Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women (2024)

ContextDespite decades of accumulated observational evidence, the balance ofrisks and benefits for hormone use in healthy postmenopausal women remainsuncertain.

ObjectiveTo assess the major health benefits and risks of the most commonly usedcombined hormone preparation in the United States.

DesignEstrogen plus progestin component of the Women's Health Initiative,a randomized controlled primary prevention trial (planned duration, 8.5 years)in which 16608 postmenopausal women aged 50-79 years with an intact uterusat baseline were recruited by 40 US clinical centers in 1993-1998.

InterventionsParticipants received conjugated equine estrogens, 0.625 mg/d, plusmedroxyprogesterone acetate, 2.5 mg/d, in 1 tablet (n = 8506) or placebo (n= 8102).

Main Outcomes MeasuresThe primary outcome was coronary heart disease (CHD) (nonfatal myocardialinfarction and CHD death), with invasive breast cancer as the primary adverseoutcome. A global index summarizing the balance of risks and benefits includedthe 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer,colorectal cancer, hip fracture, and death due to other causes.

ResultsOn May 31, 2002, after a mean of 5.2 years of follow-up, the data andsafety monitoring board recommended stopping the trial of estrogen plus progestinvs placebo because the test statistic for invasive breast cancer exceededthe stopping boundary for this adverse effect and the global index statisticsupported risks exceeding benefits. This report includes data on the majorclinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85)with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63(0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases;hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes,0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for compositeoutcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterialand venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) forcombined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28)for the global index. Absolute excess risks per 10000 person-years attributableto estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 morePEs, and 8 more invasive breast cancers, while absolute risk reductions per10000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures.The absolute excess risk of events included in the global index was 19 per10000 person-years.

ConclusionsOverall health risks exceeded benefits from use of combined estrogenplus progestin for an average 5.2-year follow-up among healthy postmenopausalUS women. All-cause mortality was not affected during the trial. The risk-benefitprofile found in this trial is not consistent with the requirements for aviable intervention for primary prevention of chronic diseases, and the resultsindicate that this regimen should not be initiated or continued for primaryprevention of CHD.

The Women's Health Initiative (WHI) focuses on defining the risks andbenefits of strategies that could potentially reduce the incidence of heartdisease, breast and colorectal cancer, and fractures in postmenopausal women.Between 1993 and 1998, the WHI enrolled 161809 postmenopausal womenin the age range of 50 to 79 years into a set of clinical trials (trials oflow-fat dietary pattern, calcium and vitamin D supplementation, and 2 trialsof postmenopausal hormone use) and an observational study at 40 clinical centersin the United States.¹ This article reportsprincipal results for the trial of combined estrogen and progestin in womenwith a uterus. The trial was stopped early based on health risks that exceededhealth benefits over an average follow-up of 5.2 years. A parallel trial ofestrogen alone in women who have had a hysterectomy is being continued, andthe planned end of this trial is March 2005, by which time the average follow-upwill be about 8.5 years.

The WHI clinical trials were designed in 1991-1992 using the accumulatedevidence at that time. The primary outcome for the trial of estrogen plusprogestin was designated as coronary heart disease (CHD). Potential cardioprotectionwas based on generally supportive data on lipid levels in intermediate outcomeclinical trials, trials in nonhuman primates, and a large body of observationalstudies suggesting a 40% to 50% reduction in risk among users of either estrogenalone or, less frequently, combined estrogen and progestin.^2-5Hip fracture was designated as a secondary outcome, supported by observationaldata as well as clinical trials showing benefit for bone mineral density.^6,7 Invasive breast cancer was designatedas a primary adverse outcome based on observational data.^3,8Additional clinical outcomes chosen as secondary outcomes that may plausiblybe affected by hormone therapy include other cardiovascular diseases; endometrial,colorectal, and other cancers; and other fractures.^3,6,9

The effect of hormones on overall health was an important considerationin the design and conduct of the WHI clinical trial. In an attempt to summarizeimportant aspects of health benefits vs risks, a global index was definedas the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonaryembolism (PE), endometrial cancer, colorectal cancer, hip fracture, or deathdue to other causes. Compared with total mortality, which may be too insensitive,this index assigns additional weight to the 7 listed diseases. Proceduresfor monitoring the trial involved semiannual comparisons of the estrogen plusprogestin and placebo groups with respect to each of the elements of the globalindex and to the overall global index.

