Methods

Stated purpose: to determine the effect of oestrogen therapy on recurrence rate and survival in women who have undergone surgery for stage I or II endometrial cancer
Stratification: stratified by stage
No, of women screened for eligibility: unclear
No. randomised: 1236 (see Notes)
No. analysed: 1236
Losses to follow‐up: none stated
Adherence to treatment: 41% in HT group, 50% in placebo group at trial end
Analysis by intention to treat: yes
No. of centres: not stated
Years of recruitment: June 1997 to January 2003
Design: parallel
Funding: National Cancer Institute grant

Participants

Included
Women post total hysterectomy and bilateral salpingo‐oophorectomy (at least) for surgically staged stage I or II endometrial cancer within 20 weeks of study entry, with indication for use of oestrogen therapy including hot flushes, vaginal atrophy, increased risk of CHD or increased risk of osteoporosis. Had to have undergone clinical exam with history, pelvic exam and chest X‐ray before study entry. Normal hepatic function and normal mammogram or negative breast biopsy within previous year
Excluded
Women with history or suspicion of breast cancer or other malignancy with exception of non‐melanoma skin cancer within past 5 years or with history of acute liver disease or thromboembolic disease
Median age: 57
Age range: 26‐91
Means of recruitment: not stated
Baseline equality of treatment groups: well balanced
Country: USA

Interventions

HT arm: 0.625 mg CEE (unopposed oestrogen)
Control arm: placebo
Duration: planned for 3 years with 2 years' additional follow‐up. Closed early with median follow‐up 35.7 months

Outcomes

Total deaths
CHD deaths
Coronary event deaths
Endometrial cancer deaths
Endometrial cancer (recurrence)

Notes

Enrolment decreased after WHI was published in July 2002. Study closed prematurely owing to poor accrual. In addition, preponderance of participants had low risk profile, so low event rate meant power unlikely to be reached with original power calculation. This study planned to enrol 2108 women.

Numbers randomised not entirely clear: Study refers to 1236 "eligible and assessable women".

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Remotely generated

Allocation concealment (selection bias)

Low risk

Remotely dispensed drugs

Incomplete outcome data (attrition bias)
All outcomes

High risk

No losses to follow‐up reported, but numbers randomised not entirely clear: Study refers to 1236 "eligible and assessable women".

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and physicians blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Review authors believe risk of bias low owing to 'hard' nature of outcomes

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No apparent source of other bias

Methods

2 × 2 double‐blinded placebo‐controlled parallel‐group RCT

Stated purpose: to assess the effect of HT on progression of subclinical atherosclerosis and cognitive effects initiated between early and late postmenopause

Stratification: not stated

No. of women screened for eligibility: 3061 (n = 2166 via telephone, n = 895 in person)

No. of women randomised: 643 (323 to HT, 320 to placebo; subgrouped by time since menopause with respect to initiation of HT)

No. of women analysed: 567 underwent cognitive baseline assessment, total of 567 women provided cognitive outcomes at 2.5 years and 455 women provided outcomes at 5 years.

Losses to f/u: 2.2% of women were lost to follow‐up, and another 10.0% discontinued participation before cognitive outcomes were assessed (14 lost to follow‐up, 22 dropouts due to adverse events, 40 discontinued for other reasons before contributing to cognitive outcomes at 2.5 years).

Adherence to treatment: Mean adherence for oestradiol or placebo was ≥ 98% for early and late group women.

Analysis by intention to treat: yes

No. of centres: 1

Years of recruitment: July 2005 and September 2008

Design: parallel

Funding: supported by National Institutes of Health grant for initial and supplemental funding of ELITE and ELITE‐Cog. Study drugs and placebo were supplied without charge or restriction by Teva Pharmaceuticals, Watson Pharmaceuticals and Abbott Laboratories.

Participants

643 healthy postmenopausal women with clinical evidence of CVD or diabetes, subgrouped by time since menopause (< 6 years since menopause (n = 271) or > 10 years since menopause (n = 372))

Included

Women with a serum oestradiol level < 25 picogram/mL and cessation of regular menses > 6 months who are < 6 years and > 10 years postmenopausal

Excluded

Clinical signs, symptoms or personal history of cardiovascular disease, indeterminate time since menopause, DM or fasting serum glucose ≥ 140 mg/dL, uncontrolled hypertension (diastolic blood pressure ≥ 110 mmHg), untreated thyroid disease, serum creatinine > 2.0 mg/dL, plasma triglyceride levels > 500 mg/dL, life‐threatening disease with prognosis < 5 years, cirrhosis or liver disease, hx of deep vein thrombosis or pulmonary embolism, history of breast cancer, current HT

Median age: 53.4 years for early, 63.6 years for late

Age range: 41‐84

Means of recruitment: telephone and in person

Baseline equality of treatment group: no statistically significant difference in baseline characteristics. Women not contributing to analysis were similar to other women in most but not all comparisons.

Country: USA

Interventions

1. Oral 17β‐oestradiol 1 mg daily with (uterine intact) or without (hysterectomy) vaginal micronised progesterone gel 4% (45 mg) 10 days per month: Study publication does not state how many women were in each group.

2. Placebo

Originally planned for 5 years, extended to 7.5 years

Outcomes

Primary study outcome

Progression of subclinical atherosclerosis ‐ not relevant for current review

Secondary outcomes

Cognitive function at 2.5 and 5 years, cardiovascular events (fatal or nonfatal MI, silent MI, sudden death), stroke, venous thromboembolism (DVT or PE), cancer (breast, uterine, ovarian, gastrointestinal, lung), bone fracture, all‐cause mortality, non‐coronary mortality

Notes

Power calculation: 506 sample size provides power of 80% needed to detect difference in rate of change in carotid artery intima media thickness and effect size of 0.22 in early and late groups combined.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation sequence generated by computer by study statistician

Allocation concealment (selection bias)

Low risk

"Stratified randomization list [was] used to prepare the study products. After determining a participant’s eligibility, clinic staff pulled the next study product in sequence from the appropriate stratum, recorded the product identification number, and dispensed the product".

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

567/643 women (88%) analysed for cognitive outcomes at 2.5 years, 455/643 (71%) at 5 years

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Investigators, participants, clinic staff and data monitors were blinded.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Not stated whether outcome assessor blinded, but most probably, as study author mentioned trial was extended before blinding was unmasked after receiving supplementary funding

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No other potential source of bias identified

Methods

Stated purpose: to determine the effect of oestrogen‐alone HT on progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting cardiovascular disease, as measured by changes in thickness of carotid artery wall
Stratification: by low‐density lipoprotein cholesterol level (threshold < 4.15 mmol/L), previous duration of HT (threshold < 5 years) and diabetes mellitus status
Blinding: participants, gynaecologists, clinical staff and image analysts. The data monitor and the data analyst were blinded to treatment assignment until analyses were completed.
No. of women screened for eligibility: 1161 prescreened by phone, 422 screened on site, of whom 52% randomised
No. randomised: 222
No. analysed: 222 for clinical outcomes

Losses to follow‐up: 33 women were not evaluable for primary study endpoints, but clinical endpoints were reported for all.
Adherence to treatment in evaluable women: During the trial, mean pill adherence was 95% in the oestradiol group and 92% in the placebo group (P = 0.08).
Analysis by intention to treat: yes
No. of centres: 1
Years of recruitment: 1994‐1998
Design: parallel
Funding: National Institute on Aging

Participants

Included
Postmenopausal women aged > 45 years, no preexisting cardiovascular disease, low‐density lipoprotein levels > 3.37 mmol/L
Excluded

Women with previous breast or gynaecological cancer, frequent hot flushes, diastolic blood pressure > 110, uncontrolled diabetes or thyroid disease, abnormal bloods, smokers
Mean age: 61.15
Age range: 51.4‐69.2
Means of recruitment: not stated
Baseline equality of treatment groups: no significant differences in demographics or clinical variables
Country: USA

Interventions

HT arm: unopposed micronised 17B‐oestradiol 1 mg daily
Control arm: placebo
Duration: 2 years

Outcomes

Primary outcomes

Carotid artery wall thickness on ultrasound
Myocardial infarction

Cerebrovascular accident
Transient ischaemic attack
Deep vein thrombosis

Pulmonary embolism

Notes

Power calculation: sample size of 200 required to detect treatment effect size (difference in carotid artery wall thickness) of 0.40 or greater with 80% power

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random numbers

Allocation concealment (selection bias)

Low risk

Blinded medication packets assigned sequentially and remotely after eligibility confirmed

Incomplete outcome data (attrition bias)
All outcomes

Low risk

33 women were not able to be evaluated for primary (physiological) study endpoints, but clinical endpoints were reported for all by ITT analysis.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants, gynaecologists, clinical staff and image analysts. The data monitor and the data analyst were blinded to treatment assignment until analyses were completed.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Adverse clinical symptoms and bleeding were assessed by the study gynaecologist, who was blinded to treatment assignment".

