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NICE sets out its stall on the menopause

NICE, the UK’s The National Institute for Health and Care Excellence, opened a six-week public consultation on its draft menopause guidelines in June. ¹ Publication is expected in November this year. The much anticipated text, which in its ‘short version’ draft format runs to 38 pages, covers diagnosis and management and is, said NICE’s clinical practice director, ‘the first guideline for the NHS on diagnosing and managing menopause’. Included in the draft is also advice to be given to women likely to go through menopause as a result of medical or surgical treatment, including those with cancer, at high risk of hormone-dependent cancer or having gynaecological surgery. Indeed, the draft cross-refers to NICE’s clinical guideline (CG80) on early and locally advanced breast cancer, and on familial breast cancer (CG164).

The draft begins with a recognition that the menopause is widespread (around a million UK women use treatment for symptoms), is varied in its symptoms, and may severely affect quality of life. Indeed, said NICE in a press statement, ‘the effects of menopause are often misunderstood and underestimated’.

As expected, hormone therapy (HRT) – or at least the controversies associated with its use – occupy a large chunk of the draft, and here too NICE seems to take an open view, noting that ‘the balance of benefits and risks of HRT use has yet to be confirmed for both patients and their healthcare providers’. However, on the thorny question of cardiovascular disease, the draft does quite clearly state that ‘HRT does not increase cardiovascular disease risk when started in women aged under 60 years’ and ‘does not affect the risk of dying from cardiovascular disease’. The draft adds that professionals ‘should be aware that cardiovascular risk factors (for example hypertension) do not automatically preclude a woman from taking HRT’, while adding the caveat that such risks ‘should be taken into account’. Nevertheless, with evidence of absolute risk rates from several randomised trials and observational studies arranged in patient-friendly tables, the draft concludes that in women aged 50 to 59 ‘HRT with oestrogen alone is associated with no, or reduced, risk of coronary heart disease’ and that ‘HRT with oestrogen and progestogen … with little or no increase’ in risk. Similarly, oral (but not transdermal) oestrogen ‘is associated with a small increase in the risk of stroke’, but that the baseline risk in women under 60 ‘is very low’.

On HRT’s association with breast cancer, which was, let’s not forget, the headline reason for alarm following publication of the first Women’s Health Initiative report in 2002, the draft states that

HRT does not affect the risk of dying from breast cancer … that HRT with oestrogen alone is associated with little or no increase in risk … but that HRT with oestrogen and progestogen can be associated with an increase in the risk of breast cancer.

This risk ‘is related to treatment duration and reduces after stopping HRT’.

Such statements seem a far cry from those first alarmist headlines of a decade ago, which, even NICE admits, prompted a fall in HRT use by almost a half. Both the WHI and Million Women Study, says the draft, focused on disease prevention and did not consider ‘the benefits in terms of symptom relief’. HRT (oral or transdermal) is thus identified as the treatment of choice for short-term menopausal symptoms; ‘doctors are advised to not routinely offer selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) as first-line treatment for vasomotor symptoms alone.’

Indeed, even for psychological symptoms HRT and cognitive behavioural therapy seem preferred to SSRIs and SNRIs (‘no clear evidence … to ease low mood’).

The draft offers detailed advice on diagnosis, particularly in the possibility of premature ovarian insufficiency, which should not be diagnosed ‘on the basis of a single blood test’. Advice is to base diagnosis on cycle history and follicle stimulating hormone (FSH) levels from two blood samples taken four to six weeks apart.

The draft ends with questions for research, which, despite the many millions so far spent, seem still clustered around HRT and its long-term safety: breast cancer risk, venous thromboembolism risk and dementia risk. The draft also asks for more evidence on the main clinical manifestations of premature ovarian insufficiency and the short- and long-term impact of the most common therapeutic interventions.

Fracture risk and SSRIs for vasomotor symptoms

Hot on the heels of NICE’s thumbs down for SSRIs as a front-line treatment for menopausal symptoms came a report in the peer-reviewed but little known BMJ journal Injury Prevention (impact factor 1.891) on the risk of fractures associated with SSRIs. ¹ However, with a press release issued by the publishers ever eager for publicity, the study was widely reported in the UK press, even if funded by the National Institutes of Health and performed in the USA.