This report pertains primarily to estrogen plus progestin use amonghealthy postmenopausal women, since only 7.7% of participating women reportedhaving had prior cardiovascular disease. During the course of the WHI trial,the Heart and Estrogen/progestin Replacement Study (HERS) reported its principalresults.¹⁰ HERS was another blinded, randomizedcontrolled trial comparing the same regimen of estrogen plus progestin withplacebo among women with a uterus; however, in HERS, all 2763 participatingwomen had documented CHD prior to randomization. The HERS findings of no overalleffect on CHD but an apparent increased risk in the first year after randomizationseemed surprising given preceding observational studies of hormone use inwomen with CHD.³ Subsequent to HERS, some investigatorsreanalyzed their observational study data and were able to detect an earlyelevation in CHD risk among women with prior CHD^11-13but not in ostensibly healthy women,¹⁴ promptingspeculation that any early adverse effect of hormones on CHD incidence wasconfined to women who have experienced prior CHD events.

The WHI is the first randomized trial to directly address whether estrogenplus progestin has a favorable or unfavorable effect on CHD incidence andon overall risks and benefits in predominantly healthy women.

Detailed eligibility criteria and recruitment methods have been published.¹ Briefly, most women were recruited by population-baseddirect mailing campaigns to age-eligible women, in conjunction with mediaawareness programs. Eligibility was defined as age 50 to 79 years at initialscreening, postmenopausal, likelihood of residence in the area for 3 years,and provision of written informed consent. A woman was considered postmenopausalif she had experienced no vagin*l bleeding for 6 months (12 months for 50-to 54-year-olds), had had a hysterectomy, or had ever used postmenopausalhormones. Major exclusions were related to competing risks (any medical conditionlikely to be associated with a predicted survival of <3 years), safety(eg, prior breast cancer, other prior cancer within the last 10 years exceptnonmelanoma skin cancer, low hematocrit or platelet counts), and adherenceand retention concerns (eg, alcoholism, dementia).

A 3-month washout period was required before baseline evaluation ofwomen using postmenopausal hormones at initial screening. Women with an intactuterus at initial screening were eligible for the trial of combined postmenopausalhormones, while women with a prior hysterectomy were eligible for the trialof unopposed estrogen. This report is limited to the 16608 women withan intact uterus at baseline who were enrolled in the trial component of estrogenplus progestin vs placebo. The protocol and consent forms were approved bythe institutional review boards for all participating institutions (see Acknowledgment).

Combined estrogen and progestin was provided in 1 daily tablet containingconjugated equine estrogen (CEE), 0.625 mg, and medroxyprogesterone acetate(MPA), 2.5 mg (Prempro, Wyeth Ayerst, Philadelphia, Pa). A matching placebowas provided to the control group. Eligible women were randomly assigned toreceive estrogen plus progestin or placebo after eligibility was establishedand baseline assessments made (Figure 1).The randomization procedure was developed at the WHI Clinical CoordinatingCenter and implemented locally through a distributed study database, usinga randomized permuted block algorithm, stratified by clinical center siteand age group. All study medication bottles had a unique bottle number andbar code to allow for blinded dispensing.

Initially, the design allowed women with a uterus to be randomized toreceive unopposed estrogen, estrogen plus progestin, or placebo. After therelease of the Postmenopausal Estrogen/Progestin Intervention (PEPI) trialresults¹⁵ indicating that long-term adherenceto unopposed estrogen was not feasible in women with a uterus, the WHI protocolwas changed to randomize women with a uterus to only estrogen plus progestinor placebo in equal proportions. The 331 women previously randomized to unopposedestrogen were unblinded and reassigned to estrogen plus progestin. These womenare included in the estrogen plus progestin group in this report, resultingin 8506 participants in the estrogen plus progestin group vs 8102 in the placebogroup. Analysis of the data excluding the women randomized before this protocolchange did not affect the results. Considerable effort was made to maintainblinding of other participants and clinic staff. When required for safetyor symptom management, an unblinding officer provided the clinic gynecologist,who was not involved with study outcomes activities, with the treatment assignment.

Study participants were contacted by telephone 6 weeks after randomizationto assess symptoms and reinforce adherence. Follow-up for clinical eventsoccurred every 6 months, with annual in-clinic visits required. At each semiannualcontact, a standardized interview collected information on designated symptomsand safety concerns, and initial reports of outcome events were obtained usinga self-administered questionnaire. Adherence to study interventions was assessedby weighing of returned bottles. The study protocol required annual mammogramsand clinical breast examinations; study medications were withheld if safetyprocedures were not performed, but these participants continued to be followedup. Electrocardiograms were collected at baseline and at follow-up years 3and 6.