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No apparent source of other bias

Methods

Stated purpose: to ascertain harms and benefits of combined HT among healthy postmenopausal Estonian women
Stratification: by centre
No. of women screened for eligibility: 39,713 (whole female population aged 50‐64 from 2 areas of Estonia)
No. randomised and consented: 777 for clinical outcomes (Veerus 2006 publication), 796 for quality of life (Veerus 2008 publication) (see Notes)
No. analysed: 777 for clinical outcomes (HT 404, placebo 373), 796 for quality of life (HT 415, placebo 381)
Losses to follow‐up: none stated
Adherence to treatment: < 40% in HT group and < 30% in placebo group by 3 years (estimated from graph)
Analysis by intention to treat: yes
No. of centres: 3
Years of recruitment: 1999‐2001
Design: parallel
Funding: academic and government grants

www.controlled‐trials.com/
ISRCTN35338757/35338757

Participants

Included
Postmenopausal women > 12 months since last period
Excluded
Women who had used hormone therapy during the past 6 months; with untreated endometrial adenomatosis or atypical hyperplasia of the endometrium; history of breast cancer, endometrial cancer or ovarian cancer; any other cancer treated less than 5 years ago; history of meningioma; myocardial infarction within the past 6 months; history of hepatitis or functional liver disorders in the past 3 months; history of deep vein thrombosis, pulmonary embolism or cerebral infarction; porphyria; hypertension greater than 170/110 mmHg despite medication; laparoscopically or histologically confirmed endometriosis
Mean age: 59
Age range: 50‐70
Means of recruitment: invitation sent to whole female population aged 50‐64 from 2 areas of Estonia
Baseline equality of treatment groups: more prior use of oral contraceptive in HT group ‐ 9.2% vs 6.4%; HT group older (59 vs 58.5)
Country: Estonia

Interventions

HT arm: combined oestrogen and progesterone as 1 daily tablet containing CEE 0.625 mg and medroxyprogesterone acetate 2.5 mg
Control arm: matching placebo
Duration: mean follow up 3.43 years (range 2‐5). Planned for 10‐year follow‐up but closed early

Outcomes

Death
CHD
Cancers
Fractures
CVD

Quality of life measured with EuroQol‐5D questionnaire at 3 years (also measured with Women's Health Questionnaire at 1 year), but no baseline measure, and results pooled for blinded and unblinded HT arms (data not reported in this review)

Notes

Women randomised before eligibility and consent checked ‐ envelopes opened only once these processes were completed. Additional 1001 women in unblinded trial arms

Designed as part of international WISDOM trial

Mean follow‐up only 3.43 years (range 2‐5) for clinical outcomes, 3.6 years for quality of life. Planned for 10‐year follow‐up but closed early

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Remotely randomised in permuted blocks

Allocation concealment (selection bias)

Low risk

Non‐transparent sealed envelopes

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No stated losses to follow‐up or drop‐outs, analysed by intention to treat. However, stated participation rates differ slightly across trial publications (796 vs 777).

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and investigators blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Assessed by entries in cancer registry ‐ review authors believe low risk of bias

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

Quality of life not measured (with EuroQol‐5D) at baseline ‐ possible baseline differences

Methods

Stated purpose: to evaluate effects of HT on progression of coronary atherosclerosis
Stratification: according to lipid lowering therapy at baseline and hospital where angiogram was performed
Blinding: participants, clinic staff and all outcome assessors blinded
Unblinding: treatment assignment available to designated member of data management staff. Questions related to adverse effects directed to gynaecology physician and nurse not connected with study
No. of women screened for eligibility: not stated
No. randomised: 309
No. analysed: 309 (for clinical events)
Losses to follow‐up: none (for clinical events)
Adherence to treatment in 248 participants evaluated was as follows: Unopposed oestrogen group took 74.5% of their prescribed medication, and combined HT group took 84%; placebo group took 85.8%. 5 women in the placebo group started to take HT.

Analysis by intention to treat: Although only 248 participants were available for the primary trial endpoint (which was biological), clinical adverse events, including outcomes of interest to this review, were reported for all participants at 3.2 years by intention to treat.
No. of centres: 6
Years of recruitment: January 1996‐December 1997
Design: parallel
Funding: grants from National Heart, Lung and Blood Institute and National Center for Research Resources General Clinical Research Center, study medications from Wyeth‐Ayerst Research

Participants

Included

Postmenopausal women aged 55‐80 years (non‐natural menses for at least 5 years, or for 1 year and FSH > 40 mu/mL or oophorectomy) with at least 1 stenosis > 30% in any single coronary artery confirmed by coronary angiography within 4 months of randomisation, baseline gynaecological examination normal
Excluded

Failure to achieve > 80% compliance during 4‐week placebo run‐in phase, breast or endometrial cancer, history of DVT or PE, symptomatic gallstones or elevated liver enzymes, fasting plasma triglycerides > 400 mg/dL, MI within 4 weeks, renal insufficiency, dye allergy, > 70% stenosis of coronary artery, uncontrolled hypertension, uncontrolled diabetes, planned or prior coronary artery bypass graft, revascularisation of only qualifying lesion (for study), inadequate baseline angiogram for study, other non‐CHD disease likely to be fatal or to prevent adequate follow‐up, participation in other intervention studies, plans to leave area within 3 years
Mean age: 66
Age range: 41.8‐79.9
Means of recruitment: media announcements, contact through hospital records and admissions, screening logs from other studies
Baseline equality of treatment groups
Country: USA
Follow‐up: 3 months, 6 months, then 6‐monthly clinic visits; annual smear and mammography, annual endometrial aspiration

Interventions

HT arm: 1 of the following
1. 0.625 mg CEE (unopposed oestrogen)
2. 0.625 mg CEE plus 2.5 mg MPA (combined continuous therapy)
Control arm: placebo
Duration: 3.2 years mean

Outcomes

Primary outcome angiographic
MI
Stroke
Death
DVT
PE

Notes

Power calculation: 80% power for primary angiographic outcome

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computerised in random blocks

Allocation concealment (selection bias)

Low risk

Computer‐displayed treatment assignment after eligible participant details entered

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up for clinical adverse events. Analysed by intention to treat

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and clinicians blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessors blinded

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

More in unopposed oestrogen group using nitrates at baseline; otherwise prognostic balance between groups

Methods

Stated purpose: to ascertain whether unopposed oestrogen reduces the risk of further cardiac events in postmenopausal women who survive a first myocardial infarction
Stratification: by clinical centre
Blinding: participants, clinicians, outcome assessors. Pharmaceutical company dispensed medication/placebo in identical numbered packages.
Unblinding: on request of family doctor or if participant withdrew from treatment (in later stages of study, only if withdrawing participant had not had a hysterectomy). Outcome assessors remained blinded throughout.
No. of women screened for eligibility: 3121 met inclusion criteria for MI (reasons for non‐participation listed in study).
No. randomised: 1017
No. analysed: 1017
Drop‐outs: Drop‐outs included 43 women in the HT group (8%) and 57 in the placebo group (11%) who did not take any of the trial medication.
Losses to follow‐up: none
Known non‐adherence with allocated treatment was as follows: At 1 year, 51% of participants on the HT arm and 31% on the placebo arm were not taking their allocated tablets regularly. At 2 years, 57% of participants on the HT arm and 37% on the placebo arm were not taking their allocated tablets regularly.
Analysis by intention to treat: yes
No. of centres: 35
Years of recruitment: July 1996‐Feb 2000
Design: parallel
Funding: Schering AG provided medication.

Participants

Included

Postmenopausal women admitted to coronary care units or general medical wards at participating centres, who met diagnostic criteria for myocardial infarction, were discharged alive within 31 days of admission

Excluded

Women with previously documented MI who had used HT or had vaginal bleeding in the 12 months before admission, history of breast, ovarian or endometrial cancer, active thrombophlebitis, history of DVT or PE, liver disease, Rotor syndrome, Dubin‐Johnson syndrome or severe renal disease
Mean age: 62 years (SD 5)
Means of recruitment: Research nurses checked hospital case notes and approached potentially eligible women if their family doctor agreed to collaborate.
Baseline equality of treatment groups: yes
Countries: England and Wales

Interventions

HT arm: unopposed oestradiol valerate 2 mg daily
Control arm: placebo
Duration: 2 years

Outcomes

Recurrent MI
Cardiac death
All‐cause death
Endometrial cancer
Breast cancer
Stroke
Thromboembolism

Notes

Power calculation: needed 1700 participants to give 80% power to detect 33.3% decrease in incidence of non‐fatal reinfarction or cardiac death (2‐sided P = 0.05)
Accrual lower than anticipated: Study closed with only 1017 participants, giving 56% power to detect above‐mentioned outcomes, assuming full compliance.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

List of random numbers generated by trial statistician in blocks of 4

Allocation concealment (selection bias)

Low risk

Women assigned consecutively to numbers kept on list accessible to statistician only

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up; analysed by intention to treat

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and clinicians blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessors blinded

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No apparent source of other bias

Methods

Stated purpose: to determine if HT alters risk of venous thromboembolism in high‐risk women
Randomisation method: computer‐generated 1:1 block randomisation with fixed block sizes of 10
Allocation method: not described
Stratification: by age < 60 years or ≥ 60 years; 37 (23 HT and 14 placebo) women did not attend all visits owing to premature termination of the study
Blinding: double‐blind
No. of women screened for eligibility: 328
No. randomised: 140 (71 HT, 69 placebo)
No. analysed: 140
Losses to follow‐up: nil, although 37 (23 HT and 14 placebo) women did not attend all visits owing to premature termination of the study
Adherence to treatment: 33 dropouts: 10 in HT group (2 wanted to be sure of being treated with oestrogen for postmenopausal symptoms, 8 had adverse effects), 23 in the placebo group (11 wanted to be sure of being treated with oestrogen for postmenopausal symptoms, 10 had adverse effects, 2 no reason stated)
Analysis by intention to treat: Main findings were not reported by intention to treat because dropouts from the placebo group were not included in the denominator for the rate of recurrent thromboembolism. We included all randomised participants in analysis for this review.
No. of centres: not stated
Years of recruitment: February 1996‐March 1999
Design: stratified double triangular sequential design
Funding: Novo‐Nordisk Pharmaceutical and research forum Ulleval University Hospital

