Oral HRT for Menopause Has Highest VTE Risk, Patches Safest

Liam Davenport

January 10, 2019

The type of hormone replacement therapy (HRT) that women use to prevent symptoms of menopause affects their risk of venous thromboembolism (VTE), with oral preparations significantly increasing the risk but transdermal products, such as patches or gels, conferring no additional risk, results of a large new UK study confirm.

Yana Vinogradova, PhD, Division of Primary Care, University of Nottingham, UK, and colleagues looked at data on more than 80,000 women aged 40 to 79 years who developed VTE and compared them with more than 390,000 women who did not.

The research, published online January 9 in BMJ, shows that although taking HRT was overall associated with an increased VTE risk compared with not taking it, the risk was confined to oral preparations, which were linked to a 58% increased risk. And even among oral preparations there was wide variation in the risk associated with individual products. Estradiol, for example, had a much lower risk than conjugated equine estrogen, for both estrogen only and combined preparations.

And there was no significant increased risk of VTE among women using transdermal HRT preparations compared with women who did not take HRT.

Stressing that VTE is a rare but serious risk associated with HRT, the team writes that the study "has provided a more detailed picture of the VTE risks for different HRT preparations and can help clinicians and women make treatment choices."

"Transdermal treatment appears to be underused, with the overwhelming preference still for oral preparations," they observe.

Experts contacted by Medscape Medical News also emphasized the overall risk of VTE with HRT is small, but said it is valuable to have data showing the varying risk associated with different HRT products, as it will help physicians and patients tailor treatment to the individual.

Not All HRT Is the Same...

Although the researchers say they "did not expect" to find a link between transdermal HRT and VTE risk because of the underlying metabolic processes, the fact is the study "showed that the vast majority of women using HRT continue to be prescribed oral preparations."

Physicians and women themselves should therefore "give greater consideration to transdermal HRT," they stress, particularly in cases where women may already have an increased background risk of VTE "because of comorbidities or obesity," for example.

Approached for comment, Tim Hillard, DM, past president of the British Menopause Society and consultant gynecologist, Poole Hospital, UK, described the study as "a welcome addition to the literature."

He told Medscape Medical News: "Whilst the results are broadly in keeping with other studies in this area, the study provides greater detail about the potential risks of a variety of different types of HRT preparations which will aid clinicians and women in making informed choices about their treatment."

"The study highlights that the term 'HRT' covers a diverse portfolio of treatments which have differing risks and that not all HRTs are the same."

Hillard added: "The...results support current clinical recommendations for individual prescribing and that transdermal HRT should be used in preference to oral treatment for women with an increased background risk of thrombosis."

And John C. Stevenson, MBBS, of the National Heart & Lung Institute and Royal Brompton Hospital, London, UK, said that the study "does not show us anything new but is useful in that it confirms what we already know."

Commenting for Medscape Medical News, he continued: "The absolute risks of VTE with HRT are extremely low, emphasizing the overall safety of HRT."

However, "For women at increased risk for VTE who require HRT, the types of hormones, dose, and route of administration are paramount to its safety."

HRT Still an Option for Women at Higher Risk of VTE

Mary Ann Lumsden, MD, PhD, spokesperson for the Royal College of Obstetricians and Gynecologists, London, UK, told Medscape Medical News that the findings "add to the existing evidence on the link between different types of HRT and risk of blood clots in women."

She agreed that the overall risk with HRT is "small, but it is very useful to have results showing the risk associated with each HRT type as it will help to inform discussions between a woman and her healthcare professional."

And Lumsden emphasized that, despite the associations with VTE, HRT "may still be an option" in women with a higher risk of blood clots. "Women should discuss this with their healthcare professional, as careful choice of regimen can minimize the increase in risk."

She nevertheless underlined that "the decision whether to use HRT should be made by a woman who has been given clear, evidence-based information and who should [also] consider other major risk factors for blood clots such as smoking or obesity."

"HRT dosage, regimen, and duration should be individualized based on a woman's medical history, family history, and symptoms."

Large Observational Study Dissects VTE Risks With Different HRTs

Use of HRT plunged after the Women's Health Initiative studies in the early 2000s raised concerns about the safety profile of HRT (including VTE risk), but more recently a number of different organizations have been stressing that it is the most effective treatment for menopausal symptoms.

