What is the level of evidence supporting the association between Hormone Replacement Therapy (HRT) and an increased risk of thromboembolism?

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From the Guidelines

There is strong evidence supporting the association between Hormone Replacement Therapy (HRT) and an increased risk of thromboembolism, with a relative risk of 2.14 (95% CI, 1.64 to 2.81) as reported in a meta-analysis of 12 studies 1. The level of evidence is based on a meta-analysis of 12 studies, including 3 randomized, controlled trials, 8 case-control studies, and 1 cohort study, which consistently demonstrated an increased risk for venous thromboembolism associated with HRT use 1.

  • The risk is highest within the first year of use, with a relative risk of 3.49 (95% CI, 2.33 to 5.59) 1.
  • The findings are consistent with the results from the estrogen and progestin arm of the WHI, which reported a 2-fold increased rate of venous thromboembolic disease in women taking CEE/MPA daily 1.
  • The USPSTF concluded that there is good evidence that HRT increases the risk for venous thromboembolism, highlighting the importance of careful evaluation and consideration of individual risk factors before initiating HRT therapy 1. Key factors to consider when evaluating the risk of thromboembolism in women using HRT include:
  • Formulation: oral estrogens carry a higher risk than transdermal preparations
  • Duration of use: risk is highest during the first year of treatment
  • Individual risk factors: pre-existing risk factors for VTE, such as obesity, prior VTE history, thrombophilia, and advanced age, substantially increase absolute risks when using HRT 1.

From the FDA Drug Label

The WHI estrogen-alone substudy reported a statistically significant increase in the risk of VTE (DVT and PE) in women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years). The WHI estrogen plus progestin substudy reported a statistically significant 2-fold greater rate of VTE in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (35 versus 17 per 10,000 women-years).

The level of evidence supporting the association between Hormone Replacement Therapy (HRT) and an increased risk of thromboembolism is high, with statistically significant increases in risk for both DVT and PE demonstrated in the studies 2.

  • The risk of VTE was increased for women receiving daily CE (0.625 mg)-alone compared to placebo.
  • The risk of VTE was also increased for women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to placebo. Key points:
  • Estrogen-alone therapy increases the risk of VTE.
  • Estrogen plus progestin therapy increases the risk of VTE. It is recommended to immediately discontinue estrogen-alone or estrogen plus progestogen therapy if a VTE occurs or is suspected.

From the Research

Level of Evidence for HRT and Blood Clots

The level of evidence supporting the association between Hormone Replacement Therapy (HRT) and an increased risk of thromboembolism is substantial, with multiple studies demonstrating a significant link between the two.

  • The risk of venous thromboembolism (VTE) is increased with the use of HRT, particularly with oral estrogen and combined estrogen-progestin therapy 3, 4, 5, 6, 7.
  • The risk is highest in the first year of use, but an increased risk persists after the first year if HRT use is ongoing 5, 7.
  • Transdermal HRT is not associated with an increased risk of thrombosis in healthy women with no background medical problems 3, 6.
  • The presence of thrombophilia, such as factor V Leiden, further amplifies the risk of venous thrombosis in women using HRT 5, 7.
  • Other risk factors, such as increasing age and being overweight, are also associated with a further increase in the risk of venous thrombosis 7.

Factors Influencing the Risk of Thromboembolism

Several factors influence the risk of thromboembolism in women using HRT, including:

  • Type of estrogen used: oral estrogen is associated with a higher risk of VTE than transdermal estrogen 4, 6.
  • Mode of delivery: transdermal HRT is associated with a lower risk of VTE than oral HRT 4, 6.
  • Presence of other predisposing factors: such as thrombophilia, increasing age, and being overweight 5, 7.
  • Duration of use: the risk of VTE is highest in the first year of use, but an increased risk persists after the first year if HRT use is ongoing 5, 7.

Study Findings

Study findings have consistently shown that HRT is associated with an increased risk of VTE, with some studies suggesting a dose-related effect and a significant difference in the relative risk of VTE between oral and transdermal HRT 4, 6, 7.

  • A systematic review and meta-analysis found that non-oral HRT did not significantly increase the risk of VTE, while oral HRT was associated with a significant increase in risk 4.
  • A population-based study found that transdermal HRT and tibolone were not associated with an increased risk of VTE, while oral estrogen and oral estrogen-progestogen were associated with a significant increase in risk 6.

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

5
Research

Hormone therapy and venous thromboembolism.

Best practice & research. Clinical endocrinology & metabolism, 2003

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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