Oral combined HRT raises the risk of venous thromboembolism by approximately two-fold

Venous thromboembolism (VTE) is an important component of the benefit-torisk equation in the use of postmenopausal hormone replacement therapy (HRT). Practitioners and women are often more concerned about breast cancer than thromboembolic complications; however, thromboembolic events are one of the commonest significant side-effects of HRT. This article summarises the data on the HRT-related VTE risk and factors that influence it.

Both observational and interventional trials have shown a significant increase in VTE risk among current HRT users.¹ The Women's Health Initiative (WHI) included clinical trials designed to test the effects of postmenopausal HRT as well as other interventions. The effects of taking combined oral HRT in 16,608 women showed that those receiving 0.625 mg of conjugated equine oestrogens (CEE) daily plus 2.5 mg medroxyprogesterone acetate (MPA) had two-fold higher rates of VTE (DVT and PE), compared to placebo.²

However, high drop-out rates may have underestimated the risk. In 10,739 women taking CEE alone, the adjusted risk of VTE was increased 1.3-fold.³ Comparison of the VTE risk with oestrogen alone, versus combined therapy, suggested that adding progestin (MPA) to oestrogen significantly increased VTE risk (P=0.03). In practical terms the estimated number of excess HRT-related VTE events in 10,000 women taking CEE plus MPA for one year is 18, whereas with oral oestrogen alone it is only eight.

The route of administration of oestrogen appears to impact on thrombosis risk. The WHI oral HRT results are unlikely to reflect the VTE risk in women using transdermal HRT.^4,5 Case-control studies in oestrogen users suggest a differential association of oral and transdermal oestrogen with VTE risk. Adjusted odds ratios for VTE with oral or transdermal oestrogen compared with non users were 4.2 and 0.9, respectively. Oral HRT increases clotting protein production through the first pass hepatic effect, which is not replicated with transdermal therapy.^6-9

C-reactive protein expression is also increased with hepatic first pass effects of oral oestrogen, potentially increasing endothelial dysfunction and thrombosis.However, these observational and mechanistic findings need to be confirmed in randomised prospective clinical trials.

Age and obesity are major risk factors for VTE.^10,11 The WHI study shows that VTE risk related to HRT use is amplified with increasing age and body mass index (BMI). The relative risk of HRT appears similar (~two-fold); however, the change is the baseline risk, with older and heavier women having a substantially larger overall number of VTE cases due to their higher age- and BMI-related baseline risks.

When both age and increased BMI are present, the effect is multiplied. It is estimated that among obese women aged 70 to 79 years, there would be 89 VTE events per 10,000 women per year taking combined HRT compared to only 46with placebo. By comparison, eight VTE events per 10,000 women per year would be expected in women aged 50 to 59 years, taking the same HRT preparation, who are of normal weight. This is the age group where postmenopausal HRT use is most common.

With oestrogen use alone, no effect was observed between increasing age, BMI and HRT use. The WHI trial also showed that aspirin or statins did not protect against VTE risk in oral HRT users.

Of the thrombophilias that predispose to thrombosis, only factor V Leiden (FVL) mutation interacts specifically with oral HRT.^2,12,13 The risk of VTE among women taking combined oral HRT who are FVL heterozygotes is 6.69-fold higher than placebo, due to similar action of both FVL and oral oestrogen on the clotting system. In high-risk women with a personal or family history of VTE, thrombophilia screening should be completed prior to HRT; however, routine screening is not recommended. In observational studies, transdermal oestrogen did not increase VTE risk in the presence of the FVL mutation.¹⁴

Surgery, fractures or immobilisation predispose to VTE^15-17 and the risk is further aggravated by HRT. Data from the secondary prevention trial evaluating the effects of CEE+MPA on the rate of new thromboembolic events in postmenopausal women with coronary heart disease showed significant interaction between HRT and risk factors, including lower limb fractures, recent inpatient surgery, or recent nonsurgical hospitalisation.^18,19 Based on these findings, it is recommended that HRT is suspended prior to surgery and that VTE prophylaxis is used.²⁰

Another form of HRT is tibolone, a synthetic steroid. Recent composite data from studies using tibolone in 7904 postmenopausal women show no evidence of increased VTE with tibolone compared to 3527 women taking placebo. Also, tibolone appears not to activate the coagulation cascade as oral oestrogens do.²¹ However, further randomised, controlled studies are needed before we can be confident VTE risk is not increased.

Summary

VTE is increasingly common as women age and are more overweight, and oral combined HRT raises the risk of VTE by approximately two-fold. The risk of VTE with HRT is multiplicative with baseline risk factors of age and body weight. The greatest attributable VTE risk with HRT will be in those with a greater BMI who are older and on oral combined HRT.

Oral oestrogen taken alone only marginally increases risk. Transdermal oestrogen does not appear to increase VTE risk, nor does oral tibolone; however, further randomised trials on both these treatments are needed. Concomitant use of aspirin or statins does not seem to attenuate the VTE risk associated with oral HRT use, and oral HRT use should be suspended in those undergoing surgery.

In practical terms, eight additional HRT-related VTEs would be expected in every 10,000 women on combined HRT for 12 months, who were of normal weight and aged 50 to 59 years - the usual age at which postmenopausal HRT is prescribed. For older and larger women the baseline risk is increased and HRT will multiply this risk by about two, so for those with risk factors, transdermal HRT or tibolone may be preferred. In those at highest risk, non-hormonal preparations for menopausal symptom relief may be more appropriate (i.e. SSRIs).

The author reports no conflict of interest.

References at http://www.medicalobserver.com.au/

 VTE and hormone replacement (130.01 KB)

References

See Medical Observer http://www.medicalobserver.com.au/

Content Updated September 2, 2009