Abstract
Introduction
The evidence assessing the venous thromboembolism (VTE) risk associated with hormone replacement therapy (HRT) is presented in the section ‘Long-term risks and benefits of HRT’ [11.1], within the menopause clinical guideline commissioned by the National Institute for Health and Care Excellence. This commentary summarises the review question addressed in the section [11.1.2], levels of evidence [11.1.3], clinical benefits and harms [11.1.7.2 and 11.1.7.5], recommendations [11.1.8] and concludes by presenting the key conclusions [11.1.7.6] and research recommendations [11.1.9] that were presented in this section of the guideline.
The introduction to the section [11.1.1] highlights the increased risk of VTE with HRT use and refers to risk factors for VTE including age, raised body mass index (BMI), immobilisation, surgery, smoking and thrombophilia. The introduction also summarises the pharmacokinetics of metabolism for oral and transdermal oestradiol. It makes reference to oral HRT administration following first-pass liver metabolism, altering the clotting cascade and this would explain the increased risk of thrombosis noted with oral administration. Transdermal oestradiol on the other hand delivers estrogen slowly into the circulation, avoiding the first-pass effect through the liver, and as a result does not alter the clotting cascade and consequently does not increase the risk of thrombosis [11.1.1]. The introduction also refers to the effect the type of progesterone used can have on the VTE risk with evidence from observational studies suggesting a greater risk with androgenic synthetic progestogens compared with natural progesterone [11.1.1].
Review question [11.1.2]
The NICE guideline development group assessed the published literature addressing the effects of HRT on VTE risk. It also assessed VTE risk in relation to age, HRT user status (past users, current users and ever users) and the effect of the different types of HRT.
Description of included studies [11.1.3]
A total of seven randomised controlled trials (RCTs) that assessed the risk of VTE with HRT compared with placebo were included in the review as well as eight comparative cohort studies which assessed the risk of VTE with HRT compared to that with no treatment. The sample sizes of the cohort studies included varied significantly and ranged from 630 to 105,825 cases.
Consideration of clinical benefits and harms [11.1.7.2]
The evidence summarised in the guidelines both from RCTs and observational data showed an increased VTE risk in current users of oral HRT compared to that in women not using HRT. However, the VTE risk was not significantly increased with transdermal administration of HRT compared to that with non-use of HRT. Subgroup analysis of observational data showed the trend to be the same if HRT was used for up to 2 years, up to 5 years or beyond 5 years. Two observational studies directly compared oral and transdermal HRT. The VTE risk was noted to be significantly increased in both studies in oral users compared to women taking HRT transdermally [11.1.7.2].
The increase in VTE risk with HRT is largely front-loaded with evidence from RCTs showing the risk to be significantly increased within the first year of oral HRT use, while evidence from observational studies showed a similar effect for up to 2 years after commencing oral HRT.
Recommendations [1.3] [11.1.8]
The guideline states the following recommendations:
‐ Oral intake of HRT is associated with an increased VTE risk compared with baseline population risk. ‐ Administering HRT transdermally in standard therapeutic doses carries no increased risk of VTE compared with baseline population risk. ‐ Consideration should be given to prescribing transdermal instead of ‘oral HRT for menopausal women who are at increased risk of VTE, including those with a BMI over 30 kg/m2’.
1
While transdermal HRT does not increase VTE risk above baseline risk, attention should be drawn to a woman’s baseline risk of VTE. An assessment of this should therefore take place to determine optimal treatment options/regimens and route of oestradiol administration.
‐ Referral to a haematologist should be considered for postmenopausal women who have an increased risk for developing VTE.
Other considerations [11.1.7.5]
Previous VTE
Observational data assessing the risk of further VTE with HRT in women with previous episodes of VTE did not show a significant difference between women taking HRT and those not using it. The guideline, however, highlighted that there may be need for special precautions for this group of women and recommended a referral for a haematology opinion before commencing/re-commencing HRT in this group. The guideline also recommended that a haematology opinion should be sought for women at increased risk of VTE (e.g. women with hereditary thrombophilia).
Obesity
The guideline acknowledged the increased risk of VTE with obesity and recommended transdermal administration of HRT for women with an increased BMI of over 30 kg/m2.
