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Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative A CME Slide Library From the Council on Hormone Education.

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Presentation on theme: "Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative A CME Slide Library From the Council on Hormone Education."— Presentation transcript:

1 Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative A CME Slide Library From the Council on Hormone Education

2 Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative Section 1: Introduction Section 2: Study Design and Methods Section 3: Baseline Characteristics Section 4: Overview of Clinical Outcomes Section 5: Cardiovascular Events Section 6: Breast Cancer Section 7: Other Cancers Section 8: Fractures Section 9: Dementia and Mild Cognitive Impairment Section 10: Mortality Section 11: Summary and Conclusions

3 Section 1: Introduction Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

4 HT = hormone therapy (estrogen alone [E-alone], estrogen plus a progestin [E+P]). The Women's Health Initiative Study Group. Control Clin Trials. 1998;19: Womens Health Initiative (WHI) Clinical Trials of HT Large, parallel, NIH-sponsored, randomized, placebo-controlled, clinical trials –Conjugated equine estrogen (CEE) alone –CEE plus medroxyprogesterone acetate (MPA) Purpose: Assess long-term risks and benefits of CEE alone and CEE/MPA in chronic disease prevention Over 27,000 women aged 50 to 79 years (mean age, ~63 years) randomized between 1993 and 1998; originally scheduled to conclude in 2005

5 Womens Health Initiative (WHI) Clinical Trials of HT CEE/MPA trial stopped in July 2002 after a mean follow-up of 5.2 years 1 CEE-alone trial stopped in March 2004 after a mean follow-up of 6.8 years 2 Trials originally designed for approximately 8 years of follow-up 1 Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Women's Health Initiative Steering Committee. JAMA. 2004;291:

6 WHI: Data and Safety Monitoring Board Recommendations on 5/31/02 Terminate CEE/MPA Study Excess of breast cancer –Crossed pre-specified monitoring boundary Global index: trend towards greater risk than benefits Continue CEE-only Study Uncertain benefit/risk ratio Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:

7 WHI: National Institutes of Health Decision on 2/2/04 Terminate CEE-alone Study Early Increased risk of stroke –Did not cross predefined stopping boundary –Deemed unacceptable in healthy women enrolled in 1° prevention trial No increased risk of heart disease or breast cancer Reduced risk of hip fracture Women's Health Initiative Steering Committee. JAMA. 2004;291:

8 Section 2: Study Design and Methods Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

9 The WHI CEE/MPA Trial 373,092 Women Initiated Screening 18,845 Provided Consent and Reported No Hysterectomy 16,608 Randomized 8506Assigned to CEE/MPA 42% discontinued study drug 6% initiated HT through own HCP Unblinded: n = 3444 HCP = health care provider. Adapted from Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: ©2002 American Medical Association. All rights reserved Assigned to Placebo 38% discontinued study drug 11% initiated HT through own HCP Unblinded: n = 548

10 The WHI CEE-Only Trial 373,092 Women Initiated Screening 11,941 Provided Consent and Reported Hysterectomy 10,739 Randomized 5310 Assigned to CEE 54% discontinued study drug 6% Initiated HT through own HCP Unblinded: n = 100 Adapted from Women's Health Initiative Steering Committee. JAMA. 2004;291: Assigned to Placebo 54% discontinued study drug 9% Initiated HT through own HCP Unblinded: n = 83

11 The Women's Health Initiative Study Group. Control Clin Trials. 1998;19: WHI HT Trials: Eligibility Criteria Postmenopausal –S/P hysterectomy (for CEE-alone) –Intact uterus (for CEE/MPA) Age 50 to 79 years at initial screening Ability and willingness to provide written and informed consent Resident in study area for 3 years following enrollment

12 The Women's Health Initiative Study Group. Control Clin Trials. 1998;19: WHI HT Trials: Exclusion Criteria Exclusions Competing risks (conditions associated with survival of <3 years) Safety reasons (eg, prior breast cancer within 10 years, low hematocrit or platelet counts) Adherence and retention concerns –Alcoholism, dementia, transportation problems Discouraged From Participating Women with moderate or severe menopausal symptoms

