Sage Journals: Discover world-class research

Abstract

Background

Eptacog alfa and eptacog beta are recombinant factor VIIa (rFVIIa) agents approved for use in hemophilia A or B with inhibitors. Our institution converted from eptacog alfa to eptacog beta as the preferred rFVIIa product. The objective of this medication use evaluation was to review the utilization of both agents and cost savings associated with the conversion.

Methods

We performed a retrospective chart review for all eptacog alfa and beta administrations from October 2023 through September 2024. We evaluated product selection and dosing as well as the occurrence of thrombosis, new bleeding events, or existing bleeding that required therapy escalation. Cost savings were estimated using wholesale acquisition costs.

Results

There were 17 patients that required 27 admissions for rFVIIa (eptacog alfa: 3, 11.1% and eptacog beta: 21, 77.8%). Three administrations (11.1%) utilized both agents. Indications included bleeding in hemophilia patients (12, 44.4%), followed by peri-procedural management (9, 33.3%), cardiac surgery (3, 11.1%), and anticoagulation reversal for life-threatening bleeding (3, 11.1%). There were 21 administrations in which eptacog beta was exclusively used (bleeding in hemophilia A (9, 33.3%), peri-procedural management (7, 25.9%), cardiac surgery (2, 7.4%), and anticoagulation reversal (3, 11.1%)). There were no thrombotic events. There were 5 patients (18.5%) who required rFVIIa dose escalation and two (7.4%) who required re-initiation of rFVIIa. Cost avoidance was estimated at $554,400 over a 12-month period.

Conclusion

We treated a small cohort of patients with eptacog beta without adverse outcomes. Other hospitals might evaluate their rFVIIa use and consider opportunities for substitution.

Keywords

hemophilia eptacog alfa eptacog beta bleeding thrombosis

Introduction

In 1999, recombinant coagulation factor VIIa (rFVIIa) (eptacog alfa, NovoSeven^®-Novo Nordisk, Princeton, NJ) received Food and Drug Administration (FDA) orphan approval for treatment of bleeding episodes in congenital hemophilia A or B with inhibitors (HABI) to factor VIII (FVIII) or factor IX (FIX), respectively.¹ Additional indications followed in subsequent years. In 2020, the FDA approved recombinant coagulation factor VIIa-jncw (eptacog beta, Sevenfact^®-HEMA Biologics, Louisville, KY) for the control of bleeding episodes in those 12 years of age or older with HABI.² Until the approval of eptacog beta, the only FDA-approved available rFVIIa agent was eptacog alfa, which limited hospital formularies to carrying eptacog alfa without any alternative option.

With an additional FDA-approved rFVIIa product on the market, our hospital used this opportunity to evaluate, from a clinical and economical perspective, whether eptacog alfa was still the most appropriate agent to maintain solely on formulary. In July 2023, our institution's Pharmacy and Therapeutics Committee voted to add eptacog beta to our formulary as the preferred rFVIIa product over eptacog alfa. Eptacog beta was considered first-line for all indications with the exception of congenital FVII deficiency, where eptacog alfa maintained preferred use.³

Eptacog alfa and eptacog beta are not considered biosimilar products and have differences pertaining to their glycosylation profiles, dosing, and affinity for the endothelial protein C receptor. Dosing of eptacog alfa for the treatment and control of breakthrough bleeding in patients with HABI is 90 micrograms/kilogram (mcg/kg) every 2 h. Dosing for eptacog beta varies; dosing for mild to moderate bleeding is either 75 mcg/kg (75 initial dose regimen (IDR)) every 3 h or 225 mcg/kg (225 IDR) for one dose, followed 9 h later by 75 mcg/kg every 3 h if bleeding continues. For severe bleeds, dosing is 225 mcg/kg for one dose, followed 6 h later by 75 mcg/kg every 2 h if bleeding continues.⁴

A medication use evaluation (MUE) is a performance improvement tool aimed at improving outcomes.⁵ An MUE can focus on patient outcomes (eg, clinical events, quality of life) or on processes surrounding medication use (eg, prescribing, dispensing). Our institution determined that an MUE after the formulary conversion would provide valuable insight into the clinical and economic impact of this change.

The purpose of this MUE was to review our institution's use of eptacog alfa and eptacog beta after the formulary change. Our aim was to compare eptacog beta prescribing to our local hospital guidelines, qualitatively report patient outcomes, and estimate cost avoidance with substitution.

