Hormone Therapy After Menopause: The Women

1
Hormone Therapy After Menopause The Womens
Health Initiative Findings

• October 26, 2012
• Jean Wactawski-Wende, PhD
• Professor and Associate Chair, Department of
  Social and Preventive Medicine, SPHHP
• Professor, Department of Gynecology-Obstetrics,
  SMBS
• Vice Provost for Strategic Initiatives
• University at Buffalo
• Buffalo, New York

2
Objective of Todays Talk

• Provide a brief background on menopausal hormone
  therapy and issues related to that in the United
  States
• Overview the WHI study
• Present the main findings of the WHI Hormone
  Therapy Trials
• Put the WHI 2002 and 2004 findings into current
  context

3
A Short History of Hormone Therapy
Progestins protect endometrium
1942 Premarin 1st Marketed in the US
Oral contraceptives cause vascular disease
Estrogens lower CHD risk
Benefit vs. Risk
Failed estrogen trials in men
Estrogens prevent bone loss
Estrogens increase endometrial cancer
Estrogens increase breast cancer
Feminine Forever
40
30
Prescriptions
(millions)
20
Estrogen
Progestin
10
0
1960
1965
1980
1985
1990
1995
1970
1975
4
Excerpt from this advertisement The physician
who puts a woman on "Premarin" when she is
suffering from the menopause usually makes her
pleasant to live with once again. It is no easy
thing for a man to take the stings and barbs of
business life, then to come home to the turmoil
of a woman "going through the change of life". If
she is not on "Premarin", that is.
5
1990s Reported Potential Benefits of Hormone
Therapy Use in Observational Studies

• Vasomotor (Hot flashes, night sweats)
• Urogenital (Dryness, infection, incontinence)
• Bone (Osteoporsis, fracture)
• Brain (Alzheimers, memory loss, cognition)
• Eyes (Macular degeneration)
• Heart (CVD, lipids)
• Colon (Colon and Rectal cancer)

6
1990sReported Potential Risks of Hormone
Therapy Use in Observational Studies

• Breast Cancer
• PE/DVT
• Gallbladder Disease
• Stroke
• Others?

7
Survey on the PRIMARY REASON PHYSICIANS PRESCRIBE
Hormone Therapy in the U.S., 1996
Source Market Measures HRT Study X, 1996 Wyeth
Ayerst
8
Recommendations in the 1990s

• 1992 American College of Obstetricians and
  Gynecologists Probable beneficial effect of
  estrogen on heart disease
• 1992 American College of Physicians
• Women who have coronary heart disease or who
  are at increased risk of coronary heart disease
  are likely to benefit from hormone therapy
• 1996 American Heart Association
• ERT does look promising as a long-term
  protection against heart attack

9
RISK OF DISEASE IN U.S. WOMEN (1993)

• Heart Disease
• 1 killer of women in the U.S.
• 1 out of 6 between the ages of 45 and 65
• 1 out of 3 over the age of 65
• Fracture
• 1 out of 6 will suffer a hip fracture
• 1 out of 2 will suffer a fracture (all combined)
• Cancer
• 1 out of 8 will develop breast cancer
• 1 out of 17 will develop colorectal cancer

10
Womens Health Initiative1993 - present

• A 12 year study of the major causes of disease
  and death in postmenopausal women.
• Goal To evaluate the balance of benefits and
  risks of the WHI interventions in postmenopausal
  women

11
WHI Hormone Study Study Population Inclusion
criteria

• Age 50-79 at baseline
• Post menopausal
• Likely to reside in the clinic area for 3 years
• Willing to provide written informed consent

12
Pool 1 Clinical Centers (30)
WHI Clinical Centers (40)
Minority Clinical Centers (10)
Seattle
Minneapolis
Detroit
Portland
Milwaukee
Buffalo
Worcester
Madison
Boston
Iowa City
Bronx
Chicago
Pittsburgh
Pawtucket
Columbus
Stony Brook
Sacramento
Newark
Reno
Cincinnati
Oakland
Washington, DC
Stanford
Winston-Salem
Los Angeles
Memphis
Chapel Hill
Orange
Torrance
San Diego
Atlanta
Tucson
Birmingham
San Antonio
Honolulu
Gainesville
Houston
Miami
13
Womens Health Initiative
2 Hormone Therapy Trials Coronary Heart Disease
FracturesAdverse effect for Breast Cancer?
27,347
3 Controlled Trials 68,135
36,282
Calcium/Vitamin D Trial Fractures Colorectal
Cancer
Dietary Modification Trial Breast Colorectal
Cancers Coronary Heart Disease
48,835
93,676
Observational Study
1 Observational Study
161,808 women total
14
WHI Hormone Program Design
Two WHI Trials on Hormone Therapy
Conjugated equine estrogen (CEE) 0.625 mg/d
Women who had NO UTERUS at start of study N
10,739
Placebo
Hysterectomy
Women who had a uterus at start of study N
16,608
CEE 0.625 mg/d medroxyprogesterone acetate
(MPA) 2.5 mg/d
Placebo
15
Hormone Trials Findings
16
2002 EstrogenProgestin Trial terminated