Participants

Included

Postmenopausal women with history of VTE, aged < 70 years, previous VTE verified by objective means (i.e. venography or ultrasonography in cases of DVT; lung scan, helical computed tomography or angiography in cases of PE)
Excluded

Current use or use of anticoagulants within past 3 months, familial antithrombin deficiency, any type of malignant disease including known, suspected or past history of carcinoma of the breast; acute or chronic liver disease or history of liver disease in which liver function tests had failed to return to normal; porphyria; known drug abuse or alcoholism; life expectancy less than 2 years; women who had taken part in other clinical trials within 12 weeks before study entry
Mean age: 55.8 years
Age range: 42‐69 years
Means of recruitment: letters to family doctors, gynaecologists and hospitals, health bulletins and media
Baseline equality of treatment groups: Baseline characteristics were similar for HT group and placebo group with regard to previous disease (coronary heart disease, hypertension, stroke, diabetes), smoking habits and serum lipids. All women had previously suffered at least 1 VTE, and the total number of previous VTEs was 75 in the placebo group and 77 in the HT group.
Country: Norway

Interventions

HT arm: 2 mg oestradiol plus 1 mg norethisterone acetate 1 mg
Control arm: placebo
Duration: planned 2 years, stopped prematurely at median 1.3 years' follow‐up

Outcomes

Venous thrombosis
Myocardial infarction

Transient ischaemic attacks
Stroke

Notes

Study was terminated early; only 140 women enrolled of 240 planned

Power calculation: At a significance level of 5% and a power of 90%, sample size was estimated to a maximum of 240 women .
After publication of results of the HERS study, which showed as a secondary endpoint increased risk of VTE, recruitment of women was discontinued in September 1998, until reviewed by the safety monitoring committee. The committee was also concerned about a non‐significant clustering of endpoints in 1 study group, without knowing treatment allocation. The committee advised on premature termination of the study, even though formal boundaries showing excess risk of VTE were not reached. The final decision on termination of the study was made in February 1999, and by the end of March 1999, all participants had completed a final follow‐up visit.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated 1:1 block randomisation with fixed block sizes of 10

Allocation concealment (selection bias)

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Main findings were not reported by intention to treat because drop‐outs from the placebo group were not included in the denominator for the rate of recurrent thromboembolism.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Blinded participants and personnel ‐ "equal‐looking" placebo

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Blinded outcome assessment

Selective reporting (reporting bias)

Low risk

Retrospectively registered protocol on trials register. Reports all expected outcomes

Other bias

Low risk

No apparent source of other bias

Methods

Stated purpose: to assess endometrial safety and bleeding patterns of 17B‐oestradiol sequentially combined with dydrogesterone
Stratification: not mentioned
Blinding: double‐blinded
No. of women screened for eligibility: 844
No. randomised: 595 (HT group 1: 117, HT group 2: 114, HT group 3: 117, HT group 4: 118, placebo group: 113 (see Interventions))
No. analysed: 442 (for endometrial cancer, which is the only outcome of interest for this review)
Losses to follow‐up: Endometrial status was evaluated by a biopsy, which was available only for women who remained on active treatment for over a year, or who received placebo and completed the 2‐year study. This resulted in 153 losses to follow‐up for this outcome (87 from active treatment groups (24%) and 50 from the placebo group (44%), plus another 16 who received no study medication).
Adherence to treatment: not reported
Analysis by intention to treat: no
No. of centres: multi‐centre (number not stated)
Years of recruitment: not stated
Design: parallel
Funding: Solvay Pharmaceutical

Participants

Included

Postmenopausal women with a uterus with amenorrhoea of at least 6 months or surgically postmenopausal (following bilateral oophorectomy without hysterectomy, more than 3 months before enrolment), FSH within normal postmenopausal range
Excluded

Abnormal (uninvestigated bleeding) vaginal bleeding, use of oestrogens and/or progestogens and/or androgens in the preceding 6 months or more, and any previous use of oestradiol pellet/implant therapy
Age range: 45‐65
Baseline equality of treatment groups: yes
Countries: Canada and Netherlands

Interventions

HT arm

1 mg/d 17B‐oestradiol/ 5 mg dydrogesterone for the last 14 days of each 28‐day cycle
1 mg/d 17B‐oestradiol/10 mg dydrogesterone for the last 14 days of each 28‐day cycle
2 mg/d 17B‐oestradiol/10 mg dydrogesterone for the last 14 days of each 28‐day cycle
2 mg/d 17B‐oestradiol/20 mg dydrogesterone for the last 14 days of each 28‐day cycle
Control arm: placebo
Duration: 26 cycles (104 weeks)

Outcomes

Endometrial cancer

Notes

Power calculation: not stated

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

High risk

Endometrial status was evaluated by a biopsy, which was available only for women who remained on active treatment for over a year, or who received placebo and completed the 2‐year study. This resulted in 153 losses to follow‐up (26%) for this outcome.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

States double‐blinded ‐ review authors believe risk of bias low owing to 'hard' nature of outcomes

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Review authors believe risk of bias low owing to 'hard' nature of outcomes

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No apparent source of other bias

Methods

Stated purpose: to determine effects of HT on clinical outcomes, including cognitive function, in elderly women
Stratification: no
Blinding: double‐blinded
Unblinding: not described
No. of women screened for eligibility: 573
No. randomised: 373 (187 to HT, 186 to placebo)
No. analysed: 373
Losses to follow‐up: 8 (6 in HT group, 2 in placebo group)
Adherence to treatment: 61% on HT, 67% on placebo
Analysis by intention to treat: yes
No of centres: 1
Years of recruitment: study conducted January 1996‐May 2001
Design: parallel
Funding: academic research funding. Pharmaceutical companies provided the drugs.

Participants

Included

Community‐dwelling women aged 65 years or older with (n = 243) or without (n = 130) a uterus, with complete medical history, physical examination and lab evaluation; tolerated HT in run‐in phase
Excluded

Women with any illnesses or taking medications that could affect bone mineral metabolism within past year, or with known contraindication to HT
Mean age: 71 years
Age range: 65‐90
Means of recruitment: advertisements, presentations, physical referrals
Baseline equality of treatment groups: yes
Country: USA; n = 373 healthy women, mean age 71.3 years, 243 with a uterus and 130 without a uterus

Interventions

Three‐month open run‐in phase on HT

1. CEE oral (0.625 mg/d) or CEE oral (0.625 mg/d) + medroxyprogesterone acetate (2.5 mg/d) in women with a uterus
2. Placebo

Outcomes

MMSE, breast cancer, DVT, clinical fractures, colon cancer (and other outcomes not relevant to this review)

Notes

Half of participants also took alendronate; all took calcium and vitamin D supplement and a multi‐vitamin.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomised lists "prepared by study statistician"

Allocation concealment (selection bias)

Low risk

Research pharmacist assigned treatment

Incomplete outcome data (attrition bias)
All outcomes

Low risk

All participants included in analysis; low losses to follow‐up (6/373)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Described as double‐blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Those who assessed the outcomes were blinded to treatment assignment... block sizes randomly determined to enhance blinding of study staff"

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

Possibly some potential for confounding from 3‐month run‐in phase on HT and concurrent use of alendronate

Methods

Stated purpose: to determine if combined HT alters risk for CHD events in postmenopausal women with established coronary disease
Stratification: by clinical centre
Blinding: participants, clinical centre staff, outcome assessors, data analysts, funders blinded
Unblinding: When required for safety or symptom control, participants reported directly to gynaecology staff, who were located separately from clinical staff, did not communicate with them about breast or gynaecological problems and were not involved in outcome ascertainment.
No. of women screened for eligibility: 3463, of whom 43% were excluded (ineligible, declined to participate, did not return for appointment or did not comply with placebo run‐in therapy)
No. randomised: 2763
No. analysed: 2763
Losses to follow‐up: vital status known for all women at end of trial. 59 women did not complete follow‐up (32 in experimental arm, 27 in placebo arm).
Adherence to treatment by women evaluated: by self‐report: at 1 year: 82% HT arm, 91% control arm; at 3 years: 75% HT arm, 81% control arm; by pill count in HT arm: at 1 year: 79%; at 3 years: 70% HT arm
Analysis by intention to treat: yes (also analysed by treatment received, with inclusion limited to women with > 80% compliance)
No. of centres: 20
Years of recruitment: February 1993‐September 1994
Design: parallel
Funding: pharmaceutical (Wyeth‐Ayerst)

UNBLINDED CONTINUATION OF HERS 1998:
N.B. Follow‐up continued unblinded, as an open‐label observational study
2321 women (93% of 2510 surviving HERS participants) followed up for a further 2.7 years ‐ originally planned for additional 4 years, but executive committee decided no further useful information likely to emerge
No. analysed: 2311 for vital status
Losses to follow‐up: 10 women (1%) not contacted at final follow‐up (2 in HT arm, 8 in control arm); of these, vital status known for 5
Adherence to treatment: Among women originally assigned to the HT group, 45% reported at least 80% compliance during the sixth year of follow‐up. Among women originally assigned to placebo, 8% reported taking HT at 6 years.

