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Objectives: Venous thromboembolism (VTE) incurs substantial costs to the UK National Health Service (NHS). Betrixaban is approved in the US for VTE prophylaxis with a recommended 35-42 days of treatment. This analysis modeled the budget impact of introducing betrixaban for extended-duration VTE prophylaxis in nonsurgical patients with acute medical illness at risk of VTE in the UK, where it is not yet licensed., Methods: The 5-year budget impact of introducing betrixaban into current prophylaxis (low molecular weight heparin and fondaparinux) was estimated for the UK NHS. The Phase 3 APEX study provided primary event (VTE, myocardial infarction, ischemic stroke, and death; all-cause or VTE-related) and treatment complications data. Literature informed risk of recurrent events and long-term complications, population, market share, and costs for treatment and management of events. Network meta-analyses informed symptomatic DVT, pulmonary embolism and VTE-related death rates in fondaparinux patients. Deterministic sensitivity analyses explored uncertainty., Results: Introducing betrixaban accrued savings of £1,290,000-£23,000,000 in years 1-5. Savings were from reduced primary VTE events, which reduced recurrent events and future complications. All sensitivity analyses showed savings., Conclusion: Introducing extended-duration VTE prophylaxis with betrixaban in the UK would accrue substantial savings annually over the next 5 years compared to current prophylaxis. Clinical trial registration: www.clinicaltrials.gov identifier is NCT01583218.

Aims: To determine the clinical effectiveness and safety of venous thromboembolism (VTE) prophylaxis using US- and Europe-approved anticoagulants relative to extended-duration VTE prophylaxis with betrixaban. Low molecular weight heparins (LMWHs), unfractionated heparin (UFH), fondaparinux sodium and placebo were each compared to betrixaban, as standard-duration VTE prophylaxis for hospitalized, non-surgical patients with acute medical illness at risk of VTE. Materials and methods: A systematic literature review was conducted up to June 2019 to identify randomized controlled trials (RCTs) of VTE prophylaxis in hospitalized, non-surgical patients with acute medical illness at risk of VTE. Studies that reported the occurrence of VTE events (including death) and, where possible, major bleeding, from treatment initiation to 20-50 days thereafter were retrieved and extracted. A Bayesian fixed effect network meta-analysis was used to estimate efficacy and safety of betrixaban compared with standard-duration VTE prophylaxis. Results: Seven RCTs were analyzed which compared betrixaban, LMWHs, UFH, fondaparinux sodium, or placebo. There were significantly higher odds (median odds [95% credible interval]) of VTE with LMWHs (1.38 [1.12-1.70]), UFH (1.60 [1.05-2.46]), and placebo (2.37 [1.55-3.66]) compared with betrixaban. There were significantly higher odds of VTE-related death with placebo (7.76 [2.14-34.40]) compared with betrixaban. No significant differences were observed for the odds of major bleeding with all comparators, VTE-related death with any active standard-duration VTE prophylaxis, or of VTE with fondaparinux sodium, compared with betrixaban. Limitations and conclusions: In this indirect comparison, betrixaban was shown to be an effective regimen with relative benefits compared with LMWHs and UFH. This indicates that betrixaban could reduce the burden of VTE in at-risk hospitalized patients with acute medical illness who need extended prophylaxis, though without direct comparative evidence, stronger conclusions cannot be drawn.

Background: Studies show that the risk of venous thromboembolism (VTE) continues post-discharge in nonsurgical patients with acute medical illness. Betrixaban is the first anticoagulant approved in the United States (US) for VTE prophylaxis extending beyond hospitalization., Objective: The aim was to establish whether betrixaban for VTE prophylaxis in nonsurgical patients with acute medical illness at risk of VTE in the US is cost-effective compared with enoxaparin., Methods: A cost-effectiveness analysis was conducted, estimating the cost per quality-adjusted life-year (QALY) gained with betrixaban (35-42 days) compared with enoxaparin (6-14 days) from a US payer perspective over a lifetime horizon. A decision tree (DT) estimated primary VTE events, thrombotic events, and treatment complications in the first 3 months based on data from the phase III Acute Medically Ill VTE Prevention with Extended Duration Betrixaban study. A Markov model estimated recurrent events and long-term complication risks from published literature. EuroQoL-5 Dimensions utility data and costs inflated to 2017 US dollars (US$) were from published literature. Results were discounted at 3.0% per annum. Deterministic and probabilistic sensitivity analyses explored uncertainty., Results: Betrixaban dominated enoxaparin, with savings of US$784 and increased QALYs of 0.017 per patient. In addition, betrixaban dominated enoxaparin across all sensitivity analyses, but was most sensitive to utilities and DT probabilities. Furthermore, probabilistic sensitivity analysis found that betrixaban was more cost-effective than enoxaparin at all willingness-to-pay thresholds., Conclusion: Betrixaban can be considered cost-effective for nonsurgical patients with acute medical illness at risk of VTE, requiring longer VTE prophylaxis from hospitalization through post-discharge.