• In May 2002, the WHI Data and Safety Monitoring
  Board recommended the EP trial be stopped based
  on
• Breast cancer risk significantly increased
• Global index supported that harm exceeding
  benefit
• No CVD protection (increased risk)

17
Balance of Risks Benefits The WHI EP Trial,
2002 (Mean Follow-up 5.6 yrs)
Risks
No Effect
Benefits
29 Increase CHD

44 Increase Ischemic Stroke
34 (Hip) Fracture Reduction
Endometrial Cancer
113 Increase Pulmonary Emboli
44 Fewer Colorectal Cancers

Death
26 Increase Breast Cancer
Threshold Level
STOPPED Early, Harm
JAMA, 2002
18
WHI EP TrialAnnual Absolute Risks and Benefits
Absolute Risks in 10,000 women treated per year Absolute Risks in 10,000 women treated per year Absolute Risks in 10,000 women treated per year
Event Placebo Estrogen Progestin
Coronary Heart Disease 30 37
Invasive Breast Cancer 30 38
Stroke 21 29
Pulmonary Embolism 8 16
Colorectal Cancer 16 10
Hip Fracture 15 10
Endometrial Cancer 6 5
Death 40 37
Global Index 151 170
Risks
Benefits
Null
Annual event estimates are cumulative, JAMA
2002
19
(No Transcript)
20
February 2004WHI Estrogen-alone Trial stopped

• In February 2004, NIH stopped the trial after 6.6
  years of intervention, based on
• Increased risk of stroke
• Low chance of establishing a overall or heart
  disease benefit

21
Balance of Risks in the WHI E-Alone Trial, 2004
(6.8 yrs)
Harm
Benefit
No Effect
Heart Disease
Reduction in Hip Fractures (39), Breast cancer
?
Increase in Stroke (39)
Colorectal Cancer
Death
Threshold Level
STOPPED Early, Excess stroke, no overall benefit
Adapted from The Womens Health Initiative
Steering Committee. JAMA. 20042911701-1712
22
Estrogen Alone (CEE)Absolute risk differences
per 10,000 person/yrs

• 12 more strokes (p.007)
• 6 fewer hip fractures (p.01)
• 56 fewer osteoporotic fractures at any site
  (plt.001)
• 7 more VTE events (ns)
• 7 fewer breast cancers (ns)
• 5 fewer CHD events (ns)
• No difference in colorectal cancer
• No difference in total mortality
• No difference in pre-defined global index

23
Lipid Levels in EP and E-alone Trials


plt 0.001
plt 0.05




Percent Change at 1 yr






NEJM 2003 349523-34
Arch Intern Med 2006 1661-9
24
Incidence of Probable Dementia in Women Age 65
by Treatment Arm
HR1.49
HR2.05
25
FDA Response 2003
BLACK BOX warning on estrogen products

• Estrogens and progestins should not be used for
  the prevention of cardiovascular disease.
• PREMARIN (conjugated estrogens tablets, USP) is a
  prescription treatment used after menopause.
  PREMARIN is used after menopause to reduce
  moderate to severe hot flashes to treat moderate
  to severe dryness, itching, and burning, in and
  around the vagina and to help reduce your
  chances of getting osteoporosis (thin weak
  bones).
• ..estrogens with or without progestins should be
  prescribed at lowest effective doses and for the
  shortest duration consistent with treatment goals
  and risks for individual woman.

26
Public Health Impactone example
27

IMS Health, National Prescription Audit Plus,
1995 July 2003, extracted August 2003.
28
(No Transcript)
29
Clinical Trial CEEMPA vs. Placebo Breast Cancer
Risk During Intervention and Postintervention
Chlebowski RT, Kuller L, Prentice R, et al. N
Engl J Med 360611-25
30
Clinical Trial Sensitivity Analysis CEEMPA vs.
Placebo Breast Cancer Risk During Intervention
and Postintervention
HR1.62 (1.10, 2.39)
HR1.26 (0.73, 2.20)
P Trend-Diff 0.005
Linear time varying Hazard Ratio during Clinical
Trial

Linear time varying Hazard Ratio during
Postintervention

HR (95 CI) based on
events accumulated in each 6 month window
31
USPSTF

• Menopausal Hormone Therapy for the Primary
  Prevention of Chronic Conditions A Systematic
  Review to Update the U.S. Preventive Services
  Task Force Recommendations
• Nelson et al. Annals Internal Medicine July
  2012.
• In conclusion, our update of evidence from
  trials published since 2002 indicates that both
  hormone therapy regimens decrease risk for
  fractures but increase risk for stroke,
  thromboembolic events, gallbladder disease, and
  urinary incontinence. Estrogen plus progestin
  also increases risk for breast cancer and
  probable dementia, whereas estrogen alone
  decreases risk for breast cancer.

32
Open Questions

• Timing Hypothesis
• Duration since menopause vs age since menopause
• Other formulations?
• Lower doses?

33
Thank our WHI participants!
34
Questions?