Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis

Introduction: Hormone therapy (HT) is an effective treatment for climacteric symptoms. Nevertheless, combined estrogen-progestin therapy and the oral route seem to entail higher risk of venous thromboembolism (VTE) than estrogen-only therapy and transdermal administration. The present study aimed to investigate the risk of thromboembolic events in postmenopausal women using non-oral estrogen compared to women using oral estrogen and control groups (women receiving placebo or non-users of HT), as well as to assess the thrombotic impact of estrogens alone vs. combined estrogen-progestin therapy. Materials and methods: Systematic review of MEDLINE, Cochrane CENTRAL, EMBASE, and ClinicalTrials.gov according to PRISMA guidelines. Results: Twenty-two studies were included in the meta-analyses (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 HT, including users of estrogens and estrogens plus progestins (OR 0.97 [0.9-1.06]), non-oral estrogen therapy (ET)only (OR 0.95 [0.81-1.10]), and non-oral combined estrogen-progestin therapy (OR 0.92 [0.77-1.09]). 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 [1.47-2.01]), oral ET-only (OR 1.43 [1.34-1.53]), and combined oral estrogen-progestin HT (OR 2.35 [1.9-2.9]). The comparison of non-oral vs. oral HT showed increased VTE risk with oral HT (OR 1.66 [1.39-1.98]). Conclusions: VTE risk was increased in postmenopausal women with no previous thromboembolic events using oral HT. Non-oral HT did not significantly affect this risk. The quality of the evidence produced in our meta-analyses is low to moderate, and further clinical trials are needed to sort out the impact of different types of progestin and different estrogen doses and administration routes on VTE risk.