All data were collected on standardized study forms by certified staffaccording to documented study procedures. Study data were entered into a localclinical center database developed and maintained by the Clinical CoordinatingCenter and provided to each site in the form of a local area network connectedto the Clinical Coordinating Center through a wide area network. Data qualitywas ensured through standard data entry mechanisms, routine reporting anddatabase checks, random chart audits, and routine site visits.

During the trial, some flexibility of the dosages of both estrogen andprogestin was allowed to manage symptoms such as breast tenderness and vagin*lbleeding. vagin*l bleeding was managed according to an algorithm that accountedfor the time since randomization, severity of the bleeding, treatment assignment,and endometrial histology. Women who had a hysterectomy after randomizationfor indications other than cancer were switched to unopposed estrogen or thecorresponding placebo without unblinding. These women are included in theoriginal randomization group for analyses.

Permanent discontinuation of study medication was required by protocolfor women who developed breast cancer, endometrial pathologic state (hyperplasianot responsive to treatment, atypia, or cancer), deep vein thrombosis (DVT)or PE, malignant melanoma, meningioma, triglyceride level greater than 1000mg/dL (11.3 mmol/L), or prescription of estrogen, testosterone, or selectiveestrogen-receptor modulators by their personal physician. Medications weretemporarily discontinued in participants who had acute myocardial infarction(MI), stroke, fracture, or major injury involving hospitalization, surgeryinvolving use of anesthesia, any illness resulting in immobilization for morethan 1 week, or any other severe illness in which hormone use is temporarilyinappropriate.

Cardiovascular Disease Coronary heart disease was defined as acute MI requiring overnight hospitalization,silent MI determined from serial electrocardiograms (ECGs), or CHD death.The diagnosis of acute MI was established according to an algorithm adaptedfrom standardized criteria¹⁶ that includedcardiac pain, cardiac enzyme and troponin levels, and ECG readings. The primaryanalyses included both definite and probable MIs as defined by the algorithm.Myocardial infarction occurring during surgery and aborted MIs were included.An aborted MI was defined as chest pain and ECG evidence of acute MI at presentation,an intervention (eg, thrombolysis) followed by resolution of ECG changes,and all cardiac enzyme levels within normal ranges. Silent MI was diagnosedby comparing baseline and follow-up ECGs at 3 and 6 years after randomization.Coronary death was defined as death consistent with CHD as underlying causeplus 1 or more of the following: preterminal hospitalization with MI within28 days of death, previous angina or MI and no potentially lethal noncoronarydisease, death resulting from a procedure related to coronary artery disease,or death certificate consistent with CHD as the underlying cause. Stroke diagnosiswas based on rapid onset of a neurologic deficit lasting more than 24 hours,supported by imaging studies when available. Pulmonary embolism and DVT requiredclinical symptoms supported by relevant diagnostic studies.

Cancer Breast, colorectal, endometrial, and other cancers were confirmed bypathological reports when available. Current data indicate that at least 98%of breast, colorectal, and endometrial cancers and 92% of other cancers weredocumented with pathological reports.

Fractures Reports of hip, vertebral, and other osteoporotic fractures (includingall fractures except those of the ribs, chest/sternum, skull/face, fingers,toes, and cervical vertebrae) were routinely ascertained. All fracture outcomeswere verified by radiology reports. Study radiographs were not obtained toascertain subclinical vertebral fractures.

This report is based on outcomes adjudicated by clinical center physicianadjudicators, as used for trial-monitoring purposes. Clinical center physicianadjudicators were centrally trained and blinded to treatment assignment andparticipants' symptoms. Future communications will report results based oncentrally adjudicated outcomes and will include a broader range of outcomeswith more extensive explanatory analyses. Since this report is presented beforethe planned study closeout, outcome information is still being collected andadjudicated. Local adjudication is complete for approximately 96% of the designatedself-reported events. To date, agreement rates between local and central adjudicationare: MI, 84%; revascularization procedures, 97%; PE, 89%; DVT, 84%; stroke,94%; invasive breast cancer, 98%; endometrial cancer, 96%; colorectal cancer,98%; hip fracture, 95%; and specific cause of death, 82%. When related cardiovascularconditions are combined (eg, when unstable angina or congestive heart failureis grouped with MI), agreement rates exceed 94% for cardiovascular diseaseand 90% for specific cause of death.

All primary analyses use time-to-event methods and are based on theintention-to-treat principle. For a given outcome, the time of event was definedas the number of days from randomization to the first postrandomization diagnosis,as determined by the local adjudicator. For silent MIs, the date of the follow-upECG applied. Participants without a diagnosis were censored for that eventat the time of last follow-up contact. Primary outcome comparisons are presentedas hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportionalhazards analyses,¹⁷ stratified by clinicalcenter, age, prior disease, and randomization status in the low-fat diet trial.