Elective surgery
The guideline indicated that transdermal administration of HRT did not significantly alter the coagulation cascade and did not increase the risk of VTE. There would therefore be no need to routinely discontinue transdermal HRT prior to elective surgery, although a discussion with the woman, the surgical and anaesthetic team would be recommended to allow an individualised plan for each case.
Type of estrogen in combined HRT preparations
Estrogens administered in various preparations HRT were noted to have an increased VTE risk and an increased VTE risk was noted with conjugated equine estrogens as well as oral oestradiol compared to that noted in women not receiving HRT. This evidence supporting this recommendation was drawn from an observational study that included approximately 500,000 women and was described low-quality evidence within the guideline. No evidence was included in the guideline to compare the VTE risk with conjugated equine estrogens to that with oestradiol.
Preparations of progestogen in combined HRT
The guideline reported that evidence from two very low-quality observational studies did not show any significant increase in the VTE risk with micronised progesterone in combined HRT compared with non-users.
A similar effect was noted for pregnane derivatives, although the evidence was also described as low-quality evidence. However, an increased risk of VTE was reported with medroxyprogesterone acetate used within HRT compared to that noted in women not receiving HRT. This was considered as moderate quality evidence from a large observational study that included more than 500,000 women.
For nor-testosterone derivatives used within combined HRT, the guideline reported that evidence from a large observational study that included approximately 500,000 women but considered of moderate quality, showed an increased VTE risk, while a further study – evidence described as very low quality – found no significant increase in risk compared to non-users.
VTE risk in relation to age [11.1.5.1]
The guideline also assessed the impact of age on the VTE risk with HRT. In the subgroup of HRT users aged 50–59, low-quality RCT evidence that included over 5000 women showed an increased VTE risk in women taking oral estrogen with progestogen compared to that noted with placebo. However, another RCT that included over 3000 women showed no increase in VTE risk in women receiving estrogen alone HRT compared to that noted with placebo in this age group. This evidence was described in the guideline as very low-quality evidence.
Practical prescribing considerations
Traditional combined HRT preparations contain synthetic progestogens and at present there are no combined preparations that allow delivery of oestradiol with progesterone in a single oral or transdermal preparation. Prescribing oestradiol transdermally with progesterone would require the former to be given by patch or gel in combination with either micronised progesterone given orally or a progesterone pessary administered vaginally.
Research recommendations [11.1.9]
Assessment of the VTE risk with different preparations of HRT. Assessment of the risk of VTE and breast cancer with oestradiol given with the levonorgestrel-releasing intra-uterine system (Mirena IUS). The need for RCTs to assess the VTE risk with oral HRT compared to that with transdermal HRT, and that with different progesterone preparations.
Key conclusions [11.1.7.6]
Oral HRT in the form of estrogen alone or estrogen plus progesterone is associated with an increased VTE risk and this association can occur shortly after commencing HRT. The VTE risk in women receiving HRT transdermally is not significantly different from that in women not taking HRT. The VTE risk may differ with different progestogens used in HRT. There is a significant increase in VTE risk with age and this needs to be considered when prescribing HRT. The increased VTE risk with HRT use ceases after treatment has been discontinued.
Summary
The evidence and recommendations presented in this section of the guideline conclude that oral HRT is associated with an increased risk of VTE that can potentially be reduced to background risk by administering HRT transdermally. Furthermore, the risk of VTE with HRT may vary with different progestogen preparations with observational data suggesting no significant increase in VTE risk with micronised progesterone and pregnane derivatives.
The recommendations state that HRT administered transdermally does not increase the risk of VTE and consideration should therefore be given to prescribing HRT transdermally for women at risk of VTE. However, attention should also be drawn to a woman’s baseline risk of VTE and the latter should be assessed and a haematology opinion sought where appropriate to determine the optimal treatment regimen.
Further research in the context of RCTs is required to compare the VTE risk with oral HRT compared with HRT administered transdermally, and that with different progesterone preparations including the levonorgestrel-releasing intra-uterine system.
This information would be useful in guiding practitioners who manage menopausal women and in counselling women during the menopausal transition and regarding their management options in this context.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Provenance
Commissioned; internally reviewed.