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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
Participating Faculty

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
There were no significant differences in the rates of major bleeding (with betrixaban for a median duration of 36 days) compared with enoxaparin for a median duration of 9 days (Table 4).1,10  Overall, 0.57% of enoxaparin-treated patients and 0.67% of betrixaban-treated patients experienced major bleeding.1 One patient in each group experienced fatal bleeding.1 Clinically relevant nonmajor bleeding (CRNM) occurred in 2.45% of betrixaban-treated patients and 1.02% of enoxaparin-treated patients.1 These cases mostly ranged from mild to moderate in severity (86%), and the majority (62%) did not require medical intervention or prolonged hospitalization.1 The most frequent CRNM bleeding events in both treatment groups were hematuria and epistaxis, each occurring in 2% of patients. Nonbleeding adverse reactions were also reported in the APEX trial.1 Table 5 summarizes the occurrence of these nonbleeding adverse reactions.1 None of these events were significantly different between the groups.

Additional Analyses From the APEX Trial

Several post hoc analyses have further evaluated the use of extended thromboprophylaxis with betrixaban in acute medically ill patients. Key data demonstrated reductions in VTE-related rehospitalization; fatal, irreversible ischemic, or bleeding events; all-cause ischemic stroke, and VTE occurrence in patients with history of prior VTE (Figures 3A- 3C).2,11,12

Gibson et al evaluated 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) in a time-to-first-event analysis.11 In patients with positive D-dimer results, betrixaban significantly reduced fatal or irreversible events at 35 to 42 days (P = .033) and at study end at 77 days (= .005) versus enoxaparin. In all randomized patients, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.08% vs 2.90%; P = .006) and 77 days (5.17% vs 3.64%; P = .002). Full dose betrixaban also reduced fatal or irreversible events through the end.11

Chi et al evaluated the effect of extended thromboprophylaxis with betrixaban on the risk of rehospitalization associated with VTE events.12 The analysis showed that betrixaban reduced the risk of VTE-related rehospitalization when compared with enoxaparin. In the overall population, there was a 56% RR with betrixaban (35-42 days) compared with enoxaparin (6-14 days). In the population of patients who received full dose betrixaban, there was a 63% RR with betrixaban compared with enoxaparin.12

Yee et al assessed the efficacy and safety of betrixaban versus enoxaparin among subjects in the mITT population with and without prior VTE events.13 The occurrence of VTE events was significantly decreased in patients with and without a history of VTE events. In patients who have had a prior VTE, 10.4% of those using betrixaban experienced VTE events compared to 18.9% of those using enoxaparin. In those who did not have a prior VTE, 3.9% of patients using betrixaban experiences a VTE compared with 4.9% of those using enoxaparin. There was no significant difference in major or clinically-relevant nonmajor bleeding in patients with and without a history of VTE events.13

Extended-duration prophylaxis with betrixaban has been shown to reduce the risk of ischemic stroke, all strokes, and transient ischemic attack, compared with standard-duration enoxaparin.12 Another study found that the occurrence of new ischemic stroke was increased with enoxaparin compared with betrixaban (0.5% vs 0.9%; P = .03), as were all types of strokes (0.6% vs 1.1%, P = .03).3

Stakeholder Perspectives Regarding the APEX Trial

According to Jeffrey Nemeth, PharmD, MPA, “the biggest message conveyed in the APEX trial was that using VTE prophylaxis for an extended period post discharge was superior to doing nothing.” When evaluating the safety data of betrixaban, Frank P. Hull, MD, noted that “the safety data presented in the APEX trial really differentiated betrixaban from the other DOACs.”

Jacqueline Glee Lenoir, PharmD, explained that the “safety results from the APEX trial were responsible for the product being added to formulary at my institution.” Lenoir observed that “betrixaban was added to formulary because it was both safe and effective in medically ill patients.”

Stakeholders concurred the higher risk patient population selected in the APEX trial was adequate and would greatly help both clinicians and prescribers with the selection of patients for treatment.

Costs and Formulary Perspectives

The economic burden associated with VTE is significant, both from a general healthcare perspective and from an individual patient perspectiveNNT.14 The NNT with betrixaban to prevent 1 irreversible event is 63, as compared with 102 for 1 symptomatic VTE, and 127 for 1 VTE-related hospitalization.15

Importantly, noted Dobesh, “betrixaban can prevent a $16,000 to $32,000 readmission for another VTE event.” He further observed that “if we have a product that is going to cost more than enoxaparin but is going to decrease hospital length of stay or reduce readmissions for subsequent VTE events, most providers and prescribers will accept that model.” The stakeholders representing managed care agreed that formulary issues with betrixaban would not be problematic if providers and prescribers used the product as it was studied and approved.