Participants

Included

Postmenopausal women younger than 80 years, with a uterus, with coronary disease (myocardial infarction, coronary artery bypass surgery, percutaneous coronary revascularisation or angiographic evidence of at least 50% narrowing of 1 or more major arteries, as documented by baseline ECG or hospital discharge summary), likely to be available for follow‐up for at least 4 years
Excluded

Women whose coronary event occurred within 6 months of randomisation, use of hormone therapy within 3 months of randomisation, serum triglycerides ≥ 300 mg/dL, history or baseline findings suggestive of venous thromboembolism, breast cancer, endometrial cancer, cervical cancer, uncontrolled hypertension, uncontrolled diabetes, severe congestive heart failure, other life‐threatening disease, alcoholism, drug abuse, history of intolerance of HT, any preexisting condition indicating unsuitability for long‐term HT or placebo therapy, > 80% compliance with placebo medication during run‐in phase
Mean age: 67 years (SD 7)
Age range: 44‐79
Means of recruitment: lists of cardiac patients, mass mailing, direct advertising
Baseline equality of treatment groups: more women in control arm on statins at randomisation (67% vs 54%). When adjusted in analyses ‐ made no statistically significant difference
Country: USA

Interventions

HT arm: conjugated equine oestrogen 0.625 mg with medroxyprogesterone acetate 2.5 mg
Control arm: placebo identical in appearance
Continuous oral regimen
Adherence to treatment defined as > 80% compliance with medication or placebo
Duration: 4.2 years, mean

FOR UNBLINDED CONTINUATION OF HERS 1998:
Continuation planned for an additional 4 years but stopped after mean additional 2.7 years, as no additional useful data anticipated

Outcomes

Coronary events (MI or coronary death)
Venous thromboembolism
Fracture
Gallbladder disease
Endometrial, breast or ovarian cancer
Death

Notes

Power calculation: 90% power to observe 24% reduction in coronary events at an average of 4.2 years' (P = 0.05) follow‐up
Further unblinded follow‐up 2.7 years (HERS II) ‐ see below

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random numbers in blocks of 4

Allocation concealment (selection bias)

Low risk

Computer displayed after participant details entered

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Vital status known for all women at end of trial. 59 women did not complete follow‐up (32 in experimental arm, 27 in placebo arm). Analysed by intention to treat

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants, clinical centre staff, data analysts and funders blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessors blinded

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

More women in control arm on statins at randomisation (67% vs 54%). When adjusted in analyses ‐ made no statistically significant difference

Methods

Stated purpose: to test whether menopausal HT initiated within 3 years of menopause can delay progression of atherosclerosis
Stratification: by study centre
No. of women screened for eligibility: 4532
No. randomised: 727 (oral HT: 230, transdermal HT: 222, placebo: 275)
No. analysed: 580
Losses to follow‐up: in oral HT, transdermal HT and placebo groups, respectively, for the following reasons: withdrawals for AEs = 16/230, 9/222, 12/275; personal reasons 11/230, 8/222, 24/275; non‐adherence 1/230, 4/222, 3/275; unknown reasons 15/230, 22/222, 18/275
Drop‐outs/adherence to treatment: 11% of women non‐adherent with treatment but included in analysis (116/580)

For KEEPS‐COG study, sample sizes were oral HT: 220, transdermal HT: 211, placebo: 262.
Analysis by intention to treat: no ‐ data not imputed for women lost to follow‐up
No. of centres: 9
Years of recruitment: 2005‐2008
Design: double‐blinded parallel‐group RCT
Funding: Aurora Foundation (not‐for‐profit) and other academic grants. Study medications provided in part by pharmaceutical companies

Participants

Included

Women aged 42‐58 within 6‐36 months of final menses

Excluded

Women post hysterectomy, BMI > 35 kg/m², low‐density lipoprotein cholesterol > 160 mg/dL, coronary artery calcium over 50 Agaston units at baseline, smoking over 10 cigarettes per day, history of diabetes, myocardial infarction, stroke, thromboembolic disease or cancer
Mean age: 52.7 years, mean 1.8 years since menopause
Age range: 42‐58
Means of recruitment: mass mailings, posters, print and online advertising, Internet web page
Baseline equality of treatment groups: high‐density lipoprotein cholesterol lower in placebo group, otherwise no statistically significant difference in baseline characteristics
Country: USA

Interventions

HT arm

0.45 mg/d oral CEE + cyclic oral micronised progesterone 200 mg/d × 12 days per month

0.05 mg/d transdermal oestradiol + cyclic oral micronised progesterone 200 mg/d × 12 days per month

Control: placebo
Duration: 4 years (original protocol was for 5 years, shortened during first year after reconsideration of study design)

Outcomes

Primary outcome: carotid artery intima media thickness

Outcomes relevant to this review: quality of life, clinical CVD events (including MI, stroke) reported as adverse events

Cognition: KEEPS‐COG ancillary study enrolled 93% of women in KEEPS 2012 (participation by invitation). Measured with MMSE

Global cognitive function also reported in a subset of participants (CEE 29, combined HT 59, placebo 36) in conjunction with magnetic resonance imaging monitoring of brain structure: data not included in this review (Kantarci 2015)

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomly sequenced blocks of 13 in a ratio 4:4:5 (oral CEE/transdermal CEE/placebo)

Allocation concealment (selection bias)

Low risk

Remotely generated sequence; database key not accessible to study personnel

Incomplete outcome data (attrition bias)
All outcomes

High risk

80% of women included in analysis for primary clinical endpoint at 4 years (580/727): 43 withdrew in each HT group, 57 withdrew in placebo group

619/693 (89%) women in KEEPS‐COG were included in analysis (85% of total KEEPS sample)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Study pharmacist provided blinded packets of study drugs for each participant.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessors blinded to study allocation

Selective reporting (reporting bias)

Low risk

Reports all expected outcomes and all outcomes planned in protocol. Reporting of AEs actively solicited

Other bias

Low risk

No other source of potential bias identified

Methods

Stated purpose: to determine whether oestrogen‐only HT affects global, cognitive or functional decline in women with mild to moderate Alzheimer's disease
Stratification: not mentioned
No. of women screened for eligibility: 153
No. randomised: 120 (CEE 0.625 mg: 42, CEE 1.25 mg: 39, placebo: 39)
No. analysed: 120
Losses to follow‐up: nil
Adherence to treatment: 23 drop‐outs (7 in placebo group, 7 in CEE 0.625 mg group, 9 in CEE 1.25 mg/d). Adherence to treatment was measured and was defined as the proportion of individuals who ingested at least 80% of the study medication but was not reported in the trial publication.
Analysis by intention to treat: yes
No. of centres: 32
Years of recruitment: not stated
Design: parallel placebo‐controlled
Funding: National Institute on Aging, Wyeth Ayerst

Participants

Included

Women with a diagnosis of probable Alzheimer's disease according to National Institute of Neurological and Communicative Disorders and Stroke‐Alzheimer Disease and Related Disorders Association Criteria in mild or moderate stage (study protocol specified MMSE score of 14‐28; several exceptions were made by the project director to allow for participants with MMSE scores as low as 12); female sex; previous hysterectomy (oophorectomy not required); older than 60 years; absence of major clinical depressive disorder (as measured by score < 17 on the Hamilton Depression Rating Scale (Ham D); normal gynaecological, breast and mammography results
Excluded

Myocardial infarction within 1 year, history of thromboembolic disease or hypercoagulable state, hyperlipidaemia, use of excluded medications (i.e. oestrogens within 3 months; current use of antipsychotics, anticonvulsants, anticoagulants, beta‐blockers, narcotics, methyldopa, clonidine or prescription cognitive‐enhancing or antiparkinson medications, including experimental medications within 60 days before baseline. Stable doses of neuroleptics, antidepressants, anxiolytics, sedatives and hypnotics were allowed). At initiation of the protocol, individuals treated with donepezil or tacrine were excluded, but a protocol amendment after 20 months of enrolment allowed stable use (minimum of 4 weeks) of these medications before screening for the study
Mean age: 75
Age range: 56‐91
Means of recruitment: not stated
Baseline equality of treatment groups: no significant differences between the 3 groups in terms of baseline and demographic characteristics
Country: USA

Interventions

HT arm
CEE oral 0.625 mg/d
CEE 1.25 mg/d
Control: placebo
Duration: 1 year

Outcomes

Primary outcome

Progression of Alzheimer's disease (Alzheimer's Disease Co‐operative Study version of the Clinical Global Impression of Change Scale)

Notes

Power calculation: 81% to detect a 29% difference in the proportion of participants who worsened in the 2 groups (60% worse in the placebo group vs 31% worse in the oestrogen group) using a 2‐tailed (alpha) =.05 (based on data from a similar trial, with 40 participants receiving placebo and 80 receiving oestrogen)
* Inclusion criteria state > 60 years, but age range at baseline was 56‐91

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated in blocks of 6

Allocation concealment (selection bias)

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up stated. Analysed by intention to treat

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

States double‐blinded; used "identically appearing tablets"

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

States double‐blinded; no further details

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

Inclusion criteria state > 60 years, but age range at baseline 56‐91

Methods

Stated purpose: to evaluate effects of HT
Stratification: not mentioned
Unblinding: code broken if a major medical complication or death occurred (13 times in HT group, 17 times in control group)
No. of women screened for eligibility: 403 (235 excluded: 74 ineligible, 31 refused, 130 no match for pair found)
No. randomised: 168
No. analysed: 168
Losses to follow‐up: none
Adherence to treatment: not mentioned
Analysis by intention to treat: yes, although any events occurring after unblinding were not recorded
No. of centres: 1
Years of recruitment: unclear ‐ study lasted 10 years and was complete by 1976
Design: parallel
Funding: not stated

Participants

Included

Postmenopausal inpatients with chronic disease (last menstrual period > 2 years previously, FSH > 105.5 mU, total urinary oestrogen < 10 micrograms/dl), never taken HT. All hospitalised for entire study period; screened with history, physical examination, medical record review; matched on the basis of chronic disease diagnosis, as follows: diabetes mellitus (14 pairs), custodial care (20 pairs), arteriosclerosis (9 pairs). Other pairs matched on the basis of chronic neurological disorders
Excluded

Acute heart disease, hypertension (blood pressure > 160/94), apparent malignancy, hysterectomy
Mean age: 55
Baseline equality of treatment groups: Correlation for diagnosis was identical. Correlation for some other risk factors was low between individual pairs, but group means were similar.
Country: New York Hospital for Chronic Diseases

Interventions

HT arm: CEE 2.5 mg daily, plus MPA 10 mg for 7 days each month
Control arm: placebo
Duration: 10 years

Outcomes

Death, myocardial infarction, "serious embolism" (pulmonary embolus), breast cancer, colon cancer, endometrial cancer, gallstones

Notes

Power calculation: not mentioned
Re generalisability: Study authors point out that almost all women had long‐term chronic disease, were hospitalised for the entire study period, had much lower than normal overall parity and had more prolonged bed rest than the average woman.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Women matched for diagnosis of chronic disease. From matched pairs, research nurse randomly selected which member would be assigned to which group. Method not described

Allocation concealment (selection bias)

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up described. Analysed by intention to treat, but any events occurring after unblinding not recorded

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

States participants and research physicians blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

States participants and research physicians blinded

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

Correlation for some baseline prognostic factors was low between individual pairs, but group means were similar.

