglyceride level greater than 1000 mg/dL
Prescription of estrogen, testosterone or SERM

- Endometrial cancer, atypia or hyperplasia not responsive to treatment
***Deep vein thrombosis or PE***
- Malignant melanoma
- Meningioma
***Triglyceride level greater than 1000 mg/dL***
- Prescription of estrogen, testosterone or SERM

- WHI Estrogen+Progestin Trial**Reasons for Permanent Discontinuation of Study Medication**

## Baseline Characteristics of E+P Participants (N=16,608) by Randomization Assignment

**Baseline Characteristics of E+P Participants (N=16,608) ****by Randomization Assignment**

## 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)****	**
- 	CHD Death	33	(0.07%)	26	(0.06%)	1.18	(0.70,1.97)
- 	Non-fatal MI	133	(0.30%)	96	(0.23%)	1.32	(1.02,1.72)
- CABG/PTCA	183	(0.42%)	171	(0.41%)	1.04	(0.84,1.28)

- †	CHD includes acute MI requiring hospitalization, silent MI determined from serial electrocardiograms and coronary deaths.  There were 8 silent MIs.

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

## Kaplan-Meier Estimates of Cumulative Hazards for CHD

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

## Clinical Outcomes (Annualized Percentage) by

**Randomization Assignment**

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

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

## Kaplan-Meier Estimates of Cumulative Hazards for Stroke

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

## Clinical Outcomes (Annualized Percentage) by

**Randomization Assignment**

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

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

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

## Kaplan-Meier Estimates of Cumulative Hazards for PE

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

## 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**

***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 Outcomes (Annualized Percentages) by Self-Reported History of CHD Related Conditions

- No prior MI or CABG/PTCA	145	(0.34%)	106	(0.26%)	1.28	(1.00,1.65)
- Prior MI or CABG/PTCA	19	(2.08%)	16	(1.60%)	1.28	(0.64,2.56)

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

## CHD

- Age
- 	**50 - 59****	****33****	****(****0.21%**)**	****19****	****(****0.13%**)**	****1.67**
- 	60 - 69	68	(**0.35%**)	51	(**0.28%**)	1.26
- 	70 - 79	63	(**0.71%**)	52	(**0.60%**)	1.18

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

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

## Interpreting WHI for CHD

- Not just another confusing report
- Provides real risk:benefit estimates to be used for treatment decisions
- Removes E + P from CHD prevention strategy
- For both Primary and Secondary CHD prevention
- Tested only one regimen, but *it cannot be assumed other formulations will have different outcomes*
- Demands the use of appropriate, randomized clinical trials to define risks and benefits of long term preventive treatments

## Current Recommendations for CHD  Risk Factor Management in Women

- Achieve and maintain ideal body weight
- Maintain regular physical activity
- Stop smoking
- BP < 140/90
- LDL < 130; *with CAD  or DM, goal LDL < 100*
- HDL > 45
- TG < 150
- DM: HbA1c < 7%; glucose control
*HT - combination CEE + MPA is not to be used for CHD primary or secondary prevention.  *
*Other formulations and doses require appropriate clinical trials*

- Mosca et al, JACC;1999:1751-5/ Circ 1999;99:2480.  Bonow, AHA Advisory, 2002