WISDOM 2007.

Methods	Objective:  To assess the long‐term benefits and risks of HT Multicentre three‐armed randomised controlled (RCT) trial involving 499 general practices; (n = 385 UK); (n = 91 Australia) and (n = 24) New Zealand. The trial was conducted between 1999 ‐ 2002, with an intended follow‐up period of ten‐years. The trial was halted early after the publication of the results from WHI I 2002, which showed no statistically significant benefit for treatment with HT compared with placebo. The median follow‐up time was 11.9 months (interquartile range: 7.1 to 19.6) for the entire trial participants and 12.8 months (range: 7.5 to 20.4 ) months for participants randomised to combination therapy.  The trial was composed of three different strata: Strata 1: Women with an intact uterus or sub‐total hysterectomy not taking HT randomised to combined oestrogen and progesterone therapy or placebo Strata 2: Hysterectomised women taking HT and randomised to oestrogen only HT or combined HT Stratum 3: Hysterectomised women not taking HT randomised to oestrogen only HT or combined HT or placebo The design therefore allowed for two main comparisons to be made: (1) combined oestrogen and progestogen therapy versus placebo, and in women who had a hysterectomy, (2) oestrogen alone versus combination oestrogen and progestogen therapy Only the baseline demographic data and results from strata 1 are reported within this report, as this was the only comparison of HT versus placebo within the trial   Recruitment:  Practice registries Screening: 14,203 screened for eligibility All women took placebo medication during run in: those who achieved 80% compliance were randomised Randomisation: Remote computer‐generated 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 Allocation: Remote computer‐generated Baseline equality of treatment groups:  No substantive differences at baseline Blinding: All participants, clinic staff, and outcome assessors blinded except when vaginal bleeding triggered a code break Analysis: ITT Funding Source: Non‐commercial medical research funding
Participants	4385 healthy women in strata one (out of a total of 5692 women randomised) were randomised to either combined HT or placebo   The mean age of the women was 63.3 years (SD: 4.7), with a mean of 14.7 years (SD: 7.1) since menopause. Post‐menopausal status was defined as the presence of no menses in the past 12 months or having undergone a hysterectomy. Women taking HT at baseline screening, who were prepared to enter the placebo controlled strata of the study, ceased therapy for three months before the run‐in phase.  During run‐in they took placebo so that at randomisation they had not taken HT for six months At baseline, 9% of women were taking oestrogen, and therefore underwent a three‐month ‘wash out ‘period prior to randomisation. 2% of the included women were of non‐white ethnic status; 18% were using HT at screening and 86% had previously used HT. In terms of risk factors for CVD: mean BMI was 28.0 kg/m2; mean systolic blood pressure was 136.5 mm Hg and mean diastolic blood pressure 73 mm Hg; 24% were current smokers; 55% were former smokers; 10% had previous angina; 3% had a previous MI; 3% had a previous stroke and 7% had diabetes. Inclusion criteria: Stated above, but only women who were 80% or more medication compliant in the run‐in period were eligible for participation in the trial Exclusion criteria: for the placebo‐controlled group oral transdermal HT use in the last six months ever use of HT implant in women with a uterus HT implant inserted in last eight months in women with a hysterectomy history of endometriosis or endometrial hyperplasia in a woman with a uterus history of invasive breast cancer, lobular carcinoma in situ (LCIS), ductal carcinoma in‐situ (DCIS), Paget's disease of the nipple or atypical hyperplasia of the breast; BRCA1 or BRCA2 mutation carrier history of melanoma invasive cancer at any other site apart from basal and squamous cell skin cancer within the last ten years history of meningioma, myocardial infarction, cerebrovascular accident, subarachnoid haemorrhage or transient ischaemic attack within the last six months history of currently active liver disease or chronic liver disease but excluding Hepatitis A unless currently active severe renal impairment gall bladder disease in a woman who had not had a cholecystectomy or of gallstones following a cholecystectomy deep vein thrombosis, pulmonary embolism or retinal vein occlusion positive thrombophilia screen (Factor V Leiden or prothrombin mutations, Protein C, Protein S or antithrombin III deficiencies, APC resistance, dysfibrinogenaemia or antiphospholipid antibodies) otosclerosis porphyria currently pregnant or taking contraceptive drugs in the last 12 months current triglyceride level (fasting) > 5.5 mmol/L active participant in any other intervention trial likely to affect trial outcomes taking tamoxifen, toremifene, raloxifene or any other selective oestrogen receptor modulator (SERM) history of hepatitis B, hepatitis C or HIV (not an exclusion criteria in New Zealand)
Interventions	HT regimen: 0.625 mg conjugated equine oestrogen in combination with 2.5 mg medroxyprogesterone acetate (MPA) daily (continuous dosage regimen) Comparator: placebo tablet daily Participants were classified as medication compliant if they took ≥ 80% of their medication throughout the trial. Trial treatment delivered 73% of time to women in combined HT arm and 86% of time to women on placebo   Follow‐up  times: four, 14, 27, 40 and 52 weeks and then at six‐month intervals.  At baseline recent cervical screening and mammography were checked and then at each follow‐up visit information was collected on all outcomes (none of the outcomes were defined), adverse events and patients other medical history Losses to follow‐up: five Dropouts: 615 (14%) had withdrawn from randomised treatment by trial closure
Outcomes	Primary outcomes: Death from CVD Angina Non‐fatal MI Fatal MI Secondary outcomes: Pulmonary embolism Venous thromboembolism  Health‐related quality of life
Notes	Powered in protocol to detect 25% reduction in CHD over ten years. This assumed an 18,000 sample size but trial stopped early with 26% of target A further 1307 women were in comparison of combined therapy vs oestrogen only and not included in this review. Events were not stratified according to time since menopause. However the mean time since menopause that treatment was started was reported for each group, 14.7 years (SD 7.1) for the control group and 14.8 years (SD 7.2) for the hormone group. For the subgroup analysis of when treatment was started, the entirety of events in this study were analysed as if all participants had started treatment more than 10 years after their menopause
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
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
Incomplete outcome data (attrition bias) All outcomes	Low risk	615 (14%) had withdrawn from randomised treatment by trial closure. Analysed by ITT
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	No apparent source of other bias