- ACRONYMS AND DEFINITIONS
- Active phase results - Results that occurred while the study was ongoing
- Case diff - # of cases (treatment - placebo) per 10,000 patients taking treatment for a year
- CI - Confidence interval
- CIMT - Carotid artery intima–media thickness
- Cumulative results - Results at the end of active phase + post-study follow-up
- HR - Hazard ratio (Treatment/placebo)
- HRT - Hormone replacement therapy
- NAMS - North American Menopause Society
- NS - Nonsignificant
- S - Statistically significant
- USPSTF - U.S. Preventive Services Task Force
- WHI - Women's Health Initiative trials
- OVERVIEW OF HRT
- When women go through menopause, they experience a wide range of symptoms, most of which are bothersome and uncomfortable. For years, hormone replacement therapy was prescribed freely to women to treat and prevent menopause-related conditions. Then in 2002, results from the Women's Health Initiative (WHI) Study were published. The WHI found that postmenopausal women taking combination (estrogen and progestin) hormone therapy for menopause symptoms had an increased risk for breast cancer, heart disease, stroke, blood clots, and urinary incontinence. These findings drastically changed the perception and prescribing of HRT. Since 2002, more information has become available that has helped to further define the risks and benefits of HRT
- Current recommendations from the NAMS and USPSTF for HRT are presented below along with results from the WHI trial and more recent ELITE trial which looked at the effects of HRT on CIMT thickness, a surrogate measure for atherosclerosis
- GUIDELINES
North American Menopause Society 2017 HRT recommendations |
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Menopause symptoms and diagnosis |
Indications for HRT
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Risks / Benefits of HRT
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Duration of HRT
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Choice of therapy
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Special populations
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USPSTF 2022 HRT Recommendations |
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- WOMEN'S HEALTH INITIATIVE TRIALS
- Overview
- The Women's Health Initiative trials (WHI) were two large studies that examined the effects of female hormone replacement therapy in postmenopausal women aged 50 - 79 years. Over the years, a number of analyses have been performed on the trial data. The information in the charts below is from a comprehensive review published in 2013 and a long-term mortality study published in 2017.
- Estrogen study (Premarin®)
- In the estrogen study, women without a uterus (s/p hysterectomy) were randomized to conjugated estrogens 0.625 mg/d (Premarin®) (5310 patients) or placebo (5429 patients)
- The active phase of the study lasted a median of 7.2 years, after which participants were followed for an additional 6 years, providing a cumulative follow-up of 13 years
- After the active phase of the study, less than 4% of participants reported using hormone replacement therapy on their own
- The primary outcome of the study was the incidence of coronary heart disease and invasive breast cancer
Premarin® 0.625 daily vs Placebo | |||
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Outcome | Active phase results (median 7.2 years) | Cumulative results (median 13 years) | Cumulative results (median 18 years) |
All-cause mortality | HR 1.03 (CI 0.88 - 1.21) NS Case diff = +3 |
HR 0.99 (CI 0.90 - 1.10) NS Case diff = -1 |
HR 0.94 (CI 0.88 - 1.01) NS |
Coronary heart disease | HR 0.94 (CI 0.78 - 1.14) NS Case diff = -3 |
HR 0.94 (CI 0.82 - 1.09) NS Case diff = -4 |
CHD mortality HR 0.89 (CI 0.75 - 1.05) NS |
Invasive breast cancer | HR 0.79 (CI 0.61 - 1.02) NS Case diff = -7 |
HR 0.79 (CI 0.65 - 97) S Case diff = -7 |
Breast cancer mortality HR 0.55 (CI 0.33 - 0.92) S |
Stroke | HR 1.35 (CI 1.07 - 1.70) S Case diff = +11 |
HR 1.15 (CI 0.97 - 1.37) NS Case diff = +5 |
NA |
Pulmonary embolism | HR 1.35 (CI 0.89 - 2.05) NS Case diff = +4 |
HR 1.15 (CI 0.87 - 1.51) NS Case diff = +2 |
NA |
Colorectal cancer | HR 1.15 (CI 0.81 - 1.64) NS Case diff = +2 |
HR 1.13 (CI 0.85 - 1.51) NS Case diff = +2 |
Colorectal cancer mortality HR 1.21 (CI 0.79 - 1.84) NS |
All fractures | HR 0.72 (CI 0.64 - 0.80) S Case diff = -61 |
✝HR 0.91 (CI 0.72 - 1.15) NS Case diff = -2 |
NA |
Deep vein thrombosis | HR 1.48 (CI 1.06 - 2.07) S Case diff = +7 |
HR 1.05 (CI 0.82 - 1.33) NS Case diff = +1 |
NA |
Probable dementia (in women ≥ 65 years old only) |
HR 1.47 (CI 0.85 - 2.52) NS Case diff = +15 |
NA | NA |
- Estrogen + progesterone study (Prempro®)
- In the estrogen + progesterone study, women who still had their uterus were randomized to conjugated estrogens 0.625 mg/d + medroxyprogesterone 2.5 mg/d (Prempro®) (8506 patients) or placebo (8102 patients)
- The active phase of the study lasted a median of 5.6 years, after which participants were followed for an additional 7 years, providing a cumulative follow-up of 13 years
- After the active phase of the study, less than 4% of participants reported using hormone replacement therapy on their own
- The primary outcome of the study was the incidence of coronary heart disease and invasive breast cancer
Prempro® 0.625/2.5 mg daily vs Placebo | |||
