Evaluation of oral anticoagulants for the extended treatment of venous thromboembolism using a mixed-treatment comparison, meta-analytic approach.
Target-specific oral anticoagulants (apixaban, rivaroxaban, and dabigatran) are widely available for the treatment of venous thromboembolism (VTE). Although analyses comparing these agents to placebo or warfarin exist, direct comparisons of these agents for extended VTE treatment have not been conducted. Therefore, this network meta-analysis aimed to evaluate the efficacy and tolerability of VKA and target-specific oral anticoagulants for extended VTE treatment using a mixed-treatment comparison, meta-analytic approach.
A comprehensive literature search of EMBASE and MEDLINE was conducted to identify relevant randomized, controlled trials published in English between 1960 and November 2013. Eligible studies investigated the extended use (≥6 months) of oral anticoagulants (apixaban, dabigatran, rivaroxaban, and/or warfarin [conventional or low dose]) and placebo in patients with confirmed VTE. Search terms included extension or extended treatment or therapy, venous thromboembolism (or VTE), deep vein thrombosis (or DVT), pulmonary embolism (or PE), and anticoagulant or anticoagulant agent. Key articles were cross-referenced for additional studies. The efficacy end points evaluated were recurrent VTE or death from any cause, DVT, and nonfatal pulmonary embolism PE. Tolerability end points included major bleeding and nonmajor or clinically relevant bleeding. The data were screened, evaluated, and entered into statistical software to generate direct and indirect comparisons of the various anticoagulants across each study. The data are reported as rate ratios and 95% credible intervals.
Ten trials were analyzed and aggregated, representing data from >14,000 patients. With respect to efficacy end points, no statistically significant between-treatment differences in the composite end point of VTE or death, nonfatal PE, or DVT were found. Major bleeding was significantly greater with warfarin versus apixaban (rate ratio, 4.24; credible interval, 1.28-25.0), and the risk for major bleeding varied somewhat with warfarin and greatly with rivaroxaban. The assessment of nonmajor or clinically relevant bleeding did not identify any meaningful differences between these agents.
The majority of the data represented in this study were derived from noninferiority trials. In the present meta-analysis, efficacy end points in the extended treatment of VTE with apixaban, dabigatran, rivaroxaban, warfarin (conventional and low dose), and placebo were not significantly different. Elevated bleeding risks were identified with rivaroxaban and warfarin; however, the wide credible intervals with rivaroxaban prevent the interpretation of these increased risks.
Rollins BM
，Silva MA
，Donovan JL
，Kanaan AO
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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
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Effectiveness and Safety of Non-vitamin K Antagonist Oral Anticoagulants for Atrial Fibrillation and Venous Thromboembolism: A Systematic Review and Meta-analyses.
The findings from the observational studies comparing the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) for atrial fibrillation (AF) and venous thromboembolism (VTE) are inconsistent. We conducted separate meta-analyses examining the efficacy/effectiveness and safety of NOACs versus VKAs by disease (AF vs VTE), study design (randomized controlled trials [RCTs] vs observational studies), and NOAC (dabigatran, rivaroxaban, apixaban, and edoxaban).
The main data sources included PubMed/MEDLINE, EMBASE, Web of Science, CINAHL, and Scopus from January 1, 2005, to February 15, 2016. We searched for Phase III RCTs and observational studies comparing NOACs versus VKAs. The primary outcomes were stroke/systemic embolism (SE) for AF; recurrent VTE/fatal pulmonary embolism (PE) for VTE; and major bleeding for both conditions. Secondary outcomes included stroke and myocardial infarction (MI) for AF, recurrent deep vein thrombosis (DVT)/PE for VTE, and mortality, intracranial hemorrhage (ICH), and gastrointestinal bleeding for both conditions. Pooled hazard ratios (HRs) were reported by using inverse variance-weighted random effects models.
A total of 13 RCTs and 27 observational studies (AF, n = 32; VTE, n = 8) were included. For AF, dabigatran and VKAs were comparable for stroke/SE risk in 1 RCT (HR, 0.77 [95% CI, 0.57-1.03]) and 6 observational studies (HR, 1.03 [95% CI, 0.83-1.27]). Rivaroxaban had a 20% decreased risk of stroke/SE in 3 RCTs (HR, 0.80 [95% CI, 0.67-0.95]) compared with VKA, but the effect was nonsignificant in 3 observational studies (HR, 0.78 [95% CI, 0.59-1.04]). Apixaban decreased stroke/systemic embolism risk (HR, 0.79 [95% CI, 0.66-0.95]) compared with VKA in 1 RCT, but edoxaban was comparable to VKA (HR, 0.99 [95% CI, 0.77-1.28]) in 1 RCT (no observational studies available for apixaban/edoxaban). Dabigatran, apixaban, and edoxaban decreased the risk of hemorrhagic stroke, mortality, major bleeding, and ICH by 10% to 71% compared with VKAs but not rivaroxaban. For VTE, NOACs and VKAs were comparable for recurrent VTE/fatal PE/DVT/PE risk in 7 RCTs and 1 observational study. The 7 RCTs demonstrated a 32% to 69% decreased risk of major bleeding for dabigatran, rivaroxaban, and apixaban compared with VKAs. No difference was shown in 1 rivaroxaban observational study (HR, 0.77 [95% CI, 0.40-1.49]) and 1 edoxaban RCT (HR, 0.84 [95% CI, 0.59-1.20]). Except for dabigatran, the NOACs had a 61% to 86% decreased risk of ICH and gastrointestinal bleeding.
Overall, NOACs were comparable or superior to VKAs. Although no observational studies are currently available for apixaban/edoxaban, a few notable inconsistencies exist for dabigatran (ischemic stroke, MI) and rivaroxaban (stroke/SE, major bleeding in VTE) between RCTs and observational studies. Individualizing NOAC/VKA therapy based on benefit/safety profiles and patient characteristics is suggested.
Almutairi AR
，Zhou L
，Gellad WF
，Lee JK
，Slack MK
，Martin JR
，Lo-Ciganic WH
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