WHI

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Rossouw JE, et al. "Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results From the Women's Health Initiative randomized controlled trial". The Journal of the American Medical Association. 2002. 288(3):321-333.
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Clinical Question

Among postmenopausal women, how does combination estrogen/progesterone hormone replacement therapy affect the incidences of skeletal fractures, CAD, breast cancer, and thrombosis?

Bottom Line

In postmenopausal women, combination HRT estrogen/progestin reduces skeletal fractures but increases rates of CAD, breast cancer, and VTE.

Major Points

At the end of the 20th century, observational studies suggested that postmenopausal hormone replacement therapy (HRT) may reduce the incidence of CAD in women,[1] at the expense of more endometrial cancer and VTE.[2] The 1998 HERS trial[3] found no difference between combined estrogen/progesterone and placebo for secondary prevention of CVD in women at five years (though there was an increased risk with hormone therapy in the first two years of follow-up). A randomized study of this medication for primary prevention of CVD in women had not yet been performed.

The 2002 Women's Health Initiative Estrogen and Progestin trial (WHI; sometimes called WHI E+P) randomized 16,608 healthy postmenopausal women to either combination HRT with estrogen/progestin or placebo. The trial was prematurely terminated after a mean follow-up of 5.2 years because of adverse events. The HRT group experienced a higher rate of CAD mortality or non-fatal MI (0.37%/yr vs. 0.30%/yr) and invasive breast cancer (0.38%/yr vs. 0.30%/yr). Furthermore, the HRT group had higher rates of VTE and strokes, although there were fewer skeletal fractures.

The WHI trial design has drawn criticism for high mean age of women on enrollment (63 years) as most of the participants were treated with reinitiation hormone therapy after more than a decade since cessation of endogenous production rather than continuation replacement therapy shortly after menopause.[4][5] As such, the "timing hypothesis" theorizes that HRT may, in fact, provide some CAD benefit in younger women soon after menopause as estrogen may be protective against development of atherosclerosis but may cause increased disease complications through prothrombotic and inflammatory effects when coronary disease has already developed.[6][1] This has been supported by a post hoc analysis of women 50-59 in the WHI E-alone cohort,[7] though this analysis has been criticized for its use of composite outcomes and rates of revascularization as a surrogate for CAD.[1]

As such, the use of estrogen with progesterone HRT for primary prevention of chronic conditions including CAD is now discouraged by multiple guidelines-issuing bodies.[2][8][5] The USPSTF cites that HRT confers an increased risk of stroke, dementia, urinary incontinence, gallbladder disease, increase risk of invasive breast cancer, VTE, and CAD.[2] Estrogen monotherapy is likewise discouraged given the negative outcomes of the related WHI E-alone[9] (2004) that demonstrated increased rates of stroke and no CAD benefit with estrogen monotherapy in postmenopausal women with hysterectomies.

Guidelines

USPSTF Menopausal hormone replacement therapy for treatment of chronic diseases (2012)[10]

  • Against use of estrogen and progestin for the prevention of chronic conditions in postmenopausal women (grade D)
  • Against the use of estrogen for the prevention of chronic conditions in postmenopausal women with hysterectomies (grade D)

AHA Prevention of CVD in women (2011)[8]

  • Hormone therapy and selective estrogen receptor modulators should not be used for primary or secondary prevention of CVD (class III level A)

ACOG Horomone therapy and heart disease (2013)[5]

  • Menopausal HRT should not be used for primary or secondary prevention of CAD

Design

  • Multicenter, randomized, double-blind, placebo controlled trial
  • N=16,608
    • Estrogen and progestin (n=8,506)
    • Placebo (n=8,102)
  • Setting: 40 US centers
  • Enrollment: 1993-1998
  • Mean follow-up: 5.2 years (stopped early)
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • CAD mortality or non-fatal MI
    • Invasive breast cancer

Population

Inclusion Criteria

  • Post-menopausal women, age 50-79 years
  • Likely to live in same area for ≥3 years

Exclusion Criteria

  • Medical condition with expected survival <3 years
  • Prior breast cancer, any non-melanoma skin cancer in prior 10 years, anemia, thrombocytopenia
  • Social situations or medical concerns likely to result in poor retention or adherence

Baseline Characteristics

From the estrogen and progestin group.

  • Demographics: Age 63.2 years (70-79 years 21.3%), White Race 83.9%, Black Race 6.5%, Hispanic 5.5%, American Indian 0.3%, Asian/Pacific Islander 2.3%
  • Prior hormones: Current 6.4%, former 19.7%, never 73.9%
    • Duration of hormone use: <5 years 69.1%, 5-10 years 19.1%, ≥10 years 11.8%
  • Baseline health data: BMI 28.5 kg/m2, SBP 128 mmHg, DBP 76 mmHg
  • PMH: Former smoker 39.9% (current 10.5%), ≥1 term pregnancy 89.9%, DM on treatment 4.4%, HTN 25.7%, HLD on treatment 12.5%, MI 1.6%, angina 2.8%, stroke 0.7%, DVT/PE 0.9%, fracture ≥55 years 13.5%
  • PSH: CABG/PCI: 1.1%
  • Family history: Breast cancer in female 16.0%
  • Medications: Statin 6.9%, ASA 19.1%
  • Gail model 5 year breast cancer risk:
    • <1%: 15.2%
    • 1%-1.99%: 63.3%
    • 2%-4.99%: 20.6%
    • ≥5%: 1%
  • Falls in prior year:
    • 0: 66.2%
    • 1: 21.0%
    • 2: 8.3%
    • ≥3: 4.5%

Interventions

Randomization to conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg daily or placebo, those on postmenopausal hormones had a 3 month washout phase before starting the intervention.

