WISDOM 2007.

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