Methods

This was a single-center MUE that was performed through retrospective electronic medical record review. The hospital's institutional review board deemed the project exempt from requiring patient consent. While the FDA does not consider eptacog alfa and eptacog beta biosimilar products, our comparison of key characteristics (Table 1) suggested the agents could be substituted and expected to have similar therapeutic effects.

Table 1.

Key Characteristics of Recombinant Factor VIIa (Eptacog Alfa and Eptacog beta).^1,2

	Recombinant Factor VIIa (Sevenfact^® / eptacog beta)	Recombinant Factor VIIa (NovoSeven^® / eptacog alfa)
Indication	Treatment and control of bleeding episodes occurring in adults and adolescents (12 years of age or older) with hemophilia A or B with inhibitors	Treatment of bleeding episodes and peri-operative management in adults and children with hemophilia A or B with inhibitors or with acquired hemophilia, congenital factor VII deficiency, Glanzmann's thrombasthenia with refractoriness to platelet transfusions with or without antibodies to platelets
Indication	Limitations of Use: Not indicated for the treatment of congenital factor VII deficiency	Limitations of Use: none
Mechanism of Action	A recombinant analog of factor VIIa, which complexes with tissue factor in the presence of calcium and phospholipids, to activate factor X into Xa and trigger the common pathway of the coagulation cascade
Pharmacokinetics	Volume of Distribution: 19.9 L (75 mcg/kg), 11.9 L (225 mg/kg) Clearance: 8 L/hour (75 mcg/kg), 5.8 L/hour (225 mcg/kg) Elimination Half-Life: 1.7 h (75 mcg/kg), 1.4 h (225 mg/kg)	Volume of Distribution: 130 +/- 37 mL/kg (90 mcg/kg) Clearance: 43 +/- 15 mL/kg/hour (90 mcg/kg) Elimination Half-Life: 3.2 +/- 0.3 h (90 mcg/kg)
Contraindications	Known allergy to rabbits or rabbit proteins, severe hypersensitivity reaction to eptacog beta or any of its components	None known
Dosing and Administration	Mild to Moderate Bleeding: 75 mcg/kg repeated every 3 h until hemostasis is achieved or 225 mcg/kg × 1 dose; if hemostasis is not achieved within 9 h, an additional 75 mcg/kg dose may be administered every 3 h as needed Severe Bleeding: 225 mcg/kg × 1 dose; if necessary, may administer additional doses 6 h later of 75 mcg/kg every 2 h	Bleeding Episodes: Congenital Hemophilia A or B with Inhibitors: 90 mcg/kg every 2 h until hemostasis is achieved, then 90 mcg/kg every 3–6 h after hemostasis is achieved for severe bleeds Acquired Hemophilia: 70–90 mcg/kg every 2–3 h until hemostasis is achieved Congenital FVII Deficiency: 15–30 mcg/kg every 4–6 h until hemostasis is achieved Glanzmann's Thrombasthenia: 90 mcg/kg every 2–6 h until hemostasis is achieved
Dosing and Administration	Administration: slow bolus intravenous injection over 1–2 min	Administration: slow bolus intravenous injection over 2–5 min
Availability and Storage	Product: single-use vials of 1 mg, 2 mg, or 5 mg lyophilized powder with sterile water for injection supplied in a pre-filled syringe for reconstitution Storage: prior to reconstitution, the kits should be stored at room temperature but may be stored between 36°F to 86°F (2 °C to 30 °C) and protected from light in the product packaging	Product: single-use vials of 1 mg, 2 mg, 5 mg, or 8 mg lyophilized powder with sterile water for injection supplied in a pre-filled syringe for reconstitution Storage: prior to reconstitution, the kits should be stored between 36°F to 77°F (2 °C to 25 °C) and protected from light in the product packaging

Given the differences in dosing between eptacog alfa and eptacog beta, a local hospital guideline was created to assist providers in determining the most appropriate rFVIIa agent and associated dose for each indication (Table 2). It should be noted that weight-based doses were rounded to the nearest full mg to reduce product waste and to address any major differences in the total cumulative dose of each product administered. Eptacog alfa was reserved for use in congenital FVII deficiency due to the lack of evidence of use of eptacog beta in this disease state and the known dosing differences in this population compared to other benign bleeding disorders that utilize rFVIIa. Eptacog beta was the recommended rFVIIa product for all other indications. Lower starting doses of eptacog beta 35 mcg/kg were recommended for delta-granule storage pool disorder and very low fixed 1–2 mg doses were given for diffuse bleeding in cardiac surgery.

