Women's Health Initiative

Women's Health Initiative
Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative A CME Slide Library From the Council on Hormone Education At the end of this presentation, participants will be able to: Describe, in general terms, the overall design of the Women’s Health Initiative (WHI), including the characteristics of the women enrolled in the trial and the clinical outcomes that were assessed. Summarize the findings from WHI on the risks and benefits associated with the use of hormone therapy (HT), and compare these results to outcomes reported in previous clinical trials and observational studies. Identify the population of postmenopausal women who are represented by the WHI participants, and to whom the study results can be generalized. Identify the population of postmenopausal women who were excluded from the WHI, and to whom the study results cannot be generalized.

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s 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

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative Section 1: Introduction

Women’s 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 The Women’s Health Initiative (WHI) evaluated 3 interventions for prevention or control of some common causes of morbidity and mortality among postmenopausal women: low-fat diet (for prevention of breast cancer, colorectal cancer, and coronary heart disease [CHD]); postmenopausal hormone therapy (HT) using conjugated equine estrogens (CEE) alone (E-only) or in combination with medroxyprogesterone acetate (MPA; combination therapy, E+P) (for the reduction of CHD risk, hip fractures, and other fractures, with increased breast cancer as a possible adverse outcome); and calcium and vitamin D supplementation (for prevention of hip fractures, other fractures, and colorectal cancer).1,2 The WHI clinical trials of HT were both randomized, double-blind, placebo-controlled studies. Designed in using the accumulated scientific evidence available at the time, these parallel trials represent the first randomized primary prevention studies to evaluate the long-term risks and benefits of HT.1 For both the CEE-only and CEE/MPA arms of the trial, over 27,000 postmenopausal women aged 50 to 79 years (mean age, ~63 years) were randomized to either active treatment or placebo at 40 US clinical centers between 1993 and For the CEE/MPA arm, a total of 16,608 women with an intact uterus at baseline were randomized to CEE/MPA or placebo.2 For the CEE-alone arm, a total of 10,739 women with prior hysterectomy were randomized to CEE alone or placebo.3 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: 1The Women’s Health Initiative Study Group. Control Clin Trials. 1998;19: 2Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 3Women’s Health Initiative Steering Committee. JAMA. 2004;291:

Women’s Health Initiative (WHI) Clinical Trials of HT
CEE/MPA trial stopped in July 2002 after a mean follow-up of 5.2 years1 CEE-alone trial stopped in March 2004 after a mean follow-up of 6.8 years2 Trials originally designed for approximately 8 years of follow-up In July 2002, the CEE/MPA arm of the WHI was stopped early because the risk for breast cancer exceeded the predetermined stopping boundary. At the time the trial was stopped, the average duration of follow-up for the CEE/MPA arm of the WHI was 5.2 years; all women had been enrolled for at least 3.5 years, and the maximum follow-up time was 8.5 years. (The study was designed to last 8.5 years.)1 Despite the early termination of the WHI CEE/MPA trial, the CEE-only arm of the trial was continued because the health risks and benefits had not been adequately determined. On March 1, 2004, the National Institutes of Health (NIH) announced their decision to stop the CEE-alone study, after a mean follow-up of 6.8 years and prior to the scheduled close-out interval of October 2004 to March Although none of the predefined stopping boundaries had been crossed, the risk of stroke was approaching the adverse-effect boundary, and interim analyses indicated that neither cardioprotection nor breast cancer risk would be demonstrated in the remaining intervention period. Considering it unacceptable to subject healthy women in a prevention trial to an increased risk of stroke, the NIH stopped the trial before its planned completion date.2 The WHI HT clinical trials were originally designed to provide a mean of about 8 years of follow-up. Two remaining components of the WHI clinical trial—one evaluating the effects of a low-fat eating pattern and the other examining the effects of calcium plus vitamin D supplementation—are continuing. 1Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: 2Women's Health Initiative Steering Committee. JAMA. 2004;291: 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI: Data and Safety Monitoring Board Recommendations on 5/31/02
Women's Health Initiative 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 On May 31, 2002, the independent Data and Safety Monitoring Board (DSMB) of the WHI reviewed data and safety limits for the hormone replacement components of the trial.1 During this review, the tenth interim analysis performed by the board, the DSMB found that adverse effects in cardiovascular outcomes seen earlier in the trial persisted, although the effects were still below the stopping boundary. However, the data revealed an excess number of cases of diagnosed breast cancer in the CEE/MPA group, with the test statistic (z score) for breast cancer crossing the stopping boundary that had been established prior to the start of the trial. The test statistic for the global index did not indicate that the benefits resulting from CEE/MPA use outweighed the risk.1 On the basis of these results, the DSMB concluded that the evidence for risk outweighed the evidence for benefit over the average of 5.2 years follow-up, and so recommended early cessation of the CEE/MPA arm of the trial.1 Because the stopping boundaries were not crossed for the CEE-only arm, and the balance of risks and benefits remained uncertain, the DSMB recommended continuation of that component of the trial. Stopping boundaries for the WHI were intentionally set at a conservative level by the DSMB. Women in the discontinued CEE/MPA arm were requested to continue having yearly mammograms and WHI clinic examinations.2 At the time the CEE/MPA trial was stopped, the DSMB recommended that the CEE-only trial should continue because the health risks and benefits remained uncertain. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2National Institutes of Health. National Heart, Lung, and Blood Institute. WHI HRT Update—2002. Available at: health/women/upd2002.htm. Accessed 06/22/02.

WHI: National Institutes of Health Decision on 2/2/04
Women's Health Initiative 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 When the WHI CEE/MPA trial was stopped, the participants in the CEE-alone trial were informed that no increase in breast cancer rates had been observed in women randomized to CEE. The DSMB continued to closely monitor the CEE-alone trial and interim data analyses through November 30, 2003, indicated that none of the predefined stopping boundaries had been crossed. The WHI investigators note, however, that the risk of stroke in women randomized to CEE was approaching the adverse effect boundary at that time. On February 2, 2004, after consulting additional advisors, the NIH made the decision to stop the CEE-alone trial. In coming to this decision, the NIH concluded that after almost 7 years of follow-up, CEE did not appear to affect the risk of heart disease, which was the primary outcome of the study. Additionally, the risk of stroke was increased to about the same level observed in the WHI CEE/MPA trial. In view of the stroke risk, and the likelihood that neither cardioprotection nor breast cancer risk would be demonstrated with continued intervention and follow-up, the NIH stopped the trial early. Women's Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative Section 2: Study Design and Methods

The WHI CEE/MPA Trial 373,092 Women Initiated Screening 18,845 Provided Consent and Reported No Hysterectomy 16,608 Randomized 8506 Assigned to CEE/MPA 8102 Assigned to Placebo 42% discontinued study drug 6% initiated HT through own HCP Unblinded: n = 3444 38% discontinued study drug 11% initiated HT through own HCP Unblinded: n = 548 Close to 17,000 women were randomized in the CEE/MPA arm of the WHI. At the time the study was stopped, all women had been enrolled for 3.5 years (average follow-up, 5.2 years; maximum of 8.5 years). During the course of the study, a considerable number of women discontinued use of the treatment that had been assigned to them (42% in the CEE/MPA group and 38% in the placebo group). These dropout rates were greater than expected when the study was originally designed. As per the intention-to-treat (ITT) protocol, data from the 42% of women who discontinued CEE/MPA and 38% who discontinued placebo were included in the analyses as if the women had adhered to the assigned study medication. Approximately 6% of women assigned to CEE/MPA and 11% of women assigned to placebo initiated hormone use through their own clinician. This rate of crossover from placebo to HT was also greater than had been originally expected. As per the ITT protocol, data from the 11% of women assigned to placebo who started using HT during the trial were included in the analyses as if the women had remained on placebo. Clinic gynecologists were unblinded to treatment assignment for many more women assigned to CEE/MPA than to placebo (3444 vs 548). The primary reason for this disparity between groups was to manage persistent vaginal bleeding in the CEE/MPA group. 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. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

The WHI CEE-Only Trial 373,092 Women Initiated Screening 11,941 Provided Consent and Reported Hysterectomy 10,739 Randomized 5310 Assigned to CEE 5429 Assigned to Placebo 54% discontinued study drug 6% Initiated HT through own HCP Unblinded: n = 100 54% discontinued study drug 9% Initiated HT through own HCP Unblinded: n = 83 Just under 11,000 women were randomized in the CEE-only arm of the WHI. At the time the study was stopped, all women had been enrolled for 5.7 years (average follow-up, 6.8 years; maximum of 10.7 years). At the study’s end, a considerable number of women had discontinued use of the treatment to which they had been assigned. Overall, the discontinuation rate was 53.8%; this rate did not differ significantly between the CEE and placebo groups. These dropout rates were greater than expected when the study was originally designed. As per the ITT protocol, data from the 54% of women who discontinued study medication were included in the analyses as if the women had adhered to the assigned study medication. Approximately 6% of women assigned to CEE and 9% of women assigned to placebo initiated hormone use through their own clinician. This rate of crossover from placebo to HT was also greater than had been originally expected. As per the ITT protocol, data from the 9% of women assigned to placebo who started using HT during the trial were included in the analyses as if the women had remained on placebo. In comparison to the high rate of unblinding experienced in the WHI CEE/MPA trial, clinic gynecologists were unblinded to treatment assignment for very few women in the WHI CEE-alone trial. Adapted from Women's Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI HT Trials: Eligibility Criteria
Women's Health Initiative 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 Participants were recruited for the WHI HT clinical trials by population-based direct mailing campaigns to age-eligible women, in conjunction with local and national media awareness programs. Eligibility was defined as age 50 to 79 years at initial screening, postmenopausal, likelihood of residence in study area for 3 years, and provision of written consent. A woman was considered postmenopausal if she had experienced no vaginal bleeding for 6 months (no bleeding for 12 months if 50–54 years of age), had had a hysterectomy, or had previously used postmenopausal hormones. For the most part, women with an intact uterus were enrolled in the CEE/MPA trial and women who had undergone hysterectomy were enrolled in the CEE-alone trial. An early protocol change eliminated a CEE-alone intervention in women with an intact uterus. The Women's Health Initiative Study Group. Control Clin Trials. 1998;19: The Women’s Health Initiative Study Group. Control Clin Trials. 1998;19:

WHI HT Trials: Exclusion Criteria
Women's Health Initiative 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 Exclusion criteria for both WHI HT clinical trials were related to medical conditions that might be associated with survival of <3 years, safety reasons (eg, prior breast cancer, other prior cancer within 10 years, low hematocrit or platelet counts), and adherence and retention concerns (eg, alcoholism, dementia). Women who reported moderate or severe menopausal symptoms were discouraged from participating in the WHI HT studies. The Women's Health Initiative Study Group. Control Clin Trials. 1998;19: The Women’s Health Initiative Study Group. Control Clin Trials. 1998;19:

WHI HT Trials: Regimens and Doses
Women's Health Initiative WHI HT Trials: Regimens and Doses CEE/MPA trial1 CEE mg/d + MPA 2.5 mg/d (n = 8506) Placebo (n = 8102) CEE-alone trial2 CEE mg/day (n = 5310) Placebo (n = 5429) In the WHI CEE/MPA trial, eligible women were randomly assigned to receive mg/d CEE plus 2.5 mg/d MPA (n = 8506) or a matching placebo (n = 8102).1 In the WHI CEE-alone trial, eligible women were randomly assigned to receive mg/d CEE (n = 5310) or a matching placebo (n = 5429).2 1Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: 2Women's Health Initiative Steering Committee. JAMA. 2004;291: 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2Women’s Health Initiative Steering Committee. JAMA. 2004;291:

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 For the WHI CEE-only and CEE/MPA studies, the primary outcomes were CHD, defined as acute myocardial infarction (MI), silent MI, or CHD death. The primary adverse outcome was invasive breast cancer. The WHI investigators were also interested in assessing the overall balance of risks and benefits of CEE and CEE/MPA use. In clinical trials, total mortality is commonly used as a global outcome measure to assess the balance of risks and benefits. However, the WHI investigators were concerned that total mortality would not be sensitive enough to capture the overall effect of HT on various aspects of health, and instead, they developed a summary measure called the “global index.” The global index was defined as the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, hip fracture, or death due to other causes. The global index did not include assessment of menopausal symptom relief, quality of life, VTE, or cognitive functioning. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI: Factors Included in the Global Index
Women's Health Initiative 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 The global index is an unweighted index defined as the first event for each participant among the following types: CHD, invasive breast cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes. The outcomes included in the global index were selected to represent diseases of serious import that long-term use of CEE/MPA might affect. The global index does not include a variety of other conditions that may have a significant impact on health and/or quality of life in postmenopausal women (eg, menopausal symptoms, diabetes, or cognitive function). The global index also failed to include the occurrence of VTE, a known risk of HT use. Thus, the validity of the global index as a summary measure of risks and benefits of HT has been questioned. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

