From the Guidelines
Estrogen hormone replacement therapy (HRT) significantly increases the risk of myocardial infarction (MI) and stroke, primarily due to its prothrombotic effects, as evidenced by the Women's Health Initiative (WHI) trial 1. The WHI trial, which is the largest and most applicable study to the target population, found that combined estrogen and progestin therapy showed a trend toward an increased risk for coronary heart disease (CHD) after 5 years of follow-up, with a hazard ratio (HR) of 1.22 [CI, 0.99 to 1.50] 1. Additionally, the trial found that women's risk for stroke is statistically significantly increased with the use of postmenopausal hormone therapy, with an HR of 1.36 [CI, 1.08 to 1.71] for estrogen-only therapy 1. The mechanisms by which estrogen HRT increases the risk of MI and stroke include:
- Promoting blood clot formation by increasing coagulation factors, particularly factors VII, X, and fibrinogen, while simultaneously reducing fibrinolytic activity
- Causing inflammatory changes in blood vessel walls, promoting atherosclerotic plaque instability and rupture The risk is most pronounced with oral estrogen formulations, as they undergo first-pass liver metabolism, amplifying these prothrombotic effects 1. The American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines recommends that hormone therapy with estrogen plus progestin, or estrogen alone, should not be given de novo to postmenopausal women after unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) for secondary prevention of coronary events, due to the increased risk of cardiovascular events and breast cancer (combination therapy) or stroke (estrogen) 1. Key points to consider:
- The risk of MI and stroke is highest during the first year of therapy and in women who start HRT more than 10 years after menopause
- Transdermal estrogen preparations may carry lower thrombotic risk as they bypass first-pass metabolism
- Women with existing cardiovascular risk factors (hypertension, diabetes, smoking, obesity) are at particularly elevated risk when using HRT and should consider alternative treatments for menopausal symptoms 1.
From the FDA Drug Label
Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes has been observed in women receiving CE compared to placebo. In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 vs 30 per 10,000 women years). In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 vs 21 per 10,000 women-years). An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke, and MI has been reported with estrogen plus progestin therapy.
The estrogen hormone replacement therapy increases the risk of MI and stroke by:
- Increasing the risk of cardiovascular events, such as myocardial infarction and stroke
- Enhancing the risk of venous thrombosis and pulmonary embolism
- Elevating the risk of coronary heart disease (CHD) events, including nonfatal myocardial infarction and CHD death
- Augmenting the risk of stroke, particularly in women receiving estrogen plus progestin therapy 2, 3 Key factors that contribute to this increased risk include:
- Pre-existing risk factors for arterial vascular disease, such as hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity
- Risk factors for venous thromboembolism, including personal or family history of VTE, obesity, and systemic lupus erythematosus
From the Research
Estrogen Hormone Replacement Therapy and Cardiovascular Risk
The relationship between estrogen hormone replacement therapy (HRT) and the risk of myocardial infarction (MI) and stroke is complex. Several studies have investigated this association, yielding mixed results.
- The risk of MI and stroke associated with estrogen HRT is influenced by various factors, including the type of estrogen used, the duration of therapy, and the presence of other risk factors 4, 5.
- Some studies suggest that certain forms of estrogen, such as transdermal estradiol, may not increase the risk of venous thromboembolism or stroke, and may even have cardioprotective effects 6.
- In contrast, other studies have found that estrogen HRT, particularly with conjugated equine estrogen (CEE), may increase the risk of MI and stroke, especially in older women or those with pre-existing cardiovascular risk factors 4, 5, 7.
- The Women's Health Initiative, a large randomized controlled trial, found that estrogen HRT with CEE plus medroxyprogesterone acetate increased the risk of stroke and MI, leading to the early termination of the trial 4, 7.
- A meta-analysis of 28 trials found that hormone replacement therapy was associated with a 29% increased risk of ischemic stroke and a 56% increased risk of death or dependency after stroke 4.
Factors Influencing Cardiovascular Risk
Several factors may influence the cardiovascular risk associated with estrogen HRT, including:
- Duration of therapy: Some studies suggest that longer duration of estrogen HRT may be associated with a reduced risk of MI 8.
- Type of estrogen: Transdermal estradiol may have a more favorable cardiovascular risk profile compared to oral estrogens or CEE 6, 5.
- Presence of other risk factors: Women with pre-existing cardiovascular risk factors, such as diabetes or hypertension, may be at increased risk of MI and stroke with estrogen HRT 4, 7.
- Age: Older women may be at higher risk of adverse cardiovascular events with estrogen HRT 4, 7.