Economic Evaluation of Andexanet Versus Prothrombin Complex Concentrate for Reversal of Factor Xa-Associated Intracranial Hemorrhage.

[Figure: see text].

Choosing the Best Approach to Warfarin Reversal After Traumatic Intracranial Hemorrhage.

BACKGROUND: Patients on warfarin with traumatic intracranial hemorrhage often have the warfarin effects pharmacologically reversed. We compared outcomes among patients who received 4-factor prothrombin complex concentrate (PCC), fresh frozen plasma (FFP), or no reversal to assess the real-world impact of PCC on elderly patients with traumatic intracranial hemorrhage (ICH). MATERIALS AND METHODS: This was a retrospective analysis of 150 patients on preinjury warfarin. Data were manually abstracted from the electronic medical record of an academic level 1 trauma center for patients admitted between January 2013 and December 2018. Outcomes were ICH progression on follow-up computed tomography scan, mortality, need for surgical intervention, and trends in the use of reversal agents. RESULTS: Of 150 patients eligible for analysis, 41 received FFP, 60 PCC, and 49 were not reversed. On multivariable analysis, patients not reversed [OR 0.25 95% CI (0.31-0.85)] and women [OR 0.38 95% CI (0.17-0.88)] were less likely to experience progression of their initial bleed on follow-up computed tomography while subdural hemorrhage increased the risk [OR 3.69 95% CI (1.27-10.73)]. There was no difference between groups in terms of mortality or need for surgery. Over time use of reversal with PCC increased while use of FFP and not reversing warfarin declined (P < 0.001). CONCLUSIONS: Male gender and using a reversal agent were associated with progression of ICH. Choice of reversal did not impact the need for surgery, hospital length of stay, or mortality. Some ICH patients may not require warfarin reversal and may bias studies, especially retrospective studies of warfarin reversal.

Emergent reversal of oral factor Xa inhibitors with four-factor prothrombin complex concentrate.

BACKGROUND: Controversy exists regarding first-line use of the recently approved reversal agent andexanet alfa due to limitations of the ANEXXA-4 study, thrombotic risks, and high medication acquisition cost. The purpose of this study was to evaluate the safety and effectiveness of 4F-PCC for the reversal of emergent oral fXa inhibitor-related bleeding. Furthermore, we aimed to evaluate a subgroup using strict ANNEXA-4 patient selection criteria. METHODS: This was a retrospective study conducted utilizing chart review of adult patients that received 4F-PCC for oral fXa inhibitor-related bleeding. The primary endpoint was the rate of clinical success defined as achieving excellent or good hemostatic effectiveness following the administration of 4F-PCC. Secondary endpoints included in-hospital mortality and arterial/venous thromboembolism, and cost compared with andexanet alfa. RESULTS: A total of 119 patients were included, with 83 patients in the ANNEXA-4 criteria subgroup. Eighty-five of the 119 patients (71%) required reversal due to intracranial bleeding. Prior to reversal, 70 patients (59%) were taking apixaban and 49 patients (41%) were taking rivaroxaban. Clinical success was achieved in 106 of 119 patients (89%) and 74 of 83 patients (90%) in the strict criteria subgroup. Three of 119 patients (2.5%) had a thrombotic event during hospital stay and the overall mortality rate was 13%. The average cost increase of andexanet alfa compared to 4F-PCC would have been $29,500 per patient. CONCLUSIONS: Administration of 4F-PCC for the reversal of oral fXa inhibitors was effective with relatively low thrombotic risk. Further direct prospective comparison of 4F-PCC to andexanet alfa is warranted.

Plasma fractionation in countries with limited infrastructure and low-/medium income: How to move forward?