Interpreting the Global Index From WHI Data
Women's Health Initiative 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 When the CEE/MPA arm of the trial was stopped, the global index indicated a trend towards greater risk than benefit in the CEE/MPA group compared with placebo.1 No effect on the global index was observed with an average of 6.8 years of use of CEE-only.2 However, points to consider when interpreting the global index data include: Relief of common menopausal symptoms (eg, vasomotor symptoms, vaginal dryness) was not included in the global index. Changes in cognitive function and quality of life were also not included. Thus, it seems likely that the global index does not accurately summarize the overall balance of risks and benefits for the majority of HT users who initiate treatment primarily for symptom relief. The degree that the global index accurately and consistently measures the overall balance of risks and benefits of HT—that is, the validity and reliability of the global index—has never been evaluated and therefore is uncertain at this time. An important question related to validity of the global index is the appropriateness of assigning equal weights to the conditions included in the index, or to assign greater weight to certain conditions. Assigning equal weights to the conditions does not capture the varying impact of these conditions on mortality rates. For example, national cancer survival data indicate a higher 5-year survival rate for breast cancer (87%) than for colorectal cancer (62%).3 In addition, most of the increase in stroke and CHD events reported by the WHI CEE/MPA trial involved nonfatal MI and nonfatal stroke events. 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2Women’s Health Initiative Steering Committee. JAMA. 2004;291: 3Ries LAG, Eisner MP, Kosary CL, et al. SEER Cancer Statistics Review, Bethesda, Md; National Cancer Institute. Available at: Accessed August 15, 2002.

WHI: Statistical Analyses
Women's Health Initiative 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 The primary outcome of the WHI HT trials was CHD (nonfatal MI and CHD death) with invasive breast cancer as the primary adverse outcome. Primary and secondary outcomes were reported as hazard ratios (HRs) with both nominal and adjusted 95% CIs (nCI and aCI, respectively). Reporting both nominal and adjusted CIs has caused a great deal of confusion about which CI is most appropriate for interpreting the statistical significance of the WHI outcomes. A generally accepted principle is to use an adjustment or correction factor in statistical analyses when these analyses involve multiple tests or comparisons. The WHI involved numerous comparisons between the treatment and placebo groups, including comparisons for CHD, breast cancer, fracture, colon cancer, stroke, and many other outcomes. Strict application of the principle of correcting for multiple comparisons would involve using only the aCIs to evaluate the statistical significance of each WHI outcome because the aCIs are calculated using an adjustment or correction factor for the multiple comparisons. An alternative that has been suggested is to use the nCIs to evaluate the statistical significance of the primary outcomes of the WHI (CHD, breast cancer) and to use the aCIs for all other outcomes. The WHI investigators noted that the aCIs were closely related to the monitoring procedures; and that their report focused primarily on results using the nominal (unadjusted) statistics. The slides in this presentation show both the nCIs and aCIs whenever both were available. Due to the correction factor, aCIs for a given outcome are always wider than nCIs for that same outcome. The relationship between the nCI and aCI is depicted in the graph to the right. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: 1.0 10.0 0.01 nCI aCI Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative Section 3: Baseline Characteristics

CEE/MPA Trial: Baseline Characteristics
Women's Health Initiative CEE/MPA Trial: Baseline Characteristics 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 years 2839 (33.4) 2683 (33.1) 60–69 years 3853 (45.3) 3657 (45.1) 70–79 years 1814 (21.3) 1762 (21.7) Race/ethnicity, n (%) White 7140 (83.9) 6805 (84.0) Minority* 1366 (16.1) 1297 (16.0) Hormone use, n (%) Never 6280 (73.9) 6204 (74.4) Past 1674 (19.7) 1588 (19.6) Current 548 (6.4) 487 (6.0) In the CEE/MPA trial of WHI1 there were no substantive differences between study groups at baseline; 8506 women were randomized into the HT group and 8102 into the placebo group. At the time of their enrollment into the WHI CEE/MPA trial, only 1/3 of the participants were younger than 60 years of age and more than 20% were in their 70s. The average age of ~63 years for enrollees in the WHI CEE/MPA study is substantially older than the age when most women initiate HT for the relief of menopausal symptoms (51 years of age for nonhysterectomized women).2 *Black, Hispanic, American Indian, Asian/Pacific Islander, or unknown. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2Taylor Nelson Sofres (TNS) Intersearch Corporation. Incidence and Persistency of Estrogen Replacement. May 17, 2000.

CEE/MPA Trial: Baseline Characteristics
Women's Health Initiative CEE/MPA Trial: Baseline Characteristics Characteristic CEE/MPA (n = 8506) Placebo (n = 8102) Body mass index, kg/m2* 28.5 (5.8) 28.5 (5.9) Never smokers, % 49.6 50.0 Current smokers, % 10.5 Diabetes, % 4.4 Hypertension, % 35.7 36.4 Statin use at baseline, % 6.9 6.8 History of MI, %† 1.6 1.9 History of CABG/PTCA, %† 1.1 1.5‡ Family history breast cancer, % 16.0 15.3 At the outset of the WHI CEE/MPA trial, there were no substantive differences between groups for body mass index (BMI), smoking, diabetes, hypertension, statin use, history of MI, and family history of breast cancer.1 More women in the placebo group had undergone coronary artery bypass grafting or percutaneous transluminal coronary angioplasty—this difference was small, but statistically significant. At baseline, approximately 50% of the women in this arm of WHI were current or prior smokers and more than 35% were hypertensive. Average BMI for both the treatment and placebo groups was 28.5 kg/m2 which indicates that the women were, in general, overweight. In fact, close to 1/3 of the women in each group were obese (BMI 30.0). As a reference, guidelines from the National Heart, Lung, and Blood Institute2 define overweight and obesity as: BMI (kg/m²) Underweight <18.5 Normal 18.5–24.9 Overweight 25.0–29.9 Obesity 30.0 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: 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2National Institutes of Health National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Executive Summary. Available at: Accessed January 27, 2003.

CEE-Alone Trial: Baseline Characteristics
Women's Health Initiative CEE-Alone Trial: Baseline Characteristics Characteristic CEE (n = 5310) Placebo (n = 5429) Mean age at screening, y (SD) 63.6 (7.3) Age group at screening, n (%) 50–59 years 1637 (30.8) 1673 (30.8) 60–69 years 2387 (45.0) 2465 (45.4) 70–79 years 1286 (24.2) 1291 (23.8) Race/ethnicity, n (%) White 4007 (75.5) 4075 (75.1) Minority* 1303 (24.5) 1354 (24.9) Hormone use, n (%) Never 2769 (52.2) 2770 (51.1) Past 1871 (35.2) 1948 (35.9) Current† 669 (12.6) 708 (13.0) In the WHI CEE-alone, there were no differences in baseline characteristics between study groups at baseline; 5310 women were randomized into the estrogen group and 5429 into the placebo group.1 At the time of their enrollment into the WHI CEE-alone trial, fewer than 1/3 of the participants were younger than 60 years and close to 1/4 were in their 70s. As observed in the CEE/MPA trial, the average age of 63û64 years for enrollees in the WHI CEE-alone study is substantially older than the age when most women initiate HT for the relief of menopausal symptoms (51 years of age for nonhysterectomized women).2 *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: 1Women’s Health Initiative Steering Committee. JAMA. 2004;291: 2Taylor Nelson Sofres (TNS) Intersearch Corporation. Incidence and Persistency of Estrogen Replacement. May 17, 2000.

CEE-Alone Trial: Baseline Characteristics
Women's Health Initiative CEE-Alone Trial: Baseline Characteristics Characteristic CEE (n = 5310) Placebo (n = 5429) Body mass index, kg/m2* 30.1 (6.1) 30.1 (6.2) Never smokers, % 51.9 50.4 Current smokers, % 10.3 10.6 Diabetes, % 7.7 7.6 Hypertension, % 48.0 47.4 Statin use at baseline, % 7.4 7.9 History of MI, % 3.1 3.2 History of CABG/PTCA, % 2.3 2.1 Family history breast cancer, % 18.0 17.1 At the outset of the WHI CEE-alone trial, there were no substantive differences between groups for BMI, smoking, diabetes, hypertension, statin use, history of MI, history of coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, or family history of breast cancer.1 At baseline, approximately 50% of the women in this arm of WHI were current or prior smokers; close to half had hypertension. Average BMI for both the treatment and placebo groups was 30.1 kg/m2, a value that is indicative of obesity (BMI 30.0). In fact, 80% of the women in the WHI CEE-alone trial were either overweight (~35%) or obese (~45%). As a reference, guidelines from the National Heart, Lung, and Blood Institute2 define overweight and obesity as: BMI (kg/m²) Underweight <18.5 Normal 18.5–24.9 Overweight 25.0–29.9 Obesity 30.0 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: 1Women’s Health Initiative Steering Committee. JAMA. 2004;291: 2National Institutes of Health National Heart, Lung, and Blood Institute. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Executive Summary. Available at: Accessed January 27, 2003.

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative Section 4: Overview of Clinical Outcomes

WHI CEE/MPA: Preliminary Results
Women's Health Initiative WHI CEE/MPA: Preliminary Results Primary Outcomes CHD Breast Cancer Stroke VTE* Endometrial Cancer Colorectal Cancer Hip Fracture Total Fracture Death Additional Outcomes 95% nCI 95% aCI The results–hazard ratios with 95% CIs–of the initial preliminary analysis from the WHI CEE/MPA trial are shown on this slide. These analyses were based on locally adjudicated results; later analyses included centrally adjudicated results. The investigators reported both nCIs and aCIs for each outcome, which has caused a great deal of confusion about which CI is most appropriate for interpreting the statistical significance of the WHI outcomes. Reporting both CIs in the same publication is rare as they tend to make interpretation of the data difficult. While a generally accepted principle is to use an adjustment or correction factor (such as the aCI) when data analysis involves multiple tests or comparisons, the WHI investigators noted that the aCIs were closely related to the monitoring procedures for the trial and that their report focused primarily on results using the nCIs. Summary of findings from this preliminary report: Only the increased risk for venous thromboembolism (VTE; deep vein thrombosis and PE) and the decreased risk for total fracture were statistically significant for both the nCI and aCI Increased risk for CHD and stroke were statistically significant for the nCI, but not the aCI Decreased risk for colorectal cancer and hip fracture were statistically significant for the nCI, but not the aCI Neither the nCI nor the aCI for invasive breast cancer were statistically significant. 0.5 1.0 5.0 2.0 Hazard Ratio *VTE includes deep vein thrombosis and PE. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

WHI CEE/MPA Results: Number of Cases/Year in 10,000 Women
Women's Health Initiative WHI CEE/MPA Results: Number of Cases/Year in 10,000 Women Risks Neutral Benefits CEE/MPA Placebo Number per Year per 10,000 Women Overall, the absolute number of cases of clinical disease per 10,000 women per year were low in WHI. The number of cases per year in 10,000 women are shown here for disease outcomes which suggested an increased risk with CEE/MPA (CHD, stroke, invasive breast cancer, PE, and VTE), those where CEE/MPA may have provided benefit (colorectal cancer and hip fractures), and those with neutral outcomes (endometrial cancers and total deaths). Not shown are numbers for total fractures, which were lower in women using CEE/MPA. CHD Strokes Breast Cancer VTE PE Endometrial Cancer Total Deaths Colorectal Cancer Hip Fractures Adapted from National Institutes of Health. National Heart, Lung, and Blood Institute. WHI HRT Update— Available at: Accessed 6/22/02. National Institutes of Health. National Heart, Lung, and Blood Institute. WHI HRT Update—2002. Available at: health/women/upd2002.htm. Accessed June 22, 2002. Manson JE, et al. N Engl J Med. 2003;349: Wassertheil-Smoller S, et al. JAMA. 2003;289: Chlebowski RT, et al. JAMA. 2003;289:

