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Hormone Replacement 2009: Seven years after WHI

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David Barad, MD CHR Grand Rounds April 14, 2009. Hormone Replacement 2009: Seven years after WHI . History. 1940: DES used for “healthy pregnancy” 1966: Feminine Forever published by Dr. Wilson 1976: Unopposed estrogen linked to endometrial cancer 1980s: Estrogen and Progestin given

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history
History
  • 1940: DES used for “healthy pregnancy”
  • 1966: Feminine Forever published by Dr. Wilson
  • 1976: Unopposed estrogen linked to endometrial cancer
  • 1980s: Estrogen and Progestin given
  • 1993 to Present: WHI
vasomotor symptoms
Vasomotor Symptoms
  • Occur in 60 - 80%
  • Severe in 15%
  • Worse in iatrogenic menopause
  • Primary reason for starting or restarting HRT
  • Primary SE of stopping HRT
mood swings
Mood Swings
  • Multifactorial: Stress, empty nesters, fatigue
  • The gamut of tears, laughter, depression
  • Estrogen/ Serotonin receptor association
  • Often reported by significant others
genitourinary atrophy
Genitourinary Atrophy
  • Vaginal dryness and burning
  • Thinned mucosa
  • May complain of pain with intercourse
  • Increased microhematuria
slide7

CHD Mortality in Men and Women by Age

Myth and paradox of coronary risk and menopause

Tunstall-Pedoe, Lancet 1998; 351: 1425-27

the evidence
The Evidence

Estrogen+ Progestin

Estrogen Only

Cohort StudiesFalkeborn, 1992Wolf, 1991Henderson, 1991Sullivan, 1990Avila, 1990Criqui, 1988Petitti, 1987LRC Prevalence Study: Bush, 1987

Framingham:Wilson, 1985

Nurses Health Sutdy: Stampfer, 1985Angiographic StudiesMcFarland, 1989Sullivan, 1988Gruchow, 1988Case-Control StudiesMann, 1994Rosenberg, 1993Croft, 1989Beard, 1989Szklo, 1984Ross, 1981Bain, 1981Adam, 1981Rosenberg, 1980Pfeffer, 1978Talbott, 1977Rosenberg, 1976

Summary Relative Risk

Cohort Studies

Falkeborn, 1992

Case-Control Studies

Psaty, 1994

Mann, 1994

Rosenberg, 1993

Thompson, 1989

Clinical Trial

0.1

1

0.01

0.1

1

0.01

10

Barrett-Connor. Annu Rev Public Health. 1998;19:55-72

whi 1993 2005 objectives and design
WHI 1993-2005: Objectives and Design
  • Addressed etiology and prevention of major causes of morbidity and mortality in
  • Postmenopausal Women
    • aged 50-59 enrolled 1993-1996
    • aged 60-79 enrolled 1993-1998
  • Three clinical trials (N=68,133)
    • Hormone Therapy (HT) to prevent CHD
    • Diet Modification (DM) to prevent cancer
    • Calcium/Vitamin D (CaD) to prevent hip fractures
  • Large observational study (N=93, 676)
  • Planned duration 8.4 years (average)

www.whi.org

www.whiscience.org

prevention trials

Health Promotion

Acute care

Rehabilitation

Prevention Trials

Secondary

Tertiary

Primary

Event

prevention trials1

Health Promotion

Acute care

Rehabilitation

Prevention Trials

Secondary

Tertiary

Primary

Event

Disease

slide12

CHD Mortality in Men and Women by Age

Myth and paradox of coronary risk and menopause

BMJ. 2002 August 10; 325(7359): 311–312.

slide13

CHD Mortality in Men and Women by Age

Myth and paradox of coronary risk and menopause

BMJ. 2002 August 10; 325(7359): 311–312.

hrt puzzle to be solved 1998
“HRT” PUZZLE TO BE SOLVED, (1998)

NOT KNOWN:

Postmenopausal Hormone Therapy for Aging

Heart Disease -

Not for Secondary Prevention AHA Position (HERS)

Primary Prevention - believed favorable

Stroke - NOT for 2ndary Prevention; primary, unknown

VTE (blood clots: lungs, PE; legs, DVT)- unfavorable

Breast Cancer - believed unfavorable

Hip Fractures - believed favorable

Vertebral Fractures - favorable?

Memory, AD - believed favorable

Gallbladder Disease - unfavorable?

