WHI II 2004.

Methods	Objective: To assess the effects on major disease incidence rates of the most commonly used post‐menopausal HT in the United States Trial type: Multicentre randomised placebo controlled primary prevention trial (RCT) involving 40 primary care sites in the United States. The trial recruitment was conducted from January 1993 to September 1998, with a mean follow‐up of 6.8 years (range: 5.7 to 10.7).  The primary aim of the trial was to assess the effects of oestrogen therapy compared to placebo on disease incident rates of CHD, hip fractures and deaths from all causes.  The primary outcome measure was CHD events (defined as acute MI requiring overnight hospitalisation, silent MI, or CHD death), with invasive breast cancer as the primary adverse outcome.  Secondary outcomes included stroke (both fatal and non‐fatal), pulmonary embolism, DVT, angina (both hospitalisation due to and confirmed), revascularisation (CABG or PCI combined), death from all causes, as well as a global index of risks and benefits defined as time to the first event among CHD, stroke, pulmonary embolism, breast cancer, colorectal cancer, hip fracture or death due to other causes to summarise overall effects.  The trial was stopped early after a mean follow‐up of 6.8 years when the National Institutes of Health (NIH) concluded that CEE alone did not appear to affect the risk of heart disease, but was associated with a significant increase in the risk of stroke, and given the likelihood that neither cardio‐protection or breast cancer risk would be demonstrated in the remaining intervention period terminated the trial on March 1, 2004   Recruitment: Letter of invitation in conjunction with media awareness programme.  Sampling method gave women from minority groups six‐fold higher odds for selection than Caucasian women and resulted in sample with 84% racially/ethnically designated “white”, 16% non‐“white” Screening: Interested women screened by phone or mail for eligibility, then attended three screening visits for history, clinical examination and tests. Three‐month washout period before baseline evaluation of women using post‐menopausal hormones at baseline screening. Lead‐in placebo pills given for at least four weeks during screening process to establish compliance with pill taking Randomisation: Centrally randomised by permuted block algorithm Stratification: By clinical centre site and age group Allocation: By local access to remote study database Baseline equality of treatment groups: No substantive differences between study groups at baseline Blinding: All participants, clinic staff, and outcome assessors blinded, with the exception of 331 participants who were unblinded from the unopposed oestrogen arm and reassigned to combined HT arm due to change in protocol Analysis: ITT Funding Source: The National Heart, Lung, and Blood Institute. Wyeth‐Ayerst Research provided the study medication
Participants	10,739 healthy post‐menopausal women who had previously undergone hysterectomy with or without an oophorectomy (including 248 in experimental arm, 183 in placebo arm who joined this study after randomisation to corresponding arms in WHI 2002 having subsequently had a hysterectomy for reasons other than cancer) were randomised to receive either daily conjugated equine oestrogen (n = 5310) or placebo (n = 5429). The mean age of the women was 63.6 years [(SD: ± 7.3; range: 50 to 79)] (Age ratio of 33%: 45%: 21% for the baseline age categories of 50 to 59, 60 to 69, 70 to 79, respectively). Included women were 75% White, 15% Black, 6% Hispanic, 1% American Indian, 1.5% Asian/Pacific Islander, and 1.5% unknown. In terms of previous hormone use: 74% were ‘never’ HT users, 20% were past users and 6% were current users (therefore requiring a three‐month washout period prior to randomisation). 53% of women had used HRT < five years, 19% for five to < 10 years, and 18% for ≥ 10 years.  In terms of risk factors for CVD: 51% were never smokers, 38.5% were past smokers, and 10.5% were current smokers. The mean BMI among the women was 28.5 kg/m2 (SD: ± 5.85); mean systolic blood pressure was 127.5 (SD: ±17.55) mm Hg and mean diastolic blood pressure was 75.7 (SD: ± 9.1). The CHD manifestations within the groups were: 4.4% were being treated for diabetes, 36% for hypertension or BP ≥ 140/90 mm Hg, 1.6% had a previous MI, 2.9% had a history of angina, 1.3% had undergone either CABG/PTCA surgery, 0.85% had suffered a previous stroke, and 0.85% had a history of DVT or PE Inclusion criteria:  women age 50 to 79 years of age at initial screening who had undergone a hysterectomy (thereby considered menopausal for enrolment purposes) Exclusion criteria: invasive cancer in the past ten years breast cancer at