darexaban and Venous-Thromboembolism

To systematically review the efficacy of 11 anticoagulants in the treatment of venous thromboembolism (VTE) after total hip or knee arthroplasty.. PubMed, Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure, Wanfang Data, VIP, and China Biology Medicine databases were electronically searched for studies assessing the efficacy of different anticoagulants for the prevention of VTE after total hip or knee arthroplasty from January 1, 2010, to January 27, 2022. Two reviewers independently screened the literature, extracted data, and graded the evidence using Confidence in Network Meta-Analysis. The network meta-analysis was then performed using Stata 16.0 software and R 4.1.0 software.. A total of 61 articles were included. The results of network meta-analysis showed that apixaban, edoxaban, fondaparinux, rivaroxaban, and darexaban were the most effective anticoagulants for the prevention of deep vein thrombosis in patients undergoing total hip or knee arthroplasty (P < .05), while there was no difference in the efficacy among the anticoagulants for the prevention of pulmonary embolism (P > .05).. Apixaban, edoxaban, fondaparinux, rivaroxaban, and darexaban have the best efficacy for the prevention of VTE after total hip or knee arthroplasty.

Topics: Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Fondaparinux; Humans; Network Meta-Analysis; Rivaroxaban; Venous Thromboembolism

Approximately 900,000 people are affected by some sort of venous thromboembolic (VTE) event every year in the United States. VTE diagnosis used to mean treatment with medications that required routine lab monitoring for safety and efficacy. Activated factor X (FXa) inhibition has emerged as a convenient pathway for management of VTE and currently three FXa inhibitors are available for anticoagulation management - rivaroxaban, apixaban, and edoxaban. Continued development of medications utilizing this pathway may offer advantages via novel pharmacokinetic or pharmacodynamic properties that may minimize the adverse effects associated with traditional anticoagulant therapy. This review summarizes the available information regarding pharmacokinetic, pharmacodynamic, and early safety and efficacy data for three factor Xa inhibitors being developed - darexaban, betrixaban and nokxaban. The studies reviewed in this article suggests that three newer agents possess the potential for promise based on early phase I and II trials.

Topics: Administration, Oral; Animals; Azepines; Benzamides; Blood Coagulation; Drug Discovery; Factor Xa Inhibitors; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiazoles; Venous Thromboembolism

Inhibition of the pathways of anticoagulation is widely used for the prevention and treatment of arterial and venous thrombosis. Vitamin K antagonists (VKAs) have been the mainstay of oral anticoagulation for more than 60 years. Their safety and effectiveness have been established in multiple clinical trials, for a variety of clinical indications. However, there are several limitations to the use of VKAs including delayed onset of action and dosage titration, numerous food and drug interactions and need for regular laboratory monitoring. To overcome some of the limitations of traditional agents, new oral anticoagulants (OACs) have been developed and evaluated.. In the present review article, the pharmacokinetic properties of darexaban are presented, along with the available preliminary clinical data. The performance of darexaban in respect to safety and efficacy compared with its competitors is further discussed.. Darexaban is a potent direct factor Xa inhibitor that demonstrated impressive pharmacokinetic properties in pre-clinical studies. It was further successfully evaluated in the ONYX program for the prevention of venous thromboembolism in patients undergoing hip replacement. Finally, in the Phase II RUBY-1 trial, darexaban was tested on the top of standard antiplatelet therapy for the prevention of ischemic events in acute coronary syndrome (ACS) patients. Despite the fact that darexaban had a relatively uneventful clinical evaluation program, its further development was recently discontinued. This decision could probably reflect the non-favorite results in commercially attractive indications, such as secondary prevention post-ACS and the increased competition for less common or short-term indications such stroke prevention in AF or VTE prophylaxis respectively.

Topics: Administration, Oral; Animals; Anticoagulants; Azepines; Benzamides; Blood Coagulation; Clinical Trials as Topic; Coronary Artery Disease; Factor Xa Inhibitors; Humans; Secondary Prevention; Thrombin; Treatment Outcome; Venous Thromboembolism

