OBJECTIVES.The objective of this study is to evaluate safety and efficacy of anticoagulants for venous thromboembolism (VTE) prophylaxis in acute medically ill adult patients.METHODS.PubMed/MEDLINE, Cochrane, and Embase were searched from inception until September 2018 for trials comparing NOACs or heparin as anticoagulant therapy in medically ill patients. A network meta-analysis(NMA) was performed using a random effect model. The outcomes were the occurrence of venous thromboembolism and mortality while secondary outcomes included the occurrence of DVT and PE. The safety outcomes were major and minor bleed.RESULTS.A total of 66,923 patients among 21 RCTs evaluating 10 anticoagulants, out of which 5 NOACs, were included in the NMA. The NMA showed no statistical significance in mortality among all comparisons but for VTE occurrence, 9 comparisons were found to be statistically significant [OR,(95% CI):Apixaban vs Enoxaparin,0.67(0.47, 0.97); Dalteparin vs Enoxaparin,0.59(0.36, 0.98); Placebo vs Enoxaparin,0.50(0.33, 0.75); Fondaparinux vs Enoxaparin, 0.50(0.28, 0.91); Rivaroxaban vs Enoxaparin,0.50(0.34, 0.75); Betrixaban vs Enoxaparin,0.43(0.25, 0.76); Rivaroxaban vs Apixaban,0.75(0.60, 0.94); Betrixaban vs Apixaban,0.64(0.42, 0.99); Betrixaban vs Nadroparin,0.45(0.21, 0.97)]. In case of major bleed 4 comparisons were reported to be statistically significant [Unfractionated Heparin(UFH) vs Enoxaparin, 2.24(1.09, 4.58); Rivaroxaban vs Enoxaparin,2.41(1.35, 4.29); UFH vs Apixaban,2.36(1.09, 5.10); Rivaroxaban vs Apixaban, 2.54(1.53, 4.22)]. According to Surface Under the Cumulative Ranking Curve, Fondaparinux was ranked as the best treatment approach for preventing mortality. Betrixaban and Apixaban were ranked as the best approaches for preventing VTE occurrence, and less Major bleed events respectively.CONCLUSIONS.Our results suggest that Enoxaparin should not be a preference for VTE prevention in acute medically ill adult patients. In the odds of major bleed Apixaban and Enoxaparin showed similar results. Although, the choice of anticoagulants for the prevention of VTE in medically ill adult patients should primarily be based on the individual patient’s characteristics, risks and in consideration of pharmacokinetics and pharmacodynamics characteristics.