Urinary Incontinence - favorable?

whi hormone trials
WHI Hormone Trials

Conjugated equine estrogens (CEE) 0.625 mg/d

Placebo

E Alone N = 10,739

YES

Hysterectomy

NO

CEE 0.625 mg/d + medroxyprogesterone acetate (MPA) 2.5 mg/d

E + P

N=16,608

Placebo

whi hormone trials baseline hypotheses
WHI Hormone Trials: Baseline Hypotheses

Anticipated Risk

Expected Benefit

Coronary Artery Disease

(Heart Attacks)

Stroke?

Breast Cancer

Threshold LevelEarly STOPPING

for HARM

Threshold LevelEarly STOPPING

for BENEFIT

  • Additional Risks:
  • Blood Clots, VTE
  • Lungs=PE; Legs=DVT
  • Additional Benefits:
  • Hip (Bone) Fractures
  • Overall Mortality

Plan to follow to 2005

(average 8.5 years)

  • Colon Cancer
  • Global Index:overall balance of benefits and risks
    • Earliest occurrence of CHD, Stroke, PE, Breast Cancer, Hip Fracture, Colorectal Cancer, Death from other causes, Endometrial Cancer
whi e p trial findings july 2002
WHI E+P Trial: Findings, July 2002

Risks

Benefits

26% Increase

Breast Cancer

Threshold Level

STOPPED Early, Clear Harm

Stopped 3.3 yrs early

* had 0.4 more yrs of data

Other Fractures

Also: DVTs

*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333

whi e p trial findings july 20021
WHI E+P Trial: Findings, July 2002

Risks

29% IncreaseCHD (Coronary Heart Disease)

Benefits

41% Increase

Stroke

33% Decrease Hip Fracture

Decreased Colorectal Cancer

113% Increase Pulmonary Emboli

26% Increase

Breast Cancer

Threshold Level

STOPPED Early, Clear Harm

Stopped 3.3 yrs early

* had 0.4 more yrs of data

Other Fractures

Also: DVTs

*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333

whi e p cancer

Total: 52.9/10,000 E+P vs 52.3/10,000

  • Breast Cancer: Increase in E+P arm reason for stopping trial
    • Not statistically significant, but exceeded preset threshold by DSMB
  • Colon Cancer: Decrease in E+P arm
  • Endometrial Cancer: No difference
WHI E+P: Cancer
whi e p cancer1

No increased risk for breast cancer during the first 2 years of combined estrogen and progesterone (E+P)

    • potentially identifying a "safe" period.
  • Marked drop in the risk for breast cancer 2 years after postmenopausal women stopped taking the hormones.
    • Cancer. Published online before print January 20, 2009. AbstractN Engl J Med. 2009 :360:573-587.
WHI E+P: Cancer
whi e p cardiovascular

CAD: Overall 29% higher rate in E+P

    • Equal number of revascularization procedures and cardiac deaths
    • Excess events in non-fatal MI group
  • Stroke:
    • Equal number of fatal strokes
  • DVT/PE:
    • 10 x number reported by USPSTF
WHI E+P: Cardiovascular
osteoporosis
Osteoporosis
  • T score > 2.5 SD below young adults
  • 10 million Americans
  • 1.5 million fractures annually
  • Hip fractures
    • 1 out of 6 women
    • 1/2 can not walk without assist
    • 1/4 die within one year of fracture
whi e p fractures

Hip fractures reduced by 34%

  • Vertebral fractures reduced
    • Only 40% symptomatic
    • No routine radiographs to screen for vertebral fractues
  • Patients with osteoporosis excluded from enrollment
WHI E+P: Fractures
whims e p

Enrolled 4500 women 65 – 79

  • Participants memory and cognitive functions were tested yearly
  • Tested rate of memory decline and for presence of dementia
  • Outcomes:
    • E+P does not protect from normal decline
    • E+P showed increase in dementia
WHIMS E+P
slide27

WHIMS E+P: Probable Dementia Hazard Ratio

4532 women, aged 65-79; followed for 4.1 years

E+P

Placebo

HR, 2.05

95% CI, 1.21__3.48

Cumulative Hazard

0 1 2 3 4 5

Years Since Randomization

No. at Risk

E+P

Placebo

2229 2112 2026 1915 1325 401

2303 2200 2125 1984 1392 477

whi estrogen only

Enrolled 10,739 women, aged 50 -79, and treated with estrogen or placebo

  • Average follow-up of 6.8 years
  • Tested primary prevention/safety estrogen
  • Outcomes:
    • Increased risk in stroke, decreased hip fx
    • No change in breast CA, CAD, colon CA
WHI Estrogen Only
whi e only trial findings march 2004
WHI E only Trial: Findings, March 2004