Although therapeutic drivers are changing over the years, and innovative biotech products are continuously modifying the clinical landscape, there is an increasing need for plasma protein therapies obtained by the fractionation of human plasma. Plasma-derived protein products therefore continue to play vital roles in the therapeutic management of various immunological disorders, deficiencies in coagulation factors or protease inhibitors, viral or bacterial infections, and trauma. Plasma fractionation is a biotechnology industry that has increased in complexity over the last 30 years to ensure that plasma-derived protein therapies exhibit optimal quality and pathogen safety profiles. Plasma-derived products are among the safest biological therapies available; in industrialized countries they are strictly and efficiently regulated in all aspects of their production chain and clinical use. Conversely, due to some technological complexities and strict adherence to regulatory requirements, a substantial barrier to entry into the field of plasma fractionation exists. Although various plasma-derived protein products are on the WHO model list of essential medicines, dramatic shortages of these products exist, especially in low-/medium income countries, while at the same time more than 9 million liters of recovered plasma in these countries are wasted annually. Lack of plasma protein products results mainly from three factors: (a) cost of imported products, (b) insufficient local supply of quality plasma for fractionation, or (c) lack of domestic industrial fractionation capacity. As the understanding of critical quality and safety factors has dramatically improved over the years, there is a need to rethink how affordable, scalable, and reliable purification and virus inactivation technologies could be introduced in countries with poor relevant infrastructures and low-/medium income. Such technologies, when properly validated and implemented, could help ensure local availability of essential plasma protein therapies and gradually fill the gap in product supply, safety and affordability that exists relative to advanced economies.

Cost comparison of andexanet versus prothrombin complex concentrates for direct factor Xa inhibitor reversal after hemorrhage.

Andexanet-alpha is a specific reversal agent for direct factor Xa inhibitors (dFXaI). We aimed to project utilization rates and cost of andexanet for reversal of dFXaI-related major hemorrhage compared to 4-factor prothrombin complex concentrates (4F-PCC). A retrospective, multicenter review was conducted between 1/1/2014 and 7/15/2018 of patients who received 4F-PCC for reversal of dFXaI-related life-threatening hemorrhages. Total hospital reimbursements/patient were calculated based on national average MS-DRG payments adjusting for Medicare discounts. The projected cost for andexanet (based on dose and insurance) and % reimbursement/patient was compared to the actual cost of 4F-PCC. Hemostasis at 24 h (excellent/good vs. poor) and 30-day thrombotic complications were assessed. Of 126 patients who received 4F-PCC to reverse dFXaI, 46 (~ 10 per-year) met inclusion criteria. The median projected cost of andexanet was $22,120/patient, compared to $5670/patient for 4F-PCC (P < 0.001). The median hospital reimbursement was $11,492/hospitalization. The projected cost of andexanet alone would exceed the entire hospital reimbursement in 74% of patients by a median of $7604, while 4F-PCC cost exceeded the total hospital payments in 7% of patients in the same cohort (P < 0.001). Hemostasis was excellent/good in 72% of patients post-4F-PCC, compared to 82% in andexanet trials. Thromboembolic events occurred in 4% of patients following 4F-PCC versus 10% in andexanet trials. The projected cost of andexanet would exceed the national average hospital reimbursement/patient in nearly 75% of patients by over $7500/hospitalization. 4F-PCC was significantly less expensive, had lower rates of thrombosis, but also lower rates of good/excellent hemostasis compared to published data for andexanet.

On-label compared to off-label four-factor prothrombin complex concentrate use: a retrospective, observational study.

