EPHT 2006.

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