WHI CEE/MPA Results: Overall Relative and Attributable Risk
Women's Health Initiative WHI CEE/MPA Results: Overall Relative and Attributable Risk Women 50 to 79 Years of Age at Baseline Event Overall HR Confidence Intervals Attributable Risk per 10,000 Women/Year Benefit per 10,000 95% Nominal 95% Adjusted CHD 1.24 1.00–1.54 0.97–1.60 6 Breast cancer 1.01–1.54 0.97–1.59 8 Strokes 1.31 1.02–1.68 0.93–1.84 7 VTE 2.11 1.58–2.82 1.26–3.55 18 PE 2.13 1.39–3.25 0.99–4.56 Colorectal cancer 0.56 0.38–0.81 0.33–0.94 Hip fractures 0.67 0.47–0.96 0.41–1.10 5 Total fractures 0.76 0.69–0.83 -- 47 This slide provides the values for the HRs, CIs, and attributable risks from the WHI CEE/MPA trial. Overall HRs for the major outcomes for CEE/MPA compared with placebo are shown in the black box. For each HR, the CIs that reached statistical significance, ie, those that did not cross 1.0, are highlighted in yellow. Summary of findings: Only the increased risk for VTE and PE, and decreased risk for colorectal cancer, were statistically significant for both the nCI and aCI. (Note: Publication of the centrally adjudicated results for total fracture did not include an aCI. The nCI for total fracture was statistically significant.) Neither the nCI nor the aCI for CHD were statistically significant. The increased risk for breast cancer and stroke were statistically significant for the nCI, but not the aCI The decreased risk for hip fracture was statistically significant for the nCI, but not the aCI With the exception of total fractures, the absolute excess risk or benefit attributable to CEE/MPA was low. The WHI findings predict that over 1 year, 10,000 women taking CEE/MPA compared with placebo might be expected to experience 6 more CHD events, 8 more invasive breast cancers, 7 more strokes, 18 more VTEs, 8 more PEs, 7 fewer invasive colorectal cancers, 5 fewer hip fractures, and 47 fewer total fractures. These risk estimates apply only to the population of women represented by the subjects who participated in the WHI, ie, older women initiating E+P for the first time who have significant risk factors for chronic disease, such as overweight/obesity and history of smoking. 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 ;289: ; Writing Group for the WHI Investigators. JAMA. 2002;288: Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290: Chlebowski RT, et al. N Engl J Med. 2004;350: Chlebowski RT, et al. JAMA. 2003;289: Manson JE, Hsia J, Johnson KC, et al. N Engl J Med. 2003;349: Wassertheil-Smoller S, Hendrix SL, Limacher M, et al. JAMA. 2003;289: Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

WHI CEE Alone: Preliminary Results
Women's Health Initiative WHI CEE Alone: Preliminary Results CHD Breast Cancer Stroke VTE Pulmonary Embolism Colorectal Cancer Hip Fracture Total Fracture Death Primary Outcomes Additional Outcomes 95% nCI 95% aCI The results of the initial preliminary analysis from the WHI CEE-alone trial are shown on this slide. These analyses were based on data available through February 29, 2004, prior to notifying participants about the ending of the trial on March 1, Subsequent reports will include additional outcomes occurring between the participants’ last routine follow-up and the date the trial was terminated. As with the CEE/MPA results, the investigators reported both nCIs and aCIs for the risk estimates. Summary of findings from this report: The risk of CHD and breast cancer was not significantly different in women assigned to CEE alone compared with those assigned to placebo The increased risk of stroke was statistically significant for the nCI, but not the aCI The increased risk for VTE did not reach statistical significance The decreased risk of total fracture was statistically significant for both the nCI and aCI The decreased risk of hip fracture was statistically significant for the nCI, but not the aCI No difference was observed between groups in the risk for colorectal cancer The risk of death was the same in both the women assigned to CEE alone and those assigned to placebo 0.5 1.0 5.0 2.0 Hazard Ratio VTE = venous thromboembolism (includes deep vein thrombosis and PE). Women's Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI CEE-Alone Results: Number of Cases/Year in 10,000 Women
Women's Health Initiative WHI CEE-Alone Results: Number of Cases/Year in 10,000 Women Risks Neutral Benefits CEE Placebo Number per Year per 10,000 Women As observed in the WHI CEE/MPA trial, the absolute number of cases of clinical disease per 10,000 women per year were low in the WHI CEE-alone trial. The number of cases per year in 10,000 women are shown here for disease outcomes which suggested an increased risk with CEE/MPA (stroke), those where CEE/MPA may have provided benefit (hip fractures), and those with neutral outcomes (VTE, CHD, invasive breast cancer, pulmonary embolism, colorectal cancer, and total deaths). Not shown are numbers for total fractures, which were substantially lower in women assigned to CEE alone, compared to those assigned to placebo (139 per 10,000 women/year among CEE users vs 195 per 10,000 women/year among those receiving placebo). Colorectal Cancer CHD Strokes Breast VTE Hip Fractures Total Deaths PE Women's Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI CEE-Alone Results: Overall Relative and Attributable Risk
Women's Health Initiative WHI CEE-Alone Results: Overall Relative and Attributable Risk Women 50 to 79 Years of Age at Baseline Event Overall HR Confidence Intervals Attributable Risk per 10,000 Women/Year Benefit per 10,000 95% Nominal 95% Adjusted CHD 0.91 0.75–1.12 0.72–1.15 5 Breast cancer 0.77 0.59–1.01 0.57–1.06 7 Strokes 1.39 1.10–1.77 0.97–1.99 12 VTE 1.33 0.99–1.79 0.86–2.08 PE 1.34 0.87–2.06 0.70–2.55 3 Colorectal cancer 1.08 0.75–1.55 0.63–1.86 1 Hip fractures 0.61 0.41–0.91 0.33–1.11 6 Total fractures 0.70 0.63–0.79 0.59–0.83 56 This slide provides the values for the HRs, CIs, and attributable risks from the WHI CEE-alone trial. Overall HRs for the major outcomes for CEE-alone compared with placebo are shown in the black box. For each HR, the CIs that reached statistical significance, ie, those that did not cross 1.0, are highlighted in yellow. Summary of findings: Only the increased risk for venous thromboembolism (VTE; deep vein thrombosis and PE) and the decreased risk for total fracture were statistically significant for both the nCI and aCI Increased risk stroke was statistically significant for the nCI, but not the aCI Decreased risk for colorectal cancer and hip fracture were statistically significant for the nCI, but not the aCI Neither the nCI nor the aCI for CHD and invasive breast cancer were statistically significant. With the exception of total fractures, the absolute excess risk or benefit attributable to CEE was low. These risk estimates apply only to the population of women represented by the subjects who participated in the WHI CEE-alone trial, that is, older women initiating estrogen use—most for the first time—who have significant risk factors for chronic disease, including obesity and a history of smoking. Women's Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative Section 5: Cardiovascular Events

WHI Results: Effect of CEE Alone on Risk of CHD
Women's Health Initiative WHI Results: Effect of CEE Alone on Risk of CHD Kaplan-Meier Estimate HR = 0.91 95% nCI = 0.75–1.12 95% aCI = 0.72–1.15 Placebo CEE In the WHI CEE-alone trial, the investigators found no significant effect of CEE alone on CHD rates. The incidence of CHD was 9% lower in the women assigned to CEE alone compared with placebo; however, this difference was not statistically significant. The overall incidence rate for CHD in the WHI CEE-alone trial was 51 per 10,000 women per year. This rate was lower than the investigators had projected during the design phase of the study. Women's Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI Results: Effect of CEE Alone on Risk of CHD by Age
Women's Health Initiative WHI Results: Effect of CEE Alone on Risk of CHD by Age Annualized Percentage of CHD Subgroup CEE Placebo HR Age (years) 50–59 0.14 0.24 0.56 60–69 0.54 0.59 0.92 70–79 0.88 0.84 1.04 In the WHI CEE-alone trial, the investigators conducted exploratory analyses to examine whether age at enrollment influenced the effects of CEE alone on clinical outcomes.1 This slide shows the risk of CHD by participant age groups at baseline and CEE use. Although the test for a treatment  age interaction was not statistically significant (P = .14), the HRs for each age group show a trend for decreased risk with younger age. The HR for women aged 50 to 59 years at baseline who were receiving CEE alone was 0.56 compared with those receiving placebo. This HR just failed to reach statistical significance (95% CI, 0.30–1.03). Little to no evidence of cardioprotection was observed in the women aged 60 to 69 years and 70 to 79 years who were assigned to CEE alone compared with those assigned to placebo. These results are consistent with accumulating evidence that estrogen’s effects in the cardiovascular system decline as years past menopause increase.2 Women's Health Initiative Steering Committee. JAMA. 2004;291: 1Women’s Health Initiative Steering Committee. JAMA. 2004;291: 2Grodstein F, et al. N Engl J Med. 2003;348:

WHI Results: Effect of CEE/MPA on Risk of CHD
Women's Health Initiative WHI Results: Effect of CEE/MPA on Risk of CHD Kaplan-Meier Estimate HR = 1.24 95% nCI = 1.00–1.54 95% aCI = 0.97–1.60 CEE/MPA Placebo This slide presents the updated Kaplan-Meier estimates of cumulative hazards for CHD based on centrally adjudicated results through the termination of the CEE/MPA arm of the trial on July 7, The July 2002 report included locally adjudicated end points reached through April 2002. In this analysis, investigators used centrally adjudicated end points for the primary coronary outcome of nonfatal myocardial infarction or death due to CHD to enhance the uniformity of the documentation of outcomes. Previous analyses were based on local adjudication. This analysis indicates that a small difference between treatment groups for total CHD events began to develop soon after randomization. However, the cumulative rates of CHD began to converge at year 6. The overall HR for CHD was 1.24, which did not reach statistical significance (95% nCI, 1.00–1.54; 95% aCI, 0.97–1.60). Manson JE, et al. N Engl J Med. 2003;349: Manson JE, et al. N Engl J Med. 2003;349:

WHI Results: Annualized Percent CHD Events by Year
Women's Health Initiative WHI Results: Annualized Percent CHD Events by Year HR = 1.24 95% nCI = 1.00–1.54 95% aCI = 0.97–1.60 Hazard Year Ratio 95% CI ( ) ( ) ( ) ( ) ( ) ( ) P = .02 for trend over time (z score = –2.36). This figure compares yearly rates (annualized percent) of CHD events in the CEE/MPA and placebo groups. Annualized percent represents the percent of women experiencing CHD events in the patient group during that particular year. For example, an annualized percent of 0.29 indicates that 0.29% of women in that treatment group had a CHD event during that year of follow-up. The annualized percent of CHD events in both the CEE/MPA and placebo group were variable, but low, ranging from 0.19% in year 3 in the placebo group to 0.56% in the 6th or more year of follow-up, also in the placebo group. The table to the right of the line graph lists the HRs and the confidence intervals for CHD events with CEE/MPA use on a year-to-year basis. The statistical test for linear trend detected a significant decrease (z score, –2.36; P = .02) in the risk associated with CEE/MPA over time. For the entire follow-up period examined, overall HR for CHD was 1.24, with a 95% nCI of 1.00–1.54 and a 95% aCI of 0.97–1.60. Year *Includes 9 silent MIs. Manson JE, et al. N Engl J Med. 2003;349: Manson JE, et al. N Engl J Med. 2003;349:

WHI: Effect of CEE/MPA on Risk of CHD by Age and Years Since Menopause
Women's Health Initiative WHI: Effect of CEE/MPA on Risk of CHD by Age and Years Since Menopause Subgroup CEE/MPA Placebo 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 10–19 20 31 (0.19) 63 (0.38) 74 (0.75) 34 (0.22) 51 (0.32) 44 (0.46) Hazard Ratio for CHD 1.27 1.05 1.44 0.89 1.22 1.71 To determine whether certain subgroups of women were at a higher or a lower risk for CHD with CEE/MPA compared to placebo, the investigators evaluated the risk of CHD in certain subgroups, such as age and years since menopause. In this analysis, no significant interaction between age or years since menopause and treatment was observed (P = 0.36 for the age analysis and P = 0.33 for years since menopause analysis), although there was a numerical trend towards a higher risk with CEE/MPA use among those women furthest from menopause. The investigators noted that the findings of the subgroup analyses should be interpreted with caution because of the small size of many of the subgroups as well as the large number of comparisons performed (approximately 36 tests were performed). 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: Manson JE, et al. N Engl J Med. 2003;349:

WHI Results: Effect of CEE Alone on Risk of Stroke
Women's Health Initiative WHI Results: Effect of CEE Alone on Risk of Stroke Kaplan-Meier Estimate HR = 1.39 95% nCI = 1.10–1.77 95% aCI = 0.97–1.99 CEE Placebo In the WHI CEE-alone trial, the risk of stroke was increased by 39% among women assigned to CEE compared with those assigned to placebo (44 vs 32 per 10,000 women per year; P = .007). This increased risk, which crossed the adverse effect monitoring boundary at the 14th planned interim analysis, was one of the key elements in the decision by the NIH to stop the CEE-alone trial after 6.8 years of follow-up (approximately 8 years of follow-up had been planned). Women's Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI Results: Effect of CEE Alone on Risk of Stroke by Age
Women's Health Initiative WHI Results: Effect of CEE Alone on Risk of Stroke by Age Annualized Percentage of Stroke Subgroup CEE Placebo HR Age (years) 50–59 0.16 1.08 60–69 0.49 0.30 1.65 70–79 0.71 0.57 1.25 In the WHI CEE-alone trial, the investigators conducted exploratory analyses to examine whether age at enrollment influenced the effects of CEE alone on clinical outcomes. This slide shows the risk of stroke by participant age groups at baseline and CEE use. The HR was highest (1.65) for women aged 60 to 69 years at baseline. Although the test for a treatment  age interaction in the entire study population was not statistically significant (P = .59), the 95% CI for the HR for women aged 60 to 69 years was statistically significant. Women's Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI Results: Effect of CEE/MPA on Risk of Stroke
Women's Health Initiative WHI Results: Effect of CEE/MPA on Risk of Stroke Kaplan-Meier Estimate HR = 1.31 95% nCI = 1.02–1.68 95% aCI = 0.93–1.84 CEE/MPA Placebo In the WHI CEE-MPA trial, the Kaplan-Meier estimates of cumulative hazards for stroke began to diverge 1 to 2 years after randomization, and this difference persisted beyond the fifth year. The overall HR for stroke was 1.31, with a significant 95% nCI of 1.02–1.68, and a nonsignificant 95% aCI of 0.93–1.84. Wassertheil-Smoller S, et al. JAMA. 2003;289: Wassertheil-Smoller S, et al. JAMA. 2003;289:

WHI Results: Effect of CEE Alone on Risk of Pulmonary Embolism
Women's Health Initiative WHI Results: Effect of CEE Alone on Risk of Pulmonary Embolism Kaplan-Meier Estimate HR = 1.34 95% nCI = 0.87–2.06 95% aCI = 0.70–2.55 CEE Placebo In the WHI CEE-alone trial, the HR for pulmonary embolism (PE) was 1.34, suggesting a 34% increased risk of PE in women assigned to CEE compared with those assigned to placebo. This HR, however, was not statistically significant. The difference in absolute risk suggested by these results is small—13 vs 10 PEs per 10,000 women per year for CEE vs placebo. Women’s Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI Results: Effect of CEE/MPA on Risk of PE
Women's Health Initiative WHI Results: Effect of CEE/MPA on Risk of PE Kaplan-Meier Estimate HR = 2.13 95% nCI = 1.39–3.25 95% aCI = 0.99–4.56 CEE/MPA Placebo In the WHI CEE/MPA trial, the Kaplan-Meier estimates of cumulative hazards for PE events separated soon after randomization and showed continuing differences throughout the observation period. The overall HR for PE was 2.31, suggesting a 2-fold increase in risk of PE among CEE/MPA users; the 95% nCI (1.39–3.25) indicated statistical significance, while the 95% aCI did not (0.99–4.56).1 It is meaningful to note that even with the use of E+P, the risk of PE among postmenopausal women remains very low, on the order of 20–30 women per 100,000. In comparison, the risk of PE associated with pregnancy is 60 women per 100,000.2 Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: ©2002 American Medical Association. All rights reserved. 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2Farmer RDT, Preston TD. J Obstet Gynaecol. 1995;15:

WHI CEE/MPA Results: Annualized Percent VTE Events by Year
Women's Health Initiative WHI CEE/MPA Results: Annualized Percent VTE Events by Year HR = 2.11 95% nCI = 1.58–2.82 95% aCI = 1.26–3.55 Hazard Year Ratio 1 3.60 2 2.26 3 1.67 5 2.49 P < .05, significant for decreasing risk over time. This figure compares yearly rates of VTE events in the CEE/MPA and placebo groups.1 The table to the right of the line graph lists the HRs for VTE on a year-to-year basis; CIs were not reported for the yearly HRs. Following an average of 5.2 years follow-up, the overall HR for VTE was 2.11, with both the 95% nCI (1.58–2.82) and the 95% aCI (1.26–3.55) indicating a significantly increased risk in CEE/MPA users. The test for a linear trend with time since randomization detected a decreasing risk of VTE with time (z = 2.45) in the CEE/MPA users; a similar trend for decreasing risk of VTE over time is observed among oral contraceptive users.2 The WHI investigators note that the results from time-trend analyses in this first WHI report should be viewed cautiously because the number of events in each year were small, the data for later years are incomplete, and risk comparisons in later years are limited to women who were not diagnosed with VTE in previous years. In the CEE-alone trial, the HR for VTE was The nominal confidence interval for this HR just failed to reach statistical significance (95% nCI, 0.99–1.79; 95% aCI, 0.86–2.08) (NOTE: The Kaplan-Meier estimate of cumulative hazards for VTE was not reported for CEE-alone trial.)3 Year Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2Lidegaard O, et al. Contraception. 2002;65: 3Women’s Health Initiative Steering Committee. JAMA. 2004;291:

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative Section 6: Breast Cancer

WHI Results: Effect of CEE Alone on Risk of Invasive Breast Cancer
Women's Health Initiative WHI Results: Effect of CEE Alone on Risk of Invasive Breast Cancer Kaplan-Meier Estimate HR = 0.77 95% nCI = 0.59–1.01 95% aCI = 0.57–1.06 Placebo CEE In the WHI CEE-alone trial, invasive breast cancer was diagnosed at a 23% lower rate in women assigned to CEE compared with those assigned to placebo. (26 vs 33 per 10,000 women per year).1 The HR for invasive breast cancer (0.77) just failed to reach statistical significance (P = .06; 95% nCI, 0.59–1.01). As shown in the following slides, these results suggesting a decreased risk of breast cancer with CEE-alone contrast sharply with the results from the WHI CEE/MPA trial. In that trial, use of CEE/MPA was associated with a small but statistically significant increased risk of invasive breast cancer.2 A direct head-to-head comparison of the results from these two trials cannot be made, however, because the trials enrolled women with different baseline characteristics (eg, hysterectomized vs non-hysterectomized; greater degree of obesity in CEE-alone participants), which may correspond with differing risk profiles. For example, research has consistently identified obesity as an important risk factor for breast cancer; therefore one would expect to see a higher rate of breast cancer in a study population with a greater amount of obesity. Women’s Health Initiative Steering Committee. JAMA. 2004;291: 1Women’s Health Initiative Steering Committee. JAMA. 2004;291: 2Chlebowski RT, et al. JAMA. 2003;289:

WHI Results: Effect of CEE/MPA on Risk of Invasive Breast Cancer
Women's Health Initiative WHI Results: Effect of CEE/MPA on Risk of Invasive Breast Cancer Unweighted HR = 1.24 95% CI, 1.01–1.54 CEE/MPA Cumulative Proportion Placebo This slide shows the cumulative proportion of women diagnosed with invasive breast cancer over time in the CEE/MPA and placebo groups. Compared to placebo, CEE/MPA use was associated with a small, but statistically significant, increase in the risk of invasive breast cancer. (HR=1.24; 95% CI, 1.01–1.54).1 Overall, the proportion of women diagnosed with invasive breast cancer was small in both the active treatment and placebo groups: CEE/MPA = 199 cases/8506 women (2.3% over 5.6 years; 41 per 10,000 women/year) Placebo = 150 cases/8102 women (1.9% over 5.6 years; 33 per 10,000 women/year) For comparison purposes, SEER incidence rates for women years2 old are: All races = 38 per 10,000 women/year Whites (84% of study population) = 40 per 10,000 women/year Thus, women assigned to CEE/MPA experienced a small but statistically significant increased risk of invasive breast cancer compared to women assigned to placebo. Absolute risk was low in both groups, and similar to risk estimates from previous observational studies. Attributable risk was 8 additional cases/10,000 women/year, which was identical to that reported in the preliminary findings. Breast cancers often take at least 5 years to progress from inception to the point at which they can be detectable. Mean patient follow-up in this updated analysis was 5.6 years. Whether E+P may have stimulated the growth of early breast cancers that were undetected at enrollment remains unanswered. Time (years) Chlebowski RT, et al. JAMA. 2003;289: 1Chlebowski RT, et al. JAMA. 2003;289: 2Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Mariotto A, Fay MP, Feuer EJ, Edwards BK (eds). SEER Cancer Statistics Review, , National Cancer Institute. Bethesda, MD,

WHI CEE/MPA Trial: Risk of Breast Cancer in Women With and Without Prior HT Use Prior HT Use None <5 Years 5 Years Overall % of Population 74.0 14.8 11.2 100 Similar to the results reported in the July 2002 report from the WHI investigators,1 the increased risk of invasive breast cancer was limited to those women with prior use of postmenopausal hormone therapy (HT).2 Women with no prior HT use comprised a large proportion of the study population (74%). The HR for breast cancer associated with CEE/MPA use in these women was only marginally greater than 1.0 and was not statistically significant. (The table below provides the data shown graphically in the slide.) 0.1 0.5 1.0 2.0 4.0 6.0 Hazard Ratio (95% CI) Chlebowski RT, et al. JAMA. 2003;289: Prior HT Use % of Study Population HR (95% CI) No prior use 74% 1.09 (0.86–1.39) <5 years of prior use 14.8% 1.70 (0.99–2.91) 5 years of prior use 11.2% 2.27 (1.00–5.15) 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2Chlebowski RT, et al. JAMA. 2003;289:

WHI CEE/MPA Trial: Characteristics of Invasive Breast Cancers
Women's Health Initiative WHI CEE/MPA Trial: Characteristics of Invasive Breast Cancers E+P (n = 199) Placebo (n = 150) P-Value Tumor size, mean ± SD (cm) 1.7 ± 1.1 1.5 ± 0.9 .04 Positive lymph nodes, % 25.9 15.8 .03 SEER stage, % Localized 74.6 82.7 Regional 24.4 14.0 .048 Metastatic 1.0 2.0 Morphology, grade, % Well differentiated 25.0 20.3 Moderately differentiated 43.3 47.7 .61 Poorly differentiated/anaplastic 31.7 32.0 Chlebowski and colleagues also compared the characteristics of the breast cancers that developed in the active treatment and placebo groups. These results indicated that tumors diagnosed in women in the E+P group were, on average, 0.2 cm larger than those diagnosed in the placebo group. In addition, E+P use was associated with a 10% greater incidence of regional spread, and 26% of breast cancers in the E+P group were node positive, compared to 16% in placebo. Differences between groups in the morphology of the cancers were not statistically significant, and the proportion of poorly differentiated or anaplastic cancers was almost identical in both groups (32%). One-quarter of the breast cancers in the E+P group were well differentiated, compared with 1/5 in placebo. No differences between groups were observed for tumor histology (data not shown). Points to consider: The standard deviation for tumor size, which indicates the degree of variance observed in tumor size in this study population, was fairly large. Standard deviations in the range of 0.9–1.1 cm suggest a variability in tumor size that is clinically meaningful in terms of differences in patient prognosis. Although statistically significant, the difference in mean tumor size between groups (0.2 cm) was small. In most cases, one would not expect this difference in tumor size to be associated with a difference in cancer stage and/or the proportion of patients with positive lymph nodes. Such differences, however, were observed in this study and additional research is needed to better understand these findings. Decisions regarding the workup of breast findings were directed by community physicians, and data on breast cancer end points was obtained by review of medical records and pathology reports. No information was provided on how lymph nodes were evaluated in the 349 cases for which results were reported. Differences in methods used to evaluate lymph nodes (eg, sentinel lymph node biopsy vs axillary dissection) may have contributed to the difference between groups in node-positive cancers. SEER = Surveillance, Epidemiology, and End Results. Chlebowski RT, et al. JAMA. 2003;289: 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 86.8 88.2 .72 Negative 13.2 11.8 PR status, % 75.0 69.9 .33 25.0 30.0 Deaths attributed to breast cancer, no. (%) 4 (2.0) 4 (2.7) No significant differences between E+P and placebo were observed for the proportion of breast cancers that were estrogen receptor-positive (ER-positive) or progesterone receptor-positive (PR-positive).1 However, the incidence of ER-positive tumors (87% in the CEE/MPA group, 88% in the placebo group) is higher than what would be expected in this age group. On average, two-thirds to three quarters of women with breast cancer in the United States have ER-positive tumors.2 ER-positive tumors are associated with better overall and disease-free survival compared to ER-negative tumors.3 This increase in the incidence of ER-positive breast cancers may be due to the high frequency of obesity in this population (34% had a body mass index 30 kg/m2).4 Obese women have a higher risk of ER-positive breast cancer compared to thinner women.5 Mortality from breast cancer was similar among patients on CEE/MPA compared to those on placebo. Four deaths attributed to breast cancer occurred in each group (2.0% of the cases in the CEE/MPA group and 2.7% of cases in the placebo group).1 ER = estrogen receptor; PR = progesterone receptor. Chlebowski RT, et al. JAMA. 2003;289: 1Chlebowski RT, et al. JAMA. 2003;289: 2Li CI, et al. J Clin Oncol. 2003;21:28-34. 3Bardou VJ, et al. J Clin Oncol. 2003;21: 4Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 5Morimoto LM, et al. Cancer Causes Control. 2002;13:

