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Supplements Extended Prophylaxis for Venous Thromboembolism in Acute Medically Ill Patients
Venous Thromboembolism in Acute Medically Ill Patients: Identifying Unmet Needs and Weighing the Value of Prophylaxis
Paul P. Dobesh, PharmD; Tania Ahuja, PharmD; George A. Davis, PharmD; Hugh Fatodu, MBA, RPh; William H. Francis, MBA, RPh; Frank P. Hull, MD; Gary L. Johnson, MD, MS, MBA; Joshua D. Lenchus, DO, BSPharm; Jacqueline Glee Lenoir, PharmD; Claudette McPherson, RN, BSN; Jeffrey Nemeth, PharmD, MPA; and Ralph J. Riello III, PharmD
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The Use of Betrixaban for Extended Prophylaxis of Venous Thromboembolism Events in Hospitalized, High-Risk Patients
Paul P. Dobesh, PharmD; Tania Ahuja, PharmD; George A. Davis, PharmD; Hugh Fatodu, MBA, RPh; William H. Francis, MBA, RPh; Frank P. Hull, MD; Gary L. Johnson, MD, MS, MBA; Joshua D. Lenchus, DO, BSPharm; Jacqueline Glee Lenoir, PharmD; Claudette McPherson, RN, BSN; Jeffrey Nemeth, PharmD, MPA; and Ralph J. Riello III, PharmD
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The Use of Betrixaban for Extended Prophylaxis of Venous Thromboembolism Events in Hospitalized, High-Risk Patients

Paul P. Dobesh, PharmD; Tania Ahuja, PharmD; George A. Davis, PharmD; Hugh Fatodu, MBA, RPh; William H. Francis, MBA, RPh; Frank P. Hull, MD; Gary L. Johnson, MD, MS, MBA; Joshua D. Lenchus, DO, BSPharm; Jacqueline Glee Lenoir, PharmD; Claudette McPherson, RN, BSN; Jeffrey Nemeth, PharmD, MPA; and Ralph J. Riello III, PharmD
  • Betrixaban is the first FDA-approved product for extended prophylaxis of venous thromboembolism (VTE) events in acute medically ill patients.
  • The betrixaban approval was based on data from the Acute Medically Ill VTE Prevention with Extended Duration Betrixaban Study (APEX) trial, which enrolled only hospitalized, acute medically ill patients who were at high risk for VTE events.
  • In the APEX trial, VTE prophylaxis with betrixaban demonstrated a significant reduction in VTE events at 35 to 42 days and was not associated with excess major bleeding compared with VTE prophylaxis with enoxaparin for 14 days, producing an overall net clinical benefit.
  • Various analyses have demonstrated that extended VTE prophylaxis with betrixaban could be considered a cost-effective regimen for hospitalized patients with acute medical illness at high risk of VTE, who require longer VTE prophylaxis extending to postdischarge period.
  • A cost-effectiveness model among a hypothetical cohort of 10,000 acutely ill medical patients estimated that betrixaban reduced the risk of death by 0.16% and was a cost-effective regimen compared with enoxaparin, saving nearly $1.8 million ($178 per patient treated).
  • A different cost-effectiveness analysis showed that extended VTE prophylaxis with betrixaban dominated standard VTE prophylaxis with enoxaparin, with a savings of $780 and increased quality-adjusted life years by 0.017 per patient.
  • For an average-sized hospital of 450 beds, treatment with betrixaban could result in 17 fewer VTE-related rehospitalizations compared with enoxaparin, and 36 fewer deaths or irreversible events leading to readmission with enoxaparin. In this analysis, betrixaban would save the hospital $447,000 annually ($182 per patient).
  • Treatment with betrixaban could potentially decrease Centers for Medicare and Medicaid VTE-related readmissions penalties for hospitals.
Am J Manag Care. 2018;24:-S0
In June 2017, the FDA approved betrixaban for the prophylaxis of venous thromboembolism (VTE) events in adult patients hospitalized for an acute medical illness who are at risk for postdischarge thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE.1 The approval was based on data from the randomized, double-blind, double-dummy, Acute Medically Ill VTE Prevention with Extended Duration Betrixaban Study (APEX) trial.2 Investigators compared the use of betrixaban for extended-duration VTE prophylaxis with a standard enoxaparin regimen in patients hospitalized with acute medical illness who had VTE risk factors.3 In this trial, investigators selected this patient cohort to test the strategy of extended prophylaxis with betrixaban.3