Methods

Stated purpose: to determine the lowest effective dose of an oestradiol transdermal delivery system for preventing bone loss in postmenopausal women
Stratification: not described
Unblinding: not described
No. of women screened for eligibility: not stated
No. randomised: 355 (0.025 mg dose: 89; 0.05 mg dose: 90; 0.075 mg dose: 89; placebo: 87)
No. analysed: 355 (data imputed for losses to follow‐up)
Losses to follow‐up: 34 (9.6%)
Adherence to treatment: 125 drop‐outs: 125 (35%) did not complete 2 years' treatment (88 in active treatment arms, 37 in placebo arm). One participant was withdrawn for failure to adhere to the treatment schedule. Overall level of adherence to treatment in women who continued with their allocated treatment is not described.
Analysis by intention to treat: yes
No. of centres: 22
Years of recruitment: not stated
Design: parallel
Funding: Proctor and Gamble Pharmaceuticals

Participants

Included

Postmenopausal, non‐osteoporotic, ambulatory women younger than 70 years of age who had had a hysterectomy, with or without bilateral oophorectomy, at least 12 months earlier. Postmenopausal status documented by serum oestrogen < 23 picograms/mL and FSH serum levels > 40 mlU/mL. Non‐osteoporotic status defined by dual energy x‐ray absorptiometry (DXA) minimum T‐score of ‐2.5
Excluded

Participants who had received oral oestrogens within 2 months of enrolment, or who had contraindications to oestrogen therapy or history of oestrogen intolerance, women with clinically significant systemic or psychiatric disorders; history of cancer (other than basal cell carcinoma in remission or uterine cancer treated by hysterectomy); history of osteomalacia, hyperparathyroidism or untreated hyperthyroidism, abnormal serum lipids, creatinine or liver enzymes; use of medications within 3 months of enrolment that could modify BMD, radiographic abnormalities of the lumbar spine on anterior/posterior or lateral view, which would preclude precise DXA measurements
Mean age: not stated
Age range: not stated
Means of recruitment: not stated
Baseline equality of treatment groups: yes
Country: USA

Interventions

HT arm: 2 patches, delivering daily dose of oestradiol: 0.025 mg, 0.05 mg or 0.075 mg
Control arm: 2 placebo patches
Duration: 2 years (26 cycles)

Outcomes

Breast cancer (regular mammograms)
Fractures

Notes

Power calculation: not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Low risk

34 (9.6%) losses to follow‐up. Analysed by intention to treat

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

States double‐blinded, double‐dummy

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

States double‐blinded, double‐dummy; "hard" outcomes

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No apparent source of other bias

Methods

Stated purpose: to compare combined and sequential therapy with respect to relief of climacteric symptoms, effects on the endometrium and on vaginal cellular maturation, steroid metabolism and side effects
Stratification: not mentioned
Unblinding: not described
No. of women screened for eligibility: 176, of whom 21 unwilling to take placebo, 2 found not postmenopausal, 2 excluded for private reasons
No. randomised: 151 (combined HT: 50, sequential HT: 50, placebo: 51)
No. analysed: 129 (in the groups to which they were allocated)
Losses to follow‐up: 22 (11 from combined group, 5 from sequential group, 6 from placebo group)
Adherence to treatment: not described
Analysis by intention to treat: no
No. of centres: 1
Years of recruitment: not stated
Design: parallel
Funding: Pharmaceutical Division, Novo Nordisk

Participants

Included

Women in early menopause (last spontaneous vaginal bleeding > 6 and < 24 months earlier), no HT within preceding 24 months
Excluded

Women with previous or current oestrogen‐dependant neoplasia, thromboembolic disease, liver or pancreatic disease, diabetes mellitus, severe obesity, disease with high or low bone turnover and medication known to influence bone metabolism or provoke induction of liver enzymes
Mean age: not stated
Age range: not stated
Means of recruitment: All 5800 women born between 1930 and 1933 in Frederiksborg County, Denmark, were invited to participate.
Baseline equality of treatment groups: yes
Country: Denmark

Interventions

HT arm
Oral oestradiol 2 mg + norethisterone 1 mg
Oral oestradiol 2 mg days 1‐22 + norethisterone acetate days 13‐22, then oestradiol 1 mg days 22‐28
Control arm: placebo
Duration: 2 years

Outcomes

Only outcomes of interest to this review: endometrial cancer, quality of life

Notes

Power calculation: not mentioned

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not described

Allocation concealment (selection bias)

Unclear risk

Not described

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

22 (15%) losses to follow‐up for endometrial cancer (11 from combined group, 5 from sequential group, 6 from placebo group), analysed by ITT. However, only 70% of women included for quality of life outcomes (loss to follow‐up rates similar across groups)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and personnel blinded ‐ identical placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

States double‐blinded ‐ no further details

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

Baseline quality of life scores on several measures appear substantially lower for placebo group.

Methods

Stated purpose: to investigate effects of oestrogen‐only and combined therapies on cardiovascular disease risk factors, as well as on endometrial status, breast changes, bone density, menopausal symptoms and quality of life factors
Stratification: by clinical centre and hysterectomy status
Blinding: participants, clinical and laboratory personnel blinded; medication packages visually indistinguishable
Unblinding: unblinding officer at each trial centre or by phone call to co‐ordinating centre; referral gynaecologist at each centre not directly involved with data collection or patient care; able to access treatment assignment for management of safety issues
No. of women screened for eligibility: approximately 1460 (states that 60% of women screened were randomised)
No. randomised: 875
No. analysed: 847 (97%)
Losses to follow‐up: 28 (CEE‐only group: 5/170, CEE + MPA sequential group: 5/174, CEE + MPA continuous group: 4/174, CEE + MPA sequential group: 5/178, placebo group: 9/174)
Adherence to treatment: drop‐out rate disproportionately high in women with a uterus assigned unopposed oestrogen: 55% had to discontinue assigned therapy, largely owing to endometrial hyperplasia. Of 847 women who attended 3‐year follow‐up, 75% with a uterus and 80% without a uterus had at least 80% adherence to treatment. (Note: 55% of women with a uterus assigned unopposed oestrogen were required to discontinue assigned therapy owing to endometrial hyperplasia.)
Analysis by intention to treat: no ‐ but 97% of women analysed by ITT
No. of centres: 7
Years of recruitment: December 1989‐February 1990
Design: parallel
Funding: research grants from National Heart, Lung and Blood Institute, National Institute of Child Health and Human Development, National Institute of Health and Human Development, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, USA

Participants

Included

Healthy postmenopausal women 45‐65 years of age, with or without a uterus; ceased menstruation 12 months before entry or had hysterectomy at least 2 months before entry and FSH levels < 40 mU/mL
Excluded

Women who had used hormones within past 3 months, women treated with thyroid hormone unless stabilised on treatment, serious illness including heart or thromboembolic disease, previous endometrial or breast cancer, contraindications to oestrogen
Mean age: 56 years (SD 4)
Age range: 45‐64
Means of recruitment: through mass media and community efforts
Baseline equality of treatment groups: Women assigned to placebo had higher mean levels of fibrinogen and low density lipoprotein‐C at baseline.
Country: USA

Interventions

HT arm: 1 of the following regimens
CEE 0.625 mg daily (unopposed oestrogen)
CEE 0.625 mg daily plus MPA 10 mg daily for first 10 days (combined sequential treatment)
CEE 0.625 mg plus MPA 2.5 mg daily (combined continuous treatment)
CEE 0.625 mg plus MP 200 mg daily for first 12 days (combined sequential treatment)
Control arm: placebo
Duration: 3 years

Outcomes

Primary endpoints: biological markers, not relevant to this review; however, the following prespecified outcomes were also measured.
Breast cancer
Endometrial cancer
Cardiovascular disease

Thromboembolism

Gallbladder disease

Notes

Power calculation: based on primary (biological) outcome: A sample of 840 women was projected to provide minimum power of 0.92 to detect differences of 5 mg/dL in HDL cholesterol for any pair‐wise comparison of treatment arms at 3 years.

