Search

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.

Objectives: This study evaluated the frequency of hospital readmissions for venous thromboembolism (VTE) and the associated costs and length of stay (LOS) among acute medically ill patients in the US using a real-world claims database analysis. Methods: Patients (≥40 years of age) at risk of VTE due to hospitalization for acute medical illnesses, based on primary hospital discharge diagnosis codes, were identified from the MarketScan databases between July 1, 2011 and March 31, 2015. Patients were required to have continuous insurance enrollment in the 6 months prior to initial (index) hospitalizations (baseline period) and in the 6 months after hospital discharge (follow-up period). The proportions of patients with VTE-related (diagnosis at any position) and VTE as primary diagnosis hospital readmissions during the follow-up period were evaluated. The associated costs and LOS for such readmissions were also determined, as well as time to VTE-related readmissions. Results: Of the study population ( n  = 12,785; mean age = 68.3 years), most were hospitalized primarily for infectious diseases (35.2%), followed by respiratory diseases (27.9%), cancer (15.7%), heart failure (11.8%), ischemic stroke (8.1%), and rheumatic diseases (1.4%). Of the overall study population, 2.1% ( n  = 268) had a VTE-related hospital readmission in the 6 months following discharge of their index hospitalization, of which 36.6% ( n  = 98) were for a primary diagnosis of VTE. Approximately 25.4% of the VTE-related hospital readmissions occurred within the first 30 days of discharge and 58.2% within 90 days. The mean cost for a hospital readmission with a primary diagnosis of VTE was $18,681 (mean LOS = 5.0 days); for readmissions with a primary diagnosis of DVT and PE, mean costs were $14,719 and $23,305, respectively. Conclusions: Among this study population of patients hospitalized for acute medical illnesses, some experienced a VTE event requiring re-hospitalization, with 25% occurring within the first 30 days after hospital discharge.

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: Venous thromboembolism (VTE) is a leading cause of preventable morbidity and mortality among hospitalized patients in the US. The objectives of this study were to examine VTE prophylaxis patterns and risk for VTE events during hospitalization and post-discharge among patients hospitalized for acute illnesses in the US., Methods: Acutely ill hospitalized patients were identified from the MarketScan databases (January 1, 2012-June 30, 2015). Proportions of patients that received inpatient and/or outpatient VTE prophylaxis were determined. VTE rates were calculated for the overall study population and for each subpopulation with each acute illness type. Risk for VTE events after the index admission was determined by Kaplan-Meier analysis., Results: Of the acutely ill patients (n = 17,895, mean age: 58.4 years), most were hospitalized for infectious diseases (40.6%), followed by respiratory diseases (31.0%), cancer (10.7%), heart failure (10.4%), ischemic stroke (6.4%), and rheumatic diseases (0.9%). Among the entire study population, 59.1% did not receive any VTE prophylaxis, and only 7.1% received both inpatient and outpatient prophylaxis. Among the overall study population, cumulative VTE rate, including during index admission and within 6 months post-discharge, was 4.6%. VTE risk in the inpatient and outpatient continuum of care remained elevated up to 30-40 days after hospital admission, with 60.1% of VTEs occurring within 40 days of hospital admission., Conclusion: In this retrospective analysis of nearly 18,000 patients hospitalized for acute illnesses, 59.1% did not receive any VTE prophylaxis and only 7.1% received VTE prophylaxis in both the inpatient and outpatient continuum of care, despite significant VTE risk extending from hospitalization into the post-discharge period., Funding: Portola Pharmaceuticals.

The objectives of this study were to examine venous thromboembolism (VTE) prophylaxis patterns and risk for VTE events during hospitalization and in the outpatient continuum of care among patients hospitalized for acute illnesses in the United States with stratification by different age groups and renal disease status. Acutely ill hospitalized patients were identified from the MarketScan databases (January 1, 2012-June 30, 2015) and grouped by age (<65, 65-74, ≥75 years old) and whether or not they had a baseline diagnosis of renal disease, separately. Of acutely ill hospitalized patients, 60.1% (n = 10 748) were <65 years old, 15.7% (n = 2803) were 65 to 74 years old, and 24.3% (n = 4344) were ≥75 years old; 32.9% (n = 5892) had baseline renal disease. Among the study cohorts, the majority of patients received no VTE prophylaxis regardless of age or baseline renal status (52.1%-63.6%). Rates of VTE during hospitalization and in the 6 months postdischarge were 4.7%, 4.6%, and 4.5% for patients <65, 65 to 74, and ≥75 years old, respectively, and 6.3% and 3.8% for patients with and without baseline renal disease. The risk for VTE was elevated for 30 to 40 days after index admission regardless of age and renal disease status.

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.)

Essentials Anticoagulants prevent venous thromboembolism but may be associated with greater bleeding risks. Bivariate analysis assumes a non-linear relationship between efficacy and safety outcomes. Extended full-dose betrixaban is favorable over standard enoxaparin in bivariate endpoint. Clinicians must weigh efficacy and safety outcomes in decision-making on thromboprophylaxis., Summary: Background Among acutely ill hospitalized medical patients, extended-duration thromboprophylaxis reduces the risk of venous thromboembolism (VTE), but some pharmacologic strategies have been associated with greater risks of major bleeding, thereby offsetting the net clinical benefit (NCB). Methods To assess the risk-benefit profile of anticoagulation regimens, a previously described bivariate method that does not assume a linear risk-benefit tradeoff and can accommodate different margins for efficacy and safety was performed to simultaneously assess efficacy (symptomatic VTE) and safety (major bleeding) on the basis of data from four randomized controlled trials of extended-duration (30-46 days) versus standard-duration (6-14 days) thromboprophylaxis among 28 227 patients (EXCLAIM, ADOPT, MAGELLAN and APEX trials). Results Extended thromboprophylaxis with full-dose betrixaban (80 mg once daily) was superior in efficacy and non-inferior in safety to standard-duration enoxaparin, and showed a significantly favorable NCB, with a risk difference of - 0.51% (- 0.89% to - 0.10%) in the bivariate outcome. Extended enoxaparin was superior in efficacy and inferior in safety (bivariate outcome: 0.03% [- 0.37% to 0.43%]), whereas apixaban and rivaroxaban were non-inferior in efficacy and inferior in safety (- 0.20% [- 0.49% to 0.17%] and 0.23% [- 0.16% to 0.69%], respectively). Reduced-dose betrixaban did not show a significant difference in either efficacy or safety (0.41% [- 0.85% to 1.94%]). Conclusions In a bivariate analysis that assumes non-linear risk-benefit tradeoffs, extended prophylaxis with full-dose betrixaban was superior to standard-duration enoxaparin, whereas other regimens failed to simultaneously achieve both superiority and non-inferiority with respect to symptomatic VTE and major bleeding in the management of acutely ill hospitalized medical patients., (© 2017 International Society on Thrombosis and Haemostasis.)

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: 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.)