13 WHI HT Trials: Regimens and Doses CEE/MPA trial 1 –CEE mg/d + MPA 2.5 mg/d (n = 8506) –Placebo (n = 8102) CEE-alone trial 2 –CEE mg/day (n = 5310) –Placebo (n = 5429) 1 Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Women's Health Initiative Steering Committee. JAMA. 2004;291:

14 WHI: Outcomes Primary outcome: coronary heart disease (CHD) events (nonfatal myocardial infarction [MI] and CHD death) Primary adverse outcome: invasive breast cancer Global index: an untested summary measure of the effects of HT on major disease outcomes recorded during the trial –Menopausal symptoms, quality of life (QOL), venous thromboembolism (VTE), and cognitive function not included Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:

15 WHI: Factors Included in the Global Index CHD event (nonfatal MI, CHD death) Breast cancer Stroke Pulmonary embolism (PE) Endometrial cancer Colorectal cancer Hip fracture Death due to other causes Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:

16 Interpreting the Global Index From WHI Data QOL was not included in the global index, therefore not considered in the risk-benefit profile for HT Global index was created for this study and has not been tested for validity Significance of assigning equal weights to various conditions has not been examined

17 WHI: Statistical Analyses Outcome comparisons presented as hazard ratios (HR) with nominal and adjusted 95% confidence intervals (CI) Nominal CI (nCI): describes variability in risk estimates that would result from a trial with a single outcome –Most appropriate for primary outcomes (CHD, breast cancer) and global index Adjusted CI (aCI): variability of risk estimates corrected for multiple comparisons –Most appropriate for all other outcomes Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:

18 Section 3: Baseline Characteristics Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

19 CEE/MPA Trial: Baseline Characteristics *Black, Hispanic, American Indian, Asian/Pacific Islander, or unknown. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Characteristic CEE/MPA (n = 8506) Placebo (n = 8102) Mean age at screening, y (SD)63.2 (7.1)63.3 (7.1) Age group at screening, n (%) 50–59 years2839 (33.4)2683 (33.1) 60–69 years3853 (45.3)3657 (45.1) 70–79 years1814 (21.3)1762 (21.7) Race/ethnicity, n (%) White7140 (83.9)6805 (84.0) Minority*1366 (16.1)1297 (16.0) Hormone use, n (%) Never6280 (73.9)6204 (74.4) Past1674 (19.7)1588 (19.6) Current548 (6.4)487 (6.0)

20 Characteristic CEE/MPA (n = 8506) Placebo (n = 8102) Body mass index, kg/m 2 *28.5 (5.8)28.5 (5.9) Never smokers, % Current smokers, %10.5 Diabetes, %4.4 Hypertension, % Statin use at baseline, % History of MI, % History of CABG/PTCA, % Family history breast cancer, % CABG/PTCA = coronary artery bypass grafting/percutaneous transluminal coronary angioplasty. *Values are means (SD); Overall incidence of prior cardiovascular disease = 7.7%; P =.04 vs CEE/MPA. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: CEE/MPA Trial: Baseline Characteristics

21 CEE-Alone Trial: Baseline Characteristics *Black, Hispanic, American Indian, Asian/Pacific Islander, or unknown. Required a 3-month washout prior to randomization. Women's Health Initiative Steering Committee. JAMA. 2004;291: Characteristic CEE (n = 5310) Placebo (n = 5429) Mean age at screening, y (SD)63.6 (7.3) Age group at screening, n (%) 50–59 years1637 (30.8)1673 (30.8) 60–69 years2387 (45.0)2465 (45.4) 70–79 years1286 (24.2)1291 (23.8) Race/ethnicity, n (%) White4007 (75.5)4075 (75.1) Minority*1303 (24.5)1354 (24.9) Hormone use, n (%) Never2769 (52.2)2770 (51.1) Past1871 (35.2)1948 (35.9) Current 669 (12.6)708 (13.0)

22 Characteristic CEE (n = 5310) Placebo (n = 5429) Body mass index, kg/m 2 *30.1 (6.1)30.1 (6.2) Never smokers, % Current smokers, % Diabetes, % Hypertension, % Statin use at baseline, % History of MI, % History of CABG/PTCA, % Family history breast cancer, % CABG/PTCA = coronary artery bypass grafting/percutaneous transluminal coronary angioplasty. *Data available for 5281 CEE and 5391 placebo participants; values are means (SD). Women's Health Initiative Steering Committee. JAMA. 2004;291: CEE-Alone Trial: Baseline Characteristics