55% of women with a uterus assigned unopposed oestrogen were required to discontinue assigned therapy owing to endometrial hyperplasia.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated blocks of variable length

Allocation concealment (selection bias)

Low risk

Allocation assignments on encrypted file loaded on computer at clinical centre and issued once eligibility confirmed (or by phone to co‐ordinating centre in case of computer failure)

Incomplete outcome data (attrition bias)
All outcomes

Low risk

28 (3%) lost to follow‐up; 97% of women analysed by intention to treat

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants, clinical and laboratory personnel blinded; medication packages visually indistinguishable

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Clinical and laboratory personnel blinded

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

Placebo group had higher levels of fibrinogen and low‐density lipoprotein C at baseline; otherwise, groups prognostically balanced

Methods

Stated purpose: to determine whether oestradiol and norethindrone HT prevents decline in delayed verbal recall in older women with normal to mildly impaired memory functioning
Stratification: none reported
Unblinding: adverse effects managed by data safety monitoring board, which did not have access to study participants
No. of women screened for eligibility: 987
No. randomised: 142
No. analysed: 128 at 2 years
Losses to follow‐up: 14 (8 in HT group, 6 in placebo group)
Adherence to treatment: 26 discontinued intervention in HT group, 16 discontinued in placebo group
Analysis by intention to treat: no, but 128/142 analysed by ITT (90%)
No. of centres: 1
Years of recruitment: 2000‐2004
Design: parallel
Funding: Canadian Institutes of Health Research, Insitute of Neurosciences Mental Health and Addiction, Shire Biochemistry. Pharmaceutical companies provided tablets.

Participants

Included

Women at least 60 years of age, at least 12 months since last menstrual cycle, normal to below‐normal scores on screening for short‐delay verbal recall, fluent in English and with normal reading and hearing abilities
Excluded

Women with dementia or history of a condition that would affect cognition; women with conditions considered to be exacerbated by oestrogen, or taking specific medications (listed in the publication) including HT within past 2 years; women received neuropsychological testing to rule out dementia
Mean age: not stated
Age range: 61‐87
Means of recruitment: advertisements, display booths (e.g. in hospitals, seniors' clubs), family physician referrals
Baseline equality of treatment groups: similar baseline scores
Country: Canada

Interventions

HT group: 1 mg 17‐B oestradiol daily for 4 days a week followed by 1 combined oestrogen/progestin ampoule (1 mg 17‐B oestradiol and 0.35 mg norethindrone) per day for 3 days a week

Control: placebo

Duration: 2 years

All women were given the same intervention, whether or not they had a uterus.

Outcomes

Short‐delay verbal recall of the California Verbal Learning Test

Adverse events, including cardiovascular events, cancer, fractures

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated

Allocation concealment (selection bias)

Low risk

Pharmacy allocation

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

10% losses to follow‐up by 2 years; those lost to follow‐up did not differ on baseline short‐delay recall scores from those who stayed in the study

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All study personnel and participants were blinded to treatment assignment for the duration of the study; placebo capsules were identical in appearance to the active capsule.

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

States that study personnel and participants were blinded ‐ no specific statement about outcome assessment

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

More women in HT group than in placebo group reported breast tenderness, vaginal bleeding and discharge, suggesting that they may have been aware that they were receiving HT.

Methods

Stated purpose: to determine whether HT or antioxidant vitamin supplements, alone or in combination, influence the progress of coronary artery disease in postmenopausal women, as measured by angiography
Stratification: clinical centre, hysterectomy status
Unblinding: adverse effects managed by gynaecologist not involved in outcome assessment who had access to treatment assignment if necessary, with permission of co‐ordinating centre
No. randomised: 211
No. analysed: 206 for clinical status at end of study
Losses to follow‐up: 5 (3 in HT group, 2 in placebo group)
Adherence to treatment: evaluated for 159/211 who had angiographic follow‐up: HT group took 67% of medication, placebo group took 70%; 9/108 women in placebo group crossed to open‐label oestrogen
Analysis by intention to treat: no ‐ but 98% of women analysed by ITT
No. of centres: 7
Years of recruitment: July 1997‐August 1999
Design: parallel
Funding: National Heart, Lung and Blood Institute contract, General Clinical Research Center grant, USA

Participants

Included

Postmenopausal women with 1 or more 15% to 75% coronary stenoses in an artery not subjected to intervention, seen on angiogram within 4 months of study entry. Postmenopausal defined as post bilateral oophorectomy, younger than 55 years of age with an FSH of 40 Mu/mL or higher or older than 55 years
Excluded

HT use within 3 months, concurrent use of more than 60 mg/d of vitamin C or 30 IU daily of vitamin E and unwilling to stop taking them; suspected breast, uterine or cervical cancer; uncontrolled diabetes or hypertension, MI within 4 weeks, elevated triglycerides or creatinine levels, symptomatic gallstones, heart failure, history of haemorrhagic stroke, bleeding diathesis, PE, DVT or untreated osteoporosis
Mean age: 65
Age range: 56‐74
Means of recruitment: recruited at clinical sites in USA and Canada
Baseline equality of treatment groups: higher prevalence of diabetes and higher fasting blood glucose levels in the HT group
Countries: USA and Canada

Interventions

HT arm: 1 of the following regimens
CEE 0.625 (oestrogen‐only therapy) ‐ for women who had had a hysterectomy
CEE 0.625 and MPA 2.5 mg daily (continuous combined therapy) ‐ for women who had not had a hysterectomy
Control arm: placebo

Duration: 3 years

In addition, this study included women who were prescribed a regimen of vitamins E and C or placebo vitamins. The only comparison considered in this review was HT/placebo vitamins vs placebo HT/placebo vitamins.

Outcomes

Primary outcome biological: change in minimum lumen diameter of qualifying coronary lesions
Outcomes of interest to review
All‐cause death
Total mortality
Cardiovascular events
Venous thromboembolism
Stroke
Breast cancer
Quality of life

Notes

Study publication pools results for women receiving unopposed and combined therapies.
Power calculation: based on primary (biological) outcome: 423 women provide 90% power to detect an effect size of at least 0.33 (corresponding to a change in minimum lumen diameter of 0.1 mm and assuming 20% of women would not undergo a follow‐up angiogram)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐randomised, permuted block design with random blocks of 2 and 4

Allocation concealment (selection bias)

Low risk

Remotely by phone call to study co‐ordinating centre

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Losses to follow‐up: 5 (3 in HT group, 2 in placebo group); 98% of women analysed by intention to treat

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants, investigators and staff at clinical centres blinded, except (when necessary) the study gynaecologist

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Participants, investigators and staff at clinical centres blinded ‐ main outcomes "hard"

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

Active group had higher prevalence of diabetes and higher fasting blood glucose levels; otherwise, groups were prognostically balanced.

Methods

Stated purpose: to determine whether 17B‐oestradiol reduces risk of recurrent stroke or death among postmenopausal women who have experienced a transient ischaemic attack or a non‐disabling ischaemic stroke
Stratification: by trial centre and risk level (3 levels)
Unblinding: study internist unblinded in the case of overriding concern about a woman's clinical care
No. of women screened for eligibility: 5296 (2772 ineligible, 1843 declined to participate, 17 unable to be randomised within protocol time frame)
No. randomised: 664 (HT: 337, placebo: 327)
No. analysed: 664
Losses to follow‐up: nil
Adherence to treatment: 34% of the oestradiol group and 24% of the placebo group dropped out. Non‐adherence to allocated treatment: overall mean: HT group: 44%; placebo: 36%. Among women who continued with treatment, adherence to treatment was 90% in both groups.
Analysis by intention to treat: yes
No. of centres: 21 (single recruitment hub)
Years of recruitment: December 1993‐May 1998
Design: parallel
Funding: National Institute of Neurological Disorders and Stroke grant, Medical Research Council of Canada grant. Mead Johnson Laboratories provided support and study drug.

Participants

Included

Postmenopausal women (i.e. amenorrhoea for at least 12 months, or having undergone hysterectomy and > 55 years of age) over 44 years of age within 90 days of a qualifying ischaemic stroke or transient ischaemic attack
Excluded

Women whose index event was disabling or occurred while taking oestrogen; women with history of breast or endometrial cancer, who had had a venous thromboembolic event while receiving oestrogen replacement therapy, had had a neurological or psychiatric disease that could complicate evaluation of endpoints or had a coexisting condition that limited life expectancy
Mean age: 71
Age range: 46‐91
Means of recruitment: admissions to 20 largest regional hospitals in Connecticut and Massachusetts; also via contact with selected neurology groups and direct referral from physicians
Baseline equality of treatment groups: yes
Country: USA

Interventions

HT arm: 17‐beta oestradiol 1 mg daily plus, for women with a uterus, a course of medroxyprogesterone acetate once a year, 5 mg daily for 12 days
Control arm: placebo
Duration: 2.8 years

Outcomes

Death or recurrent stroke
Myocardial infarction
Cognitive function

Notes

Study publication pools results for women receiving unopposed and combined therapies.
Power calculation: 652 women required to give 80% power to detect a reduction in the rate of death or non‐fatal stroke from 25% in the placebo group to 15% in the HT group (2‐tailed P = 0.05)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated at pharmacy, in blocks of 4

Allocation concealment (selection bias)

Low risk

By remote contact with trial pharmacy

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No losses to follow‐up; analysed by intention to treat

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and investigators blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Endpoint assessors blinded

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No apparent source of other bias