Two forms of CIs are presented, nominal and adjusted. Nominal 95% CIsdescribe the variability in the estimates that would arise from a simple trialfor a single outcome. Although traditional, these CIs do not account for themultiple statistical testing issues (across time and across outcome categories)that occurred in this trial, so the probability is greater than .05 that atleast 1 of these CIs will exclude unity under an overall null hypothesis.The adjusted 95% CIs presented herein use group sequential methods to correctfor multiple analyses over time. A Bonferroni correction for 7 outcomes asspecified in the monitoring plan (described herein) was applied to all clinicaloutcomes other than CHD and breast cancer, the designated primary and primaryadverse effect outcomes, and the global index. The adjusted CIs are closelyrelated to the monitoring procedures and, as such, represent a conservativeassessment of the evidence. This report focuses primarily on results usingthe unadjusted statistics and also relies on consistency across diagnosticcategories, supportive data from other studies, and biologic plausibilityfor interpretation of the findings.

Trial monitoring guidelines for early stopping considerations were basedon O'Brien-Fleming boundaries¹⁸ using asymmetricupper and lower boundaries: a 1-sided, .025-level upper boundary for benefitand 1-sided, .05-level lower boundaries for adverse effects. The adverse-effectboundaries were further adjusted with a Bonferroni correction for the 7 majoroutcomes other than breast cancer that were specifically monitored (CHD, stroke,PE, colorectal cancer, endometrial cancer, hip fracture, and death due toother causes). The global index of monitored outcomes played a supportiverole as a summary measure of the overall balance of risks and benefits. Trialmonitoring for early stopping considerations was conducted semiannually byan independent data and safety monitoring board (DSMB). Aspects of the monitoringplan have been published.¹⁹

Trial Monitoring and Early Stopping Formal monitoring began in the fall of 1997 with the expectation offinal analysis in 2005 after an average of approximately 8.5 years of follow-up.Late in 1999, with 5 interim analyses completed, the DSMB observed small butconsistent early adverse effects in cardiovascular outcomes and in the globalindex. None of the disease-specific boundaries had been crossed. In the springof 2000 and again in the spring of 2001, at the direction of the DSMB, hormonetrial participants were given information indicating that increases in MI,stroke, and PE/DVT had been observed and that the trial continued becausethe balance of risks and benefits remained uncertain.

In reviewing the data for the 10th interim analyses on May 31, 2002,the DSMB found that the adverse effects in cardiovascular diseases persisted,although these results were still within the monitoring boundaries. However,the design-specified weighted log-rank test statistic for breast cancer (z = −3.19) crossed the designated boundary (z = −2.32) and the global index was supportive ofa finding of overall harm (z = −1.62). Updatedanalyses including 2 months of additional data, available by the time of themeeting, did not appreciably change the overall results. On the basis of thesedata, the DSMB concluded that the evidence for breast cancer harm, along withevidence for some increase in CHD, stroke, and PE, outweighed the evidenceof benefit for fractures and possible benefit for colon cancer over the average5.2-year follow-up period. Therefore, the DSMB recommended early stoppingof the estrogen plus progestin component of the trial. Because the balanceof risks and benefits in the unopposed-estrogen component remains uncertain,the DSMB recommended continuation of that component of the WHI. Individualtrial participants have been informed.

There were no substantive differences between study groups at baseline;8506 women were randomized into the estrogen plus progestin group and 8102into the placebo group (Table 1a).The mean (SD) age was 63.3 (7.1) years. Two thirds of the women who reportedprior or current hormone use had taken combined hormones and one third hadused unopposed estrogen.

Prevalence of prior cardiovascular disease was low and levels of cardiovascularrisk factors were consistent with a generally healthy population of postmenopausalwomen. An assessment of commonly studied breast cancer risk factors, bothindividually and combined using the Gail model,²⁰indicate that the cohort in general was not at increased risk of breast cancer.

Vital status is known for 16025 randomized participants (96.5%),including 449 (2.7%) known to be deceased. A total of 583 (3.5%) participantswere lost to follow-up or stopped providing outcomes information for morethan 18 months. The remaining 15576 (93.8%) provided recent outcomeinformation (Figure 1).

At the time of this report, all women had been enrolled for at least3.5 years, with an average follow-up of 5.2 years and a maximum of 8.5 years.A substantial number of women had stopped taking study drugs at some time(42% of estrogen plus progestin and 38% of placebo). Dropout rates over time(Figure 2) exceeded design projections,particularly early on, but compare favorably with community-based adherenceto postmenopausal hormones.²¹ Some women inboth groups initiated hormone use through their own clinician (6.2% in theestrogen plus progestin group and 10.7% in the placebo group cumulativelyby the sixth year). These "drop-in" rates were also greater than expected.