Based on clinical outcomes from the APEX study, analyses have assessed the economic value of extended versus standard VTE prophylaxis. They demonstrated that extended VTE prophylaxis with betrixaban could be considered a cost-effective treatment for hospitalized patients with acute medical illness at risk of VTE, who require longer VTE prophylaxis from hospital admission through post-discharge.16-19

A cost-effectiveness model among a hypothetical cohort of 10,000 acutely ill medical patients, identified according to the American College of Chest Physicians (ACCP) recommendation for pharmacological VTE prophylaxis, estimated that betrixaban could reduce the risk of death by 0.16%.16 Findings also suggested that betrixaban would be a cost-effective regimen compared with enoxaparin, saving nearly $1.8 million, or $178 per patient treated.16

Another analysis estimated the cost per quality-adjusted life-year (QALY) gained for extended-duration betrixaban (35-42 days) compared with standard-duration enoxaparin (6-14 days) from a US payer perspective over a lifetime horizon. Costs encompassed treatment and management of primary events, complications, recurrent events, and primary event complications. Results showed that extended VTE prophylaxis with betrixaban was better than standard VTE prophylaxis with enoxaparin, with a savings of $780 and increased QALYs of 0.017 per patient.17

The budget impact model for an acute-care hospital with 20,000 admissions assumed that approximately 2,500 patients would potentially receive VTE prophylaxis with betrixaban.18,19 For the average 36-day period assessed by the model, the use of betrixaban would result in the avoidance of 54 VTE events (symptomatic proximal or distal DVT; asymptomatic proximal DVT; nonfatal PE; or VTE-related death). The total cost of clinical events would be $3.6 million for enoxaparin versus $2.3 million for betrixaban. Including drug plus administration costs, this would result in an overall cost savings of $447,000, or $182 per patient treated.

Stakeholders agreed that these findings, particularly those related to readmissions, could save even more if CMS penalties to hospitals for VTE readmissions were reduced. Gary L. Johnson, MD, MS, MBA, predicted that “betrixaban will not face a lot of payer barriers.” According to Johnson, “the primary barrier will be awareness by prescribers, not barriers from payers.” Hugh Fatodu, MBA, RPh, agreed. Regarding P&T review, Fatodu asserted that betrixaban “will automatically have a leg up.”

Claudette McPherson, BSN, cautioned that “pre-authorizations could be a barrier.” Because prophylaxis begins in-hospital and continues when the patient is released from the hospital, McPherson advised that “planning is important, so that on the day of discharge, the patient can get the medication.”

Conclusions 

Based on current data, betrixaban can play an essential role in the VTE prophylaxis landscape, providing protection for the entire at-risk period that extends beyond hospitalization. The next article of this supplement presents potential solutions for implementing best practices in transitional care for patients, post discharge. 

Author affiliations: New York University Langone Health, New York, NY (TA); University of Kentucky College of Pharmacy, Lexington, KY (GAD); University of Nebraska Medical Center, Omaha, NE (PPD); Johns Hopkins Healthcare, Glen Burnie, Maryland (HF); MedImpact Healthcare Systems San Diego, CA (WHF); Broward Pulmonary and Sleep Specialists, Fort Lauderdale, FL (FPH); Nova South Eastern University, Fort Lauderdale, FL (FPH); Humana, Inc., Madison, WI (GLJ); University of Miami Miller School of Medicine, Miami, FL (JDL); The Medical Center, Bowling Green, KY (JGL); University of Kentucky College of Pharmacy, Lexington, KY and Louisville, KY (JGL); Pomona Valley Hospital Medical Center, Pomona, CA (CM); Englewood Hospital and Medical Center, Englewood, NJ (JN); Yale New Haven Hospital, New Haven, CT (RJR).
Funding source: Publication support provided by Portola Pharmaceuticals, Inc.
Author disclosures: Dr Davis reports to having a board membership on the Pulmonary Embolism Response Team (PERT) Consortium Board of Directors and to receiving honoraria from the American Journal of Managed Care. Dr Dobesh reports to serving as a consultant for and receiving honoraria for Boehringer Ingelheim, the Pfizer/BMS alliance, Janssen Pharmaceuticals, Daiichi Sankyo, Inc, and Portola Pharmaceuticals. Mr Fatodu reports to serving on a paid advisory board for Daiichi Sankyo, Inc. Mr Francis reports to attending a paid advisory board for the American Journal of Managed Care. Dr Lenchus reports to serving as a consultant for Portola Pharmaceuticals. Dr Lenoir reports lecture fees for serving as a consultant, receiving honoraria, and receiving lecture fees for speaking at the invitation of a commercial sponsor for Portola Pharmaceuticals and Janssen Pharmaceuticals. She also reports stock ownership with Portola Pharmaceuticals. Dr Nemeth reports to serving as a consultant, receiving honoraria, receiving lecture fees for speaking at the invitation of a commercial sponsor for Portola Roundtable. He has also reported to receipt of payment for involvement of the preparation of this manuscript as Multi-stake holder of Portola Roundtable and to attending the ASHP Midyear 2017 Portola Dinner. Dr Riello reports to serving as a consultant for Portola Pharmaceuticals, and Johnson & Johnson. He reports to receiving honoraria from Portola Pharmaceuticals, Janssen Pharmaceuticals, and Johnson & Johnson. He also reports to receiving lecture fees for speaking at the invitation of a commercial sponsor for Portola Pharmaceuticals and Janssen Pharmaceuticals. Dr Ahuja, Dr Hull, Dr Johnson, and Ms McPherson report no relationships or financial interests with any entity that would pose a conflict of interest with the subject matter of this supplement.
Authorship information: Administrative, technical, or logistic support (RJR); analysis and interpretation of data (GAD, HF, JGL, JN); concept and design (JDL, JGL, JN, PPD); critical revision of the manuscript for important intellectual content (FPH, GAD, HF, JN, PPD, RJR, TA); drafting of the manuscript (FPH, GAD, HF, JDL, JGL, JN, PPD, RJR, WHF); presentation of unmet medical need content to roundtable group (RJR); supervision (FPH, JDL, PPD).
Address correspondence to: pdobesh@unmc.edu.
 
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