Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal womenBMJ 2007; 335 doi: https://doi.org/10.1136/bmj.39266.425069.AD (Published 02 August 2007) Cite this as: BMJ 2007;335:239
- Madge R Vickers, former head, MRC general practice research framework1,
- Alastair H MacLennan, professor, department of obstetrics and gynaecology2,
- Beverley Lawton, director women's health research centre3,
- Deborah Ford, senior statistician4,
- Jeannett Martin, former senior nurse manager1,
- Sarah K Meredith, senior clinical epidemiologist4,
- Bianca L DeStavola, reader in biostatistics5,
- Sally Rose, research fellow3,
- Anthony Dowell, professor3,
- Helen C Wilkes, senior statistician4,
- Janet H Darbyshire, director4,
- Tom W Meade, emeritus professor5
- WISDOM group
- 1MRC General Practice Research Framework, Stephenson House, London NW1 2ND
- 2University of Adelaide, Women's and Children's Hospital, Adelaide SA 5006, Australia
- 3Department of Primary Health Care and General Practice, Wellington School of Medicine and Health Sciences, New Zealand
- 4MRC Clinical Trials Unit, London NW1 2DA
- 5Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT
- Correspondence to: A H MacLennan
- Accepted 2 July 2007
Objective To assess the long term risks and benefits of hormone replacement therapy (combined hormone therapy versus placebo, and oestrogen alone versus combined hormone therapy).
Design Multicentre, randomised, placebo controlled, double blind trial.
Setting General practices in UK (384), Australia (91), and New Zealand (24).
Participants Postmenopausal women aged 50-69 years at randomisation. At early closure of the trial, 56 583 had been screened, 8980 entered run-in, and 5692 (26% of target of 22 300) started treatment.
Interventions Oestrogen only therapy (conjugated equine oestrogens 0.625 mg orally daily) or combined hormone therapy (conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily). Ten years of treatment planned.
Main outcome measures Primary outcomes: major cardiovascular disease, osteoporotic fractures, and breast cancer. Secondary outcomes: other cancers, death from all causes, venous thromboembolism, cerebrovascular disease, dementia, and quality of life.
Results The trial was prematurely closed during recruitment, after a median follow-up of 11.9 months (interquartile range 7.1-19.6, total 6498 women years) in those enrolled, after the publication of early results from the women's health initiative study. The mean age of randomised women was 62.8 (SD 4.8) years. When combined hormone therapy (n=2196) was compared with placebo (n=2189), there was a significant increase in the number of major cardiovascular events (7 v 0, P=0.016) and venous thromboembolisms (22 v 3, hazard ratio 7.36 (95% CI 2.20 to 24.60)). There were no statistically significant differences in numbers of breast or other cancers (22 v 25, hazard ratio 0.88 (0.49 to 1.56)), cerebrovascular events (14 v 19, 0.73 (0.37 to 1.46)), fractures (40 v 58, 0.69 (0.46 to 1.03)), and overall deaths (8 v 5, 1.60 (0.52 to 4.89)). Comparison of combined hormone therapy (n=815) versus oestrogen therapy (n=826) outcomes revealed no significant differences.
Conclusions Hormone replacement therapy increases cardiovascular and thromboembolic risk when started many years after the menopause. The results are consistent with the findings of the women's health initiative study and secondary prevention studies. Research is needed to assess the long term risks and benefits of starting hormone replacement therapy near the menopause, when the effect may be different.
Trial registration Current Controlled Trials ISRCTN 63718836
We thank all the research nurses, general practitioners, practice staff, and, in particular, the women who kindly participated in WISDOM.