WHI CEE/MPA Trial: Mammography Results
Women's Health Initiative WHI CEE/MPA Trial: Mammography Results % Abnormal* E+P Placebo Year 1 9.4 5.4† Overall 31.5 21.2† Yearly mammography and clinical breast exams were required in the WHI, and these mammograms were performed at more than 3000 clinics, hospitals, and practices in the US. Mammography reports from these settings were reviewed locally and coded as: negative, benign finding-negative, short interval follow-up suggested, suspicious abnormality, or highly suggestive of malignancy.1 The investigators evaluated the frequency of abnormal mammograms, which they defined as those with either a recommendation for short interval follow-up or a suspicious abnormality, or those highly suggestive of malignancy. After 1 year of follow-up, the proportion of women with abnormal mammograms was greater in the E+P group (9.4%) compared with placebo (5.4%). This pattern continued throughout the study. In comparison, in a study of screening mammography in 50 community mammography practices that were included in the National Survey of Mammography Facilities, 11% of screening mammograms had abnormal findings and required further diagnostic evaluation.2 One factor to consider in examining these findings is that, with an average age of 63 years at enrollment, some older women who initiated E+P would be expected to experience physiological changes in breast tissue that could have been interpreted as “abnormal,” but are typical of changes seen when women begin HT years after menopause. *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: 1Chlebowski RT, et al. JAMA. 2003;289: 2Brown ML, et al. AJR Am J Roentgenol. 1995;165:

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative Section 7: Other Cancers

WHI Results: Effect of CEE Alone on Risk of Colorectal Cancer
Women's Health Initiative WHI Results: Effect of CEE Alone on Risk of Colorectal Cancer Kaplan-Meier Estimate HR = 1.08 95% nCI = 0.75–1.55 95% aCI = 0.63–1.86 CEE Placebo In the WHI CEE-alone trial, no significant differences were found in the rates of colorectal cancer for women assigned to CEE vs those assigned to placebo.1 The absolute risk of colorectal cancer observed in the study was 17 cases per 10,000 women per year in the CEE group and 16 cases per 10,000 women per year in the placebo group. As shown in the following slides, in the WHI CEE/MPA trial, the risk of colorectal cancer was significantly reduced with CEE/MPA use compared with placebo.2 A direct head-to-head comparison of the results from these two trials cannot be made, however, because the trials enrolled women with different baseline characteristics (eg, hysterectomized vs non-hysterectomized; greater degree of obesity in CEE-alone participants), which may correspond with differing risk profiles. Women’s Health Initiative Steering Committee. JAMA. 2004;291: 1Women’s Health Initiative Steering Committee. JAMA. 2004;291: 2Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

WHI Results: Effect of CEE/MPA on Risk of Colorectal Cancer
Women's Health Initiative WHI Results: Effect of CEE/MPA on Risk of Colorectal Cancer Kaplan-Meier Estimate HR = 0.56 95% nCI = 0.38–0.81 95% aCI = 0.33–0.94 Placebo E+P In the WHI, 43 invasive colorectal cancers occurred in the E+P group during and average of 5.6 years of follow-up, and 72 occurred in the placebo group (HR, 0.56; 95% nCI, 0.38–0.81; 95% aCI, 0.33–0.94). This figure shows the Kaplan-Meier plots of the cumulative hazard of invasive colorectal cancer for both the E+P and placebo groups. As indicated by the plots, the difference in incidence began to emerge early in the first year of follow-up, suggesting an effect on established cancers. The invasive colorectal cancers in the E+P and placebo groups were similar in location, tumor grade, and histologic features (ie, adenocarcinoma, not otherwise specified; in adenomatous polyp; in tubulovillous adenoma; or in villous adenoma). However, cancers in the E+P group had a greater number of positive lymph nodes (mean±SD, 3.2±4.1 vs 0.8±1.7; P = .002), compared with placebo, and were more advanced (regional or metastatic disease, 76.2% vs 48.5%; P = .004). The reasons for these differences are unknown. Exploratory analyses indicated that among those women in the E+P group who were diagnosed with colorectal cancer, those with antecedent vaginal bleeding had cancers with a greater number of positive nodes, compared with those women who did not have vaginal bleeding (3.8±4.3 vs 0.7±1.5, P = .006). Abdominal pain, a change in bowel habits, and rectal bleeding are common symptoms in patients who present with colorectal cancer. The authors speculated that vaginal bleeding may have delayed some women from seeking care and may possibly account for the higher incidence of advanced cancer in the E+P group. Given this possibility, wider implementation of bowel screening among postmenopausal women using HT was recommended. Chlebowski RT, et al. N Engl J Med. 2004;350: Chlebowski RT, et al. N Engl J Med. 2004;350:

WHI Results: Hazard Ratio for Invasive Ovarian Cancer With CEE/MPA
Women's Health Initiative WHI Results: Hazard Ratio for Invasive Ovarian Cancer With CEE/MPA Placebo E+P 95% nCI 95% aCI 0.1 0.5 1.0 5.0 2.0 The WHI investigators reported a small, nonsignificant increase in ovarian cancer risk in women assigned to receive E+P compared with those assigned to placebo (HR, 1.58; 95% nCI, 0.77–3.24; 95% aCI, 0.59–4.23).1 Average follow-up time for the women included in this analysis was 5.6 years. The annual incidence rate for ovarian cancer observed among the total study population was 34 cases per 100,000 person-years. This rate is lower than the NCI SEER population-based rate of 45 cases per 100,000 person-years in women in the same age range as the WHI participants.2 The WHI investigators found no differences between treatment groups in histology, grade, or stage of disease at diagnosis. In addition, no significant interactions between group assignment and any of the following variables were observed: age, race/ethnicity, BMI, family history of breast or ovarian cancer, family history of colorectal cancer, prior use of oral contraceptives, prior exposure to E alone, or prior use of E+P.1 In summary, the incidence of ovarian cancer among E+P users in the WHI was somewhat greater than that observed in the placebo group, although the difference in incidence rates was small and not statistically significant. The authors concluded that continuous combined E+P may increase the risk of ovarian cancer. However, they added that due to the low rates of ovarian and other gynecologic cancers in the study population and the limited precision of the risk estimates, “the results should not have an appreciable influence on most women’s decision making when seeking relief for moderate to severe vasomotor symptoms.”1 Hazard Ratio 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: 1Anderson GL, et al. JAMA. 2003;290: 2National Cancer Institute. Surveillance, Epidemiology, and End results Statistical Database ( ). Available at: Accessed December 18, 2003.

WHI Results: Hazard Ratio for Endometrial Cancer With CEE/MPA
Women's Health Initiative WHI Results: Hazard Ratio for Endometrial Cancer With CEE/MPA Placebo E+P 95% nCI 95% aCI 0.1 0.5 1.0 5.0 2.0 The WHI investigators reported a small, nonsignificant reduction in the risk of endometrial cancer in women assigned to receive E+P compared with those assigned to placebo (HR, 0.81; 95% nCI, 0.48–1.36; 95% aCI, 0.40–1.64).1 Average follow-up time for the women included in this analysis was 5.6 years. The annual incidence rate for endometrial cancer observed among the total study population was 62 cases per 100,000 person-years. This rate is lower than the NCI SEER population-based rate of 83 cases per 100,000 person-years in women in the same age range as the WHI participants.2 The WHI investigators found no differences between treatment groups in histology, grade, or stage of disease at diagnosis. In addition, no significant interactions between group assignment and any of the following variables were observed: age, race/ethnicity, body mass index, hypertension, smoking status, pack-years of smoking, prior exposure to E alone, or prior use of E+P.1 In summary, the incidence of endometrial cancer among E+P users in the WHI was less that that observed in the placebo group, although the difference in incidence rates was not statistically significant. The authors noted that the WHI was the first randomized, double-blind, placebo-controlled trial to demonstrate that endometrial cancer rates among women assigned to continuous E+P are similar to those observed in women assigned to placebo.1 Hazard Ratio 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: 1Anderson GL, et al. JAMA. 2003;290: 2National Cancer Institute. Surveillance, Epidemiology, and End results Statistical Database ( ). Available at: Accessed December 18, 2003.

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative Section 8: Fractures

WHI Results: Effect of CEE Alone on Risk of Hip Fracture Kaplan-Meier Estimate HR = 0.61 95% nCI = 0.41–0.91 95% aCI = 0.33–1.11 Placebo CEE In the WHI CEE-alone trial, use of CEE was associated with a 39% reduction in the risk of hip fracture. The nCI for the HR for hip fracture (0.61) was statistically significant. Hip fracture rates were 11 vs 17 per 10,000 women per year (P = .01) in women assigned to CEE vs those assigned to placebo. Rates were similarly reduced for clinical vertebral fractures (11 vs 17 per 10,000 women per year) and total osteoporotic fractures (139 vs 195 per 10,000 women per year) with use of CEE compared with placebo. Women’s Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI: Baseline Prevalence of Osteoporosis (WHO) by DXA Femoral Neck T-scores In 6% of Participants (n = 1024) E+P Placebo 32% 58% 10% 35% 53% 12% P = .29 BMD at the total hip and lumbar spine (L2-L4) were measured in the WHI, but in only 6% of participants (1024 women). Based on this subset of WHI participants, the prevalence of osteoporosis in the study population is shown here using the WHO definition based on T-scores from the femoral neck. Overall the average T-score in the hip was about –1.0 and in the spine it was about –1.3 and did not differ by randomized group. Approximately 10% of women in the E+P group were considered to have osteoporosis based on their T-score compared to 12% in the placebo group. This difference was not statistically significant. The majority of women (53%–58%) were considered to have low bone mass and about one-third of the women had normal bone density measurements. Normal (>–1.0) Low Bone Mass (–1.0 to –2.4) Osteoporosis (–2.5 ) Cauley JA. Available at: Accessed 1/7/04. Cauley JA. Available at: Accessed 1/7/04.

