Yaffe 2006.

Methods	Stated purpose: to investigate effects of unopposed ultra‐low‐dose transdermal oestradiol on cognition and health‐related quality of life in postmenopausal women Stratification: by clinical centre No. of women screened for eligibility: 1509 (of whom 605 had 1‐week run in phase. 10/605 were non‐compliant and 1678 were found ineligible or refused to continue screening) No. randomised: 417 (treatment group: 208; placebo group: 209) No. analysed: using a time × treatment interaction. 388 at year 1, 376 at year 2 Losses to follow‐up: 40 Adherence to treatment: drop‐outs: 41. Among those who completed treatment, 84% used at least 75% of study drug during the entire 2 years. No. of centres: 9 Years of recruitment: 1999‐2000 Design: parallel Funding: industry funded
Participants	Included Women 60‐80 years of age with intact uterus, at least 5 years post menopause, normal bone density Excluded Women with unexplained uterine bleeding, endometrial hyperplasia, endometrium >mm double thickness on ultrasonography, abnormal mammogram suggestive of breast cancer, history of metabolic bone disease, cancer, coronary disease, stroke, transient ischaemic attack, VTE, uncontrolled hypertension, uncontrolled thyroid disease, liver disease, abnormal fasting triglyceride or fasting glucose, ever taken fluoride, calcitonin or bisphosphates, oestrogen or progestin within past 3 months Median age: 67 Means of recruitment: not stated Baseline equality of treatment groups: mean MMSE scores slightly higher in intervention group (P = 0.04) Country: USA
Interventions	HT arm: oestradiol patch delivering approx 0.014 mg oestradiol daily, applied to abdomen weekly Control arm: identical placebo patch Duration: 2 years All participants also received 400 mg calcium twice daily and 400 IU vitamin D daily.
Outcomes	Preplanned secondary outcomes Changes in global cognition (MMSE) Short‐Form Health Survey (SF‐36): Physical Component Scale and Mental Component Scale Bone mineral density was primary outcome (not reported here).
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Remotely by computer
Allocation concealment (selection bias)	Low risk	By pharmacy
Incomplete outcome data (attrition bias) All outcomes	Low risk	40/417 (9.5%) women lost to follow‐up; analysed by intention to treat
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	Outcome assessors blinded
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	No apparent source of other bias

Abbreviations

BMD: bone mineral density.

BMI: body mass index.

CEE: conjugated equine oestrogen.

CHD: coronary heart disease.

CVD: cardiovascular disease.

DM: diabetes mellitus.

DSM‐IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.

DVT: deep vein thrombosis.

DXA: dual‐energy X‐ray absorptiometry.

EuroQol‐5D: quality of life questionnaire.

ET: oestrogen therapy.

FSH: follicle‐stimulating hormone.

Ham D: Hamilton Depression Rating Scale.

HDL: high‐density lipoprotein.

HT: hormone therapy.

ITT: intention to treat: analysis of all randomised participants in the groups to which they were randomised.

IU: International Units.

LDL: low‐density lipoprotein.

mg: milligram.

mL: millilitre.

MI: myocardial infarction.

MMSE: Mini Mental State Examination.

MP: micronised progesterone.

MPA: medroxyprogesterone acetate.

mu: milliunits.

PE: pulmonary embolism.

RCT: randomised controlled trial.

SD: standard deviation.

VAS: visual analogue scale.

VTE: venous thromboembolism.

WHI: Women's Health Initiative.

WHIMS: Women's Health Initiative Memory Study.

Definitions

Adherence to treatment refers to the number of tablets actually taken, which is often assessed by pill counts (see Additional Table 4).
 Drop‐outs: Participants who stopped their allocated treatment (and in some cases changed to a different off‐trial treatment) but have known clinical outcomes and were included in the analysis.
 Intention to treat: Analysis of all randomised participants in the groups to which they were randomised.
 Losses to follow‐up: Participants for whom outcomes of interest were unknown (and who may or may not have had outcomes imputed by statistical analysis).