Introduction: Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors., Objective: To evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban., Materials and Methods: In vitro studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury., Results: Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035)., Conclusion: These data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.

Competing risk methods are time-to-event analyses that account for fatal and/or nonfatal events that may potentially alter or prevent a subject from experiencing the primary endpoint. Competing risk methods may provide a more accurate and less biased estimate of the incidence of an outcome but are rarely applied in cardiology trials. APEX investigated the efficacy of extended-duration betrixaban versus standard-duration enoxaparin to prevent a composite of symptomatic deep-vein thrombosis (proximal or distal), nonfatal pulmonary embolism, or venous thromboembolism (VTE)-related death in acute medically ill patients (n = 7513). The aim of the current analysis was to determine the efficacy of betrixaban vs standard-duration enoxaparin accounting for non-VTE-related deaths using the Fine and Gray method for competing risks. The proportion of non-VTE-related death was similar in both the betrixaban (133, 3.6%) and enoxaparin (136, 3.7%) arms, P = .85. Both the traditional Kaplan-Meier method and the Fine and Gray method accounting for non-VTE-related death as a competing risk showed equal reduction of VTE events when comparing betrixaban to enoxaparin (HR/SHR = 0.65, 95% 0.42-0.99, P = 0.046). Due to the similar proportion of non-VTE-related deaths in both treatment arms and the use of a univariate model, the Fine and Gray method provided identical results to the traditional Cox model. Using the Fine and Gray method in addition to the traditional Cox proportional hazards method can indicate whether the presence of a competing risk, which is dependent of the outcome, altered the risk estimate., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Among patients hospitalized with acute heart failure (HF), the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in short-term stroke prediction remains unclear., Methods: In the APEX trial, 7513 patients hospitalized for an acute medical illness were randomized to receive either extended-duration betrixaban (80 mg once daily for 35-42 days) or standard-of-care enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. Baseline NT-proBNP concentrations were obtained in 3261 patients admitted for HF. Stroke events were adjudicated by an independent clinical events committee blinded to thromboprophylaxis allocation. The association of NT-proBNP level and other risk factors and biomarkers with stroke was assessed at 77 days after randomization., Results: In univariate analysis, the risk of stroke at 77 days was associated with baseline NT-proBNP (HR 3.63 [95% CI 1.47-8.99]; P = 0.005), D-dimer (HR 2.73 [95% CI 1.03-7.20]; P = 0.043), and hsCRP (HR 3.03 [95% CI 1.36-6.75]; P = 0.007). In multivariable analysis adjusting for hsCRP and thromboprophylaxis, NT-proBNP was associated with the risk of stroke (adjusted HR 3.64 [95% CI 1.35-9.83]; P = 0.011). The interaction of NT-proBNP with the treatment effect was not significant (P int  = 0.30)., Conclusions: Baseline NT-proBNP concentration was associated with short-term stroke among patients hospitalized with acute HF. Stroke risk assessment models should consider incorporation of NT-proBNP measurement.

