VTE Risk with HRT

Rachel Wilhelm, Pharm.D., Minnesota Community Care

Background: Hormone replacement therapy (HRT) is often used to treat women with menopausal symptoms, such as hot flashes and night sweats. Estrogen and its derivatives, which come in a variety of oral and transdermal formulations, are the most commonly used treatment options. Progestin is added to therapy for women with an intact uterus to prevent estrogen-associated endometrial hyperplasia. Women who have undergone a hysterectomy may be treated with estrogen only. Unfortunately, when compared to placebo, HRT has been associated with increased risk of venous thromboembolism (VTE) due to its effects on clotting factors. However, previous studies have not been powered to detect differences in risk amongst the various HRT formulations. Additionally, the majority of our knowledge comes from the Women’s Health Initiative, in which the patient population was predominantly women in good health. Therefore, additional studies were needed to assist patients in making informed decisions regarding HRT risks.

Objective: The purpose of this study was to determine if there are differences in VTE risk based on type of HRT formulation and dosing.

Study Design: This study utilized a nested case control design, using two primary care research databases in the United Kingdom. A total of 80,396 women aged 40-79 years were registered between 1998 and 2017 and were matched with 391,494 controls. Each participant was matched with up to five controls from the same practice with the same year of birth. Exclusion criteria consisted of previous history of VTE, less than one year of medical records, or more than one type of HRT prescription written in the last 90 days.  The various formulations and regimens were compared against each other as well as against no HRT use. Overall exposure to HRT was defined as any exposure to oral or transdermal preparations. The study focused on recent exposure, since distant past exposure has not been associated with increased risk. Exposure was categorized as recent (within 90 days), past (91-365 days), or no exposure. Dose was categorized as low (<0.625 mg oral conjugated equine estrogen, <1 mg oral estradiol, <50 micrograms for transdermal estradiol) or high. Analyses adjusted for confounding factors, such as chronic and acute conditions, lifestyle factors, and social deprivation. Raloxifene use was also included in analysis, as its use for osteoporosis may be common in this patient population.

Results: The study found increased VTE risk for all oral HRT formulations, regardless of presence or absence of progestin (OR 1.58 [95% CI 1.52 - 1.64]), and this finding persisted across all age groups. Conjugated equine estrogens were associated with 17% increased risk when compared to estradiol (OR 1.49 versus OR 1.27). The formulation carrying the highest risk of VTE was conjugated equine estrogen in combination with medroxyprogesterone acetate (OR 2.1 [95% CI 1.92 - 2.31]). Estradiol in combination with dydrogesterone was associated with the lowest risk, but this product is not currently available in the United States. Overall, cyclical and continuous dosing for oral formulations were associated with increased VTE risk compared to no HRT use (OR 1.55 [95% CI 1.44 - 1.66]), but transdermal preparations were not associated with higher risk of VTE when compared to no HRT, regardless of formulation. In regard to patient characteristics, being overweight was associated with higher risk (OR 1.50 [95% CI 1.37 - 1.64]). More than half of the women who experienced VTE were aged 65 or older, and were more likely to have comorbidities (e.g., cancer, cardiovascular disease, chronic renal disease) compared to controls. Raloxifene use was associated with significantly increased VTE risk (OR 1.49 [95% CI 1.24 - 1.79]).

Conclusions: Currently, the majority of women using HRT are prescribed oral formulations. Oral conjugated equine estrogen, combined or estrogen only, are associated with higher VTE risk compared to estradiol based preparations. Higher estrogen doses are likewise associated with higher risk. However, transdermal preparations are not associated with increased risk and should thus be given greater consideration, especially in women already at increased risk due to comorbidities (i.e. age or obesity). This study provides clinicians with more information to present to patients regarding relative VTE risks when discussing therapy options.


  1. 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; 364:k4810.