ELITE 2014.

Methods	2 × 2 double‐blinded placebo‐controlled parallel‐group RCT Stated purpose: to assess the effect of HT on progression of subclinical atherosclerosis and cognitive effects initiated between early and late postmenopause Stratification: not stated No. of women screened for eligibility: 3061 (n = 2166 via telephone, n = 895 in person) No. of women randomised: 643 (323 to HT, 320 to placebo; subgrouped by time since menopause with respect to initiation of HT) No. of women analysed: 567 underwent cognitive baseline assessment, total of 567 women provided cognitive outcomes at 2.5 years and 455 women provided outcomes at 5 years. Losses to f/u: 2.2% of women were lost to follow‐up, and another 10.0% discontinued participation before cognitive outcomes were assessed (14 lost to follow‐up, 22 dropouts due to adverse events, 40 discontinued for other reasons before contributing to cognitive outcomes at 2.5 years). Adherence to treatment: Mean adherence for oestradiol or placebo was ≥ 98% for early and late group women. Analysis by intention to treat: yes No. of centres: 1 Years of recruitment: July 2005 and September 2008 Design: parallel Funding: supported by National Institutes of Health grant for initial and supplemental funding of ELITE and ELITE‐Cog. Study drugs and placebo were supplied without charge or restriction by Teva Pharmaceuticals, Watson Pharmaceuticals and Abbott Laboratories.
Participants	643 healthy postmenopausal women with clinical evidence of CVD or diabetes, subgrouped by time since menopause (< 6 years since menopause (n = 271) or > 10 years since menopause (n = 372)) Included Women with a serum oestradiol level < 25 picogram/mL and cessation of regular menses > 6 months who are < 6 years and > 10 years postmenopausal Excluded Clinical signs, symptoms or personal history of cardiovascular disease, indeterminate time since menopause, DM or fasting serum glucose ≥ 140 mg/dL, uncontrolled hypertension (diastolic blood pressure ≥ 110 mmHg), untreated thyroid disease, serum creatinine > 2.0 mg/dL, plasma triglyceride levels > 500 mg/dL, life‐threatening disease with prognosis < 5 years, cirrhosis or liver disease, hx of deep vein thrombosis or pulmonary embolism, history of breast cancer, current HT Median age: 53.4 years for early, 63.6 years for late Age range: 41‐84 Means of recruitment: telephone and in person Baseline equality of treatment group: no statistically significant difference in baseline characteristics. Women not contributing to analysis were similar to other women in most but not all comparisons. Country: USA
Interventions	1. Oral 17β‐oestradiol 1 mg daily with (uterine intact) or without (hysterectomy) vaginal micronised progesterone gel 4% (45 mg) 10 days per month: Study publication does not state how many women were in each group. 2. Placebo Originally planned for 5 years, extended to 7.5 years
Outcomes	Primary study outcome Progression of subclinical atherosclerosis ‐ not relevant for current review Secondary outcomes Cognitive function at 2.5 and 5 years, cardiovascular events (fatal or nonfatal MI, silent MI, sudden death), stroke, venous thromboembolism (DVT or PE), cancer (breast, uterine, ovarian, gastrointestinal, lung), bone fracture, all‐cause mortality, non‐coronary mortality
Notes	Power calculation: 506 sample size provides power of 80% needed to detect difference in rate of change in carotid artery intima media thickness and effect size of 0.22 in early and late groups combined.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation sequence generated by computer by study statistician
Allocation concealment (selection bias)	Low risk	"Stratified randomization list [was] used to prepare the study products. After determining a participant’s eligibility, clinic staff pulled the next study product in sequence from the appropriate stratum, recorded the product identification number, and dispensed the product".
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	567/643 women (88%) analysed for cognitive outcomes at 2.5 years, 455/643 (71%) at 5 years
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Investigators, participants, clinic staff and data monitors were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Not stated whether outcome assessor blinded, but most probably, as study author mentioned trial was extended before blinding was unmasked after receiving supplementary funding
Selective reporting (reporting bias)	Low risk	All expected outcomes reported
Other bias	Low risk	No other potential source of bias identified