Background: Extended-duration betrixaban showed a significant reduction in venous thromboembolism in the APEX trial (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study). Given the variable clinical impact of different efficacy and safety events, one approach to assess net clinical outcomes is to include only those events that are either fatal or cause irreversible harm., Methods and Results: This was a post hoc analysis of the APEX trial-a multicenter, double-blind, randomized controlled trial comparing extended-duration betrixaban versus standard-of-care enoxaparin. A composite of all fatal or irreversible safety (fatal bleeding or intracranial hemorrhage) and efficacy events (cardiopulmonary death, myocardial infarction, pulmonary embolism, and ischemic stroke) was evaluated in a time-to-first event analysis. In patients with positive D-dimer results, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.80% versus 3.54%; hazard ratio, 0.73; absolute risk reduction, 1.26%; number needed to treat, 79 [ P =0.033]) and at study end at 77 days (6.27% versus 4.36%; hazard ratio, 0.70; absolute risk reduction, 1.91%; number needed to treat, 52 [ P =0.005]) versus enoxaparin. In all patients, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.08% versus 2.90%; hazard ratio, 0.71; absolute risk reduction, 1.18%; number needed to treat, 86 [ P =0.006]) and 77 days (5.17% versus 3.64%; hazard ratio, 0.70; absolute risk reduction, 1.53%; number needed to treat, 65 [ P =0.002])., Conclusions: Among hospitalized medically ill patients, extended-duration betrixaban demonstrated an ≈30% reduction in fatal or irreversible ischemic or bleeding events compared with standard-duration enoxaparin. A total of 65 patients would require treatment with betrixaban to prevent 1 fatal or irreversible event versus enoxaparin., Clinical Trial Registration: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01583218., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: The APEX trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among hospitalized, acutely ill medical patients. The 80-mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein inhibitor., Methods: This analysis assessed the pharmacokinetics, efficacy, and safety of full- (80 mg) and reduced-dose (40 mg) betrixaban relative to enoxaparin in the APEX trial., Results: The median concentration of betrixaban among subjects administered the 80-mg dose was higher than that of the 40-mg dose (19 ng/mL vs 11 ng/mL, P<.001). In the primary analysis cohort 1 (d-dimer ≥2× upper limit of normal), the primary efficacy outcome (asymptomatic proximal deep vein thrombosis, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or venous thromboembolism-related death) was significantly reduced among subjects treated with 80 mg of extended-duration betrixaban versus enoxaparin (6.27% [95/1516] vs 8.39% [130/1549], relative risk reduction=0.26 [0.04-0.42], P=.023), and similarly in the entire primary efficacy outcome population (4.87% [122/2506] vs 7.06% [181/2562], relative risk reduction=0.30 [0.13-0.44], P=.001). There was no difference in the primary outcome for subjects treated with 40 mg betrixaban vs enoxaparin across cohorts. In addition, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin., Conclusions: The 80-mg betrixaban dose achieves higher plasma concentrations than the 40-mg dose and, in contrast to the 40-mg dose, is associated with improved efficacy across all cohorts relative to standard-dose enoxaparin without an excess risk of major bleeding in the management of medically ill subjects., (Copyright © 2016. Published by Elsevier Inc.)

Background: Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban)., Methods: Hospitalized acutely medically ill subjects (n=7513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35-42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10±4 days) for venous thromboprophylaxis. Stroke events were adjudicated by an independent, blinded event adjudication committee., Results: The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk [RR]=0.56; 95% confidence interval, 0.32-0.96; P =0.032; adjusted RR=0.43%; number needed to treat=233) and ischemic strokes (0.48% versus 0.91%; RR=0.53; 95% confidence interval, 0.30-0.94; P =0.026; adjusted RR=0.43%; number needed to treat=233) among patients treated with betrixaban versus enoxaparin through 77 days of follow-up. Among high-risk subjects, those with congestive heart failure or ischemic stroke as their index event, betrixaban reduced the risk of all-cause stroke (0.72% versus 1.48%; RR=0.49; 95% confidence interval, 0.26-0.90; P =0.019; adjusted RR=0.76%; number needed to treat=132) and ischemic stroke (0.63% versus 1.38%; RR=0.45; 95% confidence interval, 0.24-0.87; P =0.014; adjusted RR=0.75%; number needed to treat=134) compared with enoxaparin., Conclusions: Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01583218., (© 2016 American Heart Association, Inc.)

Background: Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown., Methods: Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding., Results: A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55)., Conclusions: Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.).

Randomized clinical trials have identified a population of acute medically ill patients who remain at risk for venous thromboembolism (VTE) beyond the standard duration of therapy and hospital discharge. The aim of the APEX study is to determine whether extended administration of oral betrixaban (35-42 days) is superior to a standard short course of prophylaxis with subcutaneous enoxaparin (10 ± 4 days followed by placebo) in patients with known risk factors for post-discharge VTE. Patients initially are randomized to receive either betrixaban or enoxaparin (and matching placebo) in a double dummy design. Following a standard duration period of enoxaparin treatment (with placebo tablets) or betrixaban (with placebo injections), patients receive only betrixaban (or alternative matching placebo). Patients are considered for enrollment if they are older than 40 years, have a specified medical illness, and restricted mobility. They must also meet the APEX criteria for increased VTE risk (aged ≥75 years, baseline D-Dimer ≥2× upper the limit of "normal", or 2 additional ancillary risk factors for VTE). The primary efficacy end point is the composite of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, non-fatal (pulmonary embolus) pulmonary embolism, or VTE-related death through day 35. The primary safety outcome is the occurrence of major bleeding. We hypothesize that extended duration betrixaban VTE prophylaxis will be safe and more effective than standard short duration enoxaparin in preventing VTE in acute medically ill patients with known risk factors for post hospital discharge VTE., (Copyright © 2014 The Authors. Published by Mosby, Inc. All rights reserved.)