# Presentation: 461279

## Cardiovascular Diseases

- Jacques E. Rossouw, MD
- National Heart, Lung, and Blood Institute

## WHI

**Extend follow up from 2005 to 2010**
- Long term effects of interventions (hormones, diet, calcium/vitamin D)
- Maximize scientific yield of resource (database, blood, DNA)
- Increase number of clinical outcomes
- Examine role of multiple exposures, genetic markers, and interactions between these

## WHI

**Identify those at risk**
**Subgroups**
**Lipoproteins, coagulation, inflammation**
**Genetic markers**
**Continue follow up**
**Dissipation of harm (cardiovascular, breast cancer)**
**Total mortality**
**Explore reasons for discrepancies between observational studies and clinical trials in respect of CHD**

**WHI**

## WHI

**E Trial**
**Study groups differ**
**Distinguish effects of CEE vs. CEE plus MPA**
**Early increase in risk of heart attack, stroke, and blood clots**
**No increase in risk of breast cancer at 5 years**

## Beyond WHI

**Identify markers/mechanisms of risk for coronary heart disease and stroke**
**Fundamental knowledge about cardiovascular disease**
**Do hormones affect atherosclerosis progression?**
**Do hormones trigger complications of atherosclerosis (plaque rupture, erosion, thrombosis, vasospasm)?**
**Screening out “susceptible” women**
**Selection of more promising hormone treatments**

## Why bother?

- Women will continue to use hormones for menopausal symptoms
- Need hormones with better cardiovascular profile
- No short-term risk
- Long term benefit

## Issues

- Low risk in younger women
- In HERS and WHI 52-78% increase in CHD, 3-4 fold increase in blood clots in first year
- Sample size to identify early harm
- Age 50-59 ~30,000
- Age 50-79 ~15,000
- Possible solution
- Phase I: 1-year trial to identify early CVD harm
- Phase 2: If no harm, continue trial to assess overall long-term benefit/risk

## Potential candidates for clinical trial (1) 

*Low dose conjugated equine estrogens plus medroxyprogesterone*
- Do current doses exceed the therapeutic range?
- Will lower doses provide the benefits for symptom relief and osteoporosis without incurring the risk of cardiovascular disease? And with lower risk of breast cancer?

## Potential candidates for clinical trial (2)

*Transdermal estradiol with progesterone (oral or intravaginal)*
- Test hypothesis that delay in onset of CHD in women is due to endogenous estradiol
- Mimic delivery of estradiol into the systemic circulation
- Avoid hepatic first-pass metabolism

## Some differences between oral conjugated equine estrogens (CEE) and transdermal estradiol (E2) 

|  | Oral CEE | Transdermal E2 |
| --- | --- | --- |
| LDL | -- | - |
| HDL | ++ | 0 |
| Triglycerides | ++ | 0/- |
| LDL particle size | -- | 0 |
| Coagulation/thrombolysis | ++ | 0/+ |
| Inflammation | +/- | 0 |
| Endothelial function | ++ | 0/+ |

**-** = decrease  **+** = increase  **0** = no effect

## Potential candidates for clinical trial (3)

*Selective estrogen receptor modulators (SERMs)*
- Ideal SERM
- Improves menopausal symptoms
- Prevents osteoporosis
- Has neutral or protective effect on breast and endometrial cancer
- Has neutral or protective effect on cardiovascular disease

## A Possible Approach 

- Identify mechanisms/markers of CVD risk
- Test most promising hormones in short term trials with surrogate endpoints (markers, imaging studies)
- Large randomized trials of healthy women
- Phase 1: early harm
- Phase 2: later benefit