A systematic review and meta-analysis included 8 observational studies and 9 randomised controlled trials (including WHI). In meta-analysis of observational studies, odds ratio (OR) for first time VTE in current users of oral oestrogen was 2.5 (95% CI 1.9 to 3.4) and in current users of transdermal oestrogen was 1.2 (95% CI 0.9 to 1.7) compared to non-users. Past users of oral oestrogen had a similar risk of venous thromboembolism to never users. The risk of VTE with oral oestrogens was higher in the first year of treatment (4.0, 2.9 to 5.7) compared with treatment for more than one year (2.1, 1.3 to 3.8). No noticeable difference in the risk of VTE was observed between unopposed oral oestrogen (2.2, 1.6 to 3.0) and opposed oral oestrogen (2.6, 2.0 to 3.2). Results from RCTs confirmed the increased risk of VTE among women using oral oestrogen (OR 2.1, 95% CI 1.4 to 3.1, n= 38 779). The combination of oral oestrogen and thrombogenic mutations or obesity further enhanced the risk of VTE, whereas transdermal oestrogen did not seem to confer additional risk in women at high risk of VTE.
A Cohrane review included 22 studies involving 43 637 women. Nearly 70% of the data was derived from two studies (HERS 1998; WHI 1998) evaluating oral conjugated equine oestrogen 0.625 mg, with or without continuous methoxyprogesterone (MPA 2.5 mg). Most participants were postmenopausal American women with at least some degree of comorbidity, and mean participant age in most studies was over 60 years. None of the studies focused on perimenopausal women. Combined continuous hormone therapy increased the risk of VTE (after 1 year's use: from 2 per 1000 to between 4 and 11 per 1000; RR 4.28 95% CI 2.49 to 7.34, 2 trials, n=20 993). Oestrogen-only hormone therapy increased the risk of VTE (after 1 to 2 years' use: from 2 per 1000 to 2 to 10 per 1000; after 7 years' use: from 16 per 1000 to 16 to 28 per 1000; RR 2.22, 95% CI 1.12 to 4.39, 1 trial, n=10 739).16 608 postmenopausal women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate, or placebo. Hazard ratio (HR) for VTE in oestrogen plus progestin group was 2.06 (95% CI 1.57 to 2.70) compared to placebo. Compared with women between the ages of 50 and 59 years who were taking placebo, the risk associated with hormone therapy was higher with age: HR of 4.28 (95% CI 2.38 to 7.72) for women aged 60 to 69 years and 7.46 (95% CI 4.32 to 14.38) for women aged 70 to 79 years. Compared with women who were of normal weight and taking placebo, the risk associated with taking estrogen plus progestin was increased among overweight and obese women: HR of 3.80 (95% CI 2.08 to 6.94) and 5.61 (95% CI 3.12 to 10.11), respectively. Factor V Leiden enhanced the hormone-associated risk of thrombosis compared with women in the placebo group without the mutation (HR 6.69, 95% CI 3.09 to 14.49). Other genetic variants did not modify the association of hormone therapy with VTE."?>
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