Risks

Benefits

37% Increase Stroke

(55% Increase Ischemic Stroke)

33% Decrease Hip Fracture

Threshold Level

STOPPED -

Increased Stroke

No CHD Benefit

Stopped 1.5 yrs early

* had 0.3 more yrs of data

Other Fractures

No Effect onCHD

No Increase Breast Cancer

No Effect on Colorectal Cancer

N.S. 37% Increase

Pulmonary Emboli

47% increase DVTs

*Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:321-333

slide30

Summary: WHI E+P* vs. E-Alone** Trialpublished: *July 2002 **April 2004

  • Concordant results
    • Heart Disease – no benefit (for E+P, early harm)
    • Strokes, Blood Clots – harmful
    • Fractures – beneficial
    • Dementia (if ≥ 65 yrs of age) – harmful
  • Disparate Results
    • Breast Cancer
      • Increased in E+P Trial (women with a uterus)
      • Not increased in E-Alone Trial (women with prior hysterectomy)
        • Increased breast cancer risk in women with highest baseline risk
    • Global Index
      • Increased in E+P (CEE + MPA) Trial
      • Neutral in E-Alone (CEE) Trial
whims probable dementia mci
WHIMS : Probable Dementia & MCI

N=4,532; 4.1 yrs follow-up N=2,947; 5.2 yrs follow-up

34% (NS)

105%

49% (NS)

JAMA 2003; 289:2651-2662 JAMA 2004; 291:2947-2958

whi absolute annualized risk1
WHI: Absolute (Annualized) Risk

Risk

Benefit

Risk?

Benefit?

Benefits

Risks

us prescriptions for ht 1995 aug 2003
US Prescriptions for HT 1995 - Aug 2003

WHI

E+P

HERS

WHI

E only

Hersh AL, Stefanick ML, Stafford RS JAMA 291: 2004; 291: 47-53

whi e p trial
WHI E+P Trial

12,304

74.1%

Mean =28.5 kg/m2

Mean =63.3 yrs

N

5522

33.3%

7510

45.2%

3576

21.5%

5058

30.6%

5826

35.3%

5636

34.1%

3262

19.6%

1035

6.2%

% of Enrolled Population

Prior HT Use

Age (yrs)

Body Mass Index

JAMA. 2002;288: 321-333

whi e alone trial
WHI E-alone Trial

Mean =63.6 yrs

Mean =30.1 kg/m2

5539

51.6%

N

3310

30.8%

4852

45.2%

2577

24.0%

2206

20.7%

3707

34.7%

4759

44.6%

3819

35.6%

1377

12.8%

% of Enrolled Population

Prior HT Use

Age (yrs)

Body Mass Index

JAMA. 2004;291: 1701-1712

whi ht ethnic distribution by baseline age
WHI HT : Ethnic Distribution By Baseline Age

PercentMinority

E-alone (32.7%) E+P (21.5%)

E-alone (22.0%) E+P (12.5%)

E-alone (13.9%)E+P ( 8.6%)

25

20

Percent

15

10

5

0

Black

Black

Hispanic

Black

Hispanic

Hispanic

50-59

60-69

70-79

Hysterectomy (75.3% White)

Uterus (84.0 % White )

Ann Epidemiol 2003; 13: S78-S86

chd and age interaction with cee

Age 60-69 y

Age 70-79 y

Age 50-59 y

CHD and AGE: ? Interaction With CEE

P for interaction=0.07

Arch Intern Med. 2006;166:357-365

whi coronary artery calcium study cacs

Women aged 50-59 at time of randomization into E-Alone trial (with prior hysterectomy) at 28 (of 40) WHI sites

  • After mean 7.4 years of treatment; 1.3 yrs after trial was completed

- Did not study older women in E-only trial or women in E+P trial

Baseline Characteristics (N=1064: 537 CEE, 527 Placebo)