23 Section 4: Overview of Clinical Outcomes Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

24 WHI CEE/MPA: Preliminary Results *VTE includes deep vein thrombosis and PE. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: CHD Breast Cancer Stroke VTE* Endometrial Cancer Colorectal Cancer Hip Fracture Total Fracture Death Hazard Ratio % nCI 95% aCI Primary Outcomes Additional Outcomes

25 Colorectal Cancer Endometrial Cancer WHI CEE/MPA Results: Number of Cases/Year in 10,000 Women Number per Year per 10,000 Women Adapted from National Institutes of Health. National Heart, Lung, and Blood Institute. WHI HRT Update2002. Available at: Accessed 6/22/02. CHDStrokesBreast Cancer VTEHip Fractures Total Deaths RisksNeutralBenefits CEE/MPA Placebo PE

26 Event Overall HR Confidence Intervals Attributable Risk per 10,000 Women/Year Benefit per 10,000 Women/Year 95% Nominal 95% Adjusted CHD – –1.606 Breast cancer – –1.598 Strokes – –1.847 VTE – – PE – –4.568 Colorectal cancer – –0.947 Hip fractures – –1.105 Total fractures – WHI CEE/MPA Results: Overall Relative and Attributable Risk Women 50 to 79 Years of Age at Baseline Cauley JA, et al. JAMA. 2003;290: ; Chlebowski RT, et al. N Engl J Med. 2004;350: ; Chlebowski RT, et al. JAMA. 2003;289: ; Manson JE, et al. N Engl J Med. 2003;349:523-34; Wassertheil-Smoller S, et al. JAMA. 2003;289: ; Writing Group for the WHI Investigators. JAMA. 2002;288:

27 WHI CEE Alone: Preliminary Results VTE = venous thromboembolism (includes deep vein thrombosis and PE). Women's Health Initiative Steering Committee. JAMA. 2004;291: CHD Breast Cancer Stroke VTE Pulmonary Embolism Colorectal Cancer Hip Fracture Total Fracture Death Hazard Ratio % nCI 95% aCI Primary Outcomes Additional Outcomes

28 WHI CEE-Alone Results: Number of Cases/Year in 10,000 Women Number per Year per 10,000 Women Women's Health Initiative Steering Committee. JAMA. 2004;291: RisksNeutralBenefits CEE Placebo Colorectal Cancer CHDStrokesBreast Cancer VTEHip Fractures Total Deaths PE

29 Event Overall HR Confidence Intervals Attributable Risk per 10,000 Women/Year Benefit per 10,000 Women/Year 95% Nominal 95% Adjusted CHD – –1.155 Breast cancer – –1.067 Strokes – – VTE – –2.087 PE – –2.553 Colorectal cancer – –1.861 Hip fractures – –1.116 Total fractures – – Women's Health Initiative Steering Committee. JAMA. 2004;291: WHI CEE-Alone Results: Overall Relative and Attributable Risk Women 50 to 79 Years of Age at Baseline

30 Section 5: Cardiovascular Events Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

31 CEE Placebo WHI Results: Effect of CEE Alone on Risk of CHD HR = % nCI = 0.75– % aCI = 0.72–1.15 Kaplan-Meier Estimate Women's Health Initiative Steering Committee. JAMA. 2004;291:

32 WHI Results: Effect of CEE Alone on Risk of CHD by Age Women's Health Initiative Steering Committee. JAMA. 2004;291: Annualized Percentage of CHD SubgroupCEEPlaceboHR Age (years) 50– – –

33 CEE/MPA Placebo WHI Results: Effect of CEE/MPA on Risk of CHD Kaplan-Meier Estimate Manson JE, et al. N Engl J Med. 2003;349: HR = % nCI = 1.00– % aCI = 0.97–1.60

34 Hazard YearRatio95% CI 11.81( ) 21.34( ) 31.27( ) ( ) 51.45( ) ( ) WHI Results: Annualized Percent CHD Events by Year Year P =.02 for trend over time (z score = –2.36). HR = % nCI = 1.00– % aCI = 0.97–1.60 *Includes 9 silent MIs. Manson JE, et al. N Engl J Med. 2003;349:

35 WHI: Effect of CEE/MPA on Risk of CHD by Age and Years Since Menopause The dotted vertical line indicates the overall CHD odds ratio (1.24). P-values for interaction were not significant. Manson JE, et al. N Engl J Med. 2003;349: Subgroup CEE/MPAPlacebo Number of Cases of CHD (annualized percentage) Age (years) 50–59 60–69 70–79 37 (0.22) 75 (0.35) 76 (0.78) 27 (0.17) 68 (0.34) 52 (0.55) Years Since Menopause <10 10– (0.19) 63 (0.38) 74 (0.75) 34 (0.22) 51 (0.32) 44 (0.46) Hazard Ratio for CHD

36 Women's Health Initiative Steering Committee. JAMA. 2004;291: CEE Placebo Kaplan-Meier Estimate HR = % nCI = 1.10– % aCI = 0.97–1.99 WHI Results: Effect of CEE Alone on Risk of Stroke

37 Annualized Percentage of Stroke SubgroupCEEPlaceboHR Age (years) 50– – – WHI Results: Effect of CEE Alone on Risk of Stroke by Age Women's Health Initiative Steering Committee. JAMA. 2004;291:

38 WHI Results: Effect of CEE/MPA on Risk of Stroke Wassertheil-Smoller S, et al. JAMA. 2003;289: CEE/MPA Placebo Kaplan-Meier Estimate HR = % nCI = 1.02– % aCI = 0.93–1.84

39 CEE Placebo Womens Health Initiative Steering Committee. JAMA. 2004;291: WHI Results: Effect of CEE Alone on Risk of Pulmonary Embolism Kaplan-Meier Estimate HR = % nCI = 0.87– % aCI = 0.70–2.55

40 HR = % nCI = 1.39– % aCI = 0.99–4.56 WHI Results: Effect of CEE/MPA on Risk of PE Placebo CEE/MPA Kaplan-Meier Estimate Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: ©2002 American Medical Association. All rights reserved.

41 Hazard YearRatio WHI CEE/MPA Results: Annualized Percent VTE Events by Year P <.05, significant for decreasing risk over time. Year HR = % nCI = 1.58– % aCI = 1.26–3.55 Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:

42 Section 6: Breast Cancer Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

43 CEE Placebo Womens Health Initiative Steering Committee. JAMA. 2004;291: Kaplan-Meier Estimate HR = % nCI = 0.59– % aCI = 0.57–1.06 WHI Results: Effect of CEE Alone on Risk of Invasive Breast Cancer

44 WHI Results: Effect of CEE/MPA on Risk of Invasive Breast Cancer Cumulative Proportion Time (years) Chlebowski RT, et al. JAMA. 2003;289: Placebo CEE/MPA Unweighted HR = % CI, 1.01–1.54

45 WHI CEE/MPA Trial: Risk of Breast Cancer in Women With and Without Prior HT Use Hazard Ratio (95% CI) Prior HT Use None <5 Years 5 Years Overall % of Population Chlebowski RT, et al. JAMA. 2003;289:

46 WHI CEE/MPA Trial: Characteristics of Invasive Breast Cancers SEER = Surveillance, Epidemiology, and End Results. Chlebowski RT, et al. JAMA. 2003;289: E+P (n = 199) Placebo (n = 150)P-Value Tumor size, mean ± SD (cm)1.7 ± ± Positive lymph nodes, % SEER stage, % Localized Regional Metastatic Morphology, grade, % Well differentiated Moderately differentiated Poorly differentiated/anaplastic

47 ER = estrogen receptor; PR = progesterone receptor. Chlebowski RT, et al. JAMA. 2003;289: WHI CEE/MPA Trial: Characteristics of Invasive Breast Cancers (continued) E+P (n = 199) Placebo (n = 150)P-Value ER status, % Positive Negative PR status, % Positive Negative Deaths attributed to breast cancer, no. (%)4 (2.0)4 (2.7)

48 WHI CEE/MPA Trial: Mammography Results *Abnormal mammograms included those that were associated with recommendations for short-term follow-up, showed a suspicious abnormality, or were highly suggestive of malignancy. P <.001 vs E+P. Chlebowski RT, et al. JAMA. 2003;289: % Abnormal* E+P Placebo Year Overall