Table 2.

Institution Guideline for Recombinant Coagulation Factor VIIa-jncw: Recommendations for Eptacog beta.

Criteria/Requirement	Recommendations
Notification	Hematology, hemostatic and antithrombotic stewardship, or other designated services at the hospital are to be notified when coagulation factor VIIa (recombinant)-jncw is requested; procedures at each hospital are to be determined by the local Pharmacy and Therapeutics (P&T) Committee
Indications^1,2	May be used for the treatment and control of bleeding events in adults and adolescents at least 12 years of age with congenital hemophilia A or B meeting both of the following criteria: With inhibitors, defined as a Bethesda unit inhibitor titer of at least 5 Has inadequate response, intolerance, or contraindication to activated prothrombin complex concentrate (NOT applicable to patients on emicizumab) May be used in labeled indications for which eptacog alfa is approved by Health System P&T and/or local sites Acquired hemophilia Glanzmann's thrombasthenia May be used in off-label indications for which eptacog alfa is approved by Health System P&T and/or local sites Refractory bleeding in cardiac surgery Not for use in congenital factor VII deficiency
FDA Approved Dosing & Administration²	Congenital Hemophilia A or B with Inhibitors Bleeding Episode Mild or moderate bleed: 75 mcg/kg repeated every 3 h until hemostasis is achieved Severe bleed: 75 mcg/kg every 2–3 h or 225 mcg/kg × 1 dose; if necessary, may administer additional doses 6 h later of 75 mcg/kg every 2 h For those receiving emicizumab, use the 75 mcg/kg initial dose due to a lack of in vivo data demonstrating the safety of using higher doses in this population Administer as a slow bolus intravenous injection over 1–2 min
Off-Label Dosing Guidance^1,2,11,12	Congenital Hemophilia A or B with Inhibitors Peri-operative Management Minor surgery: 75 mcg/kg immediately before surgery and every 3 h for the duration of surgery, then continued post-operatively every 3 h for 48 h, followed by a titration down to every 3–6 h until hemostasis is achieved Major surgery: 75 mcg/kg immediately before surgery and every 2–3 h for the duration of surgery, then continued post-operatively every 3 h until hemostasis is achieved, followed by a provider-directed titration as tolerated Acquired Hemophilia A Bleeding Episode Mild to moderate bleed: 75 mcg/kg repeated every 3 h until hemostasis is achieved Severe bleed: 75 mcg/kg every 2–3 h Peri-operative Management Minor surgery: 75 mcg/kg immediately before surgery and every 3 h for the duration of surgery, then continued post-operatively every 3 h for 48 h, followed by a titration down to every 3–6 h until hemostasis is achieved Major surgery: 75 mcg/kg immediately before surgery and every 2–3 h for the duration of surgery, then continued post-operatively every 3 h until hemostasis is achieved, followed by a provider-directed titration as tolerated Glanzmann's Thrombasthenia Bleeding Episode Mild, moderate, or severe bleed: 75 mcg/kg repeated every 3–6 h until hemostasis is achieved Peri-operative Management Minor surgery: 75 mcg/kg immediately before surgery and every 3 h for the duration of surgery, then continued post-operatively every 3 h for 48 h, followed by a titration down to every 3–6 h until hemostasis is achieved Major surgery: 75 mcg/kg immediately before surgery and every 2–3 h for the duration of surgery, then continued post-operatively every 3 h until hemostasis is achieved, followed by a provider-directed titration as tolerated Refractory Bleeding in Cardiac Surgery (Off-Label) 1 mg × 1 dose; may repeat additional 1 mg dose if needed for continued bleeding Administer as a slow bolus intravenous injection over 1–2 min
Warnings & Precautions²	Thrombosis: patients with a history of congenital or acquired hemophilia receiving concomitant treatment with activated or non-activated prothrombin complex concentrate or those with a history of atherosclerosis, coronary artery disease, cerebrovascular disease, crush injury, septicemia, and/or thromboembolism may be at increased risk of arterial or venous thrombosis
	Hypersensitivity: patients with known immunoglobulin E (IgE)-based hypersensitivity to casein may be at increased risk of reactions
	Neutralizing antibodies: there has been no evidence of the development of neutralizing antibodies in eptacog beta trials, however those who do not achieve adequate hemostasis with optimized dosing may be at risk and testing should be performed
Monitoring²	Obtain baseline and daily platelets, fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT), hemoglobin, and hematocrit Laboratory tests may not correlate with clinical response of eptacog beta treatment Signs and symptoms of bleeding Signs and symptoms of thrombotic events

