HRT and venous thromboembolism (VTE)

Postmenopausal hormone therapy has been associated with a 2- to 3-fold increased risk of venous thromboembolism (including deep vein thrombosis and pulmonary embolism) in observational studies and secondary prevention clinical trials.

A study undertaken by Grady et al (1) examined how the use of HRT in women with coronary artery disease affected the risk of venous thromboembolism. This revealed that HRT increased the risk of venous thromboembolism in older women with coronary artery disease.

Women's Health Initiative Study:

In the Women's Health Initiative study there was a relative risk of 2.11 at 5.2 years for the development of a thromboembolic event (comparing oestrogen plus progestogen arm vs. placebo group) (2) - this meant an increased absolute risk of 18 per 10,000 women per year.

In the Women's Health Initiative estrogen trial Participants were randomly assigned to receive conjugated equine estrogen (0.625 mg/d) or placebo (3):

• enrolled 10 739 women aged 50 to 79 years without a uterus
• deep venous thrombosis was reported in 85 women randomly assigned to receive estrogen (2.3 per 1000 person-years) and 59 randomly assigned to receive placebo (1.5 per 1000 person-years; hazard ratio, 1.47; 95% confidence interval, 1.06-2.06). The venous thromboembolism risk was highest in the first 2 years. there were no significant interactions between estrogen use and age, body mass index, or most other venous thromboembolism risk factor
• comparison of Women's Health Initiative these findings for estrogen and previous Women's Health Initiative findings for estrogen plus progestin showed that the hazard ratios for estrogen plus progestin were significantly higher than those for estrogen alone (P = .03)
• the study authors concluded that an early increased venous thromboembolism risk is associated with use of oestrogen, especially within the first 2 years, but this risk increase is less than that for oestrogen plus progestin (3)

NICE state with respect to HRT and venous thromboembolism (4)

• explain to women that:
  
  
  • the risk of venous thromboembolism (VTE) is increased by oral HRT compared with baseline population risk
    
    
  • the risk of VTE associated with HRT is greater for oral than transdermal preparations
    
    
  • the risk associated with transdermal HRT given at standard therapeutic doses is no greater than baseline population risk
    
    
    
• consider transdermal rather than oral HRT for menopausal women who are at increased risk of VTE, including those with a BMI over 30 kg/m2.
  
  
• consider referring menopausal women at high risk of VTE (for example, those with a strong family history of VTE or a hereditary thrombophilia) to a haematologist for assessment before considering HRT.

A Joint Societies Statement noted that (5):

Compared with women not on MHT, the risk of venous thromboembolism is increased by oral intake MHT. However, there is no increased risk of venous thromboembolism associated with transdermal MHT compared with women not on MHT. Also evidence from large observational studies and case-controlled studies suggests that micronized progesterone and dydrogesterone are unlikely to increase the risk of venous thrombosis compared to other progestogens.

Reference:

• (1) Grady D et al (2000). Postmenopausal hormone replacement therapy increases the of venous thromboembolic disease. The heart and estrogen/progestin replacement study. Ann Intern Med, 132, 689-96.
• (2) Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results for the Women's Health Initiative Randomized controlled trial. JAMA 2002; 288:321-333.
• (3) Curb JD et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 2006;166:772-80.
• (4) NICE (November 2015). Menopause: diagnosis and management
• (5) BMS, IMS, EMAS, RCOG and AMS Joint Statement on menopausal hormone therapy (MHT) and breast cancer risk in response to EMA Pharmacovigilance Risk Assessment Committee recommendations in May 2020