  • Age: Mean 55 years (50-54, 39.5%; 55-59, 60.5%)
  • Age at Menopause: Mean 43.5 years
  • Age at Hysterectomy: < 35 (28%); 35-39 (25%); 40-44 (22.5%); ≥ 45 (23%)
  • Ethnicity: White, ~ 75% Black, 16.5% Hispanic, 6% Asian/PI, 0.3% American Indian, <1%
  • Body Mass Index: 30.5 kg/m2; Hypertension: 35.5%; Diabetes: 6.3%
WHI Coronary Artery Calcium Study (CACS)

Manson et al,NEJM 2007; 356: 2591-2602

odds ratios for elevation in coronary artery calcium
Odds Ratios for Elevation in Coronary Artery Calcium

Intent-to-Treat Analyses Adherent Analyses

Multivariate P=0.03Multivariate P=0.004

CAC Categories

Manson et al,NEJM 2007; 356: 2591-2602

summary conclusions
Summary & Conclusions
  • Among women aged 50-59 in E-alone Trial calcified plaque burden in coronary arteries was lower in CEE group than placebo 1.3 yrs after 7.4 yrs of treatment.Did not study older women or E+P trial
  • WHI data do not suggest CHD harm for short-term therapy to relieve menopausal symptoms.

HRT and the Young at Heart: Mendelssohn ME, Karas RH. NEJM 2007; 356: 2639-2641

timing hypothesis
Timing Hypothesis
    • Timing Hypothesis: The beneficial effects of HRT in preventing atherosclerosis occur only when the therapy is initiated before advanced atherosclerosis develops.
      • Predicts that HRT is NOT beneficial when given to older women, because the underlying biologic characteristics of the vessel wall and vascular response to HRT are altered in older, more atherosclerotic vessels.
  • Age is a powerful risk factor for atherosclerosis; risk is low for majority of women aged 50-59.
secondary analyses of combined whi trials 2007

Women starting hormones close to the menopause may have fewer heart attacks and deaths due to HT compared to increases in women distant from the menopause

Provides some reassurance that younger women using hormones for the short term for relief of hot flashes and night sweats are not at increased risk of heart disease

Stroke increased irrespective of age or years since menopause (Breast cancer also increased in E+P only)

Secondary Analyses of Combined WHI Trials (2007)

Rossouw et al JAMA 2007;297:1465-1477

secondary analyses of combined whi trials 20071

Older women with moderate/severe hot flashes or night sweats appear to be at high risk if they start hormone therapy

In part explained by higher prevalence of risk factors (obesity, high blood pressure, high blood cholesterol, diabetes) in women with vasomotor symptoms

Secondary Analyses of Combined WHI Trials (2007)

Rossouw et al JAMA 2007;297:1465-1477

whi critiques

“one estrogen and one estrogen/progestin”

    • Most commonly prescribed HT
  • “Women with moderate to severe menopausal symptoms discouraged”
    • Not a study of symptoms… symptomatic women were considered to have greater noncompliance
  • QOL measurement tools
    • Standardized and highly reliable, no QOL tool for menopause existed at the initiation of the WHI
WHI Critiques
whi critiques ii

“Women with osteoporosis were excluded”

    • WHI was a prevention trial and osteporosis was one outcome
  • “Over 1200 women with previous cardiovascular events were included”
    • Prevention of repeat MI was a part of the hypothesis being tested
  • “No routine colonoscopy or bone density”
    • Bone density was performed routinely on a subset of participatnts
WHI Critiques II
the fda black box

Estrogens and progestins should not be used for the prevention of cardiovascular disease.

  • Other doses of CEE and MPA and other combinations of estrogens and progestins were not studied in the WHI and, in the absence of comparable data, these risks should be assumed to be similar
The FDA Black Box
summary

HRT is not recommended for prevention of CAD

HRT is approved for treatment of moderate to severe menopausal sx

HRT is approved for osteoporosis prevention in certain patients

For approved conditions HRT should be used in the low dose for short duration

Summary
current labeling

Treatment of moderate to severe symptoms associated with menopause

Treatment of moderate to severe symptoms associated with vaginal and vulvar atrophy assoc. with menopause

Prevention of postmenopausal osteoporosis in women at significant risk, after considering non-hormonal rx

Current Labeling
helpful websites

www.menopause.org: NAMS

http://www.cme.wisc.edu/online/menopause/sld001.htm: UW menopause review

www.4women.gov/owh: DHHS Office of Women’s Health

www.nhlbi.nih.gov/health/women/index.htm: WHI website

Helpful Websites
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