Reports were used to identify all administrations of eptacog alfa and eptacog beta between October 1, 2023, and September 30, 2024. Data extracted from the medical record included product administered (eptacog alfa or eptacog beta), dose and duration per admission, indication for rFVIIa, and adherence to institutional guidelines. Safety outcomes included the development of symptomatic arterial or venous thromboembolism and the development of suspected or confirmed new or worsening bleeding. We did not monitor for the development of neutralizing antibodies against either product given that the landmark trials that led to their drug approval (PERSEPT 1 and PERSEPT 3) reported 0% incidence. The presence or absence of thrombotic events were confirmed by an objective imaging study documented within the patient medical record. New or worsening bleeding may have been suspected based on hemoglobin and/or hematocrit trends or confirmed with imaging and was defined as bleeding occurring in a new site, bleeding that required therapy to be re-started, or existing bleeding events that required an increase in rFVIIa dose or dosing frequency. All data analyses were descriptive in nature.

We calculated cost avoidance by comparing the wholesale acquisition cost of eptacog beta ($2420/mg) to the wholesale acquisition cost of eptacog alfa ($2570/mg) in October 2023.^6,7 The cost estimates reported assume similar clinical effectiveness between the two products. We also considered the dosing differences between eptacog alfa and eptacog beta, and the associated decrease in volume of product used with eptacog beta given the lower dose and dosing frequency compared to eptacog alfa. A dose-equivalence validation was not performed.

Results

From October 2023 to September 2024, there were 17 patients with 27 admissions that required rFVIIa administration. There were 3 admissions (11.1%) where eptacog alfa was given, 21 admissions (77.8%) where eptacog beta was given, and 3 admissions (11.1%) where both eptacog alfa and eptacog beta were administered due to limitations in inventory supply (Table 3).

Table 3.

Use of Eptacog beta Versus Eptacog Alfa Between October 2023 – September 2024.

Encounter	Indication	Initial Dose of rFVIIa	Hospital Length of Stay (days)	Cumulative dose of Eptacog beta (mg) during admission	Cumulative dose of Eptacog alfa (mg) during admission
1	Acquired Hemophilia A (Bleeding)	75 mcg/kg every 3 h	8	203	-
2	Argatroban Reversal (Bleeding)	1 mg × 2 doses	1	2	-
3	Congenital Hemophilia A (Bleeding)	75 mcg/kg every 3 h	38	265	-
4	Delta-Granule Storage Pool Disorder (Prophylaxis; left total hip arthroplasty)	35 mcg/kg × 1 dose as needed	8	51	-
5	Cardiac Surgery (Bleeding)	1 mg × 1 dose	6	-	1
6	Congenital Hemophilia A (Bleeding)	75 mcg/kg every 2 h	23	200	-
7	Acquired Hemophilia A (Bleeding)	75 mcg/kg every 3 h	9	252	-
8	Acquired Hemophilia A (Bleeding)	75 mcg/kg every 3 h	30	435	-
9	Cardiac Surgery (Bleeding)	2 mg × 1 dose	7	2	-
10	Acquired Hemophilia A (Bleeding)	75 mcg/kg every 2 h	31	636	65
11	Congenital Hemophilia A (Bleeding)	75 mcg/kg every 2 h (eptacog beta); 90 mcg/kg every 2 h (eptacog alfa)	13	154	71
12	Acquired Hemophilia A (Bleeding)	75 mcg/kg every 4 h	12	130	-
13	Congenital FVII Deficiency (Prophylaxis; intramedullary fixation for right hip fracture)	15 mcg/kg × 1 dose as needed	4	-	15
14	Congenital Hemophilia A (Peri-procedural management; exploratory laparotomy and repair of appendicovesicostomy)	75 mcg/kg every 3 h	5	96	-
15	Congenital Hemophilia A (Bleeding)	75 mcg/kg every 3 h	36	720	-
16	Acquired Hemophilia A (Peri-procedural management; left wrist irrigation and debridement post left wrist wound dehiscence)	75 mcg/kg every 3 h	5	28	-
17	Acquired Hemophilia A (Bleeding)	75 mcg/kg every 4 h	5	32	-
18	Congenital Hemophilia A (Bleeding)	70 mcg/kg × 1 (eptacog alfa); 90 mcg/kg every 3 h (eptacog beta)	6	230	5
19	Acquired Hemophilia A (Bleeding)	50 mcg/kg every 4 h	9	79	-
20	Congenital FVII Deficiency (Peri-procedural management; right heart catheterization)	30 mcg/kg x1	1	-	2
21	Congenital Hemophilia A (Peri-procedural management; large volume paracentesis)	75 mcg/kg (once before and after procedure)	32	42	-
22	Fondaparinux Reversal (Bleeding)	1 mg × 1	6	1	-
23	Cardiac Surgery (Bleeding)	1 mg × 1	64	1	-
24	Intracranial Hemorrhage Post Heparin Reversal	1 mg every 2 h	7	10	-
25	Acquired Hemophilia A (Peri-procedural management; cystoscopy with ureteral stone removal and stent placement)	75 mcg/kg every 4 h	1	15	-
26	Congenital Hemophilia A (Peri-procedural management; large volume paracentesis)	75 mcg/kg × 2 (once before and after procedure)	15	14	-
27	Congenital Hemophilia A (Peri-procedural management; abdominal wound exploration)	75 mcg/kg every 2 h	17	98	-