Paul P. Dobesh, PharmD, explained that the approval of betrixaban was important for several reasons:
  • VTE events continue to occur during hospitalization and following discharge, despite the standard of care (SOC) for in-hospital prophylaxis.
  • Anticoagulation initiated during hospitalization and extended for high-risk patients, post-discharge, may reduce the risk of VTE events.
  • Extended-prophylaxis studies with other direct-oral anticoagulants (DOACs) did not demonstrate net clinical benefit or were associated with excess major bleeding.
  • In the APEX trial, treatment with betrixaban demonstrated a significant reduction in VTE events and was not associated with excess major bleeding, producing an overall net clinical benefit.


Pharmacological Properties of Betrixaban

Betrixaban has been specifically designed for VTE prophylaxis in acute medically ill patients. It has a distinct pharmacological properties from the other DOACs (Table 1).1,4-7 

Betrixaban has an effective half-life of 19 to 27 hours.2 According to Dobesh, the long half-life of betrixaban allows for true, once-daily dosing. Of the currently approved DOACs, betrixaban is the least renally excreted, with <18% cleared by the kidneys.2,4 The other DOACs  renal excretion range from 25% to 80%.2 Because betrixaban has minimal renal excretion, it only requires dose reductions in patients with severe renal impairment. Dosage adjustments are not required in patients with mild to moderate renal impairment.1

Dobesh explained that betrixaban has a consistent anticoagulant effect over 24 hours, thereby allowing for true, once-daily dosing. Compared with some other approved DOACs, betrixaban also has a decreased propensity for drug interactions, due to a lack of any cytochrome P450 mediated metabolism DOACs. Dose reductions are only required when betrixaban is administered with P-glycoprotein (P-gp) inhibitors rather than cytochrome P450 inhibitors or inducers.3  

The APEX Trial

The APEX trial included a high-risk patient population and tested the strategy of extended VTE prophylaxis with betrixaban. Patients were eligible to participate in the APEX trial if they were aged ≥40 years, had been hospitalized for a specified acute medical illness, had decreased mobility, and had specific risk factors for VTE (Table 2).3

Table 2 includes the high-risk subsets, as defined. Major exclusion criteria are presented in Table 3.3

According to William H. Francis, MBA, RPh, “managed care providers typically need to know two things: [first], is this product for everyone, and [second], is there a well-defined group of patients who would benefit from this drug?” Francis explained, “APEX trial investigators did a good job in defining a high-risk population that would most benefit from betrixaban.”

Stakeholders concurred that the high-risk patient population selected in the APEX trial was adequate and, in addition to existing risk factor tools, would help clinicians select appropriate treatments for patients.

A total of 7513 patients underwent randomization in the APEX trial. As shown in Figure 1, patients were randomized 1:1 to 2 possible cohorts1,3:
  • Betrixaban cohort (n = 3759): oral betrixaban (160 mg loading dose on day 1, followed by 80 mg once-daily for 35-42 days) + subcutaneous enoxaparin placebo (once-daily for 10 ± 4 days)
  • SOC cohort (n = 3754): subcutaneous enoxaparin (40 mg once-daily for 10 ± 4 days) + oral betrixaban placebo (once-daily for 35-42 days)
Patients with severe renal impairment (creatinine clearance, ≥15 to <30 mL/min) received dose reductions of 50% for both betrixaban and enoxaparin (ie, betrixaban 80 mg loading dose, followed by 40 mg daily or enoxaparin 20 mg daily).3 Several stakeholders did question the rationale for dose reductions in patients with severe renal impairment, since betrixaban is minimally renally excreted. Patients who were receiving concomitant P-gp inhibitors (eg, amiodarone, azithromycin, verapamil, ketoconazole, and clarithromycin) also received betrixaban dose reductions of 50%.1,3 Notably, patients with both severe renal impairment and concomitant P-gp inhibitors were excluded.