BACKGROUND: Four-factor prothrombin complex concentrate (4F-PCC) is US Food and Drug Administration approved for the urgent reversal of coagulation factor deficiency induced by a vitamin K antagonist complicated by acute major bleeding or in situations in which invasive procedures are urgently needed. Although recent evidence suggests the superiority of 4F-PCC over plasma for on-label indications, the off-label use of 4F-PCC has not been rigorously studied. STUDY DESIGN AND METHODS: Eighty-nine patients receiving 4F-PCC at a single institution from July 2016 to December 2017 were retrospectively analyzed. Two cohorts, "On-Label" and "Off-Label" uses of 4F-PCC, were evaluated, comparing patient characteristics, blood utilization, and clinical outcomes including in-hospital mortality. RESULTS: Patients receiving 4F-PCC for off-label reasons (n = 46) were younger and sicker compared to those receiving 4F-PCC for on-label reasons (n = 43). Notably, the mortality rate for off-label use was approximately twofold greater than the mortality rate for on-label use (26 of 46 [56.5%] vs. 12 of 43 [27.9%]; p = 0.006). Patients receiving 4F-PCC for off-label reasons received more units per patient of each blood component than their on-label counterparts. The average cost estimate per patient for 4F-PCC was similar (approx. $4300) in each cohort. CONCLUSION: 4F-PCC is an effective but expensive treatment option for those requiring urgent reversal of vitamin K antagonist-induced coagulopathy. However, providers should be conscious of the high costs and questionable efficacy when using 4F-PCC off-label.

Safety, efficacy, and cost of four-factor prothrombin complex concentrate (4F-PCC) in patients with factor Xa inhibitor-related bleeding: a retrospective study.

Oral factor Xa (fXa) inhibitor-related bleeding is a concerning drug safety problem. There is considerable controversy surrounding available reversal strategies. The recently approved reversal agent andexanet alfa has limited data, an unclear safety profile, and imparts a substantial financial burden. This has led to the off-label use of four-factor prothrombin complex concentrates (4F-PCC) for this indication. This study aimed to assess the safety and efficacy of 4F-PCC for the management of major bleeding related to oral fXa inhibitors. This observational, retrospective study included adult patients admitted from 2014 to 2018 who received 4F-PCC (Kcentra®) for fXa inhibitor-related major bleeding. Efficacy was assessed using criteria described by Sarode et al. Secondary outcomes included the incidence of thromboembolism, mortality, and a cost analysis comparing 4F-PCC to andexanet alfa for reversal of oral fXa inhibitors. Thirty-one patients received 4F-PCC for major bleeding associated with apixaban (55%) or rivaroxaban (45%). Intracranial hemorrhage (58%) and pericardial effusion (16%) accounted for the majority of bleeding events. Most patients received a single weight-based 4F-PCC dose of 25 units/kg (38.7%) or 50 units/kg (51.6%). Effective hemostasis was achieved in 80.6% of patients. Five patients (16%) died due to acute bleeding and no thromboembolic events were observed. Administration of 4F-PCC was effective for most patients requiring emergent reversal of anticoagulation with apixaban or rivaroxaban and was associated with a low risk of thromboembolic events. Considerable cost differences limit the use of andexanet alfa and may warrant further study of 4F-PCC for fXa inhibitor reversal.

Cost-Effectiveness of rFVIIa versus pd-aPCC in the Management of Mild to Moderate Bleeds in Pediatric Patients with Hemophilia A with Inhibitors in Mexico.

OBJECTIVE: To compare the costs and clinical consequences of treating mild-to-moderate joint bleeds with recombinant activated factor VII (rFVIIa) versus plasma-derived activated prothrombin complex concentrate (pd-aPCC) in pediatric patients with hemophilia A with inhibitors in Mexico. METHODS: A cost-effectiveness model was developed using TreeAge Pro v14.2.2 software (licensed in the USA) and adapted from a previously published model, with adjustments to reflect local clinical practice. Expert opinion was sought regarding patients' clinical management and resource utilization in Mexico to ensure that the current model was appropriate and relevant. The model compared rFVIIa and pd-aPCC for the treatment of mild-to-moderate joint bleeds in children <14 years old (assumed average weight: 30 kg). The analysis outcome was incremental cost per resolved mild-to-moderate joint bleed. One-way sensitivity analysis and probabilistic sensitivity analysis were used to assess specific assumptions and to address any uncertainty in the model. RESULTS: The cost of treating mild-to-moderate joint bleeds was lower for rFVIIa versus pd-aPCC after 7 days (MX$105,581 vs. MX$132,024), assuming complete bleed resolution. After 48 hours, rFVIIa was associated with an 8% improvement in bleed resolution versus pd-aPCC, resulting in cost savings of MX$16,754. Probabilistic sensitivity analysis indicated that rFVIIa treatment was more cost-effective than pd-aPCC in 67% (at 7 days) and 72% (at 48 hours) of Monte Carlo simulations. CONCLUSION: Accounting for model uncertainty, rFVIIa provided cost savings over pd-aPCC for the Mexican public health care payer in the management of mild-to-moderate joint bleeds in pediatric hemophilia A with inhibitors.