The most common indications for administration were acute bleeding in hemophilia patients with inhibitors (12, 44.4%) followed by peri-procedural management for hemophilia and non-hemophilia indications (9, 33.3%), cardiac surgery (3, 11.1%), and anticoagulation reversal for life-threatening bleeding (3, 11.1%). Of the hemophilia patients with acute bleeding, 7 (25.9%) administrations were in patients with acquired hemophilia with inhibitors and 5 (18.5%) in patients with congenital hemophilia with inhibitors.

In acute bleeding patients exclusively managed with eptacog beta, the average total dose of eptacog beta was 257.3 mg delivered in 2–4 hly intervals. In the peri-procedural setting, the average eptacog beta dose was 49.1 mg delivered in 1–3 doses. Eptacog alfa was administered exclusively in 3 encounters, including cardiac surgery (1, 3.7%) and peri-procedural management with congenital FVII deficiency (2, 7.4%).

Of the 27 administrations, 18 (66.6%) were fully adherent to the hospital's guideline for indications while 9 (33.3%) of the administrations were inconsistent with the guidelines, either by indication (eg management of anticoagulation-related life-threatening bleeding), the prescribed doses, or the dosing interval.

There were no thrombotic events associated with 27 eptacog alfa and eptacog beta administrations. There were 2 (7.4%) encounters that required re-initiation of eptacog beta and 5 (18.5%) requiring dose escalation to control bleeding. In four of these instances, worsening or new bleeding was triggered by an intervention (Table 4).

Table 4.

Management of Bleeding.

Patient	Indication	Description	Management
1	Acquired Hemophilia A (Bleeding)	Hemodynamically stable without melena post procedure, however after stopping eptacog beta 24 h post procedure, melena resumed with hemoglobin/hematocrit drop in addition to ongoing bleeding from right upper extremity skin wound	Resumed eptacog beta with escalated dosing of 90mcg/kg Q3H × 24 h, then back to 75 mcg/kg Q3H and plan for repeat EGD (found no active bleeding)
3	Congenital Hemophilia A (Bleeding)	Once hemostasis was achieved after initial treatment, the frequency of factor administration was weaned, and the patient went for a planned irrigation and debridement of the left finger due to infection; course was complicated by the development of post-operative bleeding	Increased frequency from eptacog beta 75 mcg/kg daily to every 3 h and extended treatment course
4	Delta-Granule Storage Pool Disorder (Prophylaxis; left total hip arthroplasty)	Received peri-operative prophylaxis for a left total hip arthroplasty; ecchymosis was noted on the left thigh with reported pain by the patient	Increased dose and frequency of eptacog beta 35 mcg/kg every 6 h to 75 mcg/kg every 3 h
8	Acquired Hemophilia A (Bleeding)	Once hemostasis was achieved after initial treatment, the frequency of factor administration was weaned, and the patient received an intra-articular steroid injection that was complicated by the development of post-procedural bleeding	Increased frequency of eptacog beta 75 mcg/kg every 12 h to every 3 h and extended treatment course
10	Acquired Hemophilia A (Bleeding)	Once hemostasis was achieved after initial treatment, the frequency of factor administration was weaned, and the patient went for endoscopy; course was complicated by the development of post-procedural bleeding and new hematochezia	Reverted from eptacog alfa to eptacog beta based on supply status and increased the frequency from every 4 h to every 2 h
15	Congenital Hemophilia A (Bleeding)	While awaiting surgery for exploratory laparotomy, patient reported feeling week with hemoglobin and hematocrit down trending; started eptacog beta 75 mcg/kg every 3 h; following day, imaging demonstrated right-sided perinephric hematoma	Transfused 2 units red blood cells and eptacog beta frequency increased to every 2 h
27	Congenital Hemophilia A (Peri-procedural management; abdominal wound exploration)	Complex history of urologic complications and procedures with some increased hematuria post exploration of abdominal wound which was not unexpected by urology	Re-started on eptacog beta 75 mcg/kg every 2 h until hematuria resolved