This double-blind, double-dummy, randomised, phase IIb study (NCT00902928) evaluated different dosing regimens of darexaban compared with enoxaparin (randomised 1:1:1:1:1 to 15 mg twice daily [bid], 30 mg once daily [qd], 30 mg bid or 60 mg qd or enoxaparin 40 mg qd) in patients undergoing elective total hip arthroplasty. Patients, investigators, pharmacists and sponsor were all blinded to treatment allocation. Darexaban administration started 6-10 hours (h) post-surgery. Enoxaparin 40 mg qd administration started 12 ± 2 h before surgery. Treatment continued for 35 days. Bilateral venography was performed on Day 10 ± 2. The primary efficacy outcome was total VTEs (composite of proximal/distal deep-vein thrombosis, pulmonary embolism) or death, at Day 12. Total VTE rates were similar across all groups. There was no apparent difference in efficacy between once- and twice-daily darexaban (odds ratio [OR] 1.00; 95% confidence interval [CI] 0.71-1.42; p=0.988), or total daily dose (30 mg/day vs 60 mg/day; OR 0.81; 95% CI 0.57-1.15; p=0.244). There was no significant difference in major and/or clinically relevant non-major bleeding between darexaban qd or bid, or between total daily doses of 30 mg or 60 mg, and also for any dosing regimen of darexaban vs enoxaparin. Darexaban was well tolerated, without signs of liver toxicity. In conclusion, darexaban, administered qd or bid, and at total daily doses of 30 mg or 60 mg, appears to be effective for VTE prevention and was well tolerated. Data suggest no significant differences between a once- or twice-daily dosing regimen.

Topics: Aged; Anticoagulants; Arthroplasty, Replacement, Hip; Australia; Azepines; Benzamides; Brazil; Canada; Double-Blind Method; Drug Administration Schedule; Elective Surgical Procedures; Enoxaparin; Europe; Female; Hemorrhage; Humans; India; Israel; Logistic Models; Male; Middle Aged; Odds Ratio; Phlebography; Risk Factors; South Africa; Time Factors; Treatment Outcome; United States; Venous Thromboembolism

To evaluate the efficacy and safety of darexaban (YM150) in Asian patients undergoing total hip or total knee arthroplasty.. In 2 phase II/III multicenter, randomized, double-blind, placebo-controlled, parallel-group studies, patients were randomized to oral darexaban 15 mg twice daily (bid), darexaban 30 mg bid, oral placebo bid, or subcutaneous enoxaparin 20 mg bid. Primary efficacy outcome for both studies was total venous thromboembolism (VTE) incidence.. Both darexaban doses were statistically significantly superior to placebo for total VTE incidence (hip study: darexaban 15 mg bid [2.9%] vs placebo [17.1%], P < .001; darexaban 30 mg bid [5.2%] vs placebo [17.1%], P = .003; and knee study: darexaban 15 mg bid [27.2%] vs placebo [52.8%], P = .002; darexaban 30 mg bid [15.5%] vs placebo [52.8%], P < .001). In both studies, the incidence of bleeding events was low across all treatment groups.. Darexaban is effective and well tolerated as VTE prophylaxis in Asian patients undergoing elective major orthopedic surgery.

Topics: Adult; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Asian People; Azepines; Benzamides; Double-Blind Method; Drug Administration Schedule; Enoxaparin; Female; Humans; Male; Orthopedic Procedures; Risk Assessment; Risk Factors; Venous Thromboembolism; Young Adult

Darexaban (YM150) is an oral direct factor Xa inhibitor in clinical development for prophylaxis of venous thromboembolism (VTE) after major orthopaedic surgery. The objective of this study was to assess the efficacy and safety of darexaban 15 mg twice daily (bid) in Japanese patients undergoing major abdominal surgery.. In a Phase III, multicentre, randomized, open-label, mechanical prophylaxis-controlled, parallel-group study, adult patients (aged ≥ 40 years) were randomized to darexaban 15 mg bid or mechanical prophylaxis, for 28 days. The primary efficacy outcome was incidence of total VTE at Day 12. Adverse events (AEs) and bleeding events were recorded throughout the study.. The total VTE incidence at Day 12 was 2.6% in the darexaban 15 mg bid group (95% confidence interval [CI]: 0.32, 9.07), compared with 15.0% (95% CI: 5.71, 29.84) in the mechanical prophylaxis group. During the investigational period, the incidence of all bleeding events was 9.5% in the darexaban 15 mg bid group and 3.9% in the mechanical prophylaxis group. In the darexaban 15 mg bid group, one patient experienced major bleeding and five patients experienced clinically relevant non-major (CRNM) bleeding. No patients in the mechanical prophylaxis group experienced major and/or CRNM bleeding. AEs were reported in 71.4% of patients in the darexaban 15mg bid group and 76.5% of patients in the mechanical prophylaxis group; the most frequent AEs across both treatment groups were constipation and insomnia. No patients died during the study.. Based on these findings, darexaban is expected to be effective for the prevention of VTE in patients undergoing major abdominal surgery. (. NCT00942435).

Topics: Abdomen; Aged; Asian People; Azepines; Benzamides; Digestive System Surgical Procedures; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Humans; Male; Mechanical Thrombolysis; Middle Aged; Orthopedic Procedures; Treatment Outcome; Venous Thromboembolism