As background to the study the press release notes that ‘SSRIs are seen as an effective alternative to hormone replacement therapy (HRT)’, seemingly reflecting more a US observation than UK. Indeed, the SSRI paroxetine was recently approved by the FDA to treat vasomotor symptoms associated with the menopause, the only non-hormonal therapy so licensed. ² A comment on the latest UK press reports by NHS Direct said that ‘in the UK SSRIs are prescribed to treat depression and various other mental health problems, though some consultants do use them off-licence for menopausal symptoms in certain cases'. ³

The study – observational in design – included 137,031 women with no mental health problems aged between 40 and 64, who started SSRIs between 1998 and 2010. They were compared with 236,294 women of the same age prescribed H2 antagonists or proton pump inhibitors (PPIs), over the same period. Analysis of the data showed that fracture rates were significantly higher among the women treated with SSRIs – 76% higher after one year, 73% higher after two years and 67% higher after five years than it was among those taking the H2 antagonists and PPIs. However, the relative risk difference was statistically significant only after the second year, suggesting SSRIs may need several months to produce clinically meaningful effects on bone mineral density.

Thus, based on their results, the authors suggest that ‘shorter duration of treatment might mitigate the risk of developing excess fractures’. Moreover, they note that,

since the number of SSRI users without psychiatric disorders is expected to increase following the FDA approval of paroxetine for the treatment of vasomotor symptoms, particularly at lower doses, future efforts should be made to examine how SSRI dose (cumulative, daily or both) might modify fracture risk over time.

In the UK, SSRIs are used mainly in the treatment of depression and other psychiatric conditions. Because this study was only in US women without mental health disorders, it won’t tell UK doctors much about risks in their patients routinely prescribed SSRIs. There is, however, some evidence of an association with fracture risk in patients with mental health disorders, and the authors say the higher risk is consistent with the biological hypothesis that fractures associated with SSRI use ‘can be at least partially attributed to anti-depressant modulation of bone homeostasis in favour of osteoclastic activity’ – which would result in lower bone mineral density.

Cardiovascular disease remains number one killer for UK women

A remarkable epidemiological analysis of several UK data sources shows that for the first time since the mid-1990s cardiovascular disease (CVD) has been overtaken by cancer as Britain’s leading overall cause of death – with 28% of deaths caused by CVD in 2012 and 29% by cancer. However, when analysed by gender, CVD was still the greatest cause of death in women, especially in younger women in whom CVD still kills more than breast cancer.

Most of these CVD deaths in young women are caused by myocardial infarction, which, an accompanying editorial notes, ‘is largely preventable’ through modification of risk factors. ² Thus, the editorial continues,

if the national effort put into the detection of breast cancer could be matched in protecting young women against myocardial infarction many more lives would probably be saved. People think that CVD continues to be a problem for men, not women. This perception is wrong when CVD is killing more women than men - and more young women than are dying from breast cancer.

However, these gender-specific trends must be seen against a background of declining CVD mortality in the overall population over the past 50 years. According to British Heart Foundation figures, age-standardised mortality rates for CVD today are around 50% lower than in 1961 for men and women, and total CVD deaths for both sexes have fallen by more than 40%, driven largely by gender-comparable declines in coronary heart disease and stroke mortality. ‘These UK mortality trends for CVD must rank among the greatest public health triumphs in the past 50 years,’ notes the accompanying editorial.

The reasons for the change in trends, of course, are the result of both treatment and prevention. A study of 2004 estimated that 58% of the decline in deaths from CHD between 1981 and 2000 was due to improvements in risk factors, such as smoking, and 48% due to treatments, particularly percutaneous coronary interventions, which in 2011 was deemed more cost effective than coronary bypass surgery. However, this report also makes it clear – from UK prescription data – that fewer women than men are prescribed CVD-related medicines, notably lipid lowering (16% men, 12% women), antiplatelet and antidiabetic medications. Only antihypertensives were prescribed more to women than to men.