Megan K. Yee

The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial

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.

Extended-Duration Betrixaban Reduces the Risk of Rehospitalization Associated With Venous Thromboembolism Among Acutely Ill Hospitalized Medical Patients: Findings From the APEX Trial (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban Trial)

Among hospitalized medically ill patients who are at risk of venous thromboembolism (VTE), pharmacological thromboprophylaxis is recommended during the period of immobilization or acute hospital stay.1 However, the risk of VTE extends beyond the standard 10- to 14-day course of anticoagulation and persists for weeks to months after hospital discharge. About half of VTE events occur after the period of index hospitalization and may require rehospitalization.2 Rehospitalization is an end point that adversely affects the morbidity and quality of life of patients and can be a major driver of healthcare costs. Indeed, a goal of patient-centered care is to be both alive and free of hospitalization. The APEX trial (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban Trial; ClinicalTrials.gov: NCT01583218) was a double-blind randomized clinical trial that compared extended-duration (35–42 days) betrixaban with standard-duration (10±4 days) enoxaparin among acutely ill hospitalized medical patients at increased risk of VTE. A reduction in VTE by extended-duration betrixaban compared with standard-duration enoxaparin has been demonstrated,3 but the impact of extended thromboprophylaxis with betrixaban on the risk of rehospitalization associated with VTE has not been studied. It was hypothesized that betrixaban would reduce VTE-related rehospitalization. The APEX trial randomized 7513 patients to either extended-duration betrixaban or standard-duration enoxaparin for VTE prophylaxis. The full-dose regimen (betrixaban 80 mg daily) was administered to patients who had a creatinine clearance of ≥30 mL/min and were not administered a strong P-glycoprotein inhibitor. VTE-related rehospitalization was …

Symptomatic Event Reduction with Extended-Duration Betrixaban in Acute Medically Ill Hospitalized Patients

Background: Approximately 15%‐30% of patients in trials of medical thromboprophylaxis will have missing compression ultrasound (CUS) data. The goal of the present analysis was to perform analyses to minimize missing data. Methods: The APEX trial randomized 7,513 acutely medically ill hospitalized patients to thromboprophylaxis with either betrixaban for 35‐42 days or enoxaparin for 6‐14 days. A modified intent‐to‐treat (mITT) analysis was performed and included all subjects administered study drug, irrespective of CUS performance, and an analysis of symptomatic events which do not require performance of a CUS (symptomatic deep vein thrombosis, nonfatal pulmonary embolism, and venous thromboembolism (VTE)–related mortality). Results: In the mITT population, betrixaban significantly reduced the primary end point (which included both symptomatic and CUS events) (165 [4.4%] vs 223 [6.0%]; relative risk = 0.75; 95% CI 0.61‐0.91; P = .003; absolute risk reduction [ARR] = 1.6%; number needed to treat [NNT] = 63). Betrixaban also reduced symptomatic VTE through day 42 (35 [1.28%] vs 54 [1.88%], hazard ratio [HR] = 0.65; 95% CI 0.42‐0.99; P = .044; ARR = 0.6%; NNT=167) as well as through day 77 (37 [1.02%] vs 67 [1.89%]; HR= 0.55; 95% CI 0.37‐0.83; P = .003; ARR = 0.87%; NNT=115) as well as the individual end point of nonfatal pulmonary embolism (9 [0.25%] vs 20 [0.55%]; HR= 0.45; 95% CI 0.21‐0.99; P = .041; ARR = 0.30%; NNT=334). On an “as‐treated” basis, 80 mg of betrixaban reduced VTE‐related mortality through day 77 (10 [0.34%] vs. 22 [0.79%]; HR=0.46; 95% CI 0.22‐0.96; P = .035; ARR = 0.45%; NNT=223). Conclusion: In an mITT analysis of all patients administered study drug, extended‐duration betrixaban reduced the primary end point as well as symptomatic events. In an as‐treated analysis, 80 mg of betrixaban reduced VTE‐related death.

Increased benefit of betrixaban among patients with a history of venous thromboembolism: a post-hoc analysis of the APEX trial

Hospitalized acute medically ill patients with a history of venous thromboembolism (VTE) are at increased risk for recurrent VTE. We characterized the efficacy and safety of betrixaban for prevention of recurrent VTE in these high risk patients. The APEX trial randomized 7513 acutely ill hospitalized medical patients at risk for developing VTE to receive either betrixaban for 35–42 days or enoxaparin for 10 ± 4 days to prevent VTE. This exploratory post-hoc analysis assessed the efficacy and safety of betrixaban versus enoxaparin among subjects with and without prior VTE. Time-to-multiple symptomatic VTE events was also calculated. Approximately 8% of subjects in both arms had prior VTE, which was associated with a fourfold increase in adjusted risk of VTE [MV OR 4.03, 95% CI 3.06–5.30, p < 0.001]. Betrixaban reduced VTE compared with enoxaparin among subjects with prior VTE [32 (10.4%) vs. 55 (18.9%), RR 0.57, 95% CI 0.38–0.86, p = 0.006, ARR 8.5%, NNT 12] and without prior VTE [133 (3.9%) vs. 168 (4.9%), RR 0.79, 95% CI 0.64–0.99, p = 0.042, ARR 1.0%, NNT 100] (interaction p > 0.05). Additionally, four subjects in the enoxaparin arm and one subject in the betrixaban arm experienced a recurrent VTE. Compared with enoxaparin, betrixaban use was associated with reduction of recurrent VTE events through the active treatment period [36 vs. 57, HR 0.63, 95% CI 0.41–0.97, p = 0.045] and through the end of study [38 vs. 71, HR 0.54, 95% CI 0.36–0.81, p = 0.004]. Prior VTE is associated with a fourfold increase in the risk of VTE among hospitalized medically ill patients. Only 12 such patients would need to be treated with betrixaban versus enoxaparin to prevent an additional VTE endpoint. Betrixaban reduced not only the first but also all recurrent VTE events in a time-to-any-event analysis.Trial registration: http://www.clinicaltrials.gov, Unique identifier: NCT01583218

