Health Risks and Benefits 3 Years After Stopping Randomized Treatment With Estrogen and Progestin

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Health Risks and Benefits 3 Years After Stopping
Randomized Treatment With Estrogen and Progestin

• Brenda Ormesher, MD
• March 25, 2008

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Background

• The Womens Health Initiative is a landmark study
  originally designed as a double-blind randomized
  control trial comparing outcomes of
  postmenopausal women given Estrogen Progestin
  vs. Placebo
• The objective of the original study was to define
  the risks and benefits of strategies that could
  potentially reduce the incidence of heart
  disease, breast and colorectal cancer, and
  fractures in postmenopausal women.

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Background

• Primary outcomes Coronary heart disease (CHD)
  including MIs and death secondary to CHD and
  invasive breast cancer as primary adverse outcome
• Secondary outcomes stroke, PE, endometrial
  cancer, hip fracture and death due to other
  causes

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Background

• Intervention phase- enrolled 16,608
  postmenopausal healthy women (ages 50-79 yrs) and
  randomly assigned to receive 0.625mg of
  conjugated equine estrogen (CEE) with 2.5mg of
  Prempro (MPA) or Placebo
• Women were enrolled from 40 clinical centers in
  the U.S. by population direct mailing campaigns
  and media announcements
• Patients were followed with q6 month end point
  ascertainment (by telephone) as well as yearly
  clinic visit with breast exam and an annual
  mammogram

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Background

• Inclusion criteria age 50-79 yrs at initial
  screening, post-menopausal (defined as no vaginal
  bleeding for 6 months or 12 months for 50- to
  54-years or had ever used postmenopausal hormones
  with a 3 month washout period) and likelihood of
  residence in the area in the next 3 years after
  initial screening
• Exclusions competing risks (such as any medical
  condition that had an associated predicted
  survival of lt3 years), safety concerns (history
  of prior breast cancer, other prior cancer in
  preceding 10 years except nonmelanoma skin
  cancer, low Hct or platelet count) and adherence
  or retention concerns (such as alcoholism or
  dementia)

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Original patient characteristics enrolled in the
Womens Health Initiative Trial
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Background

• Data from Risks and Benefits of Estrogen Plus
  Progestin in Healthy Postmenopausal Women
  Principal Results From the Womens Health
  Initiative Randomized Controlled Trial from July
  12, 2002 JAMA concluded
• Women on Estrogen Progestin regimen had a
  significantly increased risk of developing
  invasive breast cancer
• Hazard ratios CHD 1.29 (1.02-1.63), PE 2.13
  (1.39-3.25), CVA 1.41 (1.07-1.85), total CV
  disease 1.22 (1.09-1.36) breast cancer 1.26
  (1.00-1.59), colorectal cancer 0.63( 0.43-0.92),
  endometrial cancer 0.83 (0.47-1.47), total
  cancer 1.03 (0.90-1.11) hip fracture 0.66
  (0.45-0.98), total fractures 0.76 (0.69-0.85)
  and death to other causes 0.92 (0.74-1.14),
  total mortality 0.98 (0.82-1.18)
• Global risk assessment demonstrated risks
  associated with Estrogen Progestin exceeded the
  benefits HR 1.15 (1.03-1.28)
• Absolute excess risks per 10,000 person years
  attributable to estrogen plus progestin were 7
  more CHD events, 8 more strokes, 8 more PEs, and
  8 more invasive breast cancers, while absolute
  risk reductions per 10,000 person-years were 6
  fewer colorectal cancers and 5 fewer hip
  fractures. The absolute excess risk of events
  included in the global index was 19 per 10,000
  person-years.

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Background

• Study design was originally planned for 8-9 year
  follow up but was prematurely terminated on July
  7, 2002 after a mean 5.2 years follow up
  secondary to recommendation from safety
  monitoring board as the risk of invasive breast
  cancer exceeded the benefits of therapy
• This paper from March 5, 2008 specifically looked
  at what happened after intervention termination

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Methods- Post intervention Phase

• Investigators continued to follow study
  participants in accordance with initial study
  protocol after termination of the trial on July
  7, 2002 through the study designed end on March
  31, 2005 (mean participant follow up 2.4 years)
• Patients continued to be followed with biannual
  end point collection as well as yearly mammograms
  
• Data was able to be collected on 15,341
  participants of the original study (389 of women
  (2.5) who were included in the original subset
  of data published 7/12/2002 were lost to follow
  up but these women did not differ by treatment
  assignment (P0.63))

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Post intervention Results

• CVD events (including CAD, CVA, DVT and PE)
  during the post intervention period were not
  statistically significant between the CEE MPA
  group compared to placebo (HR 1.04)
• Occurrence of fractures between study groups was
  also found to be not statistically significant
  (HR 0.91)
• The incidence of invasive breast cancer,
  endometrial cancer and colorectal were not
  significantly different between the CEE MPA
  group vs. placebo (HR 1.27, HR 0.75, HR 1.08
  respectively)
• However, the incidence of all cancer became
  statistically significant in the post
  intervention phase with a HR 1.24 (1.04-1.48)
  CEE MPA annualized rate of all cancers 1.56
  compared to 1.26 in the placebo group

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Post intervention Results

• All cause death, although not a significant HR,
  had an increase in annualized rate during the
  intervention period from 0.52 and 0.53 in the
  treatment and control groups respectively to
  1.20 and 1.06 during the post intervention
  period

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Post intervention Results
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Post intervention Results
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Post intervention Results
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Author conclusions

• The increased cardiovascular risks in the women
  assigned to CEE plus MPA during the intervention
  period were not observed after the intervention.
  A greater risk of fatal and nonfatal malignancies
  occurred after the intervention in the CEE plus
  MPA group and the global risk index was 12
  higher in women randomly assigned to receive CEE
  plus MPA compared with placebo.

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My Opinion

• The study was a well designed randomized placebo
  controlled study to evaluate the use of HRT in
  healthy post-menopausal women in the U.S.
• HRT does not offer any protective events after
  discontinuation of therapy
• The risks of HRT undoubtedly outweigh the
  benefits in this patient population
• Specific to this study, further research is
  needed to examine the role of estrogen/ progestin
  on cancers as they are a significant cause of
  mortality

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My Questions

• Is the increased incidence in other cancers
  found during the post intervention study related
  to not monitoring for them during the
  intervention period? And does that suggest that
  any women on HRT should be more closely monitored
  for lung cancer?
• The risk of colorectal returned to baseline after
  the discontinuation of HRT according to the study
  results, but evolution of colon cancer takes 5-10
  years, what is the true effect of estrogen/
  progestin on colon cancer?
• The initial study had included women with history
  of HRT, what percentage of these women in both
  control and treatment groups developed cancer?
• What proportion of women with history of tobacco
  use developed cancer? Did smoking plus HRT
  increase the risk of a cancer more?

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References

• Heiss, G et al. Health Risks and Benefits 3
  Years After Stopping Randomized Treatment With
  Estrogen and Progestin. JAMA, 2008 299
  (1036-1045)
• Womens Health Initiative. Risks and Benefits of
  Estrogen Plus Progestin in Healthy Postmenopausal
  Women Principal Results From the Womens Health
  Initiative Randomized Controlled Trial. JAMA,
  2002 288 (321-333)