

HRT tablets increase risk of blood clots in women

9 January 2019


The study, undertaken by researchers at The University of Nottingham and published in the BMJ, found that the risk of developing blood clots was only increased for women using HRT in tablet form and was slightly higher for higher dosages.


Hormone replacement therapy (HRT) is used to relieve symptoms such as hot flushes and night sweats and reduce the risk of certain health conditions in women going through the menopause.

There are a range of different HRT treatments available, depending on the symptoms experienced. Some women require a drug based only on the oestrogen hormone, while others may need a combination of oestrogen and another hormone, progesterone. HRT can also be taken in different forms - by tablets, patches, gels or creams.

Although all treatments are effective in managing menopausal symptoms, an increased risk of venous thromboembolism (blood clots) is a rare, but serious, known side effect. A recently issued guideline from the National Institute for Health and Care Excellence (NICE) stressed that research results from studies trying to estimate the risk of developing blood clots as a result of HRT are still not clear, and that findings to date were not a reliable basis for decision-making by doctors or patients.

The Nottingham study aimed to provide clarity on the subject by identifying and comparing venous thromboembolism risks for all forms of HRT treatment used in the UK.

The study used data from the two largest UK primary care databases (QResearch and CPRD), which contain patient records from more than 2,000 English GP practices and associated hospital records over an 18-year period (1998-2017) to investigate real-life use and risks of blood clots for all types of HRT treatments.

The researchers compared the treatment prescription records of all women who developed blood clots with those for a group of women who did not. To ensure that the results properly reflected the effects of the different therapies, the study took into account other relevant health conditions and patient characteristics, which might have affected the risk of developing blood clots.

It found that women taking HRT tablets were up to two times more likely to be at risk/had a 70 per cent risk compared to other forms of HRT.

For tablet treatments, the risk was found to differ for two types of oestrogens. Both for single and combined hormone treatments, the risk of blood clots was 15 per cent higher for the treatments containing oestrogen manufactured from horse urine than for the synthetic oestradiol.

However, women who were using HRT in patch, gel or cream form were not found to be at risk, even at higher doses.

The results of the study could also be helpful to agencies such as NICE in the development of new best-practice guidelines.

Dr Yana Vinogradova, of the University's School of Medicine, undertook the research. The team also included Professors Julia Hippisley-Cox and Carol Coupland. Dr Vinogradova says: "Our study has shown that, for oral treatments, different tablets are associated with different risks of developing blood clots, depending on the active components. It has also confirmed that risks of thrombosis for patients using HRT treatments other than tablets (patches or gels) is very low. This lower risk has been known for more than ten years and - although patches or gels may not be acceptable in some circumstances - it was surprising to find that only 20 per cent of HRT prescriptions to date have been for non-oral treatments. Our findings are particularly important information for women, who require HRT treatment and are already at increased risk of developing blood clots."


To assess the association between risk of venous thromboembolism and use of different types of hormone replacement therapy.

Two nested case-control studies.

UK general practices contributing to the QResearch or Clinical Practice Research Datalink (CPRD) databases, and linked to hospital, mortality, and social deprivation data.

80 396 women aged 40-79 with a primary diagnosis of venous thromboembolism between 1998 and 2017, matched by age, general practice, and index date to 391 494 female controls.

Main outcome measures:
Venous thromboembolism recorded on general practice, mortality, or hospital records. Odds ratios were adjusted for demographics, smoking status, alcohol consumption, comorbidities, recent medical events, and other prescribed drugs.

Overall, 5795 (7.2%) women who had venous thromboembolism and 21 670 (5.5%) controls had been exposed to hormone replacement therapy within 90 days before the index date. Of these two groups, 4915 (85%)and 16 938 (78%) women used oral therapy, respectively, which was associated with a significantly increased risk of venous thromboembolism compared with no exposure (adjusted odds ratio 1.58, 95% confidence interval 1.52 to 1.64), for both oestrogen only preparations (1.40, 1.32 to 1.48) and combined preparations (1.73, 1.65 to 1.81). Estradiolhad a lower risk than conjugated equine oestrogen for oestrogen only preparations (0.85, 0.76 to 0.95) and combined preparations (0.83, 0.76 to 0.91). Compared with no exposure, conjugated equine oestrogen with medroxyprogesterone acetate had the highest risk (2.10, 1.92 to 2.31), and estradiol with dydrogesterone had the lowest risk (1.18, 0.98 to 1.42). Transdermal preparations were not associated with risk of venous thromboembolism, which was consistent for different regimens (overall adjusted odds ratio 0.93, 95% confidence interval 0.87 to 1.01).

In the present study, transdermal treatment was the safest type of hormone replacement therapy when risk of venous thromboembolism was assessed. Transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations.


Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ. 2019 Jan 9;364:k4810. doi: 10.1136/bmj.k4810.

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