Methods

Stated purpose: to test the hypothesis that women taking HT will have lower rates of coronary heart disease and osteoporosis‐related fractures
COMBINED HT ARM:
Stratification: by clinical centre site and age group
Re blinding: all participants, clinic staff and outcome assessors blinded, with the exception of 331 participants who were unblinded from the unopposed oestrogen arm and were reassigned to the combined HT arm owing to change in the protocol (see Notes). A further 432 women (248 in the experimental arm and 183 in the placebo arm) had a hysterectomy after randomisation (for reasons other than cancer) and were switched to unopposed oestrogen or corresponding placebo in the unopposed oestrogen study arm.
Unblinding: when required for safety or symptom management, unblinding officer, unblinded clinical gynaecologist, who was not involved with outcomes assessment. At average 5.2‐year follow‐up, 3444 women in experimental group and 548 women in placebo group had been unblinded, mainly to manage persistent vaginal bleeding.
No. randomised: 16,608 (8506 to experimental group, 8102 to placebo group)
No. analysed: 16,608
Losses to follow‐up: 583 participants (3.5%) ‐ i.e. no outcome data for > 18 months: 307 in HT arm (3%), 276 in control group (3.5%). Vital status known for 96.5%
Drop‐outs/Non‐adherence to allocated treatment: Women with adherence to treatment less than 80% (by pill count) were counted as drop‐outs. Drop‐out rates at 5.6 years were 42% in the experimental arm and 38% in the placebo group. In addition, 10.7% of women in the placebo group crossed to receive active treatment.
Analysis by intention to treat: yes (analysed with and without unblinded group in experimental arm)
No. of centres: 40
Power calculation: Sample gives 80%‐95% power for primary endpoint comparisons at 5% significance, assuming an intervention effect of 20% for CHD and 21% for combined fractures at 6‐9 year follow‐up, and an intervention effect of 22% for breast cancer at 14‐year follow up (risk ratio of 1.3 assumed for increased risk of breast cancer in intervention group).
Years of recruitment: 1993‐1998
Note: planned 8.5 years' follow‐up. Trial was stopped after mean of 5.6 years, as test statistic for breast cancer exceeded predetermined stopping boundary, and global risk index indicated risks exceeding benefits.

This study continued follow‐up for breast cancer outcomes beyond the planned trial completion date for women who consented to continue follow‐up (n = 12,788: 83% of those eligible, of whom 2.7% dropped out (Manson 2013)). Seventeen percent of surviving women declined to be re‐consented, and their data were censored for the additional follow‐up period. Baseline characteristics were evenly distributed between the 2 groups.

WHI 1998 UNOPPOSED OESTROGEN ARM:
Stratification: as above
Blinding: as above
Unblinding: as above
No. randomised: 10,739 (including 248 in experimental arm, 183 in placebo arm) joined this study after randomisation to corresponding arms in WHI 2002 and having subsequently had hysterectomy (for reasons other than cancer).
No. analysed: 10,739
Losses to follow‐up: 563
Drop‐outs/Non‐adherence to allocated treatment: Women with adherence to treatment of under 80% by pill count were counted as dropouts. The drop‐out rate was 53.8% by the end of the study (6.8 years) and did not vary significantly between study arms. In addition, 9.1% of women in the placebo arm and 5.7% in the active treatment group initiated hormone use outside of the study through their own physician.
Analysis by intention to treat: yes
No. of centres: 40
Power calculation: 12,375 participants needed to detect a 21% reduction in CHD rates over projected 9‐year average follow‐up
Years of recruitment: 1993‐1998
N.B. This arm of WHI 1998 was stopped early after a mean follow‐up of 7.1 years (planned for 9), when it was determined that the prospect of obtaining more precise evidence about effects of the intervention was unlikely to outweigh potential harms, although no predefined safety boundaries had been crossed. This study continued follow‐up for all outcomes beyond the planned trial completion date for women who consented to continue follow‐up (n = 7645; 78% of those eligible, of whom 3% dropped out). Twenty‐two percent of surviving women declined to be re‐consented, and their data were censored for the additional follow‐up period. Baseline characteristics were similar in the 2 groups, and imputation analyses suggested that this loss to follow‐up did not significantly influence study findings.

WHIMS ANCILLARY STUDY:
WHI 1998 enrolled 7479 participants who were free of probable dementia and were 56‐79 years of age. Of these, 4532 were from the combined HT arm of WHI 1998 [WHI 1998 (WHIMS:combined arm) and 2947 were from the unopposed oestrogen arm [WHI 1998 (WHIMS:unopposed oestrogen arm)]. Overall, 92.4% of eligible women participated.

Years of recruitment: May 1996‐December 1999
Analysis by intention to treat: all analysed by ITT for planned primary and secondary outcomes. For a third outcome (global cognitive function), which was not formally preplanned, 178 participants (3.9%) were excluded from the combined arm (151 because relevant follow‐up data were missing, and 27 because they consented to join WHIMS more than 6 months after WHI treatment assignment, by which time treatment effects may already have been under way), and 139 (4.7%) were excluded from the unopposed oestrogen arm (109 owing to missing follow‐up data and 30 as the result of enrolment 6 months or more after randomisation).
Adherence to allocated treatment (i.e. proportion taking > 80% of study medication): unopposed oestrogen arm: year 1: 77.2% in HT group vs 84.1% in placebo group; year 6: 42%% in HT group vs 47.8% in placebo group; combined HT arm: year 1: 71% in HT group vs 83% in the placebo group; year 4: 49% in HT group vs 61% in placebo group.

Power: designed to provide > 80% power to detect an observed 40% relative reduction in the incidence rate of clinically diagnosed all‐cause dementia
Duration: Mean time from randomisation to WHI 1998 to the last WHIMS cognitive screening examination was 4.05 years for women in the combined HT arm and 5.21 years for women in the unopposed oestrogen arm.

WHISCA ANCILLARY STUDY

Randomised in 1999

Enrolled 2304 women who had been enrolled in WHIMS for a mean of 3 years (1106 women from WHIMS: combined arm; 886 from WHIMS: unopposed oestrogen arm)

Re‐randomised in 2004‐2005 for further follow‐up to September 2007; 84% of the original cohort agreed to continue (n = 1933). Those who participated were more likely than those who did not to be younger, non‐smokers, free of diabetes and cardiovascular disease and prior users of oral contraceptives, and to have higher MMSE scores. Among ongoing participants, active and placebo groups had similar characteristics.

Participants

COMBINED HT ARM
Included

Postmenopausal women (no vaginal bleeding for 6 months, or for 12 months for 50‐54 year olds; any use of postmenopausal hormones), with a uterus, aged 50‐79 at initial screening, likely to reside in area for 3 years, provision of written informed consent
Excluded

Medical condition predictive of survival time < 3 years, invasive cancer in past 10 years (except non‐melanoma skin cancer), breast cancer at any time or suspicion of breast cancer at baseline screening, acute myocardial infarction, stroke, transient ischaemic attack in previous 6 months, known chronic active hepatitis or severe cirrhosis, blood counts indicative of disease, severe hypertension or current use of oral corticosteroids, femoral neck bone mineral density more than 3 standard deviations below the corresponding age‐specific mean, endometrial cancer or endometrial hyperplasia at baseline, malignant melanoma, pulmonary embolism or deep vein thrombosis that was non‐traumatic or had occurred in the previous 6 months, bleeding disorder, lipaemic serum and hypertriglyceridaemia diagnosis, current use of anticoagulants or tamoxifen, PAP smear or pelvic abnormalities, unwillingness or inability to complete baseline study requirements, alcoholism, drug dependency, mental illness, dementia, severe menopausal symptoms inconsistent with assignment to placebo, inability or unwillingness to discontinue current HT use or oral testosterone use, inadequate adherence with placebo run‐in, unwillingness to have baseline or follow‐up endometrial aspirations, active participant in another randomised clinical trial
Mean age: 63 years (SD 7)
Age range: 50‐79. Age ratio of 33%:45%:21% for baseline age categories of 50‐59, 60‐69 and 70‐79, respectively (enrolment targeted to achieve ratio of 30:45:25)
Recruitment: letter of invitation in conjunction with media awareness programme. Sampling method gave women from minority groups 6‐fold higher odds of selection than Caucasian women and resulted in a sample with 84% racially/ethnically designated "white", and 16% non‐"white"
Screening: Interested women were screened by phone or mail for eligibility, then attended 3 screening visits for history, clinical exam and tests. Three‐month washout period before baseline evaluation of women using postmenopausal hormones at baseline screening. Lead‐in placebo pills given for at least 4 weeks during screening process to establish compliance with pill taking
Baseline equality of treatment groups: no substantive differences between study groups at baseline
Country: USA

UNOPPOSED OESTROGEN ARM
Included

Postmenopausal women who had undergone hysterectomy (therefore considered postmenopausal for enrolment purposes), aged 50‐79 at initial screening, likely to reside in area for 3 years, provision of written informed consent
Excluded

As above
Mean age: 64
Age range: 50‐79.

Age ratio of 33%:45%:21% for baseline age categories of 50‐59, 60‐69 and 70‐79, respectively (enrolment targeted to achieve ratio of 30:45:25)
Recruitment: as above
Screening: as above
Baseline equality of treatment groups: no substantive differences between study groups at baseline
Country: USA

WHIMS ancillary study
Included

Participants in either arm of WHI 1998, at least 65 years of age and free of probable dementia

WHISCA ANCILLARY STUDY

Women from 14 of the WHIMS clinical sites

Interventions

COMBINED HT ARM
Experimental group: combined oestrogen and progesterone as 1 daily tablet containing conjugated equine oestrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg
Control group: matching placebo
Duration: 5.6 years (mean duration of treatment)

Permanent discontinuation of medication: women who developed breast cancer, endometrial hyperplasia not responsive to treatment, endometrial atypia, endometrial cancer, deep vein thrombosis, pulmonary embolus, malignant melanoma, meningioma, triglyceride level over 1000 mg/dL, prescription of oestrogen, testosterone or selective oestrogen‐receptor modulators by their personal physician
Temporary discontinuation of medication: women who had acute MI, stroke, fracture, major injury involving hospitalisation, surgery involving anaesthesia, illness resulting in immobilisation for longer than 1 week, other severe illness for which hormone use is temporarily inappropriate

N.B. WHI 1998 (WHIMS) investigators reported outcomes according to study arm (unopposed oestrogen or combined HT therapy) and also (as per protocol) reported results pooled across the 2 arms. However, results showed significant baseline prognostic differences between the 2 arms (see Quality Table). We have not pooled the results in this review.

