British Menopause Society respond to letter from MHRA

Published: 29th October 2019

In September, the British Menopause Society wrote to the Medicines and Healthcare Products Regulatory Agency (MHRA) using the Freedom of Information Act to raise concerns about the recently issued 'drug safety alert' concerning HRT. The MHRA issued new recommendations to GPs as a result of a study published online in the Lancet in August, linking Hormone Replacement Therapy to an increased risk of breast cancer.

One month later, the MHRA issued their response. The medical advisory council of the BMS has reviewed these responses and the following letter was sent to Dr June Raine, interim CEO of the MHRA:

25 October 2019

Dr June Raine
Interim Chief Executive Officer
MHRA

Dear Dr Raine,

Thank you for your response dated 7 October 2019 to the queries raised by the British Menopause Society and our Freedom of Information request dated 9th September.

We would like to raise two further Freedom of Information requests and some further queries in response to the comments raised in your reply.

Under the Freedom of Information Act the British Menopause Society would like to raise the following requests for information:-

1. The MHRA update recommended using the lowest dose of HRT. However, the Lancet paper that the recommendation was based on, did not demonstrate a dosage effect. Please can you provide information upon what evidence the MHRA recommendation was based.

2. The MHRA response indicated that the relative risk of coronary artery disease during use of combined oestrogen-progestogen HRT was slightly increased. Please can you provide information upon what evidence the MHRA recommendation was based.

The British Menopause Society would also appreciate comments and clarification from the MHRA on the following points:-

1. The MHRA response indicated that additional senior experts in statistics and epidemiology were invited to further input into the interpretation of the findings from the Lancet paper.

It also indicated that there were menopause experts on the panel, but we do not see evidence of this. We believe an expert would be someone with considerable experience coupled with a substantial academic output in the field.

We do believe it would be helpful if the MHRA would consider discussing the findings from the Lancet paper and their application with senior academic menopause experts from the relevant advisory bodies. This would follow the same concept to that used for statistics and epidemiology and would be very useful given the complexity of the data and the potential impact of the recommendations on clinical practice and on menopause care provision, as well as the advice that women may receive following on from the updated MHRA recommendations.

Please can the MHRA advise if it would consider discussing the findings from the Lancet paper and their application with senior academic menopause experts from the relevant advisory bodies.

2. The MHRA indicated in their response to the British Menopause Society that the conclusion of the Boardman et al. 2015 Cochrane showed no cardiovascular benefit with HRT.

The conclusion of the Cochrane analysis, however, was for the overall review (women who commenced HRT under the age of 60 and those who commenced HRT after the age of 60 combined). The Cochrane review abstract and main text demonstrated a significant reduction in cardiovascular events, cardiovascular mortality and all-cause mortality in women who commenced HRT within 10 years of onset of menopause compared to placebo, as referred to in the next point below.

Please could the MHRA confirm that it does recognise that the Cochrane analysis showed a significant reduction in cardiovascular events, cardiovascular mortality and all-cause mortality in women who commenced HRT under the age of 60 as referred to above.

3. The MHRA indicated in their response to the British Menopause Society that the reports on the cardiovascular benefits with HRT were from subgroup analysis and included small numbers in each group.

However, the Cochrane analysis findings that showed reduction in all-cause mortality were from placebo controlled RCTs with a total number of 9,088 women. This showed a significant reduction in all-cause mortality of 16/1000 with HRT compared to 22/1000 with placebo. RR 0.70, 95%CI 0.52 to 0.95.

The Cochrane analysis also noted a significant reduction in coronary heart disease (including reduction in cardiovascular mortality) from placebo controlled RCTs including a total of 8,311 women. This showed a significant reduction in coronary heart disease (death from cardiovascular causes and non-fatal myocardial infarction) of 10/1000 with HRT compared to 18/1000 with placebo. RR 0.52, 95%CI 0.29 to 0.96.

For the group of women who commenced HRT more than 10 years after the menopause, both WHI long-term-follow up and Cochrane analysis showed no significant reduction, but relevant to mention, no significant increase in the risk of cardiovascular events, cardiovascular mortality or all-cause mortality in women who started HRT beyond the age of 60.