Based on a mg-to-mg conversion of eptacog beta for eptacog alfa at the hospital's wholesale acquisition cost, our estimated cost savings over the MUE period was $554,400. If we adjust for differences in dosing (75 mcg/kg vs 90 mcg/kg) and dosing interval (every 3 h vs every 2 h) between the two products, the estimated cost savings increases to more than $800,000.

Discussion

We completed a retrospective MUE following a formulary change in which eptacog beta became the preferred rFVIIa agent. Using an internal hospital guideline to support selection and dosing, we used eptacog beta for patients that required treatment for acute bleeding events associated with HABI (congenital or acquired), peri-procedural management associated with HABI (congenital or acquired), bleeding associated with platelet disorders, or refractory bleeding during cardiac surgery. Eptacog beta was also used to reverse life-threatening bleeding associated with heparin, argatroban, and fondaparinux. We used eptacog alfa to manage congenital FVII deficiency per hospital protocol due to a lack of data for eptacog beta in this indication.

Substituting medications with similar therapeutic intent is challenging. Our local guideline contains information for indication, dosing, and dosing frequency although does not include all possible scenarios where rFVIIa may be a last option for life-threatening bleeding. For this particular substitution the dosing and frequency were slightly lower with eptacog beta compared with eptacog alfa due to differences in the molecular structure; however, providers were so accustomed to the eptacog alfa dosing that the switch required reinforcement of education and dosing recommendations. Quality improvement tools like MUEs are intended to identify opportunities for performance change. While some of these inconsistencies in following guidelines are attributed to a lack of familiarity in utilizing a new product, inventory management also represented a barrier early on where inadequate supply led to the use of both products in individual patients.

While there were no thrombotic complications, a small number of patients required escalation of dosing and/or re-initiation of therapy, which is not an uncommon occurrence in this population. This could have occurred regardless of the agent prescribed given the complexity and difficulty in controlling bleeding events in patients with HABI, especially if also undergoing procedures.⁸

We estimated that the hospital avoided spending approximately $800,000 for medication expense over the MUE period. Cost avoidance is a difficult measure to track and apply across health-systems due to individual health-system contracting, differences in purchasing structure such as 340B qualifications, the use of consignment programs, differences in group purchasing organizations, as well as changing prices due to market competition.

Eptacog beta (Sevenfact^®) is FDA approved for bleeding in patients 12 years and older with congenital HABI while eptacog alfa (NovoSeven^®) has additional approval for treatment of acquired hemophilia, congenital FVII deficiency, and Glanzmann's thrombasthenia. The agents have no head-to-head comparative trials. In the PERSEPT 1 trial, eptacog beta was evaluated for mild, moderate, and severe bleeding events in patients 12 years of age and older with HABI.⁹ Eptacog beta was administered at the 75 IDR or the 225 IDR as described previously. The primary efficacy endpoint, hemostatic control of bleeding at 12 h, was observed with both dosing regimens (84.9% for 75 IDR and 93.2% for 225 IDR). In the PERSEPT 3 trial, eptacog beta was employed to prevent excessive bleeding during surgical procedures.¹⁰ Patients received eptacog beta 200 mcg/kg for major procedures and 75 mcg/kg for minor procedures immediately prior to surgery. Subsequent post-operative doses of 75 mcg/kg every 2 to 24 h were administered for 2–5 days. The primary efficacy endpoint, good or excellent hemostasis at 48 h, was achieved in 66.7% of major surgery patients and in all patients undergoing minor procedures. There was no development of neutralizing antibodies against eptacog beta noted in either trial. Given this finding, we did not monitor for the development of neutralizing antibodies in our study but this could be considered if hemostasis is suboptimal despite adequate dosing and dosing interval.