At the time of this report, clinic gynecologists had been unblindedto treatment assignment for 3444 women in the estrogen plus progestin groupand 548 women in the placebo group, primarily to manage persistent vagin*lbleeding. During the trial, 248 women in the estrogen plus progestin groupand 183 in the placebo group had a hysterectomy.

Blood lipid levels, assessed in an 8.6% subsample of fasting blood specimenscollected from women at baseline and year 1, showed greater reductions inlow-density lipoprotein cholesterol (−12.7%) and increases in high-densitylipoprotein cholesterol (7.3%) and triglycerides (6.9%) with estrogen plusprogestin relative to placebo (data not shown), consistent with HERS and PEPI.^10,22 Systolic blood pressure was, on average,1.0 mm Hg higher in women taking estrogen plus progestin at 1 year, risingto 1.5 mm Hg at 2 years and beyond (data not shown). Diastolic blood pressuresdid not differ.

Cardiovascular Disease Overall CHD rates were low (Table2). The rate of women experiencing CHD events was increased by 29%for women taking estrogen plus progestin relative to placebo (37 vs 30 per10000 person-years), reaching nominal statistical significance (at the.05 level). Most of the excess was in nonfatal MI. No significant differenceswere observed in CHD deaths or revascularization procedures (coronary arterybypass grafting or percutaneous transluminal coronary angioplasty). Strokerates were also higher in women receiving estrogen plus progestin (41% increase;29 vs 21 per 10000 person-years), with most of the elevation occurringin nonfatal events. Women in the estrogen plus progestin group had 2-foldgreater rates of venous thromboembolism (VTE), as well as DVT and PE individually,with almost all associated CIs excluding 1. Rates of VTE were 34 and 16 per10000 person-years in the estrogen plus progestin and placebo groups,respectively. Total cardiovascular disease, including other events requiringhospitalization, was increased by 22% in the estrogen plus progestin group.

Cancer The invasive breast cancer rates in the placebo group were consistentwith design expectations. The 26% increase (38 vs 30 per 10000 person-years)observed in the estrogen plus progestin group almost reached nominal statisticalsignificance and, as noted herein, the weighted test statistic used for monitoringwas highly significant. No significant difference was observed for in situbreast cancers. Follow-up rates for mammography were comparable in the estrogenplus progestin and placebo groups. Colorectal cancer rates were reduced by37% (10 vs 16 per 10000 person-years), also reaching nominal statisticalsignificance. Endometrial cancer incidence was not affected, nor was lungcancer incidence (54 vs 50; HR, 1.04; 95% CI, 0.71-1.53) or total cancer incidence.

Fractures This cohort experienced low hip fracture rates (10 per 10000 person-yearsin the estrogen plus progestin group vs 15 per 10000 person-years inthe placebo group). Estrogen plus progestin reduced the observed hip and clinicalvertebral fracture rates by one third compared with placebo, both nominallysignificantly. The reductions in other osteoporotic fractures (23%) and totalfractures (24%) were statistically significant (all associated CIs exclude1).

The global index showed a nominally significant 15% increase in theestrogen plus progestin group (170 vs 151 per 10000 person-years). Therewere no differences in mortality or cause of death between groups (Table 3).

The Kaplan Meier estimates of cumulative hazards (Figure 3) for CHD indicate that the difference between treatmentgroups began to develop soon after randomization. These curves provide littleevidence of convergence through 6 years of follow-up. The cumulative hazardsfor stroke begin to diverge between 1 and 2 years after randomization, andthis difference persists beyond the fifth year. For PE, the curves separatesoon after randomization and show continuing adverse effects throughout theobservation period. For breast cancer, the cumulative hazard functions arecomparable through the first 4 years, at which point the curve for estrogenplus progestin begins to rise more rapidly than that for placebo. Curves forcolorectal cancer show benefit beginning at 3 years, and curves for hip fractureshow increasing cumulative benefit over time. The difference in hazard ratesfor the global index (Figure 4)suggests a gradual increase in adverse effects compared with benefits forestrogen plus progestin through year 5, with a possible narrowing of the differenceby year 6; however, HR estimates tend to be unstable beyond 6 years afterrandomization. Total mortality rates are indistinguishable between estrogenplus progestin and placebo.

