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Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial

BMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e6409 (Published 09 October 2012) Cite this as: BMJ 2012;345:e6409
  1. Louise Lind Schierbeck, registrar1,
  2. Lars Rejnmark, associate professor, consultant2,
  3. Charlotte Landbo Tofteng, staff specialist 11,
  4. Lis Stilgren, consultant3,
  5. Pia Eiken, consultant, senior endocrinologist4,
  6. Leif Mosekilde, professor, senior consultant2,
  7. Lars Køber, professor, consultant5,
  8. Jens-Erik Beck Jensen, associate professor, consultant1
  1. 1Department of Endocrinology, Hvidovre Hospital, Kettegård alle 30, 2650 Hvidovre, Denmark
  2. 2Department of Medicine and Department of Endocrinology and Internal Medicine, Århus University Hospital, Åarhus, Denmark
  3. 3Department of Endocrinology, Svendborg Hospital, Svendborg, Denmark
  4. 4Department of Cardiology, Nephrology, and Endocrinology, Hillerød Hospital, Hillerød, Denmark
  5. 5Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
  1. Correspondence to: L L Schierbeck louise.schierbeck{at}gmail.com
  • Accepted 16 September 2012

Abstract

Objective To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women.

Design Open label, randomised controlled trial.

Setting Denmark, 1990-93.

Participants 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.

Interventions 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.

Main outcome measure 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.

Trial registration ClinicalTrials.gov NCT00252408.

Footnotes

  • Novo Nordisk, Novartis, and Leo Pharma Denmark provided the study drug free of charge.

  • Contributors: LM contributed to the original design. J-EBJ, LLS, and LK planned the present study. LM, PE, LLS, CLT, LR, and J-EBJ implemented the study at different sites. LR retrieved data from national registers. LR, LK, CLT, and LLS organised the database. LLS and LK had principal responsibility for the statistical analysis of the data and are the guarantors. LLS, LK, LR, and J-EBJ were active in the interpretation of the results. The manuscript was drafted by LLS and reviewed by all authors. All authors have approved the final report.

  • Funding: This study was funded by the University of Aarhus, Karen Elise Jensen’s Foundation, Novo Nordic, Novartis, and LEO Pharma. None of the funders had any influence on the study design, interpretation of data, or the decision to publish the results.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: PE is on the advisory board of Nycomed, Novartis and is involved in the speaker’s bureau with Amgen, Novartis, Eli Lilly, and GSK; J-EBJ is on the advisory board and speaker’s bureau of Nycomed, Eli Lilly, Novartis, MSD, and Amgen; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This study was approved by the Danish National Committee on Health Research Ethics in 1990.

  • Data sharing: Additional data from the study database are available on request from the corresponding author louise.schierbeck{at}gmail.com.

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