WHI Results: Mean Change in BMD During 3 Years of E+P
Women's Health Initiative WHI Results: Mean Change in BMD During 3 Years of E+P In 6% of Participants (n = 1024) Total Hip Placebo HT Spine Mean Change in BMD From Baseline (%) BMD at the total hip and lumbar spine (L2-L4) were measured in a subset of WHI participants (1024 women total). As shown here, CEE/MPA treatment for up to 3 years showed consistent positive effects on both hip and spine BMD. In the HT-treated group, total hip BMD increased a mean of 1.7% after 1 year of treatment and 3.7% by Year 3, significantly greater (P < .001) than women in the placebo group who experienced a loss at year 1 and a nominal improvement (0.14%) at Year 3. Similar differences were observed for BMD at the lumbar spine. A total of 194 (36%) women in the E+P group and 249 (32%) women in the placebo group had Year 6 BMD measurements (not shown). By Year 6, the percentage increase in lumbar spine BMD was 7.5% in women in the active treatment group compared with 2.6% in in women on placebo. Data on Year 6 hip BMD was not reported. These findings are consistent with previously published observational and clinical data demonstrating an increase in BMD with CEE/MPA treatment. Follow-up (years) Cauley JA, et al. JAMA. 2003;290: Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290:

WHI Results: Fracture Outcomes
Women's Health Initiative WHI Results: Fracture Outcomes 0.5 1.0 2.0 Hip Vertebral Lower Arm/ Wrist Total 95% nCI 95% aCI Hazard Ratio Consistent with the initial report of fracture prevention in WHI,1 the updated analysis by Cauley et al2 found that CEE/MPA treatment significantly reduced the risk of fracture in postmenopausal women after an average follow-up period of 5.6 years. Using 95% nCIs to evaluate statistical significance, mg/d CEE plus 2.5 mg/d MPA reduced the risk of hip fracture by one third (HR, 0.67; 95% nCI, 0.47–0.96). CEE/MPA also reduced the risk of vertebral fracture (HR, 0.65; 95% nCI, 0.46–0.92), lower arm/wrist fractures (HR, 0.71; 95% nCI, 0.59–0.85), and total fractures (HR, 0.76; 95% nCI, 0.69–0.83). A 95% aCIwas reported for hip fracture, but not for the other fractures. When the aCI for hip fracture (95% aCI, 0.41–1.10) is used, the difference in risk for hip fracture is not significant. These findings are consistent with previously published observational data and data from clinical trials on the benefit of HT in reducing fracture risk. Adjusted confidence interval reported only for hip fracture. Cauley JA, et al. JAMA. 2003;290: 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290:

WHI Results: Effect of CEE/MPA in Preventing Fractures
Women's Health Initiative WHI Results: Effect of CEE/MPA in Preventing Fractures Number of Fractures/Year in 10,000 Women During the 5.6 years of follow-up in WHI, a total of 8.6% of women in the E+P group and 11.1% of women in the placebo group experienced fracture. Overall fracture rates per 10,000 person-years in the placebo group compared with the E+P treatment group are shown here. Fracture rates for the placebo and CEE/MPA groups, respectively, were: hip fractures, 16 and 11; clinical vertebral, 17 and 11; lower arm/wrist, 62 and 44; and total fractures, 199 and 152. Type of Fracture Cauley JA, et al. JAMA. 2003;290: Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290:

WHI Results: Effect of CEE/MPA on Risk of Hip Fracture
Women's Health Initiative WHI Results: Effect of CEE/MPA on Risk of Hip Fracture Kaplan-Meier Estimate HR = 0.67 95% nCl = 0.47–0.96 95% aCI = 0.41–1.10 Cumulative Hazard Placebo E+P The Kaplan-Meier estimate of cumulative hazard based on data from the 5.6 years of follow-up in the WHI shows increasing cumulative benefit of E+P on hip fracture over time, with differences between treatment groups developing soon after randomization. The difference in the cumulative incidence of hip fractures between women assigned to CEE/MPA and those assigned to placebo increased over time. The overall HR for hip fracture was 0.67 (95% nCI, 0.47–0.96), suggesting a 33% reduction of hip fracture risk among E+P users. When the 95% aCI is used for evaluation, the difference in risk of hip fracture is not significant (95% aCI, 0.41–1.10). Time (year) Cauley JA, et al. JAMA. 2003;290: Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290:

WHI Results: Effect of CEE/MPA on Risk of Lower Arm/Wrist Fracture
Women's Health Initiative WHI Results: Effect of CEE/MPA on Risk of Lower Arm/Wrist Fracture Kaplan-Meier Estimate HR = 0.71 95% nCl = 0.59–0.85 Placebo E+P Cumulative Hazard The Kaplan-Meier estimate of cumulative hazard based on data from the 5.6 years of follow-up in the WHI shows increasing cumulative benefit of E+P on lower arm/wrist fracture over time, with differences between treatment groups developing soon after randomization. The difference in the cumulative incidence of lower arm/wrist fractures between women assigned to E+P and those assigned to placebo increased over time. The overall HR for lower arm/wrist fracture was 0.71 (95% nCI, 0.59–0.85), suggesting a 29% reduction of hip fracture risk among CEE/MPA users. Time (year) Adjusted confidence interval not reported. Cauley JA, et al. JAMA. 2003;290: Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290:

WHI Results: Effect of CEE/MPA on Risk of Vertebral Fracture
Women's Health Initiative WHI Results: Effect of CEE/MPA on Risk of Vertebral Fracture Kaplan-Meier Estimate HR = 0.65 95% nCl = 0.46–0.92 Cumulative Hazard Placebo E+P The Kaplan-Meier estimate of cumulative hazard based on data from the 5.6 years of follow-up in the WHI shows increasing cumulative benefit of E+P on vertebral fracture over time, with differences between treatment groups developing soon after randomization. The difference in the cumulative incidence of vertebral fractures between women assigned to E+P and those assigned to placebo increased over time. The overall HR for vertebral fracture was 0.65 (95% nCI, 0.46–0.92), suggesting a 35% reduction of vertebral fracture risk among CEE/MPA users. Time (year) Adjusted confidence interval not reported. Cauley JA, et al. JAMA. 2003;290: Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290:

WHI Results: Effect of CEE/MPA on Risk of Total Fracture
Women's Health Initiative WHI Results: Effect of CEE/MPA on Risk of Total Fracture Kaplan-Meier Estimate Placebo HR = 0.76 95% nCl = 0.69–0.83 E+P Cumulative Hazard The Kaplan-Meier estimate of cumulative hazard based on data from the 5.6 years of follow-up in the WHI shows increasing cumulative benefit of E+P on total fracture over time, with differences between treatment groups developing soon after randomization. The difference in the cumulative incidence of total fractures between women assigned to E+P and those assigned to placebo increased over time. The overall HR for total fracture was 0.76 (95% nCI, 0.69–0.83), suggesting a 24% reduction of hip fracture risk among CEE/MPA users. Time (year) Adjusted confidence interval not reported. Cauley JA, et al. JAMA. 2003;290: Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290:

WHI: Summary Fracture Risk Score
Women's Health Initiative WHI: Summary Fracture Risk Score WHI Investigators1 developed a summary fracture risk score guided by the methods used to develop the FRACTURE Index2 Predictive validity of FRACTURE Index has been shown2 Validity of WHI fracture risk score not established WHI reported fracture risk score showed moderate predictive strength for hip fracture1 To test whether the effects of CEE/MPA differed in women according to their risk of hip fracture, Cauley et al1 developed a summary fracture risk score for participants in WHI guided by the methods used by Black et al2 to develop the FRACTURE Index. The WHI investigators reported that the fracture risk score demonstrated moderate predictive strength for hip fracture within the WHI population. These results are not unexpected, however, because the score is based on the data from these women. Therefore, the validity of the WHI fracture risk scores is unknown at this time and requires further study. 1Cauley JA, et al. JAMA. 2003;290: 2Black DM, et al. Osteoporosis Int. 2001;12: 1Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290: 2Black DM, et al. Osteoporosis Int. 2001;12:

WHI: Summary Fracture Risk Score
Women's Health Initiative WHI: Summary Fracture Risk Score Differences between FRACTURE Index and WHI risk score1,2: WHI score includes age, prior fracture after age 55 years, current smoking, and BMI 22.4 kg/m2 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 The WHI fracture risk score included age, prior fracture after age 55 years, current smoking, and BMI 22.4 kg/m1. The FRACTURE Index, which has demonstrated predictive validity, also includes age, prior fracture, and current smoking. The FRACTURE Index includes weight rather than BMI. More importantly, the FRACTURE Index includes 2 factors for which the WHI investigators did not have data for all women: maternal hip fracture after age 50, and whether use of arms is usually required to assist in standing up from a chair.2 The FRACTURE Index includes total hip BMD T-score if it is available; when hip BMD is included, the FRACTURE Index has somewhat better specificity and positive predictive value than when it is not.2 1Cauley JA, et al. JAMA. 2003;290: 2Black DM, et al. Osteoporosis Int. 2001;12: 1Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290: 2Black DM, et al. Osteoporosis Int. 2001;12:

HR for Global Index: Stratified by Fracture Risk Scores
Women's Health Initiative HR for Global Index: Stratified by Fracture Risk Scores Fracture Risk* 0.5 1.0 2.0 Highest Middle Lowest The WHI investigators used the summary fracture risk score to evaluate whether the overall balance of risks and benefits of CEE/MPA varied by a woman’s risk for fracture. To accomplish this, the investigators examined the HRs for the global index (a measure created by the WHI investigators to assess the overall balance of risks and benefits of HT) in women stratified into tertiles by their fracture risk scores. As shown in this slide, among women in the lowest fracture risk tertile, the global index HR was 1.20 (95% nCI, 0.93–1.58); in the middle tertile the HR was 1.23 (95% nCI, 1.04–1.46); and in the highest tertile of risk the HR was 1.03 (95% nCI, 0.88–1.24). Based on this analysis of the global index as stratified by fracture risk, the WHI authors concluded there was no evidence of an overall net benefit of CEE/MPA, even in women at high risk of fracture. Although not stated by the authors, the nonsignificant HR of 1.03 in the highest tertile of risk suggests there is also no evidence of net harm in those women. Importantly, neither the global index measure nor the fracture risk assessment in WHI have been validated; therefore, any conclusions based on these models need to be interpreted with caution. Hazard Ratio (95% nCI) *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: Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290: Black DM, et al. Osteoporosis Int. 2001;12:

Summary: WHI Results and Considerations
Women's Health Initiative 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 fracture1 This benefit has not been demonstrated in a similarly low-risk population with any other osteoporosis therapy Consistent with the known skeletal benefits of estrogen, results from WHI demonstrate that CEE/MPA can significantly improve BMD and decrease risk of hip and other osteoporosis-related fractures. This benefit was observed in a large population of women not specifically selected for being at increased risk of fracture, and was seen in women at low to moderate fracture risk. 1Cauley JA, et al. JAMA. 2003;290: Cauley JA, et al, for the Women's Health Initiative Investigators. JAMA. 2003;290:

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

Women’s Health Initiative Memory Study (WHIMS)
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 impairment1 Effect of CEE/MPA on global cognitive function2 The Women’s Health Initiative Memory Study (WHIMS) was an ancillary study to the WHI and enrolled participants from both its estrogen-only and E+P arms. The WHIMS used the 3MSE to screen for probable dementia, the study’s primary outcome, and mild cognitive impairment, as well as to assess global cognitive function.1,2 Patients who scored below designated cut points on the 3MSE underwent additional clinical evaluation, including a neuropsychological and neurological work-up. Cases were adjudicated by a central adjudication committee (Kappa = .66). 1Shumaker SA, et al. JAMA. 2003;289: 2Rapp SR, et al. JAMA. 2003;289: 1Shumaker SA, et al. JAMA. 2003;289: 2Rapp SR, et al. JAMA. 2003;289:

WHIMS: Dementia and Mild Cognitive Impairment
Women's Health Initiative WHIMS: Dementia and Mild Cognitive Impairment 4532 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 WHIMS1 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 4532 postmenopausal women aged 65 years or older without probable dementia were recruited from 39 of 40 WHI centers and enrolled in the CEE/MPA arm of the WHIMS. On July 8, 2002, CEE/MPA was discontinued because of increased health risks in women receiving combined HT. The mean time between the date of randomization into WHI and the last 3MSE for all WHIMS participants was 4.05 (SD, 1.19) years.1 On March 2, 2004, the NIH announced it was ending the CEE-only component of the WHI trial, and thus of the WHIMS, approximately 1 year before its planned completion.2 According to the NIH, preliminary data suggested that there was a trend toward an increased risk of probable dementia and/or mild cognitive impairment in women given unopposed estrogen when compared to those given placebo. Publication of the results from the estrogen arm of both the WHI and WHIMS is forthcoming. 1Shumaker SA, et al. JAMA. 2003;289: 1Shumaker SA, et al. JAMA. 2003;289: 2National Institutes of Health, U.S. Department of Health and Human Services. NIH/NHLBI News Release. March 2, 2004.

