Risks and benefits of estrogen plus progestin

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National Institutesof Health National Heart,
Lung, and Blood Institute Womens Health
Initiative (WHI) Clinical Trials and
Observational Study Presentations by WHI
Principal Investigators
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WHI Clinical Centers (40)
Clinical Center
Minority Clinical Center
Seattle, WA
Minneapolis, MN
Portland, OR
Buffalo, NY
Milwaukee, WI
Detroit, MI
Worcester, MA
Madison, WI
Boston, MA
Bronx, NY
Iowa City, IA
Pittsburgh, PA
Pawtucket, RI
Chicago, IL
Stony Brook, NY
Columbus, OH
Newark, NJ
Reno, NV
Cincinnati, OH
Sacramento, CA
Oakland, CA
Washington, DC
Stanford, CA
Winston-Salem, NC
Memphis, TN
Los Angeles, CA
Chapel Hill, NC
Torrance, CA
Orange, CA
Atlanta, GA
San Diego, CA
Tucson, AZ
Birmingham, AL
San Antonio, TX
Honolulu, HI
Gainesville, FL
Houston, TX
Miami, FL
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WHI CT Sample Size, Outcomes, Follow-up Women,
aged 50-79 Total CT 68,133

Diet Modification (DM) Trial Primary Outcomes
Breast Colorectal Cancer Secondary
Outcome Coronary Heart Disease
(CHD) Hormone Trials Primary Outcome CHD
Secondary Outcomes Hip Fracture, Breast
Cancer Ancillary Study Memory
Average 8.5 year Follow-up
DM 48,836
11.8 Overlap
Hormone 27, 347
Average 8.5 year Follow-up
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WHI CaD Outcomes, Relationship to CT
Total CT 68,133
Calcium Vitamin D (CaD) Primary Outcome
Hip Fracture Secondary Outcomes Other
Fractures, Colorectal Cancer

DM 48,836
CaD 36,282
at 1st (or 2nd) Annual Visit
53.3 of CT
Hormone 27, 347
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WHI Relationship of OS to CT
The Observational Study (OS) is a complement to
the Clinical Trial
Women screened for the DM or HT trials could
enroll in the OS, if they were ineligible for the
CT, or chose not to join either DM or HT trials.

• Purpose of OS
• To improve risk prediction of cardiovascular
  disease, cancers, fractures, and all-cause
  mortality (death) in postmenopausal women
• To create a resource of data and biological
  samples which can be used to identify new risk
  factors and/or disease biomarkers
• To examine impact of changes in lifestyle and
  risk factors on disease and mortality

OS 93, 676
Total WHI Sample (CTOS) 161,809
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The Womens Health Initiative (WHI)
Postmenopausal Hormone Program Background and
Rationale
Marcia L. Stefanick, Ph.D. Associate Professor
of Medicine and of Gynecology and Obstetrics,
Stanford University PrincipaI Investigator,
Stanford Chair, WHI Steering Committee
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A Brief History of Hormone Therapy
Observational Studies suggest Benefits Risks
1942 FDA approved Estrogen for treatment of
menopausal symptoms
E associated with fewer fractures higher BMD
OCs associated with blood clots, heart attacks
E associated with lower CHD
E associated with higher breast cancer
E associated with uterine cancer
Feminine forever
2000 Br CA EP E only
EP lower CHD
Progestins protect uterus
CEE in men blood clots, heart attacks
1995 PEPI E vs EP
1997 HERS- EP blood clots 1998 HERS 1st yr
heart attacks no 4yr benefit 2001 AHA position
Prescriptions (Millions)
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Observational Studies are Biased

• Women who use Hormones over an extended time
  differ from those who dont, in many ways besides
  HT use. Compared to non-users, estrogen users
  are generally
• Literature is based mostly on estrogen without
  progestin

• less obese
• less likely to smoke
• more physically active
• more highly educated
• more likely to go to doctors regularly
• more likely to check cholesterol, BP, etc.
  ( have mammograms other screening)
• less likely to consume high fat diet and salt

Differences could explain why hormone users have
a lower CHD
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WHI Hormone Trials Specific Aims

• To test whether Estrogen Progestin (EP) - or-
  Estrogen Only (E-Alone)
• reduce the incidence of Coronary Heart Disease
  and other Cardiovascular Disease
• reduce the incidence of all osteoporosis-related
  fractures and hip fractures, separately
• increase the risk of breast cancer
• To determine the balance of risks and benefits of
  menopausal hormones on the overall health of
  postmenopausal women.

