Elsevier

The Lancet

Volume 362, Issue 9382, 9 August 2003, Pages 428-432
The Lancet

Articles
Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk

https://doi.org/10.1016/S0140-6736(03)14066-4Get rights and content

Summary

Background

Oral oestrogen-replacement therapy (ERT) activates blood coagulation and increases the risk of venous thromboembolism (VTE) in postmenopausal women. Transdermal ERT has little effect on haemostasis, but data assessing its effect on thrombotic process are scarce. We aimed to examine the effect of the route of oestrogen administration on VTE risk.

Methods

We did a multicentre hospital-based case-control study of postmenopausal women in France. During 1999–2002, we recruited 155 consecutive cases with a first documented episode of idiopathic VTE (92 with pulmonary embolisms and 63 with deep venous thrombosis), and 381 controls matched for centre, age, and time of recruitment.

Findings

Overall, 32 (21%) cases and 27 (7%) controls were current users of oral ERT, whereas 30 (19%) cases and 93 (24%) controls were current users of transdermal ERT. After adjustment for potential confounding variables, the odds ratio for VTE in current users of oral and transdermal ERT compared with non-users was 3·5 (95% CI 1·8–6·8) and 0·9 (0·5–1·6), respectively. Estimated risk for VTE in current users of oral ERT compared with transdermal ERT users was 4·0 (1·9–8·3).

Interpretation

Oral but not transdermal ERT is associated with risk of VTE in postmenopausal women. These data suggest that transdermal ERT might be safer than oral ERT with respect to thrombotic risk.

Introduction

Postmenopausal women are often prescribed oestrogen-replacement therapy (ERT) to treat menopausal symptoms and to prevent osteoporosis. Harmful effects of ERT include breast cancer1 and VTE. ERT might also increase the risk of coronary heart disease and stroke.1

Despite evidence that oral oestrogen activates blood coagulation in postmenopausal women2 and might be thrombogenic,3 ERT has long been believed to have little effect on the risk of VTE.4 Early studies of VTE risk in ERT users provided inconclusive results.4 However, results of recent observational studies showed consistent associations between current use of ERT and increased risk of VTE in postmenopausal women.5, 6, 7, 8, 9, 10 These findings have been confirmed by randomised clinical trials.11

Most previous studies of VTE risk in ERT users were done in women using oral oestrogen.12 Transdermal oestrogen is widely used in European countries, especially in France, and has little or no effect on haemostasis.13 Clinical data assessing the effect of transdermal ERT on thrombotic processes are scarce. Therefore, we did a case-control study to investigate the effect of the route of oestrogen administration on VTE risk.

Section snippets

Selection and ascertainment of cases and controls

During 1999–2002, we recruited 155 consecutive cases with a first documented episode of idiopathic VTE at seven teaching hospitals in France. Eligible cases were postmenopausal women aged 45–70 years and living in the vicinity of the recruiting hospitals. Women were excluded if they reported a previous episode of VTE; had a contraindication for ERT (history of breast cancer, VTE, valvular cardiopathy, coronary heart disease, or stroke); or had a predisposing factor for VTE (history within the

Results

Table 1 shows the characteristics of the study population. Mean body-mass index was higher in cases than in controls. Cases were more likely than controls to have reported family history of VTE and history of varicose veins. 24 diabetic controls were matched to cases with either hypertension or obesity and, therefore, a higher proportion of controls than cases reported diabetes. However, the proportion of women at high risk was similar among cases and controls (28% and 26%, respectively).

Discussion

Our data show an increased risk of VTE in current users of oral ERT compared with non-users. Current users of oral ERT seem to be at higher risk of VTE than users of transdermal ERT. There was no association between VTE risk and use of transdermal ERT.

Our results for current users of oral ERT are consistent with previous data. Observational studies reported a greatly increased risk of VTE in current users of oral ERT.4 This finding is in accord with those in recent randomised trials,11 and

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