Tests for linear trends with time since randomization, based on a Coxproportional hazards model with a time-dependent covariate, detected no trendwith time for CHD, stroke, colorectal cancer, hip fracture, total mortality,or the global index (Table 4).There was some evidence for an increasing risk of breast cancer over timewith estrogen plus progestin (z = 2.56 compared witha nominal z score for statistical significance of1.96) and a decreasing risk of VTE with time (z = −2.45).These results must be viewed cautiously because the number of events in eachinterval is modest, the data in later years are still incomplete, and lateryear comparisons are limited to women still at risk of their first event forthat outcome.

Cardiovascular Disease A small subset of women (n = 400; average follow-up, 57.4 months) inWHI reported conditions at baseline that would have made them eligible forHERS, ie, prior MI or revascularization procedures. Among these women withestablished coronary disease, the HR for subsequent CHD for estrogen plusprogestin relative to placebo was 1.28 (95% CI, 0.64-2.56) with 19 vs 16 events.The remaining women, those without prior CHD, had an identical HR for CHD(145 vs 106; HR, 1.28; 95% CI, 1.00-1.65). Few women with a history of VTEwere enrolled, but these data suggest a possibility that these women may beat greater risk of future VTE events when taking estrogen plus progestin (7vs 1; HR, 4.90; 95% CI, 0.58-41.06) than those without a history of VTE (144vs 66; HR, 2.06; 95% CI, 1.54-2.76). For stroke, prior history did not conferadditional risk (1 vs 5 in women with prior stroke; HR, 0.46; 95% CI, 0.05-4.51;126 vs 80 with no prior stroke; HR, 1.47; 95% CI, 1.11-1.95). No noteworthyinteractions with age, race/ethnicity, body mass index, prior hormone use,smoking status, blood pressure, diabetes, aspirin use, or statin use werefound for the effect of estrogen plus progestin on CHD, stroke, or VTE.

Breast Cancer Women reporting prior postmenopausal hormone use had higher HRs forbreast cancer associated with estrogen plus progestin use than those who neverused postmenopausal hormones (among never users, 114 vs 102; HR, 1.06; 95%CI, 0.81-1.38; for women with <5 years of prior use, 32 vs 15; HR, 2.13;95% CI, 1.15-3.94; for women with 5-10 years of prior use, 11 vs 2; HR, 4.61;95% CI, 1.01-21.02; and for women with ≥10 years of prior use, 9 vs 5;HR, 1.81; 95% CI, 0.60-5.43; test for trend, z =2.17). No interactions between estrogen plus progestin and age, race/ethnicity,family history, parity, age at first birth, body mass index, or Gail-modelrisk score were observed for invasive breast cancer.

Because a number of women stopped study medications during follow-up,several analyses were performed to examine the sensitivity of the principalHR estimates to actual use of study medications. Analyses that censored awoman's event history 6 months after becoming nonadherent (using <80% ofor stopping study drugs) produced the largest changes to estimated effectsizes. This approach increased HRs to 1.51 for CHD, to 1.49 for breast cancer,to 1.67 for stroke, and to 3.29 for VTE. Analyses attributing events to actualhormone use ("as treated," allowing for a 6-month lag) produced more modestchanges to these estimates. Analyses excluding women randomized during theperiod when the unopposed-estrogen component was open to women with a uterusand analyses stratifying by enrollment period did not substantially affectthe results. These analyses suggest that the intention-to-treat estimatesof HRs may somewhat underestimate the effect sizes relative to what wouldbe observed with full adherence to study medications.

The WHI provides evidence from a large randomized trial that addressesthe important issue of whether most women with an intact uterus in the decadesof life following menopause should consider hormone therapy to prevent chronicdisease. The WHI enrolled a cohort of mostly healthy, ethnically diverse women,spanning a large age range (50-79 years at baseline). It is noteworthy thatthe increased risks for cardiovascular disease and invasive breast cancerwere present across racial/ethnic and age strata and were not influenced bythe antecedent risk status or prior disease. Hence, the results are likelyto be generally applicable to healthy women in this age range. At the timethe trial was stopped, the increases in numbers of invasive breast cancers,CHD, stroke, and PE made approximately equal contributions to harm in theestrogen plus progestin group compared with placebo, which were not counterbalancedby the smaller reductions in numbers of hip fractures and colorectal cancers.

Even though the trial was stopped early for harm from breast cancer,a sufficient number of CHD events had occurred by 5.2 years of average follow-upto suggest that continuation to the planned end would have been unlikely toyield a favorable result for the primary outcome of CHD. Even if there werea reversal of direction toward benefit of a magnitude seen in the observationalstudies (ie, a risk reduction of 55%) during the remaining years, conditionalpower analyses indicate that less than 10% power remained for showing potentialbenefit if the trial continued.