UNOPPOSED OESTROGEN ARM
Experimental group: 0.635 mg CEE daily
Control arm: placebo
Permanent discontinuation of medication: as above

WHIMS ANCILLARY STUDY
As for either arm of WHI 1998 above

Outcomes

COMBINED HT ARM
Cardiovascular disease: acute MI, silent MI, coronary death, stroke, pulmonary embolus
Cancer: breast, colorectal, endometrial, other cancers
Fractures: hip, vertebral, osteoporotic

UNOPPOSED OESTROGEN ARM
As above (with the exception of endometrial cancer)

WHIMS ANCILLARY STUDY
Cognitive function
Mild cognitive impairment
Dementia
For assessment of outcomes, women in WHIMS underwent up to 4 phases of testing as follows.
1. Participants underwent cognitive screening with the Modified MMSE at baseline and annually.
2. Women who scored below an education‐adjusted cut‐off point proceeded to a battery of psychoneurological tests and standardised interviews, plus interviews with a designated informant (friend or relative).
3. Clinical assessments by local physicians.
4. CT and blood tests to rule out reversible pathology.
All cases judged locally as probable dementia were independently evaluated by 2 adjudicators blinded to the diagnosis, as were 50% of cases of mild cognitive impairment and 10% of all cases without dementia.
Mild cognitive impairment defined as per current DSM IV criteria ‐ operationally defined as follows: poor performance (< 10th percentile) on a battery of neuropsychological tests, report of mild functional impairment from designated informant, no evidence of a psychiatric or medical explanation for the cognitive decline, absence of dementia
Dementia defined as per DSM‐IV criteria

Notes

N.B. The original WHI protocol allowed women with a uterus to be randomised to receive unopposed oestrogen. As evidence emerged (from the PEPI trial) that this could be unsafe, 331 participants with a uterus in the intervention group in the unopposed oestrogen arm were reassigned to the intervention group in the combined HT arm. Both arms closed early: Combined arm at 5.6 years (8.5 planned); oestrogen‐only arm at 6.8 years (9 planned)

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centrally randomised by permuted block algorithm

Allocation concealment (selection bias)

Low risk

By local access to remote study database

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Combined HT arm: 583 participants (3.5%) lost to follow‐up. Vital status known for 96.5%

For 11‐year breast cancer outcomes in the combined HT arm, 17% of women had withdrawn. Imputation analyses and comparison of baseline characteristics suggested that this did not significantly influence effect estimates.

Oestrogen‐only arm: 563 (5%) ‐ analysed by intention to treat

WHISCA: for ongoing follow‐up (2004‐2007), 16% of women withdrew. Clinical and demographic characteristics of those continuing differed from those discontinuing, but active and placebo groups did not differ significantly.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All participants and clinic staff were blinded, with the exception of 331 participants who were unblinded from the unopposed oestrogen arm and reassigned to the combined HT arm owing to a change in protocol.

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessors blinded

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Unclear risk

In the unopposed oestrogen arm, greater use of aspirin at bedtime in the placebo group at baseline
In the combined HT arm, lower prevalence of stroke and higher percentage of participants using statins in the active treatment group at baseline

Methods

Stated purpose: to assess long‐term benefits and risks of HT
Stratification: by hysterectomy status and intended use of HT: women with no uterus and unwilling to take placebo randomised to CEE or combined HT. Equal probability of any treatment within each stratum
No. of women screened for eligibility: 14,203
No. randomised: 4385; 2196 on combined therapy, 2189 on placebo (see Notes)
No. analysed: 4385
Losses to follow‐up: 5
Adherence to treatment: 615 (14%) had dropped out from randomised treatment by trial closure. Trial treatment delivered 73% of time to women in combined HT arm and 86% of time to women on placebo
Analysis by intention to treat: yes
No. of centres: 384 UK, 91 Australian and 24 New Zealand general practitioner practices
Years of recruitment: 1999‐2002
Design: parallel
Funding: non‐commercial medical research funding

Participants

Included

Postmenopausal women 50‐69 years of age

Excluded

History of breast cancer, any other cancer in past 10 years except basal or squamous cell skin cancer, endometriosis or endometrial hyperplasia, venous thromboembolism, gallbladder disease, MI, unstable angina, cardiovascular accident, subarachnoid haemorrhage, transient ischaemic attack, use of HT within past 6 months, unlikely to be able to give informed consent
Mean age: 63
Age range: 50‐69
Means of recruitment: general practitioner practice registers
Countries: UK, Australia, New Zealand

Interventions

HT arm: daily CEE 0.625 mg plus medroxyprogesterone acetate 2.5 mg (for women with or without a uterus), or daily CEE 0.625 (for women without a uterus)
Control arm: placebo
Duration: planned for median 10 years, but prematurely closed after median 11.9 months (range 7.1‐19.6)

Women with a uterus within 3 years of last period, those aged 50‐53 and older women with unacceptable breakthrough bleeding took medroxyprogesterone acetate 5.0 mg.

Women with a uterus who experienced unacceptable spotting or bleeding on the above therapy were offered open‐label CEE 0.625 mg plus medroxyprogesterone acetate 10.0 mg daily for the last 14 days of a 28‐day cycle.

All women took placebo medication during run‐in: Those who achieved 80% compliance were randomised.

A further 1307 women were randomised to a comparison of oestrogen‐only vs combined HT: These results are not reported here.

Outcomes

Major cardiovascular disease (primary)
Osteoporotic fractures (primary)
Breast cancer
Mortality
VTE
CVD
Dementia (no follow‐up data collected)
Adverse events

Quality of life (reported among 3721 women with an intact uterus or subtotal hysterectomy, among whom 1862 were randomised to combined HT and 1859 to placebo). A variety of overall and symptom‐specific measures were used, including EuroQoL‐5D (which measures health‐related quality of life) and a generic VAS scale (which measures quality of all aspects of life) ‐ only these 2 measures are included in this review

Notes

Powered in protocol to detect 25% reduction in CHD over 10 years ‐ this assumed an 18,000 sample size, but trial stopped early with 26% of target

A further 1307 women were included in comparison of combined therapy vs oestrogen only and were not included in this review.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Remote computer‐generated

Allocation concealment (selection bias)

Low risk

Remote computer‐generated

Incomplete outcome data (attrition bias)
All outcomes

Low risk

615 (14%) had withdrawn from randomised treatment by trial closure; analysed by intention to treat

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

All participants and clinic staff blinded except when vaginal bleeding triggered a code break

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All outcome assessors blinded except when vaginal bleeding triggered a code break

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No apparent source of other bias

Methods

Stated purpose: to investigate effects of unopposed ultra‐low‐dose transdermal oestradiol on cognition and health‐related quality of life in postmenopausal women
Stratification: by clinical centre
No. of women screened for eligibility: 1509 (of whom 605 had 1‐week run in phase. 10/605 were non‐compliant and 1678 were found ineligible or refused to continue screening)
No. randomised: 417 (treatment group: 208; placebo group: 209)
No. analysed: using a time × treatment interaction. 388 at year 1, 376 at year 2
Losses to follow‐up: 40
Adherence to treatment: drop‐outs: 41. Among those who completed treatment, 84% used at least 75% of study drug during the entire 2 years.
No. of centres: 9
Years of recruitment: 1999‐2000
Design: parallel
Funding: industry funded

Participants

Included

Women 60‐80 years of age with intact uterus, at least 5 years post menopause, normal bone density

Excluded

Women with unexplained uterine bleeding, endometrial hyperplasia, endometrium >mm double thickness on ultrasonography, abnormal mammogram suggestive of breast cancer, history of metabolic bone disease, cancer, coronary disease, stroke, transient ischaemic attack, VTE, uncontrolled hypertension, uncontrolled thyroid disease, liver disease, abnormal fasting triglyceride or fasting glucose, ever taken fluoride, calcitonin or bisphosphates, oestrogen or progestin within past 3 months

Median age: 67
Means of recruitment: not stated
Baseline equality of treatment groups: mean MMSE scores slightly higher in intervention group (P = 0.04)
Country: USA

Interventions

HT arm: oestradiol patch delivering approx 0.014 mg oestradiol daily, applied to abdomen weekly
Control arm: identical placebo patch
Duration: 2 years
All participants also received 400 mg calcium twice daily and 400 IU vitamin D daily.

Outcomes

Preplanned secondary outcomes
Changes in global cognition (MMSE)
Short‐Form Health Survey (SF‐36): Physical Component Scale and Mental Component Scale

Bone mineral density was primary outcome (not reported here).

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Remotely by computer

Allocation concealment (selection bias)

Low risk

By pharmacy

Incomplete outcome data (attrition bias)
All outcomes

Low risk

40/417 (9.5%) women lost to follow‐up; analysed by intention to treat

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and investigators blinded

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Outcome assessors blinded

Selective reporting (reporting bias)

Low risk

All expected outcomes reported

Other bias

Low risk

No apparent source of other bias