1 Hormone Replacement Therapy (HRT)

2 Recent MHRA/CHM advice Drug Safety Update 2007; 1(2):2-4 The decision to prescribe HRT should be based on a thorough evaluation of the potential benefits and potential risks of treatment. Healthcare professionals should assess every womans overall risk, including cardiovascular risk, particularly in those older than 60 years who have increased baseline risk of serious adverse events. Evidence for the risks of HRT in women who had premature menopause is limited. However, the baseline risk of adverse events in these younger women is low, and the balance of benefits and risks may be more favourable than in older women.

3 Benefits from HRT Drug Safety Update 2007; 1(2):2-4 Menopausal symptoms HRT effectively relieves vasomotor symptoms. In most cases, 2–3 years therapy is sufficient, but some women may need longer. For all women, the lowest effective dose should be used for the shortest time. Osteoporosis HRT is effective for prevention of osteoporosis, but its beneficial effect on bone diminishes soon after stopping treatment. Because of the risks associated with long-term use, HRT should be used for prevention of osteoporosis only in women who are unable to use other medicines that are authorised for this purpose.

4 Effects on fracture of the femur Drug Safety Update 2007; 1(2):2-4 From placebo group in oestrogen-only arm of WHI From placebo group in oestrogen+progestogen arm of WHI

5 Harms from HRT – cancers Drug Safety Update 2007; 1(2):2-4 Breast cancer The risk of breast cancer is increased in women who take HRT for several years. Combined HRT has been associated with the highest risk. For oestrogen-only HRT, risk is lower than with combined HRT. Some studies have not shown an increased risk for oestrogen- only HRT. Risk increases with duration of use and returns to baseline within a few years of stopping treatment. HRT, especially combined therapy, may increase mammographic density, which may adversely affect radiological detection of breast cancer. Ovarian cancer Observational studies suggest that long-term use of oestrogen- only or combined HRT may be associated with a small increased risk of ovarian cancer. Risk returns to baseline a few years after stopping treatment.

6 Effects on cancers Drug Safety Update 2007; 1(2):2-4

7 Harms from HRT – CV disease (1) Drug Safety Update 2007; 1(2):2-4 Coronary heart disease (CHD) RCTs found increased CHD risk in women who started combined HRT more than 10 years after menopause. Very few RCTs have assessed younger, newly menopausal women, and some have suggested a lower relative risk in these women compared with older women. The low baseline risk of CHD in most younger women, and the very low attributable risk due to HRT, means that their overall CHD risk is likely to be low. No increased risk of CHD with use of oestrogen-only HRT has been identified to date. Importantly, there are no data from RCTs to suggest a cardiovascular benefit with oestrogen-only or combined HRT. Healthcare professionals should assess carefully every womans risk of CHD before prescribing HRT, irrespective of her age or time since menopause.

8 Harms from HRT – CV disease (2) Drug Safety Update 2007; 1(2):2-4 Stroke Increased risk of stroke (mostly ischaemic) with oestrogen-only and combined HRT. Increase in relative risk similar irrespective of age. Baseline risk of stroke increases with age and therefore older women have a greater absolute risk. Limited observational data suggest that stroke risk may depend on oestrogen dose. Venous thromboembolism (VTE) Oral HRT increases the risk of VTE (DVT or PE). Events are more likely in the first year of use. Risk appears higher with combined HRT than with oestrogen-only HRT. Risk associated with other routes of administration not established, but it may be lower with transdermal HRT.

9 Effects on CVD Drug Safety Update 2007; 1(2):2-4

10 Alternatives to HRT CKS guidance. January 2008 For many women, lifestyle adjustments, education, and reassurance may be sufficient. Vaginal lubricants and vaginal moisturizers can help ease vaginal dryness and related symptoms. Other potential treatments for menopausal symptoms include tibolone, clonidine, various antidepressants and testosterone. Complementary therapies are widely used, but are not recommended –few efficacy or safety data available –some herbs e.g. soy foods, gingseng, black cohosh and red clover have oestrogenic properties –Black cohosh also possibly associated with hepatic impairment EMEA Committee on Herbal Medicinal Products (HMPC)

11 Benefits and risks of tibolone Drug Safety Update 2007; 1(2):5-6 Benefit-risk balance in licensed indications In younger women, the risk profile of tibolone is broadly similar to that for conventional combined HRT. For women older than about 60 years, the risks associated with tibolone start to outweigh the benefits because of the increased risk of stroke. Before starting tibolone, every womans overall risk of stroke, breast cancer, and, in those with an intact uterus, endometrial cancer should be assessed carefully, taking into consideration any baseline risk factors, the increased risk due to tibolone use, and her therapeutic preferences. Healthcare professionals should weigh the increased risk of stroke with tibolone against the increased risk of breast cancer with combined HRT for women with a uterus.

12 Results from the WHI trial JAMA 2002;288: HR for HRT vs. Placebo (95%CI) Events per 10,000py for placebo Events per 10,000py for HRT Excess events per 10,000 py CHD (non-fatal MI & CHD death) 1.29 ( ) Stroke1.41 ( ) Breast cancer1.26 ( ) VTE2.11 ( ) Hip fracture0.66 ( ) Colorectal cancer 0.63 ( ) Total mortality0.98 ( ) 5352NS

13 Summary 80% of women experience menopausal symptoms and 45% find them distressing. For many women, lifestyle adjustments, education, and reassurance are sufficient. HRT is the main treatment –Tibolone is an alternative, but note risks and benefits. For individual women, need to weigh benefits of HRT against side-effects. Reassess appropriateness of treatment annually –Treatment longer than 5 years needs careful thought.