The WHI finding that estrogen plus progestin does not confer benefitfor preventing CHD among women with a uterus concurs with HERS findings amongwomen with clinically apparent CHD,¹⁰ withthe Estrogen Replacement for Atherosclerosis trial, in which estrogen plusprogestin did not inhibit progression,²³ andwith a trial in women with unstable angina that did not observe a reductionin ischemic events.²⁴ The finding of an increasedrisk after initiation of treatment in WHI is similar to HERS. In HERS, after4.1 and 6.8 years of follow-up, hormone therapy did not increase or decreaserisk of cardiovascular events in women with CHD.²⁵The WHI extends these findings to include a wider range of women, includingyounger women and those without clinically apparent CHD, and indicates thatthe risk may persist for some years.

Unlike CHD, the excess risk of stroke in the estrogen plus progestingroup was not present in the first year but appeared during the second yearand persisted through the fifth year. Preliminary analyses indicate that themodest difference in blood pressure between groups does not contribute muchto an explanation of the increase in strokes (data not shown). The findingsin WHI for stroke are consistent with but somewhat more extreme than thoseof HERS, which reported a nonsignificant 23% increase in the treatment group.²⁶ The results were also more extreme than those ofthe Women's Estrogen and Stroke Trial of estradiol (without progestin) inwomen with prior stroke, which found no effect of estrogen on recurrent strokesoverall but some increase in the first 6 months.²⁷Trials of the effect of estradiol on carotid intima-media thickness have yieldedconflicting results.^28,29 At least1 observational study has suggested that that use of estrogen plus progestinis associated with higher risk of stroke than estrogen alone.¹⁴In WHI, there was no indication that excess strokes due to estrogen plus progestinwere more likely to occur in older women, in women with prior stroke history,by race/ethnicity, or in women with high blood pressure at baseline. Therefore,it appears that estrogen plus progestin increases the risk of strokes in apparentlyhealthy women.

Venous thromboembolism is an expected complication of postmenopausalhormones, and the pattern over time in WHI is consistent with the findingsfrom HERS and several observational studies.^30,31

The WHI is the first randomized controlled trial to confirm that combinedestrogen plus progestin does increase the risk of incident breast cancer andto quantify the degree of risk. The WHI could not address the risk of deathdue to breast cancer because with the relatively short follow-up time, fewwomen in the WHI have thus far died as a result of breast cancer (3 in theactive treatment group and 2 in the placebo group). The risk of breast canceremerged several years after randomization. After an average follow-up of about5 years, the adverse effect on breast cancer had crossed the monitoring boundary.The 26% excess of breast cancer is consistent with estimates from pooled epidemiologicaldata, which reported a 15% increase for estrogen plus progestin use for lessthan 5 years and a 53% increase for use for more than 5 years.³²It is also consistent with the (nonsignificant) 27% increase found after 6.8years of follow-up in HERS.³³

With more common use of estrogen plus progestin, several epidemiologicalstudies have reported that estrogen plus progestin appears to be associatedwith greater risk of breast cancer than estrogen alone.^34-37In the PEPI trial, women in the 3 estrogen plus progestin groups had muchgreater increases in mammographic density (a predictor of breast cancer) thanwomen in the estrogen or placebo groups.³⁸In WHI, the HR for estrogen plus progestin was not higher in women with afamily history or other risk factors for breast cancer, except for reportedprior use of postmenopausal hormones. This may suggest a cumulative effectof years of exposure to postmenopausal hormones.

Endometrial cancer rates were low and were not increased by 5 yearsof estrogen plus progestin exposure. Close monitoring for bleeding and treatmentof hyperplasia may contribute to the absence of increased risk of endometrialcancer.

The reduction in colorectal cancer in the hormone group is consistentwith observational studies, which have suggested fairly consistently thatusers of postmenopausal hormones may be at lower risk of colorectal cancer.³⁹ The mechanisms by which hormone use might reducerisk are unclear. Results from other trials of postmenopausal hormones willhelp resolve the effects of hormones on colorectal cancer.⁴⁰

The reductions in clinical vertebral fractures, other osteoporotic fractures,and combined fractures supported the benefit for hip fractures found in thistrial. These findings are consistent with the observational data and limiteddata from clinical trials⁴¹ and are also consistentwith the known ability of estrogen (with or without progestin) to maintainbone mineral density.⁴² The WHI is the firsttrial with definitive data supporting the ability of postmenopausal hormonesto prevent fractures at the hip, vertebrae, and other sites.