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WHI Hormone Program Study Population Inclusion
criteria

• Age 50-79 at baseline
• Post menopausal, defined as
• No uterine bleeding for 6 months
• (12 mo, if aged 50-54)
• Current/prior use of menopausal hormones
• Post hysterectomy with symptoms
• Likely to reside in the clinic area for 3 years
• Willing to provide written informed consent

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WHI EstrogenProgestin TrialBackground circa 1992

• Suspected benefits of hormones
• ? risk of Coronary Heart Disease (CHD)
• ? risk of Osteoporotic (hip/other) Fracture
• (? risk of colorectal cancer, suspected later)
• Suspected risks of hormones
• ? risk of Breast Cancer
• ? risk of Blood Clots Pulmonary Emboli (lungs),
  Deep Vein Thromboses (legs)
• (based on Oral Contraceptive literature, later,
  HERS)

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WHI Hormone Program Design
CEE (Conjugated equine estrogens) 0.625 mg/d
YES
N 10,739
Placebo
Hysterectomy
CEE 0.625 mg/d medroxyprogesterone acetate
(MPA) 2.5 mg/d
NO

N 16,608
Placebo
Initially CEE only (N331), CEEMPA, or
Placebo
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WHI Hormone Sample Size, Outcomes, Follow-up
Women, aged 50-79 Total HT trials 27,347
Hormone Trials Primary Outcome
Coronary Heart Disease Secondary Outcomes
Hip Fracture Other Fractures Breast
Endometrial Cancers WHI Memory Study (WHIMS)
- for women 65 - Memory
Average Follow-up 5.2 years
EP 16,608
E only 10,739
Average 8.5 years
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WHI HRT Baseline Age DistributionMean SD
HystX-E only 63.6 7.3 Uterus-EP 63.3 7.1
60-69 E45 EP45
70-79 E24 EP22
50-59 E31 EP33
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WHI HRT Minority Distribution HystX
2657/10,739 (24.7) Uterus N 2663/16,608
(16.0)Total HRT N 5320/27,347 (19.5)
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EstrogenProgestin Study Participants

• 16,608 women joined this part of the study.
• The E P trial was for women who still had a
  uterus when they joined WHI Hormone Study
• Participants were assigned by chance to take
  active EP or inactive (placebo) pills.
• The estrogen plus progestin combination we
  studied is identical to Prempro
• (The estrogen is identical to the most common
  dose of Premarin)

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Outcomes Monitored by DSMB

• Cardiovascular disease
• Heart attacks (Coronary Heart Disease, CHD)
• Strokes
• Blood Clots in the Lungs (Pulmonary Emboli)
• Breast Cancer
• Colorectal cancer
• Endometrial (uterine) cancer
• Hip Fractures
• Deaths from other causes
• Global Index (includes all of the above) -
  Defined to provide index of overall balance of
  benefits and risks

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Trial monitoring for benefitEarly stopping
considerations required

• Evidence of Coronary Heart Disease benefit
• Statistical rules based on OBrien-Fleming (OBF)
  procedures using a 0.025-level, one-sided test
• AND
• Global index supportive of benefit
• Statistical rules based on OBF procedures using a
  0.05-level, one-sided test

OBF OBrien PC, Fleming TR. Biometrics.
197935549-556.
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Trial monitoring for riskEarly stopping
considerations required

• Evidence of increased breast cancer
• OBF procedure using a 0.05-level one-sided test.
  
• OR
• Evidence of increases in CHD, stroke, PE, hip
  fracture, colorectal cancer, endometrial cancer,
  or death from other causes
• OBF procedure using a 0.05-level one-sided test,
  with Bonferroni correction.
• AND
• Global index supportive of overall harm (Z

Freedman, et al. Control Clin Trials.
199617509-525.
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At the request of WHI Data Safety Monitoring
Board, HT Participants were informed (April
2000) that

• There was a small increase in the number of heart
  attacks, strokes, and blood clots in the legs and
  lungs, in women receiving active hormones,
  compared to women taking placebo.
• It was believed that this difference was reduced
  and may disappear after 2 years (as in HERS).

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WHI Data Safety Monitoring Board required that
HT Participants be informed (June 2001) that

• After an average of 4 years of follow-up, there
  were more heart attacks, more strokes, and more
  PE and DVT, in active hormone group (EP
  E-Alone combined) vs placebo
• Fewer than 1 of women had any one of these
  events per year in either active or placebo group
• Case-Control Biomarker Study was Initiated
• Factor V Leiden, Prothrombin (G20210A) mutation,
  Selected Coagulation Inflammation factors, etc.

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NHLBI accepted DSMB recommendation to stop WHI
Estrogen Progestin Trial (May 2002)

• After an average of 5.2 years
• Women in Estrogen Progestin trial told to stop
  study pills risks of EP exceed the benefits.
• Participants in the EP trial continue to be
  monitored, to determine how long risks or
  benefits persist, over time
• Women in Estrogen-Alone study asked to continue
  study pills balance of benefits and risks is
  unclear.
• At this time, no increased risk of breast cancer
  has been seen in women taking estrogen only, vs
  placebo.
• E-Alone participants will continue to be closely
  monitored.

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Results of Estrogen plus Progestin Use in Health
Postmenopausal Women Implications for Clinical
Practice

• Risk of Cardiovascular Disease and Stroke
• Marian C. Limacher, M.D. (Gainesville)
• Risk of Fracture
• Rebecca D. Jackson, M.D. (Columbus)
• Risk of Cancer
• Rowan T. Chlebowski, M.D., Ph.D. (Harbor-UCLA)