Table 1. Non-WHI key randomised controlled trials of MHT and main outcomes.

Trial	N	Intervention	Outcomes	Effect
Kronos Early Oestrogen Prevention Study (KEEPS) [51, 52]	Healthy menopausal women, aged 40-58 years; 4 years; n=727	Randomised to either oral CEE (0.45 mg/day), or transdermal 17β-estradiol (t-E2), 50 mcg/d, each with 200 mg of oral progesterone for 12 days per month, or placebo for 48 months	Annual change in coronary artery intima media thickness (CIMT); coronary artery calcium score	No differences between groups
Early versus Late Postmenopausal Treatment with Estradiol randomised trial (ELITE) [53]	643 healthy postmenopausal women; median 5 years	Randomly assigned to receive either oral 17β-estradiol (1 mg/day, plus progesterone (45 mg) vaginal gel administered sequentially (once daily for 10 days of each 30-day cycle, intact uterus) or placebo (plus sequential placebo vaginal gel for women without a uterus)	Primary outcome: Change in CIMT every six months. Coronary atherosclerosis (cardiac computed tomography)	Early postmenopausal women: CIMT increased by 0.0078 mm per year in the placebo group compared with 0.0044 mm per year in the 17β-estradiol group (p=0.008) Late postmenopausal women, CIMT no difference (p=0.29) Cardiac CT measurements not different
Danish Osteoporosis Prevention Study (DOPS) [54]	1006 healthy recently postmenopausal women aged 45-58 years	Randomised to MHT or placebo. MHT: triphasic oestradiol and norethisterone acetate (intact uterus); 2 mg/day estradiol (hysterectomised)	Primary endpoint: composite of death, admission to hospital for heart failure and myocardial infarction.	After 10 years of intervention, HR: 0.48; 95% CI: 0.26 to 0.87 Mortality: HR: 0.57; 95%CI: 0.30 to 1.08 Breast cancer: HR: 0.58; 95%CI: 0.27 to 1.27 DVT: 2.01; 95%CI: 0.18 to 22.16 Stroke: HR: 0.77; 95%CI: 0.35 to 1.70.
Heart and Estrogen/progestin Replacement Study (HERS) Research Trial[49]	2763 women with coronary disease, <80 years old (mean 66.7 years), postmenopausal with an intact uterus.	Randomised to either 0.625 mg CEE plus 2.5 mg of MPA or matched placebo	Primary outcome: nonfatal myocardial infarction or coronary heart disease (CHD) death	Relative hazard (RH), 0.99; 95% CI: 0.80 to 1.22 DVT: RH: 2.89; 95% CI: 1.50 to 5.58 Gallbladder disease: RH: 1.38; 95% CI: 1.00 to 1.92
Women’s International Study of long Duration Oestrogen after Menopause (WISDOM) [55]	6,498 women, mean age 62.8 years	2196 women were randomised to either estrogen only therapy (CEE 0.625 mg orally daily) or combined hormone therapy (CEE plus MPA 2.5/5.0 mg orally daily) and 2189 to matched placebo	Major cardiovascular events, venous thromboembolism, cancer	Major cardiovascular events (7 vs 0; p=0.016) Venous thromboembolism HR: 7.36; 95% CI: 2.20 to 24.60 Cancer: HR: 0.88; 95%CI: 0.49 to 1.56 Cerebrovascular events: HR: 0.73; 95%CI: 0.37 to 1.46 Fractures: HR: 0.69; 95%CI: 0.46 to 1.03 Mortality: HR: 1.60; 95%CI: 0.52 to 4.89

^*CEE: conjugated equine estrogen; MPA: medroxyprogesterone acetate; CIMT: carotid intima media thickness; HR: hazard ratio; DVT: deep vein thrombosis; RH: relative hazard