At the end of the trial, the global index indicated that there weremore harmful than beneficial outcomes in the estrogen plus progestin groupvs the placebo group. The monitored outcomes included in the global indexwere selected to represent diseases of serious import that estrogen plus progestintreatment might affect, and do not include a variety of other conditions andmeasures that may be affected in unfavorable or favorable ways (eg, gallbladderdisease, diabetes, quality of life, and cognitive function). The data on theseand other outcomes will be the subject of future publications. All-cause mortalitywas balanced between the groups; however, longer follow-up may be needed toassess the impact of the incident diseases on total mortality.

The absolute excess risk (or risk reduction) attributable to estrogenplus progestin was low. Over 1 year, 10000 women taking estrogen plusprogestin compared with placebo might experience 7 more CHD events, 8 morestrokes, 8 more PEs, 8 more invasive breast cancers, 6 fewer colorectal cancers,and 5 fewer hip fractures. Combining all the monitored outcomes, women takingestrogen plus progestin might expect 19 more events per year per 10000women than women taking placebo. Over a longer period, more typical of theduration of treatment that would be needed to prevent chronic disease, theabsolute numbers of excess outcomes would increase proportionately.

During the 5.2 years of this trial, the number of women experiencinga global index event was about 100 more per 10000 women taking estrogenplus progestin than taking placebo. If the current findings can be extrapolatedto an even longer treatment duration, the absolute risks and benefits associatedwith estrogen plus progestin for each of these conditions could be substantialand on a population basis could account for tens of thousands of conditionscaused, or prevented, by hormone use.

This trial tested only 1 drug regimen, CEE, 0.625 mg/d, plus MPA, 2.5mg/d, in postmenopausal women with an intact uterus. The results do not necessarilyapply to lower dosages of these drugs, to other formulations of oral estrogensand progestins, or to estrogens and progestins administered through the transdermalroute. It remains possible that transdermal estradiol with progesterone, whichmore closely mimics the normal physiology and metabolism of endogenous sexhormones, may provide a different risk-benefit profile. The WHI findings forCHD and VTE are supported by findings from HERS, but there is no other evidencefrom clinical trials for breast cancer and colorectal cancer, and only limiteddata from trials concerning fractures.

Importantly, this trial could not distinguish the effects of estrogenfrom those of progestin. The effects of progestin may be important for breastcancer and atherosclerotic diseases, including CHD and stroke. Per protocol,in a separate and adequately powered trial, WHI is testing the hypothesisof whether oral estrogen will prevent CHD in 10739 women who have hada hysterectomy. The monitoring of this trial is similar to that for the trialof estrogen plus progestin. At an average follow-up of 5.2 years, the DSMBhas recommended that this trial continue because the balance of overall risksand benefits remains uncertain. These results are expected to be availablein 2005, at the planned termination.

The relatively high rates of discontinuation in the active treatmentarm (42%) and crossover to active treatment in the placebo arm (10.7%) area limitation of the study; however, the lack of adherence would tend to decreasethe observed treatment effects. Thus, the results presented here may underestimatethe magnitude of both adverse effects on cardiovascular disease and breastcancer and the beneficial effects on fractures and colorectal cancer amongwomen who adhere to treatment.

The fact that the trial was stopped early decreases the precision ofestimates of long-term treatment effects. A longer intervention period mighthave shown more pronounced benefit for fractures and might have yielded amore precise test of the hypothesis that treatment reduces colorectal cancer.Nonetheless, it appears unlikely that benefit for CHD would have emerged bycontinuing the trial to its planned termination. The trial results indicatethat treatment for up to 5.2 years is not beneficial overall and that thereis early harm for CHD, continuing harm for stroke and VTE, and increasingharm for breast cancer with increasing duration of treatment. This risk-benefitprofile is not consistent with the requirements for a viable interventionfor the primary prevention of chronic diseases.

The WHI trial results provide the first definitive data on which tobase treatment recommendations for healthy postmenopausal women with an intactuterus. This trial did not address the short-term risks and benefits of hormonesgiven for the treatment of menopausal symptoms. On the basis of HERS and othersecondary prevention trials, the American Heart Association recommended againstinitiating postmenopausal hormones for the secondary prevention of cardiovasculardisease.⁴³ The American Heart Association madeno firm recommendation for primary prevention while awaiting the results fromrandomized clinical trials such as WHI, and stated that continuation of thetreatment should be considered on the basis of established noncoronary benefitsand risks, possible coronary benefits and risks, and patient preference.

Results from WHI indicate that the combined postmenopausal hormonesCEE, 0.625 mg/d, plus MPA, 2.5 mg/d, should not be initiated or continuedfor the primary prevention of CHD. In addition, the substantial risks forcardiovascular disease and breast cancer must be weighed against the benefitfor fracture in selecting from the available agents to prevent osteoporosis.