Hormone replacement therapy is not recommended for menopausal symptoms in women with increased risk of thromboembolism. However, when treatment is considered essential because of severe symptoms, transdermal oestrogen is the drug of choice.
The recommendation is strong because of moderate effect size for avoiding patient important adverse outcomes.
A meta-analysis 4 investigating the risk of venous thromboembolism (VTE) included 22 trials (9 case-control studies, 9 cohort studies, and 4 randomized controlled trials). As compared to control groups, VTE risk was not increased with non-oral hormone replacement therapy (HRT), including users of estrogens and estrogens plus progestins (OR 0.97, 95% CI 0.9 to 1.06), non-oral estrogen therapy (E-only) (OR 0.95, 95% CI 0.81 to 1.10), and non-oral combined estrogen-progestin therapy (OR 0.92, 95% CI 0.77 to 1.09). Conversely, increased risk of VTE was observed as compared with control groups in users of oral HRT, including users of estrogens and estrogens plus progestins HRT (OR 1.72, 95% CI 1.47 to 2.01), oral E-only (OR 1.43, 95% CI 1.34 to 1.53), and combined oral estrogen-progestin HRT (OR 2.35, 95% CI 1.9 to 2.9). The comparison of non-oral vs. oral HRT showed increased VTE risk with oral HRT (OR 1.66, 95% CI 1.39 to 1.98).
Two nested case-control studies 3using UK databases assessed the risk of VTE and use of different types of HRT (n=80396). Overall, 5795 (7.2%) women who had VTE and 21 670 (5.5%) controls had been exposed to HRT within 90 days before the index date. Of these two groups, 4915 (85%) and 16 938 (78%) women used oral therapy, respectively, which was associated with a significantly increased risk of VTE compared with no exposure (adjusted OR 1.58, 95% CI 1.52 to 1.64), for both oestrogen only preparations (OR 1.40,95% CI 1.32 to 1.48) and combined preparations (OR 1.73, 95% CI 1.65 to 1.81). Estradiol had a lower risk than conjugated equine oestrogen for oestrogen only preparations (OR 0.85, 95% CI 0.76 to 0.95) and combined preparations (OR 0.83, 95% CI 0.76 to 0.91). Compared with no exposure, estradiol with dydrogesterone had the lowest risk (OR 1.18, 95% CI 0.98 to 1.42). Transdermal preparations were not associated with risk of VTE, which was consistent for different regimens (OR 0.93, 95% CI 0.87 to 1.01).
A Cohrane review [Abstract] 2 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).
A systematic review and meta-analysis 1 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.
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