49 Section 7: Other Cancers Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

50 CEE Placebo Womens Health Initiative Steering Committee. JAMA. 2004;291: Kaplan-Meier Estimate HR = % nCI = 0.75– % aCI = 0.63–1.86 WHI Results: Effect of CEE Alone on Risk of Colorectal Cancer

51 WHI Results: Effect of CEE/MPA on Risk of Colorectal Cancer Placebo E+P Chlebowski RT, et al. N Engl J Med. 2004;350: HR = % nCI = 0.38– % aCI = 0.33–0.94 Kaplan-Meier Estimate

52 WHI Results: Hazard Ratio for Invasive Ovarian Cancer With CEE/MPA Incidence rate of invasive ovarian cancer for the total study population was 34 cases per 100,000 person-years. Anderson GL, et al. JAMA. 2003;290: Hazard Ratio % nCI 95% aCI E+P Placebo

53 WHI Results: Hazard Ratio for Endometrial Cancer With CEE/MPA Incidence rate of endometrial cancer for the total study population was 62 cases per 100,000 person-years. Anderson GL, et al. JAMA. 2003;290: Hazard Ratio E+P % nCI 95% aCI Placebo

54 Section 8: Fractures Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

55 HR = % nCI = 0.41– % aCI = 0.33–1.11 CEE Placebo Womens Health Initiative Steering Committee. JAMA. 2004;291: WHI Results: Effect of CEE Alone on Risk of Hip Fracture Kaplan-Meier Estimate

56 WHI: Baseline Prevalence of Osteoporosis (WHO) by DXA Femoral Neck T-scores Normal (>–1.0) Low Bone Mass (–1.0 to –2.4) E+PPlacebo P =.29 Cauley JA. Available at: Accessed 1/7/04. In 6% of Participants (n = 1024) 32% 58% 10% 35% 53% 12% Osteoporosis ( –2.5 )

57 Placebo HT WHI Results: Mean Change in BMD During 3 Years of E+P Follow-up (years) Cauley JA, et al. JAMA. 2003;290: Mean Change in BMD From Baseline (%) Total Hip Spine In 6% of Participants (n = 1024)

58 WHI Results: Fracture Outcomes Hip Vertebral Lower Arm/ Wrist Total Hazard Ratio 95% nCI 95% aCI Adjusted confidence interval reported only for hip fracture. Cauley JA, et al. JAMA. 2003;290:

59 WHI Results: Effect of CEE/MPA in Preventing Fractures Number of Fractures/Year in 10,000 Women Type of Fracture Cauley JA, et al. JAMA. 2003;290:

60 HR = % nCl = 0.47– % aCI = 0.41–1.10 WHI Results: Effect of CEE/MPA on Risk of Hip Fracture Kaplan-Meier Estimate Time (year) Cumulative Hazard Placebo E+P Cauley JA, et al. JAMA. 2003;290:

61 WHI Results: Effect of CEE/MPA on Risk of Lower Arm/Wrist Fracture Adjusted confidence interval not reported. Cauley JA, et al. JAMA. 2003;290: Kaplan-Meier Estimate Time (year) Cumulative Hazard HR = % nCl = 0.59–0.85 Placebo E+P

62 WHI Results: Effect of CEE/MPA on Risk of Vertebral Fracture Adjusted confidence interval not reported. Cauley JA, et al. JAMA. 2003;290: Kaplan-Meier Estimate Time (year) Cumulative Hazard HR = % nCl = 0.46–0.92 Placebo E+P

63 Cumulative Hazard Time (year) WHI Results: Effect of CEE/MPA on Risk of Total Fracture Adjusted confidence interval not reported. Cauley JA, et al. JAMA. 2003;290: Kaplan-Meier Estimate HR = % nCl = 0.69–0.83 Placebo E+P

64 1 Cauley JA, et al. JAMA. 2003;290: Black DM, et al. Osteoporosis Int. 2001;12: WHI: Summary Fracture Risk Score WHI Investigators 1 developed a summary fracture risk score guided by the methods used to develop the FRACTURE Index 2 Predictive validity of FRACTURE Index has been shown 2 Validity of WHI fracture risk score not established –WHI reported fracture risk score showed moderate predictive strength for hip fracture 1