Hemophilia Burden of Disease: A Systematic Review of the Cost-Utility Literature for Hemophilia.

BACKGROUND: Prophylaxis with clotting factor replacement products is recommended by the Medical and Scientific Advisory Council of the National Hemophilia Foundation as the optimal therapy for the prevention of bleeding episodes in individuals with severe hemophilia A or B (< 1 IU per dL endogenous factor VIII or factor IX activity, respectively). Prophylaxis is associated with an improved health-related quality of life and has been shown to be cost-effective compared with on-demand therapy. However, the overall cost of treatment remains high, particularly among patients with a greater propensity to bleed. The overall value of hemophilia treatments and their associated benefits, measured in quality-adjusted life-years (QALYs), and dollar costs compared with other interventions can be evaluated through the use of cost-utility analyses (CUAs). Previous CUA studies in hemophilia have focused primarily on patients with more severe forms of hemophilia and on prophylaxis compared with on-demand treatment. However, to our knowledge, no studies to date have utilized QALYs as a standardized outcome measure to systematically evaluate the relative cost-effectiveness of current hemophilia treatment options. OBJECTIVE: To systematically review the CUA literature of hemophilia treatments and demonstrate the challenges in producing cost-utility evidence compared with other rare diseases. METHODS: We conducted a systematic literature review using the Tufts Medical Center Cost-Effectiveness Analysis Registry and the National Health Service Economic Evaluation Database for English-language CUAs published from 2000 through 2015 with the search terms hemophilia, haemophilia, factor VIII, or factor IX. Two trained reviewers independently reviewed every study to extract relevant data. Incremental cost-effectiveness ratios were converted to 2014 U.S. dollars using exchange rates for currency conversion and the Consumer Price Index to adjust for inflation. RESULTS: Our search yielded 52 studies, 11 of which met our inclusion criteria. The cost-effectiveness of hemophilia treatments varied widely based on variations in the study designs, including differences in time horizon, discount rates, and medical interventions. CONCLUSIONS: We found the cost-effectiveness of hemophilia treatments to be broadly comparable to that of other orphan drugs. Improved standardization of future CUA studies will be important for further evaluation of the cost-effectiveness of hemophilia treatments. DISCLOSURES: This research was funded by Biogen, which provided an unrestricted research grant to the Center for the Evaluation of Value and Risk in Health at Tufts Medical Center. Biogen and Sobi reviewed and provided feedback on the manuscript. The authors had full editorial control of the manuscript and provided final approval of all content. The authors report no conflict of interest regarding the material discussed in this article. Neumann and Chambers are employed at the Center for the Evaluation of Value and Risk in Health at Tufts Medical Center. Thorat was an employee of Center for Evaluation Value and Risk in Health, Tufts Medical Center when the analyses were carried out. Chambers has participated on advisory boards for Sanofi and Astellas Pharma.

Comparison of blood product use and costs with use of 3-factor versus 4-factor prothrombin complex concentrate for off-label indications.

