Below is a letter from the BMS to the MHRA on the new recommendations for HRT use.
The medical advisory council of the BMS has reviewed the recommendations issued by the Medicines and Healthcare Products Regulatory Agency (MHRA) on 30 August. The following letter was sent to Dr June Raine, interim CEO of the MHRA.
9 September 2019
Dr June Raine
Interim Chief Executive Officer
Dear Dr Raine,
The British Menopause Society is writing to raise serious concerns about the recommendations in the drug safety alert ‘Hormone replacement therapy (HRT): further information on the known increased risk of breast cancer with HRT and its persistence after stopping’, published by the MHRA on 30 August 2019.
This recommendation followed on from a meta-analysis of 24 prospective observational studies published online in the Lancet on 30 August 2019. The median year of diagnosis of breast cancer cases from North America included in the review was 1999 and for the European studies was 2007.
The meta-analysis noted a duration-dependent risk of increased breast cancer diagnosis with both unopposed oestrogen and combined HRT, risk with the latter being greater. A modifying effect was noted for obesity. There was no evidence of a dosage effect and vaginal oestrogen exposure appeared to be without adverse impact. The review only included a small number of women on micronised progesterone.
The overall findings from this meta-analysis are not new and are in keeping with the NICE menopause guideline 2015 recommendations. The review of the observational data by NICE showed similar findings to those reported in the Lancet paper. However, the conclusions in the NICE guideline came from the combined review of the observational and RCT evidence. The latter was not included in the Lancet paper meta-analysis and appears not to have been considered in the MHRA recommendations.
The review did not report on breast cancer mortality. It would be relevant to note that long-term follow up of the Women’s Health Initiative (WHI) RCT up to 13 years showed no significant difference in breast cancer mortality or all-cause mortality with MHT compared to placebo. In addition, WHO and Eurostat data showed a decline in European breast cancer mortality over the last three decades in women of all ages. This steady decline pre-dated by over a decade, the sustained worldwide fall in HRT prescribing following publication of WHI and the Million Women Study in the early 2000s. The reduction is likely to be related to treatment improvements and earlier diagnosis including the impact of screening and is less likely to be related to the changing patterns in HRT use.
The MHRA recommendations indicated that ‘HRT should be used at the lowest dose (amount) for the shortest amount of time’. The Lancet paper that this recommendation was based on, showed no dosage effect with oestrogen. It is, therefore, unclear what evidence this recommendation is based upon.
HRT has been shown to be very effective in controlling troublesome menopausal symptoms that could cause significant distress to many women. In addition, large randomised data have shown a significant beneficial effect of HRT on bone health and a protective effect against osteoporosis. Furthermore, Cochrane analysis in 2015 showed that HRT was associated with a significant reduction in cardiovascular disease, cardiovascular mortality and all-cause mortality in women under the age of 60. The latter was further supported by recent WHI RCT data published this week that showed a decrease in all-cause mortality in women with prior bilateral salpingo-oophorectomy who commenced oestrogen alone HRT between the ages of 50 and 59.
Our view is that this meta-analysis provides important additional information on the risk of breast cancer with HRT that should be explained to women to help them make an informed choice. However, we believe that arbitrary limits should not be placed on the dose or duration of usage of HRT. The decision whether to take HRT, the dose of HRT used and the duration of its use should be made on an individualised basis after discussing the benefits and risks with each patient. This should be considered in the context of the overall benefits obtained from using HRT including symptom control and improving quality of life as well as considering the bone and cardiovascular benefits associated with HRT use.
The British Menopause Society looks forward to receiving your comments on the above and would hope that the MHRA will review its recommendations on this issue.
Mr Haitham Hamoda
British Menopause Society
Ms Sara Moger
British Menopause Society
On behalf of the Medical Advisory Council of the British Menopause Society