65 1 Cauley JA, et al. JAMA. 2003;290: Black DM, et al. Osteoporosis Int. 2001;12: WHI: Summary Fracture Risk Score Differences between FRACTURE Index and WHI risk score 1,2 : –WHI score includes age, prior fracture after age 55 years, current smoking, and BMI 22.4 kg/m 2 –FRACTURE Index includes age, prior fracture after age 50 years, maternal hip fracture after age 50 years, weight 125 lbs, current smoking, use of arms to stand from a chair, and total hip BMD (if available) 2

66 HR for Global Index: Stratified by Fracture Risk Scores Highest Middle Lowest Hazard Ratio (95% nCI) Fracture Risk* *Stratified by tertiles of summary fracture risk scores; the WHI Global Index measure and WHI Fracture Risk Score have not been validated. Cauley JA, et al. JAMA. 2003;290:

67 Summary: WHI Results and Considerations CEE/MPA significantly decreased the risk of hip fractures, vertebral fractures, and all other fractures in a population not specifically selected for being at increased risk of fracture 1 This benefit has not been demonstrated in a similarly low-risk population with any other osteoporosis therapy 1 Cauley JA, et al. JAMA. 2003;290:

68 Section 9: Dementia and Mild Cognitive Impairment Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

69 Womens Health Initiative Memory Study (WHIMS) 1 Shumaker SA, et al. JAMA. 2003;289: Rapp SR, et al. JAMA. 2003;289: Ancillary study to the WHI, a randomized, multicenter study of CEE alone and CEE plus MPA Primary outcome measure: probable dementia Two studies from WHIMS have been published –Effect of CEE/MPA on probable dementia and mild cognitive impairment 1 –Effect of CEE/MPA on global cognitive function 2

70 WHIMS: Dementia and Mild Cognitive Impairment 1 Shumaker SA, et al. JAMA. 2003;289: postmenopausal women with a uterus and free of probable dementia, aged 65 years, were recruited from WHI centers and enrolled in the E+P arm of the WHIMS 1 Study drug administration was stopped early –Mean time between randomization and last 3MSE in WHIMS was 4.05 years The ending of the CEE-only component of WHI and WHIMS ~1 year before its planned completion was announced by the NIH on March 2, 2004

71 Outcome E+P (n = 2229) Placebo (n = 2303)HR (95% CI) Probable dementia, n (1.21–3.48) Follow-up, mean (SD), years4.01 (1.21)4.06 (1.18) Rate per 10,000 person-years4522 Mild cognitive impairment, n (0.74–1.55) Follow-up, mean (SD), years3.99 (1.23)4.04 (1.20) Rate per 10,000 person-years6359 Cases of Probable Dementia and Mild Cognitive Impairment Shumaker SA, et al. JAMA. 2003;289:

72 Cumulative HR for a Diagnosis of Mild Cognitive Impairment Shumaker SA, et al. JAMA. 2003;289: HR, % CI, 0.74–1.55 CEE/MPA Placebo Number of Events CEE/MPA Placebo

73 Cumulative HR for a Diagnosis of Probable Dementia Shumaker SA, et al. JAMA. 2003;289: HR, % CI, 1.21–3.48 CEE/MPA Placebo Number of Events CEE/MPA Placebo32339

74 Classification of Probable Dementia Cases by Treatment Assignment Shumaker SA, et al. JAMA. 2003;289: Number (%) of Cases Dementia TypeCEE/MPA (n = 40)Placebo (n = 21) Vascular dementia5 (12.5)1 (4.8) Alzheimers disease20 (50.0)12 (57.1) Other dementia types Mixed type5 (12.5)3 (14.3) Normal pressure hydrocephalus2 (5.0)0 Parkinson01 (4.8) Frontal lobe type2 (5.0)0 Alcohol related1 (2.5)0 Other dementia3 (7.5)2 (9.5) Etiology unknown2 (5.0)2 (9.5)