The Cochrane analysis was also supported by data from the Finnish nationwide reimbursement register and the Finnish national Cause of Death Register reported by Mikkola et al. 2015. A total of 489,105 women who used HRT from 1994 to 2009 (3.3 million HRT exposure years) were included. Cardiovascular mortality was significantly reduced by 18% to 54% in HRT users compared to age-matched background population. The risk of stroke death was also reduced by 18% to 39%. Risk of all-cause mortality in HRT users was reduced by 12% to 38%. In absolute terms, among 1,000 women using any HRT for at least 10 years, the risk reductions indicated 19 fewer deaths related to cardiovascular disease and 7 fewer stroke related deaths.

Further, Salpeter et al. 2009 reported a meta-analysis that included pooled data from 19 randomised trials that included 16,000 women (mean age 55 years) followed up for 83,000 patient-years. The study showed a significant reduction in all-cause mortality with HRT intake compared to no treatment (RR 0.73, 95%CI 0.52 to 0.96). A similar conclusion was noted when data from 8 observational studies were added to the analysis (RR 0.72, 95%CI 0.62 to 0.82).

In addition, a recent long-term FU report from the WHI study by Manson et al. 2019 included a total sample size of 9,939 women aged 50-79 and of these 1,129 women were aged 50-59. The report showed a significant reduction in all-cause mortality HR 0.68, 95%CI 0.48 to 0.96 in women aged 50-59 who received oestrogen therapy after bilateral salpingo-oophorectomy compared to those who received placebo.

Please could the MHRA confirm that it does recognise the above Cochrane review findings, the evidence by Mikkola et al. 2015 and Salpeter et al. 2009 as well as the WHI findings by Manson et al. 2019 and the significant reduction in cardiovascular mortality and all-cause mortality associated with HRT intake noted in these reports.

4. The MHRA response indicated that the relative risk of coronary artery disease during use of combined oestrogen-progestogen HRT is slightly increased.

Cardiovascular disease remains a leading cause for morbidity and mortality in women. The British Heart Foundation has indicated that 24,000 women die from coronary heart disease each year in the UK, more than double the number of deaths associated with breast cancer reported to be approximately 11,400 women per year. Given the potential cardiovascular beneficial effects reported with HRT initiated in women under the age of 60, as referred to above, this is a further aspect that should be considered as part of the benefits / risks assessment when counselling women about HRT.

In addition to the potential cardiovascular benefits, HRT has been shown to have a significant protective effect against osteoporosis and related fragility fractures.

Osteoporosis is estimated to affect more than two million women in England and Wales. It is estimated that 1 in 2 women in the UK will suffer a fracture after the age of 50 and the International Osteoporosis Foundation reports that a 50 year old woman has a 2.8% risk of death related to hip fracture during her remaining lifetime. The National Osteoporosis Guideline Group (NOGG) estimates there are 536,000 fractures every year in the UK caused by osteoporosis and mortality rates with femur fractures are estimated to be 20% within the first year.

The NICE menopause guideline review assessed 20 RCTs that included sample sizes from 36 to 16,608 cases and 21 comparative cohort studies which included sample sizes from 157 to 170,852 cases. The evidence from RCTs in women in current users of HRT showed a significant reduction in the risk of any fracture compared with women not using HRT. The evidence from comparative cohort studies showed reduced risk of any and all fractures with current HRT use compared with non-use of HRT, whether previous or never use.

A systematic review and meta-analysis by Zhu et al. 2015 included a total of 28 studies with 33,426 participants and 2,516 fracture cases. Their meta-analysis noted a significant reduction in total fractures with HRT (RR 0.74, 95%CI 0.69 to 0.80), hip fractures (RR 0.72, 95%CI 0.53 to 0.98 as well as for vertebral fractures (RR 0.63, 95% CI 0.44 to 0.91).

In addition, to the above, it is also very relevant to make reference to the impact of the menopause on women’s quality of life and the beneficial effect that HRT has in that respect. Menopausal symptoms affect 70-80% of all women and these are described as severe in 25%. The average duration of menopausal symptoms has been reported to be 7 years with up to a third of women reported to experience symptoms beyond that. A national survey by the British Menopause Society in 2016 showed that women reported on average 7 menopause related symptoms with 79% experiencing vasomotor symptoms, 22% experiencing unexpected sleeping problems / insomnia, 20% experiencing difficulty with memory / concentration and 18% experiencing unexpected joint aches. 42% of women indicated that the symptoms were worse or much worse than suspected. 50% of women said their symptoms had impacted their home life and 36% said the menopause impacted their social life.