Clinically suspected deep vein thrombosis (DVT) events were confirmed using ultrasonography or other vascular-imaging techniques, while pulmonary embolism (PE) events were confirmed using either a computed tomography scan, a ventilation-perfusion lung scan, pulmonary angiography, or autopsy. Patients without clinically confirmed VTE events received ultrasonography after the last dose of study medication or matching placebo between days 35 and 42. All patients were followed for 30 ± 5 days after assessments (day 77).3

End Points

The primary efficacy end point was a composite of:3
  • Asymptomatic proximal DVT, as detected by compression ultrasound between days 32 and 42
  • Symptomatic proximal or distal DVT
  • Symptomatic nonfatal pulmonary embolism
  • Death from VTE between days 1 and 42
The composite of symptomatic VTE through day 42 was the secondary end point.3 The primary safety outcome was the occurrence of major bleeding at any point until 7 days after the discontinuation of all study medications.3 The occurrence of clinically relevant nonmajor bleeding was also assessed. Bleeding events in the APEX trial were classified using criteria from the International Society on Thrombosis and Haemostasis (ISTH).3,8

Baseline Characteristics

Baseline characteristics were generally well balanced between the 2 treatment groups.1 Overall, 55% of patients were female. The most prevalent acute medical illnesses at hospitalization were heart failure (45%), acute infection without septic shock (29%), respiratory failure (12%), ischemic stroke (11%), and rheumatic disorders (3%). The mean age was 76.4 years. The majority of patients (68.6%) were aged ≥75 years. Ninety-seven percent of patients were severely immobilized at study entry and 62% had D-dimer ≥2 x upper limit of normal (ULN).1

Joshua D. Lenchus, DO, BSPharm, observed that the baseline characteristics in the APEX trial were indicative of high-risk patients. “The study was very robust in patients over the age of 75 years with heart failure,” he said.

Efficacy Results

Efficacy analyses for the FDA-approved label were based on the modified intention-to-treat (mITT) population in the APEX trial.1 The mITT population consisted of all patients who had received at least 1 dose of study medication and, on follow up, had reached one or more primary or secondary efficacy outcome components.1 Results for the primary efficacy analysis included the mITT population who received the full (80 mg) or reduced (40 mg) dose of betrixaban. Additional analyses were performed for patients in the mITT population, stratified by betrixaban dose of 80 mg or 40 mg.1  

Following are results for the composite primary end point:
  • There were significantly fewer VTE events with betrixaban (4.4%) compared with enoxaparin (6%) in the overall mITT population (Figure 2A).1 The relative risk reduction (RR) was 25% and the absolute risk of reduction (AR) was 1.6%. The number needed to treat (NNT) to prevent one primary end point was 63.
  • When including patients from the mITT population who received only full dose betrixaban (80 mg), there were also significantly fewer VTE events with betrixaban compared with enoxaparin (4.2% vs 6.2%) (Figure 2B).1 The RR was 37.1% and the AR was 2%, with an NNT of 50.9
The occurrence of symptomatic VTE events at 42 days was also significantly improved with betrixaban in both groups.1 In the overall mITT population, 1.5% of patients who received enoxaparin and 0.9% of patients who received betrixaban experienced a symptomatic VTE .1 In the full dose betrixaban cohort, 1.4% of patients who received enoxaparin and 0.8% of patients who received betrixaban experienced a symptomatic VTE.1

Results for patients who were randomized to half dose betrixaban (patients with severe renal impairment or receiving P-gp inhibitors) were also reported. Similar VTE rates were reported with half dose betrixaban and enoxaparin (6-14 days followed by placebo).1

Safety Results

 
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