Editor's Choice - efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials.

The aim was to perform a review of the efficacy and safety of new oral anticoagulants (NOAs) in the management of venous thromboembolism (VTE). This was a systematic review and meta-analysis. On March 26, 2014, Medline, Embase, and the Cochrane trial register were searched for randomized controlled trials (RCTs) comparing the NOAs dabigatran, rivaroxaban, apixaban, and edoxaban with vitamin K antagonists (VKAs) in VTE treatment and secondary prevention. Two investigators assessed the methodological quality of the RCTs. The main study outcomes (efficacy, safety and net clinical benefit) were expressed as risk ratios (RR) with 95% confidence interval (CI). Ten RCTs, mostly with low risk of bias, with nearly 38,000 patients, were identified. In six trials of treatment, NOAs were equally effective as VKAs in preventing recurrent symptomatic VTE (RR 0.89, 95% CI 0.75-1.05), but major bleeding occurred less often (1.08% vs. 1.73% for VKAs, RR 0.63, 95% CI 0.51-0.77), leading net clinical benefit to favor NOAs (RR 0.79, 95% CI 0.70-0.90). Fatal bleeding occurred less often with NOAs (0.09% vs. 0.18% for VKAs), a difference that approached statistical significance (RR 0.51, 95% CI 0.26-1.01). In three secondary prevention trials, NOAs reduced VTE recurrence rates to 1.32% (vs. 7.24% with placebo, RR 0.17, 95% CI 0.12-0.24) and fatal pulmonary embolism (PE) (including unexplained deaths) to 0.1% (vs. 0.29% for placebo, RR 0.37, 95% CI 0.10-1.38) at the expense of clinically relevant non-major bleeding (4.3% vs. 1.8% for placebo, RR 2.32, 95% CI 1.65-3.35), but not major bleeding. All-cause mortality rate was reduced to 0.41% with NOAs (vs. 0.86% with placebo, RR 0.38, 95% CI 0.18-0.79). Net clinical benefit favored NOAs (RR 0.21, 95% CI 0.15-0.29), and NNT was 18. Compared to VKAs, NOAs are not only effective in treating VTE but also safer in terms of bleeding, thereby conferring clinical benefit. Their safety and efficacy was confirmed further in secondary prevention trials.

Kakkos SK ，Kirkilesis GI ，Tsolakis IA 《-》

Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta-analysis.

Acute venous thromboembolism (VTE) is a common disease associated to significant morbidity and mortality. We systematically reviewed and meta-analysed clinical outcomes with direct oral anticoagulants (DOAC: dabigatran, rivaroxaban, apixaban or edoxaban) for treatment of acute VTE. We used MEDLINE and CENTRAL, clinical trials registers, conference proceedings, and websites of regulatory agencies to identify randomised clinical trials of DOAC compared with conventional treatment [parenteral anticoagulant followed by a vitamin K antagonist (VKA)] for acute VTE. Two investigators independently extracted data. Relative risk of recurrent VTE, bleeding events, deaths and a net clinical endpoint (composite of recurrent VTE, major bleeding, and death) were estimated using a random effect meta-analysis (RevMan software). Six trials including 27,127 patients were selected. The risk of recurrent VTE was similar with the DOAC and standard treatment (relative risk 0.91, 95% confidence interval 0.79 to 1.06). The DOAC reduced the risk of major bleeding in comparison with standard treatment (0.62, 0.45 to 0.85) (absolute risk difference, -0.6%; 95% confidence interval -1.0% to -0.3%), but there was heterogeneity across trials in the relative risk of bleeding. No between treatment differences were found in the relative risk of all-cause mortality (0.98, 0.84 to 1.14). The DOAC and conventional treatment differed on the net clinical endpoint (0.85, 0.75 to 0.97). Subgroup analyses in relevant subgroups (index pulmonary embolism, heparin lead-in, age, gender, renal function, presence of cancer), as well as sensitivity analyses, were consistent with the main analysis. The DOAC seem as effective as, and probably safer than standard treatment of acute VTE. The relative efficacy and safety of the DOAC was consistent across a wide range of patients.

Gómez-Outes A ，Terleira-Fernández AI ，Lecumberri R ，Suárez-Gea ML ，Vargas-Castrillón E ... -  《-》

Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis.

New direct oral anticoagulants (NOACs) constitute a novel treatment option for acute venous thromboembolism (VTE), with practical advantages. Individual studies have demonstrated comparable efficacy to that of vitamin K antagonists (VKAs) and have suggested a more favorable safety profile . We performed a meta-analysis to determine the efficacy and safety of NOACs as compared with those of VKAs in patients with acute VTE. We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials Registry up to October 2013. Eligible studies included phase 3 trials comparing NOACs with VKAs in patients with acute VTE. Relative risks (RRs), absolute risk differences and numbers needed to treat (NNTs) to prevent one event were calculated for recurrent VTE, fatal pulmonary embolism (PE), overall mortality, major bleeding, and other bleeding complications, with random-effects models. Five studies were included, investigating four NOACs (rivaroxaban, dabigatran, apixaban, and edoxaban) in 24 455 patients with acute VTE. RRs for recurrent VTE, fatal PE and overall mortality for NOACs vs. VKAs were 0.88 (95% confidence interval [CI] 0.74-1.05), 1.02 (95% CI 0.39-5.96), and 0.97 (95% CI 0.83-1.14), respectively. The RR for major bleeding was 0.60 (95% CI 0.41-0.88). The NNT with NOACs instead of VKA to prevent one major bleed was 149. The RR and NNT for fatal bleeding were 0.36 (95% CI 0.15-0.87) and 1111. A fixed-effect network analysis did not demonstrate significant differences between individual NOACs and rivaroxaban. NOACs have comparable efficacy to that of VKAs, and are associated with a significantly lower risk of bleeding complications, although the NNT to prevent one major bleed was relatively high.

van der Hulle T ，Kooiman J ，den Exter PL ，Dekkers OM ，Klok FA ，Huisman MV ... -  《-》

Dabigatran, rivaroxaban and apixaban for extended venous thromboembolism treatment: network meta-analysis.

Alotaibi G ，Alsaleh K ，Wu C ，Mcmurtry MS ... -  《-》

New oral anticoagulants for the treatment of venous thromboembolism.

New oral anticoagulants, acting either as direct factor-Xa or thrombin inhibitors, have been evaluated for the acute and long-term treatment of venous thromboembolism (VTE). Dabigatran and rivaroxaban are as effective as conventional therapy (heparin/vitamin K antagonists) without safety concerns. Rivaroxaban allows a single-drug regimen even in patients with pulmonary embolism, while dabigatran requires 5-7 days of initial heparin treatment. The results of clinical trials with apixaban and edoxaban will become available in the coming months. Rivaroxaban, apixaban and dabigatran are more effective than placebo for the extended treatment of VTE. Apixaban is effective in both therapeutic and prophylactic doses. Considering both efficacy and bleeding complications, all these agents have a favorable net clinical benefit. Dabigatran is as effective and safe as warfarin for the extended treatment of VTE. It is conceivable that the new oral anticoagulants will become the standard therapy for VTE in the next years.

Agnelli G ，Becattini C ，Franco L 《-》