Association of D-dimer Levels with Clinical Event Rates and the Efficacy of Betrixaban versus Enoxaparin in the APEX Trial

Background  Elevated D-dimer concentrations are associated with an increased risk of venous thromboembolism (VTE). However, they may also provide prognostic value. The present analysis sought to study the association of D-dimer levels with VTE event rates and the efficacy of betrixaban versus enoxaparin in the APEX trial. Methods  Hospitalized acutely medically ill subjects ( n  = 7,513) 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. D-dimer was assessed using a central core laboratory measurement. Results  For every 0.25 µg/mL increase in D-dimer concentration, there was a 2% increase in the relative risk of experiencing the primary efficacy endpoint (asymptomatic deep vein thrombosis [DVT], symptomatic DVT, nonfatal pulmonary embolism, or VTE-related death) in both the betrixaban ( p  < 0.001) and enoxaparin ( p  < 0.001) treatment arms. Among D-dimer-positive (≥ 2 × upper limit of normal; corresponding to ≥ 1.00 µg/mL) subjects, extended-duration betrixaban reduced the risk of experiencing the primary efficacy outcome (5.4% [ n  = 124] vs. 7.6% [ n  = 170]; odds ratio = 0.69; 95% confidence interval: 0.55–0.88; absolute risk reduction = 2.2%, number needed to treat = 46, p  = 0.003). There was no interaction between D-dimer and the treatment effect ( p int  = 0.53). Conclusion  Extended-duration betrixaban was superior to standard-duration enoxaparin, irrespective of D-dimer level at baseline. To prevent one VTE event, 46 D-dimer-positive patients would need to be treated with betrixaban.

SECURE PCI: how important can a subgroup analysis be?

Among acute coronary syndrome (ACS) and stable coronary artery disease patients, the effect of a loading dose of statin, prior to revascularization, has been assessed in several observational studies and randomized controlled trials (1-3). A high dose of statin before percutaneous or surgical revascularization was associated with a decreased risk of periprocedural myocardial infarction (MI), contrast induced—acute kidney injury and, finally, improved clinical outcomes (4,5). The underlying mechanism was hypothesized to be related to the complex pleiotropic effects of statins which improve endothelial function, stabilize the atherosclerotic plaque, and decrease the vascular inflammation (6).

Betrixaban for first-line venous thromboembolism prevention in acute medically ill patients with risk factors for venous thromboembolism

ABSTRACT Introduction: Compared to other direct oral anticoagulants, betrixaban has a longer half-life, smaller peak-trough variance, minimal renal clearance, and minimal hepatic Cytochrome P (CYP) metabolism. The Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial evaluated the efficacy and safety of extended duration betrixaban compared to standard duration enoxaparin in acutely ill hospitalized patients. Areas covered: This article describes the role of betrixaban in the prevention of venous thromboembolism (VTE) in acutely ill medical patients. This article provides a consolidated summary of the primary APEX study findings as well as prespecified and exploratory substudies. This article also provides a review of the results of studies in which other direct factor Xa inhibitors have been evaluated in an extended duration regimen in this patient population. Expert commentary: While previous agents have demonstrated that extended duration VTE prophylaxis can be efficacious, betrixaban is the first agent to demonstrate efficacy without an increase in major bleeding. The totality of the data from the APEX trial supports extended duration betrixaban for VTE prophylaxis in the acute medically ill patient population. As such, betrixaban has been approved in the USA for extended VTE prophylaxis in at-risk acute medically ill patients.

D-Dimer Levels and Effect of Rivaroxaban on Those Levels and Outcomes in Patients With Acute Coronary Syndrome (An ATLAS ACS-TIMI 46 Trial Substudy)

D-dimer has been used as both a diagnostic and prognostic biomarker in the assessment of patients with venous thromboembolism, but its prognostic value in the setting of arterial acute coronary syndromes (ACS) and the ability of pharmacotherapy to reduce D-dimer in ACS is less well characterized. It was hypothesized that elevated baseline D-dimer would be associated with poor clinical outcomes in ACS, and that Factor Xa inhibition with Rivaroxaban would reduce D-dimer acutely and chronically. The ATLAS ACS TIMI-46 trial assessed the safety and efficacy of rivaroxaban compared with placebo in ACS patients. A subset of subjects had a D-dimer measured at baseline (n = 1,834, 52.5%). A univariate and multivariable logistic regression assessed the relation between baseline D-dimer and a composite end point of cardiovascular death, myocardial infarction, or stroke through 6 months. The Wilcoxon rank sum test was used to compare change in D-dimer level between the treatment groups from baseline. Baseline D-dimer was associated with the composite efficacy outcome in a univariate logistic regression (odds ratio 1.15, 95% confidence interval 1.03 to 1.29, p = 0.015) and a multivariable logistic regression (odds ratio 1.13, 95% confidence interval 1.00 to 1.28, p = 0.048). Rivaroxaban administration lowered D-dimer levels compared wth placebo after administration of the first dose of study drug (p = 0.026), at day 30 (p < 0.001) and day 180 (p < 0.001). In conclusion, elevated baseline D-dimer was associated with an increased risk of the composite outcome within 6 months of the ACS event and administration of the Factor Xa inhibitor rivaroxaban was associated with lower D-dimer levels compared with placebo after the first dose, at day 30 and day 180.