Postmenopausal Hormone Replacement Therapy for Prevention of Chronic Conditions Review of Evidence f

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Postmenopausal Hormone Replacement Therapy for
Prevention of Chronic ConditionsReview of
Evidence for the USPSTF

• Heidi D. Nelson MD, MPH
• Oregon Evidence-based Practice Center
• Oregon Health Science University

Oregon EPC
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Evidence Considered by the USPSTF

• Systematic review of published literature
  (1966-2001) conducted by EPC (JAMA 2002
  288872-881).
• Womens Health Initiative RCT results on combined
  CEE/MPA arm (JAMA 2002288321-333).
• Heart and Estrogen/progestin Replacement Study
  RCT (HERS) and observational follow-up (HERS II)
  results after 6.8 years (JAMA 200228858-66).

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Methodology

• Explicit, evidence-based.
• Systematic search/review of studies of HRT and
  primary prevention of specific clinical
  conditions.
• Evaluate quality of individual studies based on
  established criteria.

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USPSTF Levels of Evidence
I At least one well-conducted RCT II-1 Controlle
d trials without randomization II-2 Well-designed
cohort or case-control studies, preferably
from multiple sites II-3 Multiple time-series
with or without intervention. Dramatic
before-after results (e.g. penicillin) III Exp
ert opinion
Oregon EPC
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USPSTF - Strength of Evidence

• Good Well-designed studies in representative
  populations with important health outcomes
• Fair Sufficient evidence, but limited by number
  quality or consistency of studies
  generalizability to practice or intermediate
  health outcomes
• Poor Insufficient due to limited number or
  power, flaws in design or conduct, gaps in
  evidence, or lack of evidence on most important
  outcomes.

Oregon EPC
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Systematic Evidence Reviews

• Osteoporosis bone density and fractures
• Breast cancer incidence and mortality
• Venous thromboembolism deep vein thrombosis
  and/or pulmonary embolism
• Cognitive function and dementia
• Cardiovascular disease
• - Coronary heart disease incidence and mortality
• - Stroke incidence and mortality
• - Combined cardiovascular disease incidence and
  mortality

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Brief Reviews

• Colorectal cancer
• Endometrial cancer
• Ovarian cancer
• Cholecystitis

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Limitations of Systematic Review

• Few RCTs of estrogen.
• HRT use often based on self-report.
• HRT use defined differently across studies.
• Type of estrogen, use of progestin, dose, and
  regimen are not well defined or analyzed
  separately.
• Users differ from nonusers in important ways that
  are not well measured or controlled for.
• Not studied in nonwhite, non middle-class
  populations.

Oregon EPC
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Fractures(RR or HR with 95 CI)
Nominal CI used for main outcomes (CAD, breast
cancer), adjusted CI used for secondary
outcomes. Adjusted results (age and predictors
of specific outcomes).
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Colorectal Cancer(RR or HR with 95 CI)
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Colorectal Cancer
Ever use - colon cancer 0.80 (0.74 -
0.86) Ever use - rectal cancer 0.81 (0.72 -
0.92) Current use - colorectal 0.66 (0.59 -
0.74)
18 observational studies, users tended to be
healthier, less obese, more physically active,
have healthier diets Am Jour Med
1999106(5)574-82.
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Uncertain Benefit Dementia Risk Meta-analysis
of 12 studies with important methodologic
limitations Cohort Case-control Pooled
estimates
Ever use of HRT RR 0.66 (0.53 - 0.82)
Fixed effects Random effects
0.1 1.0 10.0
Relative Risk
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Cardiovascular Events(RR or HR with 95 CI)
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Stroke(RR or HR with 95 CI)
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Venous Thromboembolism(RR or HR with 95 CI)
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Breast Cancer(RR or HR with 95 CI)
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Breast Cancer Incidence 51 case-control
studies Current use 1.21 (plt0.001) Ever
use 1.14 (plt0.001) Long-term (gt5 years) 1.35
(1.21 - 1.49) 9 RCTs Ever use 0.85 (0.38 -
1.89)
Lancet 19973501047-1059. BMJ 1997315149-53.
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Cholecystitis(RR or HR with 95 CI)
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Endometrial Cancer

• Unopposed estrogen use is associated with
  endometrial hyperplasia and endometrial cancer.
• Risk for endometrial cancer does not appear to be
  increased when combining estrogen and progestin.
• Current practice is to use combined HRT for women
  without prior hysterectomies.

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Ovarian Cancer

• 5 meta-analyses and 15 case-control studies no
  consistent effect or dose-response effects.
• 2 large prospective cohorts suggest modest
  increased risk with estrogen (RR 1.2-1.6), higher
  with longer use (RR 2 to 3) third study found no
  increase.
• One study suggests risk higher with E than EP.
• Data suggestive but inconsistent.

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Effects of Progestin DoseFindings from USPSTF
Review
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Effects of Progestin DoseFindings from USPSTF
Review
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Events Prevented with HRT (Per Year in 10,000
Women 65-74 Years)
USPSTF WHI
57
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9
6
6
5
4
Hip Fractures
Colon Cancer Cases
Vertebral Fractures
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Events Caused with HRT (Per Year in 10,000 Women
65-74 Years)
USPSTF WHI
53.5
3
18
1.5
12
0
7
8
8
CHD Events
Breast Cancer Cases
VTE Events
Strokes
Cholecystitis Cases
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Summary of Evidence
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Summary of Evidence