75 Patient Adherence in WHIMS 2534 participants (55.9%) were nonadherent at some point during the trial Nonadherent patients stopped study medication, took less than 80% of pills, or started HT outside of the trial When nonadherent participants were censored 6 months after first becoming nonadherent, the number of probable dementia cases that occurred before censoring was reduced from 41 to 21 in the E+P group and from 20 to 6 in the placebo group (HR, 3.22; 95% CI, 1.25–8.29; P =.02) Shumaker SA, et al. JAMA. 2003;289:

76 Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: WHI: Effect of E+P on Stroke Incidence Events (per 10,000 person-years) Year of Follow-up

77 Related Study WHISCA – Womens Health Initiative Study on Cognitive Aging Ancillary study to WHIMS Designed to determine if estrogen or E+P reduces the rate of cognitive decline in women 65 years of age Planned 6-year follow-up

78 What WHIMS and WHISCA Cannot Address Whether there is a critical period of initiation of HT for prevention of –Cognitive aging –AD Whether dose, types of HT, or duration of treatment may have different effects

79 Observational vs Randomized Studies Observational Prospective Studies Typical patterns of HT use (age, treatment) Mostly E alone Risk for AD Womens Health Initiative Memory Study (WHIMS) Only women 65 years of age CEE + MPA Risk of all-cause dementia HT and AD

80 Section 10: Quality of Life Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

81 WHI Quality of Life (QOL) Study Health and functional statusRAND-36 Depression CES-D Sleep quality WHI Insomnia Rating Scale Satisfaction with sexual functioning 1 item with 4-point response scale Cognitive functioning mMMSE Menopausal symptoms 5-item checklist CES-D = Center for Epidemiological Studies-Depression; mMMSE = modified Mini-Mental State Examination. Hays J, et al. N Engl J Med. 2003;348: QOL-Related Assessments

82 One-Year Change in RAND-36 Scores Change From Baseline at Year 1 * For all parameters except depression, higher numbers indicate a positive effect and lower numbers indicate a negative effect. *P <.01 compared with placebo at Year 1. Hays J, et al. N Engl J Med. 2003;348: *

83 For all parameters except depression, higher numbers indicate a positive effect and lower numbers indicate a negative effect. *P <.01 compared with placebo at Year 1. Hays J, et al. N Engl J Med. 2003;348: One-Year Change in Other QOL-Related Measures Change From Baseline at Year 1 * 0 0 Depression Sleep Disturbance Satisfaction With Sex mMMSE

84 WHI QOL: Summary of Findings The WHI 1 found –No significant clinical QOL benefit on any of the outcomes, including general health, vitality, mental health, or sexual satisfaction –A statisticallybut not clinicallysignificant benefit in sleep disturbance, physical functioning, and body pain at 1 year Findings were similar to HERS 2 –No improvement in QOL was seen with E+P use in older, asymptomatic, postmenopausal women 1 Hays J, et al. N Engl J Med. 2003;348: Hlatky MA, et al. JAMA. 2002;287:591-7.

85 WHI QOL: Study Considerations Only 12% of participants reported moderate or severe vasomotor symptoms Unclear how moderate and severe vasomotor symptoms were defined Vaginal symptoms were not evaluated Outcome scores were high at baseline, limiting potential for therapy to increase them further 63% of the participants were 10 years postmenopausal No validated menopausal QOL tools used Hays J, et al. N Engl J Med. 2003;348:

86 Section 10: Mortality Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

87 CEE Placebo Womens Health Initiative Steering Committee. JAMA. 2004;291: WHI Results: Effect of CEE-Alone on Total Mortality Kaplan-Meier Estimate HR = % nCI = 0.88– % aCI = 0.81–1.32

88 WHI Results: Causes of Death* in the CEE/MPA Trial *Causes of death for placebo versus CEE/MPA were not statistically different. n = number of patients; % = annualized % calculated from average exposure over 60 months. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Outcome CEE/MPA (n = 8506) n (%) Placebo (n = 8102) n (%) Total deaths231 (0.52)218 (0.53) Adjudicated deaths215 (0.49)201 (0.49) Cardiovascular65 (0.15)55 (0.13) Breast cancer3 (0.01)2 (<0.01) Other cancer104 (0.24)86 (0.21) Other known cause34 (0.08)41 (0.10) Unknown cause9 (0.02)17 (0.04)