any time or suspicion of breast cancer at baseline screening endometrial cancer or endometrial hyperplasia at baseline malignant melanoma acute MI, stroke, TIA or pulmonary embolism deep vein thrombosis that was non‐traumatic or that had occurred in the previous six months known chronic active hepatitis or severe cirrhosis blood counts indicative of disease bleeding disorder lipaemic serum and hypertriglyceridaemia diagnosis current use of anticoagulants or tamoxifen papanicolaou smear or pelvic abnormalities severe hypertension current use of oral corticosteroids bleeding disorder; for reasons of adherence or retention: 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 alcoholism drug dependency mental illness dementia
Interventions	HT regimens: 0.625 mg conjugated equine oestrogen daily (CEE) (continuous dosage regimen) Comparator: identical placebo tablet daily Medication adherence was defined as participants taking > 80 study pills, and was monitored by weighing medication bottles at each clinic visit.  Medication adherence data for each trial year were not reported, but by the time of study termination 53.8% of women had stopped taking study medication. Therefore only 46.2% of women remained medication compliant. Compliance rates did not differ significantly between the two trial arms.  At 6.8 years follow‐up 5.7% of women in the HT arm had initiated hormone use through their own physician and 9.1%  of women in the placebo arm had also initiated hormone use (drop‐in) Follow‐up times: Baseline, and then every six‐month, with an annual clinic visit. At baseline participants completed a medical, reproductive history and psychosocial questionnaire; ECG, and underwent breast examination and gynaecological examination. Mammograms and breast examinations were repeated annually and ECGs were repeated at visit years three and six.  Participant attrition rates were low.  Over the 6.8 year follow‐up 5.2% [total n = 563; (HT: n = 262; placebo: n = 301)] women withdrew [n = 321 (HT: n = 136; placebo: n = 185)] were considered lost to follow‐up [n = 142 (HT: n = 126; placebo: n = 116)], or stopped providing outcome data for more than 18‐months.  Vital status at the end of the trial was therefore known for 10,176 (94.8%) of randomised participants, including 580 (5.4%) known to be deceased
Outcomes	Primary outcomes: CHD (defined as acute MI requiring overnight hospitalisation, silent MI, or CHD death) Death from CVD Non‐fatal MI (defined as acute MI requiring overnight hospitalisation, silent MI) Secondary outcomes: Death from any cause Stroke (fatal and non‐fatal combined) Angina (confirmed) Revascularisation (CABG or PCI combined) Pulmonary embolisms Venous thrombosis (pulmonary embolism plus DVT combined) HRQoL not included in the analyses; length of follow‐up: 7.1 years
Notes	The sample size calculation was adequate so the trial was powered to detect differences between the HT and placebo groups in terms of CVD events.  All outcomes were prespecified and defined a prior, and reported in the trial results. All study personnel, except the study gynaecologist were ‘blinded’. The gynaecologist was ‘unblinded’ if necessary to treatment group, but separate from the rest of the trial team, and therefore ‘blinding’ is likely to have been maintained.  Participant attrition rates were low at 5.2%.  However, medication compliance rates were low, with only 46.2% of women still medication compliant at 6.8 years follow‐up.  This is likely to have ‘diluted’ the true effects, both positive and negative, of oestrogens relative to placebo relative to what might be observed with full medication adherence.  Additionally, the trial was stopped early which would have further decreased the power to detect differences between the two trial arms, and reduced the precision of the estimated effects for the outcomes assessed.  Events for this trial were reported stratified according to the time since menopause that treatment was started. This allowed accurate allocation of events, specifically: death, coronary heart disease (death from cardiovascular causes and non‐fatal myocardial infarction), stroke and venous thromboembolism, to subgroup analysis according to whether treatment was started < 10 years or > 10 years after the menopause
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
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All participants and clinic staff blinded, with the exception of 331 participants
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	563 participants (5.2%) withdrew, were lost to follow‐up, or stopped providing outcome information for more than 18 months Analysis conducted on ITT basis
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	No apparent source of other bias