Does the MHRA recognise that there are other potential benefits from taking HRT that women should be counselled about and that advice to women should not be focused solely on the risks of breast cancer, but on the overall benefits / risks on an individualised basis?

5. We would like to highlight that some of the studies included in the Lancet meta-analysis had methodological limitations. A key example of this is that one of the main studies contributing to the meta-analysis had a significantly increased risk of breast cancer at 4 months from commencement of recruitment (RR 1.19, 95%CI 1.09 to 1.30 for users of oestrogen-only and RR 1.41, 95%CI 1.31 to 1.52 for users of combined HRT). It is highly unlikely that breast cancer would develop within 4 months from recruitment and this would therefore suggest that a significant proportion of women had breast cancer at the time of entry into the study; this should be considered when interpreting the findings from the meta-analysis.

Does the MHRA recognise this limitation and its potential impact on the interpretation of the findings of the Lancet meta-analysis?

The British Menopause Society remains of the view that the meta-analysis reported in the Lancet provides important additional information on the risk of breast cancer with HRT. However, the British Menopause Society strongly feels that this should not be interpreted in isolation and needs to be discussed in the context of the overall benefits and risks associated with HRT to help women make an informed choice.

We believe that no arbitrary limits should be placed on the dose or duration of usage of HRT. This decision should be made on an individualised basis after discussing the benefits and risks with each patient and should be considered in the context of the overall benefits obtained from using HRT including symptom management and improved quality of life as well as the cardiovascular and bone protective effects associated with HRT.

The British Menopause Society looks forward to receiving the information that it has requested above under the Freedom of Information Act and to the comments of the MHRA on the other points that have been raised in this letter.

Yours sincerely
Mr Haitham Hamoda Chairman
British Menopause Society
E: haitham.hamoda@nhs.net

Ms Sara Moger
Chief Executive
British Menopause Society
E: sara.moger@bms-whc.org.uk

On behalf of the Medical Advisory Council of the British Menopause Society

References:

1. Boardman HM, Hartley L, Eisinga A, et al. Hormone therapy for preventing cardiovascular disease in postmenopausal women. Cochrane Database Syst Rev 2015; 3: CD002229.

2. Manson JE, Aragaki AK, Bassuk SS et al. WHI Investigators. Menopausal Estrogen-Alone Therapy and Health Outcomes in Women With and Without Bilateral Oophorectomy: A Randomized Trial. Ann Intern Med. 2019 (Ahead of print). doi: 10.7326/M19-0274.

3. Mikkola TS, Tuomikoski P, Lyytinen H et al. Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality. Menopause. 2015 Sep;22(9):976- 83. doi:

10.1097/GME.0000000000000450.

4. Salpeter SR, Cheng J, Thabane L et al. Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women. Am J Med. 2009 Nov;122(11):1016-1022.e1. doi: 10.1016/j.amjmed.2009.05.021.

5. National Institute for Health and Care Excellence. Menopause: clinical guideline – methods, evidence and recommendations, (NG23), Version 1.5, www.nice.org.uk/guidance/ng23/evidence/fullguideline-559549261.

6. Zhu L, Jiang X, Sun Y, Shu W. Effect of hormone therapy on the risk of bone fractures: a systematic review and meta-analysis of randomized controlled trials. Menopause. 2016; 23(4):461-70. doi: 10.1097/GME.0000000000000519.

7. Avis NE, Carolina N and Crawford SL. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA 2015; 175: 531–539.

8. The British Menopause Society. https://thebms.org.uk/wp-content/uploads/2016/04/BMS- NationalSurvey-MARCH2017.pdf

9. Beral V, Reeves G, Bull D, Green J; Million Women Study Collaborators. Breast cancer risk in relation to the interval between menopause and starting hormone therapy. J Natl Cancer Inst. 2011; 103(4):296-305. doi: 10.1093/jnci/djq527.