To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1007/s11739-017-1714-9 Byline: Claudio Cimminiello (1), Paolo Prandoni (2), Giancarlo Agnelli (3), Giovanni Di Minno (4), Hernan Polo Friz (5), Francesco Scaglione (6), Patrizia Boracchi (7), Giuseppe Marano (7), Job Harenberg (8) Keywords: Anticoagulants; Low molecular weight heparin; Venous thromboembolism; Evidence-based practice; Meta-analysis Abstract: Subjects undergoing major orthopedic surgery and acutely ill hospitalized medical patients represent a population at medium--high risk for venous thromboembolism (VTE). They are treated with low molecular weight heparin (LMWH) and direct oral anticoagulants [DOACs] for VTE prevention. We conducted a meta-analysis of phase III randomized clinical trials evaluating LMWH enoxaparin versus DOACs for prophylaxis of VTE by combining studies including patients undergoing elective total hip and knee replacement surgery, and acutely ill hospitalized medical subjects. Studies were searched using PubMed, MEDLINE, and EMBASE databases until December 2016. Differences in clinical outcomes for efficacy and safety endpoints between treatment groups were expressed as risk differences with 95% confidence intervals (95% CI), using random effects regression models. Fourteen RCTs were considered (60,467 subjects). Overall mortality, symptomatic deep venous thrombosis, non-fatal pulmonary embolism (PE) major bleeding (MB) and clinically relevant non-major bleeding (CRNMB) are not different between treatment regimens. Treatment with LMWH enoxaparin is associated with a lower risk of fatal PE plus VTE-related death compared therapy with DOACs (RD = 0.040%, 95% CI 0.001--0.080%, p = 0.0434). Subgroup analysis shows an incidence of MB (RD = 0.181%, 95% CI 0.029--0.332%, p = 0.0033) and CRNMB (RD = 0.546%, 95% CI 0.009--1.082%, p = 0.0462) in patients treated with 40 mg OD enoxaparin compared to DOACs. In major orthopedic surgery and acutely ill hospitalized medical patients, DOACs do not offer clear advantages in terms of clinical efficacy compared to enoxaparin. The advantage of the latter in terms of major and CRNMB, when used at a dose of 40 mg, is statistically significant, but small in terms of clinical relevance. Author Affiliation: (1) Studies and Research Center of the Italian Society of Angiology and Vascular Patholog (SocietAaAaAeA Italiana di Angiologia e Patologia Vascolar SIAPAV), via Gorizia 22, 20144, Milan, Italy (2) Vascular Medicine Unit, Department of Cardiothoracic and Vascular Sciences, University of Padua, Via Giustiniani 2, 35128, Padua, Italy (3) Internal and Cardiovascular Medicine-Stroke Unit, University of Perugia, Piazzale Menghini 1, 06100, Perugia, Italy (4) Department of Clinical and Experimental Medicine, Federico II, University Hospital, Via S. Pansini 5, Naples, Italy (5) Department of Medicine, Vimercate Hospital, Azienda Ospedaliera di Desio e Vimercate, via Santi Cosma e Damiano 10, 20871, Vimercate, Italy (6) Department of Oncology and Onco-Hematology, University of Milan, Via Vanvitelli 32, 20129, Milan, Italy (7) Laboratory of Medical Statistics, Department of Clinical Sciences and Community Health, Epidemiology and Biometry G. A. Maccacaro, University of Milan, Via C. Vanzetti 5, 20133, Milan, Italy (8) Medical Faculty Mannheim, Ruprecht-Karls University Heidelberg, Theodor-Kutzer Ufer 1-3, 68167, Mannheim, Germany Article History: Registration Date: 24/07/2017 Received Date: 15/03/2017 Accepted Date: 24/07/2017 Online Date: 29/07/2017 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s11739-017-1714-9) contains supplementary material, which is available to authorized users.