Publications

Published: November 2003

HRT - New advice from the Medicines Adverse Reactions Committee

Prescriber Update 24(2): 24-25
November 2003

Following consideration of new data, the Medicines Adverse Reactions Committee has updated its advice on the safety of hormone replacement therapy as outlined below:

• Before hormone replacement therapy (HRT) is initiated or continued, women should be advised that the use of HRT is associated with an increased risk of pulmonary embolism, stroke and breast cancer.  These risks increase with age and duration of use.  Additionally, in women aged 65 years and older, HRT use is associated with an increased risk of developing dementia.
• HRT remains an appropriate treatment only for women with moderate to severe vasomotor symptoms of the menopause.  It has no role in the primary or secondary prevention of cardiovascular or cerebrovascular disease.
• HRT should be taken at the lowest dose for the shortest period of time necessary to control symptoms.  The need for continuing treatment should be reviewed at 6-monthly intervals.

New data confirms MARC advice

Since the Medicines Adverse Reactions Committee (MARC) issued its advice¹ about HRT in September 2002, several new studies^2-4 examining the safety of HRT have been reported.  These studies confirm the findings of the WHI study⁵ published in 2002, namely that use of combined oestrogen and progestogen HRT is associated with increased risk of developing breast cancer, stroke, pulmonary embolism and heart disease.

Two studies, the Women's Health Initiative Memory Study⁶ and the Million Women Study³ have provided important new information about the safety of both combined HRT and oestrogen-only HRT.

Use of combined HRT in older women may increase the risk of dementia

The Women's Health Initiative Memory Study⁶ (WHIMS) is a double-blind, placebo-controlled randomised study conducted as an ancillary of the WHI study.⁵  The primary aim of WHIMS was to determine whether treatment with combined HRT decreased the risk of developing dementia from all causes in women aged 65 years and above.  The results of the study demonstrated that combined HRT doubled the risk of developing dementia (RR 2.05; 95% CI 1.21-3.48), predominantly of the Alzheimer's type.  This increased risk would result in an additional 23 cases of dementia per 10,000 women per year.  The risk becomes apparent after one year of treatment with combined HRT.

Increase in breast cancer risk not confined to combined HRT

The Million Women Study³ is an observational study of over one million women aged 50-64 years presenting for routine breast screening in the United Kingdom.  The main aim of the study was to investigate the relationship between various patterns of HRT use and breast cancer incidence and mortality.

The Million Women study provided significant new information demonstrating that:

• the risk of breast cancer first becomes apparent within one to two years of commencing HRT and increases with duration of use;
• use of combined HRT is associated with a higher risk of developing breast cancer (RR 2.00; 95% CI 1.91-2.09, compared to no use) than oestrogen-only regimens (RR 1.30; 95% CI 1.22-1.38, compared to no use);
• all forms of HRT (including continuous and sequential HRT regimens, oestrogen-only HRT, HRT patches and implants) are associated with an increased risk of developing breast cancer;
• use of tibolone (a steroid exhibiting oestrogenic, progestogenic and androgenic activity) is associated with an increased risk of developing breast cancer (RR 1.45; 95% CI 1.25-1.67, compared to no use); and
• the risk of breast cancer decreases after stopping HRT, and within five years the residual risk is not significantly different from that observed for never-users of HRT.

Number of additional breast cancers from HRT use (compared to no HRT use) per 1000 women by age 65³

MARC recommends 6-monthly review of patients on HRT

While the absolute risk of developing breast cancer associated with HRT use is small, the overall benefit-risk assessment for HRT indicates that other than for short-term use, the risks of treatment outweigh the benefits.  The MARC therefore does not recommend the long-term use of HRT and advises that prescribers discuss the need for continued HRT every six months with patients using any HRT regimen.  When a decision is made to stop HRT, it should be withdrawn gradually. Information on how to reduce HRT can be found in the 2002 HRT Guideline Update on the New Zealand Guidelines Group website: www.nzgg.org.nz

References

1. MARC 2002 HRT advice: Letter to health professionals, issued September 2002. www.medsafe.govt.nz/Profs/PUarticles/HRTLtrToDr.htm
2. Chlebowski RT, Hendrix SL, Langer RD, et al for Women's Health Initiative (WHI) Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA 2003;289(3):3243-3253.
3. Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419-427.
4. Li CI, Malone KE, Porter PL, et al. Relationship between long durations and different regimens of hormone therapy and risk of cancer. JAMA 2003;289(24):3254-3263.
5. Writing Group for the Women's Health Initiative (WHI) Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative randomised controlled trial. JAMA 2002;288(3):321-333.
6. Shumaker SA, Legault C, Rapp SR, et al for Women's Health Initiative Memory Study (WHIMS) Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. JAMA 2003;289(20):2651-2662.