Our institutional guidelines recommend the 75 IDR for hemophilia-related indications, including surgical procedures. Dosing in our patients varied and, in some instances, eptacog beta was dosed every 4 h. Additionally, in procedures (some of which would be considered major), dosing of eptacog beta remained at the 75 mcg/kg IDR. This MUE demonstrated new or worsening bleeding in seven patients, six of them with hemophilia-related bleeding with or without procedural intervention. Given the data from the PERSEPT 1 and 3 trials, it may be necessary to re-evaluate internal hospital guidelines to allow for higher doses of the 225 IDR, especially if bleeding is not improving; however, it is important to note that higher dosing is not recommended in patients receiving concomitant emicizumab which represents the majority of our patient population. Additionally, it may be reasonable to consider higher peri-procedural initial doses of 200 mcg/kg, particularly in major procedures. Our institution has a hemostatic and antithrombotic stewardship (HAT) service that is a partnership between the inpatient hematology team and HAT pharmacist that assesses all factor dosing daily and discusses the dose, frequency, escalation, and de-escalation plans to ensure optimal usage.

There were three cases of anticoagulation reversal for life-threatening bleeding with rFVIIa outside of our clinical guidelines. Limited data exist for managing direct thrombin inhibitor and fondaparinux related bleeding. Factor VIIa administration may be considered to manage major refractory bleeding when the benefit is thought to outweigh the thrombotic risk.¹¹ Additionally, while protamine has universally been employed for heparin reversal, we had one case where life-threatening bleeding continued after heparin administration despite adequate doses of protamine and eptacog beta was used. Reversal dosing guidance was not initially included in our internal hospital guidelines but given the use of eptacog beta in three instances in this MUE without safety concerns, hospital guidelines could be updated for future use if deemed appropriate by clinical experts and hospital leadership.

The use of rFVIIa in cardiac surgery is supported by retrospective case series with eptacog alfa. In general, rFVIIa at low doses (20 mcg/kg) is associated with less transfusions, re-exploration, and less blood loss.¹² Typically, rFVIIa is given in instances where bleeding remains refractory to other interventions, including the use of blood products. In our MUE, we demonstrated two cases where eptacog beta was used in this scenario. These are the first reported uses of eptacog beta for this indication; there were no safety signals associated with its use.

Our MUE is limited to a single center with a small number of patients. The disease states explored are very rare in the general population and our hospital was the first in our health system to make the formulary interchange, which did not allow us to expand to other sites to broaden the sample size. Furthermore, eptacog beta became our preferred rFVIIa product for all indications other than congenital FVII deficiency after the formulary interchange, which did not allow us to perform a direct comparator analysis between the two products. The retrospective nature of the study made it difficult to fully capture an understanding of some of the complications observed, including new or worsening bleeding. Given the novelty of a new rFVIIa being added to formulary and general unfamiliarity with the product, we also saw some clinician variation in dosing and uses that were inconsistent with internal hospital guidelines; however, with continued use, educational initiatives, and evaluations to trigger improvements, we anticipate more streamlined practices moving forward. Additionally, drug acquisition costs may vary by institution and/or regional location and is it important to note that cost savings with formulary switches are dependent on several factors, including group purchasing organization contracts, consignment contracts, and institutional dosing practices. Therefore, the cost savings associated with our formulary interchange may not be universally applicable to other institutions. However, this MUE is helpful in reporting novel cases where eptacog beta use has not been published before and we therefore believe our experience may offer opportunities for others to evaluate if substitution of rFVIIa products may reduce hospital expenses through direct costs or through reduced frequency of medication administration.

Conclusion

Our institution converted from eptacog alfa to eptacog beta as the preferred rFVIIa product. Despite limited clinical trial data for use of eptacog beta in some indications, a small cohort of patients were treated without adverse outcomes. Overall, the transition to use of eptacog beta was accepted by providers. Other hospitals may consider evaluating their rFVIIa use and consider opportunities for substitution.

Footnotes

Acknowledgements

Not applicable.

ORCID iDs

Alyssa R. George

Katelyn W. Sylvester

Dareen M. Kanaan

John R. Fanikos

Jean M. Connors

Nathan T. Connell

Ethical Considerations and Consent to Participate

The Ethics Committee of the Mass General Brigham Institutional Review Board waived the need for ethics approval and patient consent for the collection, analysis and publication of the retrospectively obtained and anonymized data for this non-interventional study.