89 Year WHI CEE/MPA Trial: Annualized Percent of All-Cause Deaths by Year P = NS for trend over time. HR = % nCI = 0.82– % aCI = 0.70–1.37 Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Hazard YearRatio

90 Section 11: Summary and Conclusions Risks and Benefits of Hormone Therapy: An Overview of Findings From the Womens Health Initiative

91 Summary of CEE/MPA Study The overall risks of CEE mg/d plus MPA 2.5 mg/d exceeded the benefits after an average of 5.2 years of follow-up in asymptomatic women ages 50 to 79 years at initial screening Results from WHI indicate that CEE mg/d plus MPA 2.5 mg/d should not be initiated or continued for the primary prevention of CHD Risks for cardiovascular disease and breast cancer must be weighed against the benefit for fracture and colon cancer Conclusions of the WHI Writing Group Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:

92 Summary of CEE-Alone Study In women with prior hysterectomy, the use of CEE-alone –increases the risk of stroke –decreases the risk of hip fracture –does not affect the incidence of CHD A possible reduction in breast cancer with use of CEE alone requires further study CEE alone not recommended for chronic disease prevention Conclusions of the WHI Writing Group Women's Health Initiative Steering Committee. JAMA. 2004;291:

93 Interpretation of the Results from the WHI HT Trials Average age at screening was 63 years; studies stopped when two-thirds or more of patients were 68 years Results cannot be extrapolated to the typical population using HT –Majority of women initiate HT to alleviate menopausal symptoms –Women with moderate-to-severe menopausal symptoms were discouraged from participating –75% of HT users initiate therapy within 5 years of menopause; mean age of menopause, 51 years Womens Health Initiative Steering Committee. JAMA. 2004;291: ; Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33; Newton KM, et al. J Womens Health. 1997;6:459-65; The Women's Health Initiative Study Group. Control Clin Trials. 1998;19:61-109; McKinlay SM, et al. Maturitas. 1992;14:103-15; Brett KM, Chong Y. Hormone Replacement Therapy: Knowledge and Use in the United States. Hyattsville, Md: National Center for Health Statistics; 2001:1-29.

94 Interpretation of the Results from the WHI HT Trials Results may not relate to lower doses of these drugs or other estrogens or progestins, or other formulations or routes of administration In the absence of clinical trial data, one cannot assume greater safety of other estrogens and/or progestins Other Considerations

95 Treatment Discontinuation & Crossover Interpretation of the CEE/MPA Results Rates of discontinuation were high –CEE/MPA = 42% –Placebo = 38% A number of women initiated HT with their own clinicians –CEE/MPA = 6.2% –Placebo = 10.7%

96 Unblinding Interpretation of the CEE/MPA Results Clinic gynecologists were unblinded to treatment assignment at higher rate in CEE/MPA group –41% unblinded in CEE/MPA –7% unblinded in placebo Effects of unblinding in CEE/MPA group unclear; could influence patient monitoring for breast cancer and other conditions in the global index

97 National Institutes of Health. National Heart, Lung, and Blood Institute. New Facts About: Estrogen/Progestin Hormone Therapy. July 9, Available at: Accessed 7/15/02. WHI: NIH Recommendations HT should not be continued or started to prevent heart disease For osteoporosis prevention, women should consult their doctor and weigh the benefits of HT against their personal risks; alternate treatments are available While short-term use was not studied, women taking HT for relief of menopausal symptoms may reap more benefits than risks Risk/benefit profiles must be individualized for each patient Women should talk with their doctor about their personal risks and benefits

98 American College of Obstetricians and Gynecologists. Statement on the Estrogen Plus Progestin Trial of the Womens Health Initiative. July 9, Available at: press_releases/nr cfm. Accessed 7/15/02. WHI: American College of Obstetrics and Gynecology (ACOG) Advisory Women who have been taking HT for a number of years should not panic, but discuss their individual situation with their physician With respect to womens short-term use of HT for relief of menopausal symptoms, it may be reasonable for women to continue use for this purpose, since the benefits are likely to outweigh the risks Regarding a womens short-term use of HT for relief of menopausal symptoms, ACOG continues to recommend that this be a personal, individualized decision, made after consultations between a woman and her physiciantaking into account a womans individual benefits and risks from such use


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