title: Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial.
abstract: OBJECTIVE
  To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women.
  
  
  METHODS
  Open label, randomised controlled trial.
  
  
  METHODS
  Denmark, 1990-93.
  
  
  METHODS
  1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values. 502 women were randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control). Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded values for postmenopausal serum follicle stimulating hormone.
  
  
  METHODS
  In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped after about 11 years owing to adverse reports from other trials, 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.
  
  
  METHODS
  The primary endpoint was a composite of death, admission to hospital for heart failure, and myocardial infarction.
  
  
  RESULTS
  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 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 v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 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 v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 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.
  
  
  CONCLUSIONS
  After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00252408.
authors.affiliation: Department of Endocrinology, Hvidovre Hospital, Kettegård alle 30, 2650 Hvidovre, Denmark. louise.schierbeck@gmail.com
authors.forename: Louise Lind
authors.initials: LL
authors.lastname: Schierbeck
authors.forename: Lars
authors.initials: L
authors.lastname: Rejnmark
authors.forename: Charlotte Landbo
authors.initials: CL
authors.lastname: Tofteng
authors.forename: Lis
authors.initials: L
authors.lastname: Stilgren
authors.forename: Pia
authors.initials: P
authors.lastname: Eiken
authors.forename: Leif
authors.initials: L
authors.lastname: Mosekilde
authors.forename: Lars
authors.initials: L
authors.lastname: Køber
authors.forename: Jens-Erik Beck
authors.initials: JE
authors.lastname: Jensen
mesh_terms: D001943:Breast Neoplasms / Q000401:mortality; D003280:Contraceptives, Oral, Synthetic / Q000627:therapeutic use; D003718:Denmark / Q000453:epidemiology; D004958:Estradiol / Q000627:therapeutic use; D004967:Estrogens / Q000627:therapeutic use; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D005500:Follow-Up Studies; D006333:Heart Failure / Q000401:mortality*; D020249:Hormone Replacement Therapy / Q000009:adverse effects / Q000379:methods / Q000401:mortality*; D006760:Hospitalization; D006801:Humans; D008875:Middle Aged; D009203:Myocardial Infarction / Q000401:mortality*; D009369:Neoplasms / Q000401:mortality*; D009640:Norethindrone / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077563:Norethindrone Acetate; D017698:Postmenopause; D011446:Prospective Studies; D012306:Risk; D020521:Stroke / Q000453:epidemiology; D013997:Time Factors; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000401:mortality
chemical_list: D003280:Contraceptives, Oral, Synthetic; D004967:Estrogens; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D000077563:Norethindrone Acetate; D009640:Norethindrone