Outcomes

Presented as estrogen and progestin vs. placebo.

Primary Outcomes

CAD mortality or non-fatal MI
0.37%/yr vs. 0.30%/yr (HR 1.29; 95% CI 1.02-1.63)
Invasive breast cancer
0.38%/yr vs. 0.30%/yr (HR 1.26; 95% CI 1.00-1.59)

Secondary Outcomes

Global index

Defined as first event for each participant for CAD, stroke, PE, breast cancer, endometrial cancer, colorectal cancer, hip fracture, or all-cause mortality.

1.70%/yr vs. 1.51%/yr (HR 1.15; 95% CI 1.03-1.28)
CAD mortality
0.07%/yr vs. 0.06%/yr (HR 1.18; 95% CI 0.70-1.97)
Non-fatal MI
0.30%/yr vs. 0.23%/yr (HR 1.32; 95% CI 1.02-1.72)
Stroke
0.29%/yr vs. 0.21%/yr (HR 1.41; 95% CI 1.07-1.85)
Fatal: 0.04%/yr vs. 0.03%/yr (HR 1.20; 95% CI 0.58-2.50)
Non-fatal: 0.21%/yr vs. 0.14%/yr (HR 1.50; 95% CI 1.08-2.08)
VTE
0.34%/yr vs. 0.16%/yr (HR 2.11; 95% CI 1.58-2.82)
DVT: 0.26%/yr vs. 0.13%/yr (HR 2.07; 95% CI 1.49-2.87)
PE: 0.16%/yr vs. 0.08%/yr (HR 2.13; 95% CI 1.39-3.25)
Invasive breast, endometrial, or colorectal cancer
1.14%/yr vs. 1.11%/yr (HR 1.03; 95% CI 0.90-1.17)
Invasive breast: 0.38%/yr vs. 0.30%/yr (HR 1.26; 95% CI 1.00-1.59)
Endometrial: 0.05%/yr vs. 0.06%/yr (HR 0.83; 95% CI 0.47-1.47)
Colorectal: 0.10%/yr vs. 0.16%/yr (HR 0.63; 95% CI 0.43-0.92)
Hip, vertebral, or other osteoporotic fracture
1.47%/yr vs. 1.91%/yr (HR 0.76; 95% CI 0.69-0.85)
Hip: 0.10%/yr vs. 0.15%/yr (HR 0.66; 95% CI 0.45-0.98)
Vertebral: 0.09%/yr vs. 0.15%/yr (HR 0.66; 95% CI 0.44-0.98)
Other osteoporotic: 1.31%/yr vs. 1.70%/yr (HR 0.77; 95% CI 0.69-0.86)
All-cause mortality
0.52%/yr vs. 0.53%/yr (HR 0.98; 95% CI 0.82-1.18)

Additional Analyses

Change in lipid levels from baseline to 1 year

In a 8.6% population subsample

LDL-cholesterol: 12.7% greater reduction in E+P
HDL-cholesterol: 7.3% greater increase in E+P
Triglycerides: 6.9% greater increase in E+P
Blood pressure
SBP at one year: 1 mmHg higher in E+P group
DBP at one year: No difference

Criticisms

  • Only tested a single dose of a single formulation of the hormones
  • High discontinuation in the treatment arm (42%) and crossover to the treatment arm (10.7%)
  • Unclear of the effects of estrogen or progestin individually
  • Does not guide short-term use for treatment of perimenopausal symptoms
  • A primary prevention trial against CAD should randomize younger, newly postmenopausal women to HRT to prevent formation of plaques[4]

Funding

  • National Heart, Lung, and Blood Instituted
  • Medication and placebo donated by Wyeth-Ayerst Research

Further Reading

  1. 1.0 1.1 1.2 Barrett-Connor E. "Hormones and heart disease in women: The timing hypothesis." American Journal of Epidemiology. 2007;166(5):506-510.
  2. 2.0 2.1 2.2 Moyer VA, et al. Menopausal hormone therapy for the primary prevention of chronic conditions: U.S. Preventative Services Task Force Recommendation statement. Annals of Internal Medicine. 2013;158:47-54.
  3. Hulley S, et al. "Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women." JAMA. 1998;280(7)605-613.
  4. 4.0 4.1 Multiple authors. "Letters: Risks of postmenopausal hormone replacement." JAMA. 2002;288(22):2820-2824
  5. 5.0 5.1 5.2 American College of Obstetricians and Gynecologists Committee on Gynecologic Practice. "Hormone therapy and heart disease. Committee Opinion No. 565." Obstetircs and Gynecology." 2013;121:1407–1410.
  6. Manson JE and Bassuk SS. "Invited commentary: Hormone therapy and risk of coronary heart disease: Why renew the focus on the early years of menopause?" American Journal of Epidemiology. 2007;166(5):511-517.
  7. Hsia J, et al. "Conjugated equine estrogens and coronary heart disease: The Women's Health Initiative." Archives of Internal Medicine. 2006;166(3)357-365.
  8. 8.0 8.1 Mosca L, et al. "Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease in Women—2011 Update: A Guideline From the American Heart Association." Circulation. 2011;123(11):1243-62.
  9. Anderson GL, et al. "Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women's Health Initiative randomized controlled trial." JAMA. 2004;291(14)1701-1712.
  10. USPSTF Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions. Published 2012-10. Current 2013-01. Accessed 2013-06-22.