Contributors: MRV was the principal investigator for WISDOM; wrote the application for funding with HCW and TWM; grantee of UK funding; responsible for trial design, protocol development, trial procedures, and overall management; contributed to data analysis and interpretation; and drafted the paper and contributed to the final report. AHM was the principal investigator in Australia; contributed to trial design, trial procedures, analyses, and interpretation of data; grantee of Australian funding; and corresponding author of final paper. BL was the co-principal investigator in New Zealand; contributed to the trial design, trial procedures, interpretation of data; and management of trial conduct and cessation; grantee of New Zealand funding. DF contributed to the trial protocol, trial procedures, data management, analyses and interpretation of data, and writing of the final report. JM was responsible for training and coordination of UK research nurses and quality control and contributed to the analysis and writing of the final report. SKM was co-investigator and clinical epidemiologist; contributed to trial design, trial procedures, analyses and interpretation of data, and writing the final report. BLDeS supervised data management and carried out statistical analyses and contributed to presentation and interpretation of the results and to writing of the final report. SR was co-investigator and project manager of the trial in New Zealand; contributed to the trial design, interpretation of data, and management of trial conduct and cessation. AD was joint principal investigator in New Zealand; contributed to trial design, trial procedures, interpretation of data, and management of trial conduct and cessation. HCW was responsible for statistical design including pilot studies, trial protocol and procedures, data management, analysis and writing of report; UK funding grantee. JHD was principal investigator in UK after retirement of TWM; contributed to later trial management, data analysis, and writing of final report. TWM was principal investigator in UK and grantee of UK funding; contributed to trial design, management, and writing of the final report.
Other members of the WISDOM team. Abdalla M, statistical analysis, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine. Allen P, Balen H, Bastick R, Brown H, Foulger K, Fox S, Glynn V, Hall A, Hand L, Hill A, Leathem C, Mackinnon W, Marshall E, Williams A, regional training nurses; Collins N, O'Conner B, trial managers; Ghali M, Furness P, Islam MZ, software design for electronic data collection and management; Harrild K, statistical analysis and data management; Knott C, Taylor L, implementation of trial protocol and management, research nurse support; Walgrove MA, contributed to protocol, developed manual, nurse support; Welton AJ, contributed to trial protocol and management; Zhu C-Q, statistician; Zuhrie SR, development of trial protocol and medical advice; MRC General Practice Research Framework, London. Griffith E, data manager and pharmacy control; Ryan P, co-investigator in South Australia, co-grantee of Australian funding; Discipline of Public Health, University of Adelaide, Australia. Komesaroff P, senior investigator in Victoria, University of Monash, Victoria, Australia. Marley J, senior investigator in NSW and co-grantee of Australian funding, University of Newcastle, New South Wales, Australia. Paine BJ, trial coordinator, Discipline of Obstetrics and Gynaecology, University of Adelaide. Stocks NP, medical director, Discipline of General Practice, University of Adelaide.
Sources of funding: UK Medical Research Council, British Heart Foundation, Department of Health for England, Scottish Office, Welsh Office, Department of Health and Social Services for Northern Ireland, Royal Australian and New Zealand College of Obstetricians and Gynaecologists, Australasian Menopause Society, National Health and Medical Research Council (NHMRC), National Heart Foundation of Australia, The Cancer Council of South Australia, The Cancer Society of New Zealand (Wellington Branch), NHS R&D Executive (service support and excess treatment costs). MRC, in collaboration with the other UK funders, established a Trial Steering Committee (which reported annually to the MRC) with an independent chairman and independent Data Monitoring and Ethics Committee (which considered unblinded group data, took account of external developments relevant to the progress of the trial, and made recommendations to the steering committee). The funders in Australia and New Zealand monitored local progress and received reports on progress from the UK steering committee. The principal investigators from Australia and New Zealand were non-voting members of the UK steering committee.
Competing interests: WISDOM was run and funded independently of industry. The funding bodies had no influence on the results except for the early curtailment of the trial by the MRC. Wyeth Ayerst provided active drugs and matched placebo but had no other involvement in the trial. All authors have declared no direct conflicts of interest. AHM and BL have received research grants and lecture honoraria from a variety of industry sources not associated with WISDOM.
Ethical approval: UK approval was granted by the South Thames Regional Health Authority Multicentre Research Ethics Committees and by the relevant local research ethics committees. Australian approval was given by the human research ethics committees for the universities of Adelaide, Newcastle, and Monash and by the Royal Australian College of General Practitioners' National Research and Evaluation Ethics Committee. New Zealand approval was given by the Wellington Regional Ethics Committee and the Auckland and Canterbury ethics committees.
- Accepted 2 July 2007