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Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy

Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy. The Women’s Health Initiative Randomized Controlled Trial JAMA 2004;291:1701-1712. Postmenopausal Hormone Use. Observational studies suggested 30%– 50% reduction in cardiac risk

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Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy

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  1. Effects of Conjugated Equine Estrogen in Postmenopausal Women with Hysterectomy The Women’s Health Initiative Randomized Controlled Trial JAMA 2004;291:1701-1712.

  2. Postmenopausal Hormone Use • Observational studies suggested • 30%– 50% reduction in cardiac risk • 8% – 30% increase in breast cancer • Strong benefit for osteoporosis • In 1980’s – 90’s • Increasing use of hormone therapy for long-term cardiovascular disease prevention

  3. WHI Hormone TrialSpecific Aims • Primary Endpoint: To test whether CEE reduces the incidence of CHD and other CVD • Definition of CHD: Nonfatal MI plus CHD death • Primary Safety Endpoint: To assess whether CEE increases the risk of breast cancer • Secondary Endpoints: To test whether CEE reduces the incidence of hip fractures and all osteoporosis-related fractures separately

  4. Women’s Health InitiativeTimeline 1993 1998 1990 2005

  5. WHI Hormone Trial Design 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

  6. Eligibility • Age 50-79 years at first screen • Postmenopausal • Likely to reside in clinic area for at least 3 years • Providing written informed consent

  7. Severely underweight Severe hypertension (>200/105) Severe menopausal symptoms Substance abuse, mental illness, dementia History of: Cancer in last 10 years Melanoma any time Stroke or heart attack in last 6 months Previous fractures treated with hormones Any condition likely to limit survival < 3 yrs Excluded if: So these were generally healthy women and this was a primary prevention trial

  8. Follow-up Methods • 6 weeks after randomization: phone contact • Assess symptoms • Reinforce adherence • Every 6 months: phone or clinic contact • Assess adherence • Assess symptoms • Determine if outcomes had occurred • Annually: clinic visit • Mammograms + clinical breast exams • Assess adherence • Assess symptoms • Determine if outcomes had occurred

  9. Study Medication Use • Intolerable symptoms e.g., breast tenderness • Reduced number of days of treatment • No unblinding for management • Major event possibly related to hormones • Study meds stopped • Temporarily for fracture, immobilization, surgery • Permanently for breast CA, DVT/PE, malignant melanoma, meningioma, TG > 1000 mg/dl, if participant’s health provider prescribed open label hormones • Resumption up to participant’s health provider for MI or stroke • No unblinding for discontinuation of medications

  10. Ascertainment of Outcomes • Self report of diagnosis/hospitalization • Medical records obtained • Local WHI physician adjudicated (coded) events (blinded to treatment assignment) • Central adjudication (blinded to treatment assignment) • CHD • Stroke • VTE • Cancer • Hip fractures

  11. Events during the Hormone Trial • April 2000 – Participants notified of increase in CV events during first 2 years • July 2001 – Participants informed risk does not disappear after 2 years • July 2002 – • E+P trial intervention terminated due to increased breast cancer risk and overall risks exceeding benefits; Principal results published (JAMA 2002;288:331-333). • E alone trial is continued. • February 2004 – NIH terminates E-alone intervention due to increased stroke risk and absence of CHD benefit • March 1, 2004 – E- alone participants stop study pills

  12. Baseline Characteristics of women in the WHI Estrogen alone trial

  13. Age at entry

  14. Age of E-alone participants at entry Percent

  15. Race/Ethnicity Percent

  16. Age at hysterectomy

  17. Bilateral Oophorectomy

  18. History of Hormone Use

  19. Duration of prior hormone use

  20. Body Mass Index

  21. Smoking Status

  22. Medical History * 441 (4.1%) women with “hard” CHD events prior to enrollment (> 6mos)

  23. CHD Risk Status at Entry

  24. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N Mean SD N Mean SD Age (yrs) at screening 5310 63.6 7.3 5429 63.6 7.3 BMI (kg/m2) 5281 30.1 6.1 5391 30.1 6.2 Systolic BP (mm Hg) 5310 130.4 17.5 5429 130.2 17.6 Diastolic BP (mm Hg) 5310 76.5 9.2 5429 76.5 9.4

  25. CEE Placebo N % N % Ethnicity White 4007 75.5 4075 75.1 Black 782 14.7 835 15.4 Hispanic 322 6.1 333 6.1 American Indian 41 0.8 34 0.6 Asian/Pacific Islander 86 1.6 78 1.4 Unknown 72 1.4 74 1.4 Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment

  26. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % Treated diabetes 410 7.7 411 7.6 Treated for hypertension 2386 48.0 2387 47.4 or BP > 140/90 High cholesterol 694 14.5 766 15.9 requiring pills Statin use at baseline 394 7.4 427 7.9 Aspirin (>80mg) use 1030 19.4 1069 19.7 at baseline

  27. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % History of MI 165 3.1 172 3.2 History of angina 308 5.8 306 5.7 History of CABG/PTCA 120 2.3 114 2.1 History of stroke 76 1.4 92 1.7 History of DVT or PE 87 1.6 84 1.5