Cases of Probable Dementia and Mild Cognitive Impairment
Women's Health Initiative Cases of Probable Dementia and Mild Cognitive Impairment Outcome E+P (n = 2229) Placebo (n = 2303) HR (95% CI) Probable dementia, n 40 21 2.05 (1.21–3.48) Follow-up, mean (SD), years 4.01 (1.21) 4.06 (1.18) Rate per 10,000 person-years 45 22 Mild cognitive impairment, n 56 55 1.07 (0.74–1.55) 3.99 (1.23) 4.04 (1.20) 63 59 Overall, the number of women diagnosed with probable dementia or mild cognitive impairment was small. Of the 4532 patients enrolled in the study, 61 participants from 31 of the 39 study centers were diagnosed with probable dementia. Forty of these cases were in the CEE/MPA group, and 21 were in the placebo group. The HR for probable dementia among women receiving CEE/MPA compared with those given placebo was 2.05 (95% CI, 1.21–3.48; P = .01). Therefore, for every 10,000 women aged 65 years or older with risk-factor profiles similar to those of WHIMS participants, an additional 23 cases of probable dementia might be observed among women taking CEE/MPA compared with women taking placebo. There was no statistically significant difference in the risk of being diagnosed with mild cognitive impairment among women receiving CEE/MPA compared with those receiving placebo (HR, 1.07; 95% CI, 0.74–1.55; P = .72). Among the 56 women in the CEE/MPA group and the 55 women in the placebo group initially diagnosed with mild cognitive impairment, 11 women in the CEE/MPA group and 10 women in the placebo group were eventually diagnosed with probable dementia. Since early postmenopausal women were not included in the study, it is unclear whether these results can be applied to early postmenopausal women taking HT for symptom relief. Shumaker SA, et al. JAMA. 2003;289: Shumaker SA, et al. JAMA. 2003;289:

Cumulative HR for a Diagnosis of Mild Cognitive Impairment CEE/MPA Placebo HR, 1.07 95% CI, 0.74–1.55 Number of Events CEE/MPA Placebo The risk of a diagnosis of mild cognitive impairment in the CEE/MPA group was similar to the risk reported in the placebo group (HR, 1.07; 95% CI, 0.74–1.55). The differences between groups in cumulative hazards for a diagnosis of mild cognitive impairment were minimal throughout the 5-year study. The number of diagnoses of mild cognitive impairment per year ranged from 4 at year 5 in the CEE/MPA group to 18 at year 3 in the placebo group and at year 2 and 3 in the CEE/MPA group. Shumaker SA, et al. JAMA. 2003;289: Shumaker SA, et al. JAMA. 2003;289:

Cumulative HR for a Diagnosis of Probable Dementia
Women's Health Initiative Cumulative HR for a Diagnosis of Probable Dementia CEE/MPA Placebo HR, 2.05 95% CI, 1.21–3.48 Number of Events CEE/MPA Placebo Although the numbers of patients diagnosed with probable dementia each year were small, cumulative HRs indicate that the risk of being diagnosed with probable dementia began to increase among patients taking CEE/MPA compared with those taking placebo 1 year after randomization. These differences continued through the 5-year study, at least through year 4. Overall, the rate of a diagnosis of probable dementia in the CEE/MPA group compared with that observed in the placebo group was 2.05 (95% CI, 1.21–3.48). Shumaker SA, et al. JAMA. 2003;289: Shumaker SA, et al. JAMA. 2003;289:

Classification of Probable Dementia Cases by Treatment Assignment
Women's Health Initiative Classification of Probable Dementia Cases by Treatment Assignment Number (%) of Cases Dementia Type CEE/MPA (n = 40) Placebo (n = 21) Vascular dementia 5 (12.5) 1 (4.8) Alzheimer’s disease 20 (50.0) 12 (57.1) Other dementia types Mixed type 3 (14.3) Normal pressure hydrocephalus 2 (5.0) Parkinson Frontal lobe type Alcohol related 1 (2.5) Other dementia 3 (7.5) 2 (9.5) Etiology unknown There were too few cases to examine the effects of CEE/MPA on specific subtypes of dementia, including AD, in the WHIMS. AD was the most common classification of probable dementia cases, with 20 cases (50.0%) in the CEE/MPA group and 12 cases (57.1%) in the placebo group.1 Other dementia classifications reported in both groups included vascular dementia and mixed-type dementia. Five patients taking CEE/MPA were classified as having vascular dementia, compared with 1 patient receiving placebo. Among patients taking CEE/MPA, 2 cases of probable dementia were classified as normal pressure hydrocephalus and 2 were classified as frontal lobe type. One case of probable dementia in the placebo group was classified as a Parkinson type dementia. The etiology was unknown in 2 cases in each group. Although 75 participants had a stroke during the follow-up period (39 in the CEE/MPA group and 36 in the placebo group), only 1 patient diagnosed with probable dementia had a stroke during the study before her diagnosis. Two others diagnosed with probable dementia in the CEE/MPA group had a history of stroke. Investigators hypothesized that the increased risk of stroke observed with CEE/MPA may contribute to the increased risk of probable dementia. Although the risk of probable dementia was increased in WHIMS participants without a history of stroke, it is possible that these patients may have experienced small, undetected cerebrovascular events, which could increase the risk of probable dementia.2 Recent studies suggest that the pathophysiological mechanisms and clinical symptoms of AD and vascular dementia may overlap,1 and standard clinical diagnostic methods tend to favor a classification of AD over vascular dementia when both may be present.3 Shumaker SA, et al. JAMA. 2003;289: 1Shumaker SA, et al. JAMA. 2003;289: 2Vermeer SE, et al. N Engl J Med. 2003;348: 3Kalaria RN, et al. Neurobiol Aging. 1996;17:

Patient Adherence in WHIMS
Women's Health Initiative 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) At some time during the trial, 2,534 participants (55.9%) were nonadherent. A patient who was nonadherent either: Stopped study medication by her own decision or for protocol-based safety reasons Took less than 80% of her pills between dispensing and collection Started prescribed postmenopausal HT outside of WHI The earliest date of nonadherence was selected, and follow-up data were censored 6 months later for secondary analyses examining the impact of nonadherence on the effects of E+P. When nonadherent patients were censored, the number of probable dementia cases that occurred before censoring was 21 in the CEE/MPA group and 6 in the placebo group. In the analysis including only compliant patients, the HR for a diagnosis of probable dementia with CEE/MPA compared with placebo was 3.22 (95% CI, 1.25–8.29; P = .02). The specific diagnoses for compliant patients were not presented. Shumaker SA, et al. JAMA. 2003;289: Shumaker SA, et al. JAMA. 2003;289:

WHI: Effect of E+P on Stroke Incidence
Women's Health Initiative WHI: Effect of E+P on Stroke Incidence Events (per 10,000 person-years) One of the hypotheses for the increase in all-cause dementia in the HT group reported in the WHIMS is that it reflects the increase in the risk of stroke or silent ischemic disease reported in the estrogen-plus-progestin arm of the WHI. This slide shows the number of cases of stroke per 10,000 person-years as a function of year of follow-up and as a function of whether the women were randomized to receive E+P or E alone. The E+P group had an increased incidence of stroke at Years 2, 3, and 4 that tended to reverse at Year 6. These data parallel those for dementia, which demonstrated an increase in probable all-cause dementia in Years 2, 3, and 4. Thus the incidence of dementia seems to follow that of stroke, supporting the idea that the E+P might have increased dementia by exacerbating ischemic stroke, even if silent. Year of Follow-up Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:

Related Study WHISCA – Women’s 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 The Women’s Health Initiative Study on Cognitive Aging (WHISCA) is an ancillary study to the WHIMS. The design is similar in that women are evaluated annually for 6 years. WHISCA will evaluate whether HT reduces age-related cognitive and memory decline, and will also look at the rate of change in memory/cognitive function for HT users compared with nonusers, and whether the addition of a progestin to an estrogen-alone regimen modifies the effect of estrogen on cognitive abilities. Stanford Prevention Research Center. Available at Accessed March 11, 2004.

What WHIMS and WHISCA Cannot Address
Women's Health Initiative 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 WHIMS and WHISCA were designed to evaluate the effects of HT on cognitive aging and AD. However, questions about the existence of a critical period for initiation of HT and about different dose regimens and formulations of HT are not likely to be answered by these trials.

Observational vs Randomized Studies
Women's Health Initiative Observational vs Randomized Studies HT and AD Observational Prospective Studies Typical patterns of HT use (age, treatment) Mostly E alone  Risk for AD Women’s Health Initiative Memory Study (WHIMS) Only women 65 years of age CEE + MPA  Risk of all-cause dementia This summary slide delineates the differences between observational, prospective studies on HT and AD and the WHIMS. The two differ not only in method but also in types of women studied. The observational trials involve the typical patterns of use of HT (ie, early initiation). In contrast, the WHIMS studied only women aged 65 years and older. Older women had to be included because they had a probability of developing dementia within the short time frame of the study. A second difference is that, in the observational studies, women were taking mostly unopposed estrogen, since it was not known at the time that nonhysterectomized women should be taking a progestin to protect their uteri. A final difference between the observational studies and the WHIMS is the outcome measure: the former focused on a decreased risk of AD, whereas the latter focused on an increased risk of all-cause dementia, including vascular dementia. It remains unknown whether there was an increase in the risk of AD in the WHIMS, since the statistical power was insufficient to address that question.

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative Section 10: Quality of Life

WHI Quality of Life (QOL) Study
Women's Health Initiative WHI Quality of Life (QOL) Study QOL-Related Assessments Health and functional status—RAND-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 Variables assessed in the WHI Quality of Life (QOL) study1 included health-related functioning, depression, sleep quality, sexual functioning, cognitive functioning, and menopausal symptoms. The RAND-36 survey was the primary instrument used to assess health and functional status. Although this instrument measures health-related functioning, it was not designed to assess some other variables (like sense of well-being) that help determine QOL in postmenopausal women. Depression was assessed by using the Center for Epidemiological Studies-Depression (CES-D) scale, which is a validated scale for evaluating depressive disorders. However, sleep functioning was assessed by using a 5-item scale developed for the WHI (the WHI Insomnia Rating Scale), which included questions relating to sleep initiation, maintenance, and quality, but did not address measurable variables such as duration of REM sleep. Sexual functioning was assessed with a single question with a 4-point response scale ranging from 1 (very unsatisfied) to 4 (very satisfied). Such a method is unlikely to adequately evaluate sexual functioning, which is both multidimensional and multifactorial. Additionally, marital status of the participants was not reported. The modified Mini-Mental State Examination (mMMSE) was administered to participants 65 years of age to assess cognitive functioning. The investigators assessed menopausal symptoms using 5 items from the symptom checklist that was used in the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial.2 Symptoms assessed were hot flushes, night sweats, mood swings, forgetfulness, and difficulty concentrating. Each item had 4 response categories: none, mild, moderate, and severe. No assessment of vaginal symptoms (an indication for HT) was made. CES-D = Center for Epidemiological Studies-Depression; mMMSE = modified Mini-Mental State Examination. Hays J, et al. N Engl J Med. 2003;348: 1Hays J, et al. N Engl J Med. 2003;348: 2Greendale GA, et al. Obstet Gynecol. 1998;92:982-8.