In 2017, the North American Menopause Society reiterated this with a new position statement, and in 2015, the UK National Institute for Health and Care Excellence issued its first ever guidance on use of HRT for menopausal symptoms.

Vinogradova and colleagues note that previous studies assessing the VTE risk associated with different HRT treatments either did not distinguished between the types of estrogen or progestogen or were powered to analyze only the most common preparations.

Oral HRT formulations can be estrogen only (unopposed) using conjugated equine estrogen or estradiol, or estrogen combined with progestogen (opposed). Progestogens in combined formulations include medroxyprogesterone acetate or newer agents such as norgestrel, dydrogesterone, or drospirenone.

To examine the VTE risk associated with specific HRT formulations in greater detail, Vinogradova and colleagues conducted their nested case control studies of women with a primary diagnosis of VTE between 1998 and 2017.

The women were registered at UK primary care practices in the QResearch or Clinical Practice Research Datalink (CPRD) databases and were matched by year of birth with up to five controls from the same practice. The first date of diagnosis of VTE for cases became the "index date" for matched controls.

They were able to identify 52,137 cases and 259,542 controls on the QResearch database, and 28,259 cases and 131,952 controls on the CPRD database.

The women were aged 40 to 79 years (average age, 64 years), and over 90% were white or had no ethnicity recorded. The mean body mass index (BMI) was between 27.3 and 29.5 kg/m2. Between 40.8% and 58.6% were current or former smokers.

Exposure to HRT was categorized as recent (within 90 days before the index date), past (91-365 days), or no exposure.

The study's main focus was on recent exposure to HRT, say the researchers, because a previous study has shown that past exposure is not associated with increased risk of VTE.

Women with VTE were more likely than controls to be aged 65 years or older and were more likely to have comorbidities, including cancer (21% vs 7%), cardiovascular disease (13% vs 9%), and chronic renal disease (8% vs 5%). Cases were also more likely than those without VTE to have had a recent medical event.

Most Women, 80%, Use Oral Formulations of HRT

Across the two databases, 7.2% of women with VTE had been exposed to HRT in the previous 90 days, compared with 5.5% of controls.

Of the women exposed to HRT, 85% of cases and 78% of controls had taken oral preparations, while 14% of cases and 19% of controls had used transdermal HRT only, and 1.8% and 1.4%, respectively, had used both.

On multivariate adjusted analyses, any HRT exposure in the past 90 days was associated with a significantly increased risk of VTE versus no exposure, at an odds ratio of 1.43 (P < .001).

Oral HRT preparations were associated with a significantly increased risk of VTE, at an odds ratio of 1.58 (P < .001), with estradiol based preparations associated with a lower VTE risk than conjugated equine estrogen based oral preparations.

Conjugated equine estrogen combined with medroxyprogesterone acetate was associated with the highest VTE risk, at an odds ratio of 2.10 (P < .001), compared with no HRT exposure.

And the lowest risk compared with no exposure for an oral HRT preparation was seen with estradiol with dydrogesterone, at an odds ratio of 1.18 (P = .09).

Meanwhile, transdermal HRT was not associated with the risk of VTE, at an odds ratio of 0.93 (P = .07).

The finding for transdermal HRT preparations was consistent for different regimens. Most (> 80%) of the transdermal preparations were prescribed in the form of patches, with only small proportions of women having subcutaneous and gel preparations.

Nine Extra Cases of VTE per 10,000 Patient-Years With Oral HRT

Across all age groups, the number needed to harm with oral HRT was 1076, meaning there would be an extra nine cases of VTE per 10,000 women-years in women taking oral HRT compared with those who were not.

This number rose to 18 cases per 10,000 women-years with conjugated equine estrogen with medroxyprogesterone acetate.

The number of cases of VTE associated with oral HRT use overall also increased with age, from eight cases per 10,000 women-years at ages 40 to 54 years to 37 cases per 10,000 women-years at ages 64 to 79 years.

The team points out there is also a need to investigate different HRT preparations for "a complementary detailed study of cancer risks," in particular breast cancer, to give "a more complete picture."

"We are preparing such a study based on the same data sources."

There was no external funding for this study, and the authors declare no support from any organization for the research. Hippisley-Cox is professor of clinical epidemiology at the University of Nottingham and an unpaid director of QResearch, a not-for-profit organization that is a joint partnership between the University of Nottingham and EMIS. She is also a paid director of ClinRisk.

BMJ. Published January 9, 2019. Full text

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