Consent for Publication

Not applicable.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interest

Dr. George, Dr. Sylvester, Dr. Kanaan, and Dr. Reddy report no disclosures. John Fanikos discloses consultant fees from Pfizer and research support from Serb Pharmaceuticals. Dr. Connors discloses consulting fees from Abbott Laboratories, Anthos Therapeutics, Bristol-Myers Squibb, Janssen Pharmaceuticals, Perosphere Technologies, Pfizer, Roche, and Sanofi S.A. Dr. Connell discloses consulting fees from Takeda, Genentech, Sanofi Genzyme, Pfizer, Bayer, and Medzown and honorarium from Octapharma AG.

Data Availability

Raw data were generated at Brigham and Women's Hospital. Derived data supporting the findings of this study are available from the corresponding author on request.

Statements and Declarations

The SQUIRE 2.0 checklist was used when writing our report.

References

NovoSeven [prescribing information]. Novo Nordisk, Inc., July 2014. Accessed July 3, 2024. https://www.fda.gov/media/70442/download.

Sevenfact [prescribing information]. HEMA Biologics, November 2022. Accessed July 3, 2024. https://sevenfact.com/Sevenfact_PI.pdf.

Mills

Gardner

Thorlund

, et al. A users’ guide to understanding therapeutic substitutions. J Clin Epidemiol. 2014;67(3):305–313. doi: 10.1016/j.jclinepi.2013.09.008. Epub 2013 Dec 2. PMID: 24291506.

Youkhana

Batsuli

Acharya

, et al. Real-world effectiveness of eptacog beta in patients with haemophilia and inhibitors: A multi-institutional case series. Haemophilia. 2024;30(6):1321–1331. doi: 10.1111/hae.15094. Epub 2024 Sep 19. PMID: 39297369; PMCID: PMC11659498.

Afanasjeva

Burk

Cunningham

, et al. ASHP Guidelines on medication-use evaluation. Am J Health Syst Pharm. 2021;78(2):168–175. doi: 10.1093/ajhp/zxaa393. PMID: 33399190.

Lexicomp Online [database online]. Wolters Kluwer Clinical Drug Information Inc, 2024. Accessed February 23, 2024. https://www.wolterskluwer.com/en/solutions/uptodate/enterprise/lexidrug.

McKesson Connect. https://connect.mckesson.com/portal/. Accessed July 3, 2024.

Pishko

Doshi

. Acquired hemophilia A: Current guidance and experience from clinical practice. J Blood Med. 2022;11(13):255–265. doi: 10.2147/JBM.S284804. PMID: 35592586; PMCID: PMC9112043.

Wang

Lawrence

Quon

, et al. PERSEPT 1: A phase 3 trial of activated eptacog beta for on-demand treatment of haemophilia inhibitor-related bleeding. Haemophilia. 2017;23(6):832–843.

10.

Escobar

Luck

Averianov

, et al. PERSEPT 3: A phase 3 clinical trial to evaluate the haemostatic efficacy of eptacog beta (recombinant human FVIIa) in perioperative care in subjects with haemophilia A or B with inhibitors. Haemophilia. 2021;27(6):911–920.

11.

Vavra

Lutz

Smythe

. Recombinant factor VIIa to manage major bleeding from newer parenteral anticoagulants. Ann Pharmacother. 2010;44(4):718–726. doi: 10.1345/aph.1M447. Epub 2010 Mar 16. PMID: 20233918.

12.

Cotter

Sharma

Campton

, et al. Very low-dose recombinant factor VIIa administration for cardiac surgical bleeding reduces red blood cell transfusions and renal risk: A matched cohort study. Blood Coagul Fibrinolysis. 2021;32(7):473–479. doi: 10.1097/MBC.0000000000001079. PMID: 34650021.

13.

Ogrinc

Davies

Goodman

, et al. SQUIRE 2.0 (Standard for Quality Improvement Reporting Excellence): Revised publication guidelines from a detailed consensus process. BMJ Qual Saf. 2016;25(12):986–992.

Real World Experience with use of Coagulation Factor VIIa at an Academic Medical Center

Abstract

Background

Methods

Results

Conclusion

Keywords

Introduction

Methods

Results

Discussion

Conclusion

Footnotes

Acknowledgements

ORCID iDs

Ethical Considerations and Consent to Participate

Consent for Publication

Funding

Declaration of Conflicting Interest

Data Availability

Statements and Declarations

References