WHI I 2002.

Methods	Objective: To assess the major health benefits and risks of the most commonly used combined hormone preparation in the United States   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 5.2 years (range: 3.5 to 8.5); planned duration 8.5 years. The primary aim of the trial was to assess the effects of oestrogen in combination with progestin 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 non‐fatal MI and 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 percutaneous coronary intervention (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, invasive breast cancer, stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture or death due to other causes to summarise overall effects.  Late in 1999, the National Institutes of Health Data and Safety Monitoring Board (DSMB) observed small but consistent early adverse effects in cardiovascular outcomes and in the global index.  However, none of the disease specific monitoring boundaries had been crossed. These adverse CV effects continued throughout 2000 and 2001, but the trial continued because the balance of risks and benefits remained uncertain.  The trial was finally stopped early after a mean follow‐up of 5.2 years in May 2002, when the DSMB found that the adverse effects in CVD persisted, although these remained within the monitoring boundaries, but the weighted log‐rank test statistic for breast cancer had crossed the designated stopping boundary, and the global index was supportive of a finding of overall harm.  The trial was therefore terminated at the end of May 2002   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	16,608 healthy post‐menopausal women were randomised to receive either daily conjugated equine oestrogen in combination with progestin (n = 8506) or placebo (n = 8102). Post‐menopausal was defined as no vaginal bleeding for six months (12 months for 50 to 54 years), or having ever used post‐menopausal hormones.  The mean age of the women was 63.25 years [(SD: 7.1) (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 (enrolment targeted to achieve ratio of 30: 45: 25)   Included women were 84% White, 7% Black, 5% Hispanic, 0.4% American Indian, 2.2% Asian/Pacific Islander, and 1.4 % 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).  70% of women had used HT < five years, 18% for five to < ten years, and 12% for ≥ 10 years   In terms of risk factors for CVD: 50% were never smokers, 39.5% were past smokers, and 10.5% were current smokers. The mean BMI among the women was 28.5 kg/m2; mean systolic blood pressure was 128 (SD: ± 17.5) 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, 1.8%  had a previous MI, 2.9% had angina, 1.3% had undergone either CABG/PTCA surgery, 0.9% had suffered a previous stroke, and 0.9% had DVT or PE.†; 12.7% had elevated cholesterol levels requiring medication, 6.7% were using statins at baseline, and 19.6% aspirin   Inclusion criteria: age 50 to 79 years at initial screening post‐menopausal likelihood of residence in the area for three years informed consent    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 or deep vein thrombosis that was nontraumatic 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 PAP smear or pelvic abnormalities severe hypertension current use of oral corticosteroids 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   †  Prior to the publication of the results of HERS I in 1997, (which led to a change in the inclusion criteria) women with a history of venous thromboembolism (VTE) were eligible for inclusion. From this point onwards women with indicated prior VTE were excluded. At this point 171 women with a history of VTE had been enrolled into the trial
Interventions	HRT regimens: 0.625 mg conjugated equine oestrogen plus 2.5 mg medroxyprogesterone acetate (MPA) daily   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 40% of women had stopped taking study medication (HRT: 42%; placebo: 38%). Therefore only 60% of women remained medication compliant.  At 5.2 years follow‐up 6.2% of women in the HT arm had initiated hormone use through their own physician and 10.7%  of women in the placebo arm had also initiated hormone use (drop‐in) Follow‐up times: baseline, and then every six months. At baseline participants had a clinical examination, including breast and pelvic examination with Papanicolaou test and endometrial evaluation, a screening mammogram and standardised 12‐lead electrocardiogram (ECG). Fasting total cholesterol, low‐density lipoprotein (LDL) cholesterol, high‐density lipoprotein (HDL) cholesterol, and triglyceride levels were measured in a subsample of participants.  Annual examinations included mammograms and clinical breast examinations. ECG results were collected at three‐ and six‐year follow‐up. Participant attrition rates were low. Over the 5.2 year follow‐up 3.5% [total n = 583; (HRT: n = 307; placebo: n = 276)] women withdrew, were considered lost to follow‐up, or stopped providing outcome data for more than 18‐months. Vital status at the end of the trial was therefore known for 15,576 (96.5%) of randomised participants, including 580 (2.7%) 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: 5.6 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, and adverse 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 very low at 3.5%.  However, medication compliance rates were low, with only 60% of women still medication compliant at 5.2 year follow‐up.  This is likely to have ‘diluted’ the true effects, both positive and negative, of the HT combination therapy compared 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	583 participants (3.5%) 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