  28. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % Hormone use Never 2769 52.2 2770 51.1 Past 1871 35.2 1948 35.9 Current 669 12.6 708 13.0 Duration of prior hormone use (years) <5 1352 53.2 1412 53.1 5 - 10 469 18.5 515 19.4 10+ 720 28.3 732 27.5

  29. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % Parity Never pregnant / 489 9.3 461 8.5 no term pregnancy >1 term pregnancy 4779 90.7 4932 91.5 Age at first birth <20 1193 28.1 1234 28.0 20 - 29 2846 67.0 2914 66.1 30+ 210 4.9 260 5.9

  30. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % Female relative had 893 18.0 870 17.1 breast cancer

  31. Baseline Characteristics of E-alone Participants (N=10,739) by Randomization Assignment CEE Placebo N % N % Fracture at age 55+ 676 14.0 643 13.2 Falls in last 12 months 0 3300 67.0 3230 64.8 1 975 19.8 1024 20.5 2 422 8.6 478 9.6 3 or more 231 4.7 255 5.1

  32. Cumulative Drop-out and Drop-in Rates by Randomization Assignment and Follow-up Time

  33. Intermediate Outcomes

  34. Lipid Levels (8.6% subsample) Percent change, 1 yr

  35. Clinical Outcomes

  36. CEE and Coronary Heart Disease Events (Annualized %) by randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted * CHD † 177 (0.49%) 199 (0.54%) 0.91 (0.75,1.12) (0.72,1.15) CHD Death 54 (0.15%) 59 (0.16%) 0.94 (0.65,1.36) (0.54,1.63) Non-fatal MI 132 (0.37%) 153 (0.41%) 0.89 (0.70,1.12) (0.63,1.26) * Adjusted for multiple comparisons across time (OBF procedures). A Bonferroni adjustment for 6 outcomes was applied to all outcomes other than CHD, Breast Cancer and the global Index. † CHD includes acute MI requiring hospitalization, silent MI determined from serial electrocardiograms and coronary deaths. There were 14 silent MIs.

  37. Kaplan-Meier Estimates of Cumulative Hazards for CHD CHD HR, 0.91 95% nCI, 0.75-1.12

  38. CHD events by years since randomization P-value for trend with time, 0.02.

  39. Risk of CHD events by prior disease

  40. CEE and Stroke Events (Annualized %) By randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted Stroke 158 (0.44%) 118 (0.32%) 1.39 (1.10,1.77) (0.97,1.99) Fatal stoke 15 (0.04%) 14 (0.04%) 1.13 (0.54,2.34) (0.38,3.36) Non-fatal stroke 114 (0.32%) 85 (0.23%) 1.39 (1.05,1.84) (0.91,2.12)

  41. Kaplan-Meier Estimates of Cumulative Hazards for Stroke Stroke HR, 1.39 95% nCI, 1.10-1.77

  42. Risk of stroke by prior disease

  43. CEE and Venous Thromboembolic Events (Annualized %) By randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted VTE† 101 (0.28%) 78 (0.21%) 1.33 (0.99,1.79) (0.86,2.08) DVT† 77 (0.21%) 54 (0.15%) 1.47 (1.04,2.08) (0.87,2.47) PE† 48 (0.13%) 37 (0.10%) 1.34 (0.87,2.06) (0.70,2.55) † VTE, venous thromboembolic disease; DVT, deep vein thrombosis; PE, pulmonary embolism

  44. Kaplan-Meier Estimates of Cumulative Hazards for PE PE HR, 1.34 95% nCI 0.87-2.06

  45. CEE and Cardiovascular Disease Events (Annualized %) By randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted Total CVD 811 (2.25%) 746 (2.01%) 1.12 (1.01,1.24) (0.97,1.30)

  46. CEE and Cancer Incidence (Annualized %) By randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted Invasive breast 94 (0.26%) 124 (0.33%) 0.77 (0.59,1.01) (0.57,1.06)cancer Colorectal cancer 61 (0.17%) 58 (0.16%) 1.08 (0.75,1.55) (0.63,1.86) Total cancer 372 (1.03%) 408 (1.10%) 0.93 (0.81,1.07) (0.75,1.15)

  47. Kaplan-Meier Estimates of Cumulative Hazards for Breast Cancer Invasive Breast Cancer HR, 0.77 95% nCI, 0.59-1.01

  48. Kaplan-Meier Estimates of Cumulative Hazards for Colorectal Cancer Colorectal Cancer HR, 1.08 95% nCI, 0.75-1.55

  49. CEE and Fracture Events (Annualized %) By randomization assignment 95% CI CEE Placebo Hazard Ratio Nominal Adjusted Hip fracture 38 (0.11%) 64 (0.17%) 0.61 (0.41,0.91) (0.33,1.11) Vertebral fracture 39 (0.11%) 64 (0.17%) 0.62 (0.42,0.93) (0.34,1.13) Total fracture 503 (1.39%) 724 (1.95%) 0.70 (0.63,0.79) (0.59,0.83)

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