Menopausal hormone 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 could be 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 menopausal hormone therapy (HT), 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 HT, including users of estrogens and estrogens plus progestins HT (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 HT (OR 2.35, 95% CI 1.9 to 2.9). The comparison of non-oral vs. oral HT showed increased VTE risk with oral therapy (OR 1.66, 95% CI 1.39 to 1.98).
Two nested case-control studies 3 using UK databases assessed the risk of VTE and use of different types of MHT (n=80396). Overall, 5795 (7.2%) women who had VTE and 21 670 (5.5%) controls had been exposed to HT 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 (1.18, 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 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.
A systematic review 5 included 33 studies (6 trials and 27 prospective observational studies) with a total of 2 588 327 women. The current data suggested that oral and transdermal HT, in dose-dependent manner and irrespective of HT formulation, increased thromboembolic risk, as well as risk of stroke. However, transdermal estrogen with <50μg/day of estrogen combined with micronized progesterone appeared to be the safer choice with respect to thrombotic and stroke risk. The timing of HT initiation and duration may be important factors to consider when prescribing HT especially in women with adverse cardiometabolic profile and pre-existing conditions.
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