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Outcome | Active phase results (median 5.6 years) | Cumulative results (median 13 years) | Cumulative results (median 18 years) |
All-cause mortality | HR 0.97 (CI 0.81 - 1.16) NS Case diff = -1 |
HR 0.99 (CI 0.91 - 1.08) NS Case diff = -1 |
HR 1.02 (CI 0.96 - 1.08) NS |
Coronary heart disease | HR 1.18 (CI 0.95 - 1.45) NS Case diff = +6 |
HR 1.09 (CI 0.96 - 1.24) NS Case diff = +3 |
CHD mortality HR 1.05 (CI 0.89 - 1.23) NS |
Invasive breast cancer | HR 1.24 (CI 1.01 - 1.53) S Case diff = +9 |
HR 1.28 (CI 1.11 - 1.48) S Case diff = +9 |
Breast cancer mortality HR 1.44 (CI 0.97 - 2.15) NS |
Stroke | HR 1.37 (CI 1.07 - 1.76) S Case diff = +9 |
HR 1.16 (CI 1.00 - 1.35) NS Case diff = +5 |
NA |
Pulmonary embolism | HR 1.98 (CI 1.36 - 2.87) S Case diff = +9 |
HR 1.26 (CI 1.00 - 1.59) NS Case diff = +4 |
NA |
Colorectal cancer | HR 0.62 (CI 0.43 - 0.89) S Case diff = -6 |
HR 0.80 (CI 0.63 - 1.01) NS Case diff = -3 |
Colorectal cancer mortality HR 1.01 (CI 0.69 - 1.49) NS |
Endometrial cancer | HR 0.83 (CI 0.49 - 1.40) NS Case diff = -1 |
HR 0.67 (CI 0.49 - 0.91) S Case diff = -3 |
NA |
All fractures | HR 0.76 (CI 0.69 - 0.83) S Case diff = -51 |
✝HR 0.81 (CI 0.68 - 0.97) S Case diff = -5 |
NA |
Deep vein thrombosis | HR 1.87 (CI 1.37 - 2.54) S Case diff = +12 |
HR 1.24 (CI 1.01 - 1.53) S Case diff = +4 |
NA |
Probable dementia (in women ≥ 65 years old only) |
HR 2.01 (CI 1.19 - 3.42) S Case diff = +23 |
NA | NA |
- ELITE TRIAL
- Overview
- Observational studies have found a beneficial effect of hormone replacement therapy (HRT) on coronary heart disease while large, randomized controlled trials have not. One proposed reason for the discrepancy is that the timing of HRT in relation to menopause plays a role. It has been theorized that the beneficial effect occurs if HRT is prescribed closer to menopause (typically within 2 years), but does not occur if prescribed later (typically > 10 years after menopause).
- The ELITE trial was a randomized controlled trial designed to evaluate the timing of HRT in relation to menopause and its effects on carotid artery intima–media thickness (CIMT), a surrogate measure for atherosclerosis
- The Elite trial enrolled 643 postmenopausal women without a history of coronary artery disease
- Patients were stratified by duration of time since menopause with early postmenopause being < 6 years since menopause, and late postmenopause being ≥ 10 years since menopause
Main inclusion criteria
- Postmenopausal
- No history of CAD
- No regular menses for at least 6 months or surgically-induced menopause
- Estradiol level < 25 pg/ml
Main exclusion criteria
- Diabetes
- Serum triglycerides > 500 mg/dl
- SBP > 160 | DBP > 110
- History of DVT or PE
- Hormone therapy within 1 month of screening
Baseline characteristics
- Median age: 55 years (early) | 64 years (late)
- Median time since menopause: 3.5 years (early) | 14.3 years (late)
- Median LDL: 136 mg/dl (early) | 132 mg/dl (late)
- Median BP: 116/76 (early) | 118/74 (late)
Randomized treatment groups
- Group 1 (297 patients): Estradiol 1mg once daily. Women with a uterus also received progesterone vaginal gel (45 mg) for 10 days during each 30-day cycle.
- Group 2 (299 patients): Placebo once daily. Women with a uterus also received placebo vaginal gel for 10 days during each 30-day cycle.
- Randomization was stratified based on duration of time since menopause: early postmenopause (< 6 years since menopause), late postmenopause (≥ 10 years since menopause)
Primary outcome: The rate of change in intima–media thickness of the far wall of the right distal common carotid artery, assessed by
means of computer image processing of B-mode ultrasonograms that were obtained at two baseline examinations (averaged to obtain the baseline CIMT value) and every 6 months during
trial follow-up
Results
Duration: Median of 5 years | |||
Outcome | HRT | Placebo | Comparisons |
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Primary outcome (early postmenopause) | 0.0044 mm/yr | 0.0078 mm/yr | p=0.008 |
Primary outcome (late menopause) | 0.0100 mm/yr | 0.0088 mm/yr | p=0.29 |
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Findings: Oral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum.
- Summary
- In the ELITE trial, HRT in early menopause had a beneficial effect on carotid intima-media thickness (CIMT). HRT in late menopause had no significant effect on CIMT.
- It's important to note that CIMT is a surrogate marker for atherosclerosis, and it is unknown what effect HRT has on meaningful outcomes like heart attack and stroke. Niacin has also been shown to have a favorable effect on CIMT, but in large, randomized controlled trials, it did not improve cardiovascular outcomes. The fact that CAC scoring and CT-angiography findings at the end of the study were not different between the groups also casts doubt on any cardioprotective effects from HRT.
- The main takeaway from this trial is that HRT for up to 5 years in early menopause (< 6 years) does not appear to have a negative effect on cardiovascular health
- BIBLIOGRAPHY
- 1 - PMID 24084921 - Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials, JAMA (2013)
- 2 - PMID 28898378 - Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality, JAMA (2017)
- 3 - PMID 28650869 - The 2017 hormone therapy position statement of The North American Menopause Society, Menopause (2017)
- 4 - USPSTF website