The Cochrane review in 2015 includes 19 randomized controlled trials (RCTs) with a total of 40,410 post-menopausal women «Boardman HM, Hartley L, Eisinga A, ym. Hormone the...»1.
In all, 5/19 menopausal hormone therapy (MHT) primary prevention studies included multinational, mainly white (>80%) outpatients whose per oral hormone therapy was initiated under 60 years of age or fewer than 10 years after menopause (mean age 58.2 yrs, n= 29 298).
Intervention: MHT regimens were in e original trial (Danish Osteoporosis Prevention Study, DOPS 2012, n= 1006) 2 mg 17-ß oestradiol +/ norethisterone acetate ) and in four others conjugated equine estrogen CEE+/- medroxyprogesterone acetate (MPA).The review excluded RCTs in which MHT was delivered to the body via either patches, tablets, creams, troches, an intrauterine device, vaginal ring, gels or injections compared with placebo or no treatment. Comparison intervention was placebo or no treatment in all included RCTs.
Those who started MHT less than 10 years after the menopause had lower all-cause mortality (RR 0.70, 95% CI 0.52 to 0.95) and coronary heart disease (CHD) (composite of death from cardiovascular causes and non-fatal myocardial infarction) (RR 0.52, 95% CI 0.29 to 0.96). However, they were at increased risk of venous thromboembolism (RR 1.74, 95% CI 1.11 to 2.73) compared to placebo or no treatment. There was no strong evidence of effect on risk of stroke in this group.
In those who started treatment more than 10 years after the menopause there was high quality evidence that it had little effect on death or CHD between groups but there was an increased risk of stroke (RR 1.21, 95% CI 1.06 to 1.38, high quality evidence) and venous thromboembolism (RR 1.96, 95% CI 1.37 to 2.80, high quality evidence).
Comment: The findings are dominated by the three largest trials using mainly conjugated equine oestrogen (CEE), which is not used in Finland.
Danish Osteoporosis Prevention Study (DOPS), Denmark 1990-93, with 16-year follow-up is an open label, randomised controlled trial «Schierbeck LL, Rejnmark L, Tofteng CL, ym. Effect ...»2, included 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone (S-FSH) values. Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded postmnenopausal values for S-FSH. In all, 502 women were randomly allocated to receive menopausal hormone therapy (MHT) and 504 to receive no treatment (control).
The women in the treated group with an intact uterus started treatment with 2 mg synthetic 17-β-estradiol for 12 days, 2 mg 17-β-estradiol plus 1 mg norethisterone acetate for 10 days, and 1 mg 17-β-estradiol for six days. In women who had undergone hysterectomy, first line treatment was 2 mg 17-β-estradiol a day a total mean follow-up time of 15.8 years.
Intervention was stopped after about 11 years, but participants were followed for death, cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses were carried out on women who took more than 80% of the prescribed treatment for five years.
At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval (CI) 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group versus 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group versus 17 in control group, 0.58, 0.27 to 1.27; P=0.17). The hazard ratio for deep vein thrombosis (2 in treated group versus 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group versus 14 in control group) was 0.77 (0.35 to 1.70). After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer.
Comment: Intervention is comparable with Finnish MHT practice. The study used composite outcome.
The nationwide registry based study «Mikkola TS, Tuomikoski P, Lyytinen H, ym. Estradio...»3 evaluated the risk of death caused by coronary heart disease (CHD), stroke, or any disease among users of estradiol-based menopausal hormone therapy (MHT) in Finland. A total of 489,105 women who used MHT from 1994 to 2009 (3.3 million MHT exposure years), as indicated in the nationwide reimbursement register and the national Cause of Death Register, were followed for 15 years. Mortality risk in MHT users with varying duration of exposure (≤1 y, >1 to 3 y, >3 to 5 y, >5 to 10 y, or >10 y) was compared with that in an age-matched background population including MHT users.
In all, 489 105 women initiated MHT at the mean age of 52.2 years between 1994 and 2009. They used any MHT for a mean of 6.7 years, estrogen therapy (ET) for a mean of 3.9 years, and estrogen-progesteron therapy (EPT) for a mean of 4.5 years. Follow-up comprised 3.3 million MHT exposure years. A total of 28,734 MHT users died during follow-up; among the deaths, 3,843 were caused by CHD and 2,464 were caused by stroke.
Risk of CHD death was reduced in MHT users. The risk reduction (18%) was already significant for HT exposure of 1 year or less, and the risk further decreased with exposure times of more than 1 year to 3 years (33%) and 3 to 5 years (38%). In absolute terms, use of any MHT would mean 2 to 19 fewer CHD deaths per 10,000 follow-up years; use of ET would mean 3 to 24 fewer CHD deaths per 10,000 follow-up years; and use of EPT would mean 2 to 19 fewer CHD deaths per 10,000 follow-up years.
Risk of all-cause mortality was reduced in MHT users by 12% to 38%, almost in linear relationship with duration of exposure. For all-cause mortality, use of any HT would mean 8 to 60 fewer deaths per 10,000 follow-up years; use of ET would mean 12 to 78 fewer deaths per 10,000 follow-up years; and use of EPT would mean 8 to 57 fewer deaths per 10,000 follow-up years.
The risk reductions for CHD, stroke, or all-cause mortality did not differ between women who started use of any HT before age 60 years and women who started use of any HT at age 60 years or older.
Risk of stroke death was also reduced by 18% to 39%, but this reduction was not clearly related to HT exposure time.
Comment: Observational data may be prone to healthy-woman bias.