One-Year Change in RAND-36 Scores
Women's Health Initiative One-Year Change in RAND-36 Scores * * This figure illustrates mean changes in RAND-36 scores from baseline to year 1 in the CEE/MPA and placebo groups. For all variables, higher numbers indicate a positive effect and lower numbers indicate a negative effect. For women taking CEE/MPA, small but statistically significant benefits were reported for physical functioning and bodily pain (P < .01) compared with women taking placebo. In the WHI study population, 1 year of CEE/MPA use did not significantly affect women’s scores for general health, energy and fatigue, social functioning, mental health, and physical role limitations. At 3 years (data not shown) there were no significant differences between groups for any of the variables evaluated. An important consideration in interpretation of these results is that mean baseline scores for each of these subscales were very high—close to the best possible score in some cases—and considered normal. Therefore, the potential to observe meaningful increases in these scores in the WHI was severely limited. 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: Hays J, et al. N Engl J Med. 2003;348:

One-Year Change in Other QOL-Related Measures
Women's Health Initiative One-Year Change in Other QOL-Related Measures Depression Sleep Disturbance Satisfaction With Sex mMMSE * This figure illustrates mean changes in other QOL-related scores from baseline to year 1 in the CEE/MPA and placebo groups. For all variables except depression, higher numbers indicate a positive effect and lower numbers indicate a negative effect. For women taking CEE/MPA, a small but statistically significant benefit was reported for sleep disturbance (P < .01) compared with women taking placebo. In the WHI study population, 1 year of CEE/MPA use did not significantly affect women’s scores for depression or satisfaction with sex, nor was there a significant change in mMMSE score compared with placebo. At 3 years (data not shown) there were no significant differences between groups for any of the variables evaluated. An important consideration in interpretation of these results is that mean baseline scores for each of these subscales were very high—close to the best possible score in some cases—and considered normal. Therefore, the potential to observe meaningful increases in these scores in the WHI study was severely limited. 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: Hays J, et al. N Engl J Med. 2003;348:

WHI QOL: Summary of Findings
Women's Health Initiative WHI QOL: Summary of Findings The WHI1 found No significant clinical QOL benefit on any of the outcomes, including general health, vitality, mental health, or sexual satisfaction A statistically—but not clinically—significant benefit in sleep disturbance, physical functioning, and body pain at 1 year Findings were similar to HERS2 No improvement in QOL was seen with E+P use in older, asymptomatic, postmenopausal women In summary: The report from the WHI on QOL benefits associated with E+P use found no significant clinical QOL benefit on any of the QOL-related outcomes assessed, including general health, vitality, mental health and depressive symptoms, or satisfaction with sexual functioning. The WHI investigators did find that E+P use was associated with a statistically significant but not clinically significant benefit in sleep disturbance, physical functioning, and body pain at one year but not at 3 years. The results from this WHI1 analysis are comparable to findings from HERS2: no improvement in QOL was observed in older asymptomatic postmenopausal women using E+P. 1Hays J, et al. N Engl J Med. 2003;348: 2Hlatky MA, et al. JAMA. 2002;287:591-7. 1Hays J, et al. N Engl J Med. 2003;348: 2Hlatky MA, et al. JAMA. 2002;287:591-7.

WHI QOL: Study Considerations
Women's Health Initiative 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 In interpreting the results of this study, some important factors should be taken into consideration: At the start of the study, moderate or severe symptoms were reported by only 12% of the participants. Because vasomotor symptoms can have a significant effect of QOL, a study that includes more women with moderate or severe symptoms might have different outcomes. The methods used to determine which women had moderate or severe vasomotor symptoms at baseline remains unclear. No specific changes in vaginal symptoms, which are a known indication for HT, were assessed. Scores on almost all of the QOL-related assessments were high at baseline for both placebo and treatment groups, which suggests that any therapeutic intervention would have been unlikely to increase these scores further. Because the mean age of participants was 63 years and most of the women were at least 10 years postmenopausal, the study population does not represent early postmenopausal women who are more likely to have moderate to severe vasomotor symptoms, or other menopausal symptoms that may affect QOL. While a number of accepted, validated tools exist for assessing QOL in postmenopausal women, the WHI investigators did not use any of them in their evaluation of QOL and HT. In summary, this analysis from the WHI did not address the question of whether E+P improves QOL in women with moderate to severe menopausal symptoms. Similarly, it does not address how important a QOL benefit might be to symptomatic women and how QOL benefits may affect the overall risk-benefit assessment for HT in symptomatic women. Hays J, et al. N Engl J Med. 2003;348: Hays J, et al. N Engl J Med. 2003;348:

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative Section 10: Mortality

WHI Results: Effect of CEE-Alone on Total Mortality Kaplan-Meier Estimate HR = 1.04 95% nCI = 0.88–1.22 95% aCI = 0.81–1.32 CEE Placebo In the WHI CEE-alone trial, 580 deaths occurred among the women enrolled in the study. As shown in the Kaplan-Meier graph in this slide, total mortality rates did not differ among women assigned to CEE compared with those assigned to placebo. Similarly, cause-specific mortality did not differ between the CEE and placebo groups (data not shown). Women’s Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI Results: Causes of Death* in the CEE/MPA Trial
Women's Health Initiative WHI Results: Causes of Death* in the CEE/MPA Trial Outcome CEE/MPA (n = 8506) n (%) Placebo (n = 8102) n (%) Total deaths 231 (0.52) 218 (0.53) Adjudicated deaths 215 (0.49) 201 (0.49) Cardiovascular 65 (0.15) 55 (0.13) Breast cancer 3 (0.01) 2 (<0.01) Other cancer 104 (0.24) 86 (0.21) Other known cause 34 (0.08) 41 (0.10) Unknown cause 9 (0.02) 17 (0.04) This table details the causes of deaths that occurred in the CEE/MPA arm of the WHI. There were no significant differences in mortality or cause of death between the CEE/MPA and placebo groups during the observational period of 5.2 years. Longer-term changes in mortality could not be determined. Of the adjudicated deaths, only 30% were due to cardiovascular events. *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: Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

WHI CEE/MPA Trial: Annualized Percent of All-Cause Deaths by Year
Women's Health Initiative WHI CEE/MPA Trial: Annualized Percent of All-Cause Deaths by Year HR = 0.98 95% nCI = 0.82–1.18 95% aCI = 0.70–1.37 Hazard Year Ratio 1 1.24 2 0.96 3 1.06 5 0.87 P = NS for trend over time. This figure compares yearly rates of total deaths in the CEE/MPA and placebo groups. The table to the right of the line graph lists the HRs for all-cause deaths on a year-to-year basis. CIs were not reported for the yearly HRs. The test for linear trend with time since randomization detected no significant trend over time for total deaths. Overall, the HR for all-cause deaths was 0.98 (95% aCI, 0.70–1.37), indicating no difference in mortality between the CEE/MPA and placebo groups. Year Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

Risks and Benefits of Hormone Therapy: An Overview of Findings From the Women’s Health Initiative Section 11: Summary and Conclusions

Summary of CEE/MPA Study
Women's Health Initiative Summary of CEE/MPA Study Conclusions of the WHI Writing Group 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 In summary, results from the WHI’s clinical trial on the use of HT indicate that CEE mg/d plus MPA 2.5 mg/d should not be initiated or continued for the primary prevention of CHD. When HT use is considered, its risks for cardiovascular disease and breast cancer must be weighed against its benefit in reducing the risk of fracture and colon cancer. Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288: Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:

Summary of CEE-Alone Study
Women's Health Initiative Summary of CEE-Alone Study Conclusions of the WHI Writing Group 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 The WHI investigators concluded that, in women aged 50 to 79 years with prior hysterectomy, use of CEE alone did not affect CHD rates but did increase the risk of stroke. The investigators noted that the lower rate of breast cancer observed in the CEE group (compared with placebo) was unexpected and did not reach statistical significance. Taking into consideration the totality of monitored outcomes, the results of the CEE-alone trial suggest an overall balance of risks and benefits, and no effect on total mortality, with an average of 6.8 years of CEE use. Based on these findings, the investigators conclude that the findings demonstrate no overall benefit of CEE alone for chronic disease prevention in postmenopausal women. They add, however, that the findings do support the current US Food and Drug Administrations recommendations for the use of CEE alone for the treatment of menopausal symptoms at the smallest effective dose for the shortest possible time. Women's Health Initiative Steering Committee. JAMA. 2004;291: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

Interpretation of the Results from the WHI HT Trials
Women's Health Initiative 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 Several considerations should be taken into account in interpreting the WHI findings: The average age at initial screening of WHI was ~63 years old.1 The average age for nonhysterectomized women to initiate HT is 51 years.2 When the study was stopped in 2002, two-thirds of the participants were 68 years or older. 42% of the women in the CEE/MPA group and 38% of the women in the placebo group discontinued study medication at some time during the trial. The high rate of discontinuation in the CEE/MPA group and the crossover of women from placebo to CEE/MPA (10.7%) may have influenced the study results. Women’s 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. 1Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288: 2Taylor Nelson Sofres (TNS) Intersearch Corporation. Incidence and Persistency of Estrogen Replacement. May 17, 2000. Additional references: Newton KM, et al. J Womens Health. 1997;6: The Women's Health Initiative Study Group. Control Clin Trials. 1998;19: McKinlay SM, et al. Maturitas. 1992;14: Brett KM, Chong Y. Hormone Replacement Therapy: Knowledge and Use in the United States. Hyattsville, Md: National Center for Health Statistics; 2001:1-29.

Interpretation of the Results from the WHI HT Trials
Women's Health Initiative Interpretation of the Results from the WHI HT Trials Other Considerations 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 Additional considerations: The WHI trial used only one dose regimen for HT (0.625 mg/d CEE, and 2.5 mg/d MPA). The findings do not necessarily generalize to lower doses of these drugs or other estrogens or progestins, alternate routes of administration, or regimens other than continuous therapy. Outcome information for the WHI is still being collected. When the CEE/MPA arm of the study was discontinued, women in the CEE/MPA group were instructed to discontinue study medication, but continue having yearly mammograms and WHI clinic exams.1 1National Institutes of Health. National Heart, Lung, and Blood Institute. WHI HRT Update—2002. Available at: health/women/upd2002.htm. Accessed June 22, 2002.

Interpretation of the CEE/MPA Results
Women's Health Initiative Interpretation of the CEE/MPA Results Treatment Discontinuation & Crossover 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% Several considerations should be taken into account in interpreting the WHI findings: 42% of the women in the E+P group and 38% of the women in the placebo group discontinued study medication at some time during the trial. 6.2% of the women in the E+P group and 10.7% of the women in the placebo group initiated hormone use through their own clinicians. The high rate of discontinuation in the E+P group and the crossover of women from placebo to HT may have influenced the study results.

Interpretation of the CEE/MPA Results
Women's Health Initiative Interpretation of the CEE/MPA Results Unblinding 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 Additional considerations: Clinic gynecologists for 3,444 (41%) of the 8,506 women in the CEE/MPA group were unblinded to treatment assignment (primarily to facilitate management of vaginal bleeding). The effect of this large difference in unblinding rates is unclear, and may have affected patient monitoring and diagnosis.

WHI: NIH Recommendations
Women's Health Initiative 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 In response to publication of the WHI results, the NIH’s NHLBI released recommendations for estrogen plus progestin use. In the document the authors did not specify the type of estrogen or progestin, but their comments were written in light of the WHI study of CEE/MPA. The NIH stressed that women should not be unduly alarmed by the WHI results, and the increased risk for an individual women is small. Key NIH recommendations are as follows: HT should not be continued or started to prevent heart disease. Women should consult their doctor about other methods of prevention, such as lifestyle changes, and cholesterol- and blood pressure-lowering drugs. For osteoporosis prevention, women should consult their doctor and weigh the benefits against their personal risks for heart attack, blood clots, and breast cancer. Alternate treatments also are available to prevent osteoporosis and fractures. 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. National Institutes of Health. National Heart, Lung, and Blood Institute. New Facts About: Estrogen/Progestin Hormone Therapy. July 9, Available at: Accessed July 15, 2002.

WHI: American College of Obstetrics and Gynecology (ACOG) Advisory
Women's Health Initiative 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 women’s 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 women’s 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 physician—taking into account a woman’s individual benefits and risks from such use In response to the WHI report, the American College of Obstetricians and Gynecologists (ACOG) issued a statement on the implications of the findings for clinicians and their patients. Points emphasized in the ACOG statement: The preliminary data reported from the WHI represent an increased breast cancer risk of less than 1% per year for an individual woman. The WHI did not focus on short-term risks and benefits of HT. It may be reasonable for women to continue short-term use of combined HT for relief of vasomotor symptoms, as the benefits from short-term therapy are likely to outweigh the risks. ACOG continues to recommend that the decision to use HT should be a personal and individualized one. A woman’s individual benefits and risks should be addressed in consultation with a physician. American College of Obstetricians and Gynecologists. Statement on the Estrogen Plus Progestin Trial of the Women’s Health Initiative. July 9, Available at: press_releases/nr cfm. Accessed 7/15/02. American College of Obstetricians and Gynecologists. Statement on the Estrogen Plus Progestin Trial of the Women’s Health Initiative. July 9, Available at: Accessed July 15, 2002.

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