PURPOSE: Results of a comparison of blood product use and cost outcomes with use of 3-factor versus 4-factor prothrombin complex concentrate (PCC) for indications other than warfarin reversal are presented. METHODS: Consecutive patients who received 3-factor PPC (PCC3) or 4-factor PCC (PCC4) for non-warfarin-related indications at 2 U.S. hospitals during a 19-month period were identified. The primary outcome was in-hospital blood product use, with a focus on plasma use. Total hemostasis costs, intensive care unit (ICU) and hospital lengths of stay, and other outcomes were evaluated. RESULTS: Indications for PCC3 use (n = 118) or PCC4 use (n = 64) included intraoperative bleeding, nonintraoperative bleeding, coagulopathy of liver disease, and reversal of direct-acting oral anticoagulant effects. The proportion of patients who received plasma was 56.8% with PCC3 use versus 53.1% with PCC4 use (p = 0.643); the corresponding median volumes of plasma received were 638 mL (interquartile range [IQR], 550-1,355 mL) and 656 mL (IQR, 532-1,136 mL), respectively. The median total hemostasis costs were $5,559 (IQR, $3,922-$8,159) with PCC3 use and $7,771 (IQR, $6,366-$9,205) with PCC4 use (p < 0.001). CONCLUSION: PCC3 use and PCC4 use were associated with similar blood product use, ICU length of stay, hospital length of stay, and in-hospital mortality when given for non-warfarin-related indications. However, relative to PCC3 use, PCC4 use was associated with an increase in costs that was primarily due to drug costs.

[Cost of clotting factors in hospitalization]. / Coût des facteurs antihémophiliques en hospitalisation.

OBJECTIVES: Hemophilia is a rare genetic disease, characterized by uncontrolled bleeding. Injections of clotting factor are the principal are the principal treatment. This drug is very expensive. The objectives of this study are to determine the cost of clotting factor for in patients and the factor impacting this cost. METHODS: A retrospective study was carried on hemophiliac in patients between 1 January 2014 and 31 December 2015 in Cochin hospital and having received at least an injection of clotting factor during their hospitalization. A collection of clinical data and treatments received during the hospitalization was realized for every patient. RESULTS: Fifty-one patients were included in the study with a total of 68 hospitalizations. The median cost of clotting factors by hospitalization was 16,908€. The median part of clotting factors on the total cost of the hospitalization was 68.2%. The cost of factors by stay was higher for the severe haemophiliacs (P=0.015) and for the major surgeries (P<0.0001). The daily median cost of clotting factors was 3124€. This cost was higher at the haemophiliacs B (P=0.0112), the severe haemophiliacs (P<0.0001) and the haemophiliacs with inhibitor (P=0.0053). CONCLUSIONS: Clotting factors represent the most part of the cost of hospitalization of a haemophiliac. Their cost in hospitalization varies according to many factors. It may evolve with the arrival of long-acting clotting factors.

Impact of Prothrombin Complex Concentrate on Blood Use, Cost, and Outcomes in Heart Transplantation.

BACKGROUND: Left ventricular assist device (LVAD) recipients undergoing heart transplantation have increased bleeding risk. We compared conventional warfarin reversal with fresh frozen plasma vs 4-factor prothrombin complex concentrate (PCC) and the effect on transfusion requirements, blood bank costs, and clinical outcomes. METHODS: A retrospective review identified 60 consecutive LVAD recipients undergoing heart transplantation divided into two groups: 30 (no PCC) received fresh frozen plasma and 30 (PCC) received PCC. Patient characteristics, intraoperative and postoperative transfusion requirements, short-term clinical outcomes, and blood bank costs were compared. PCC association with transfusion requirements was assessed by multivariate linear regression. RESULTS: Patients who received PCC were younger (50 ± 11 vs 57 ± 13 years, p = 0.02), fewer had ischemic cardiomyopathy (23% vs 60%, p = 0.01), had more than one prior sternotomy (7% vs 30%, p = 0.04), and had higher preoperative hemoglobin (11.8 ± 1.8 vs 10.4 ± 1.8 g/dL, p = 0.01). The PCC group had a significantly shorter bypass time (185 vs 217 minutes, p = 0.01), received less fresh frozen plasma (2 vs 5 units, p = 0.03), cryoprecipitate (0 vs 2 units, p = 0.05), and total blood products (9 vs 13.5 units, p = 0.03) intraoperatively, and was less likely to require delayed sternal closure (3% vs 23%, p = 0.05). On multivariate linear regression, PCC was significantly associated with decreased intraoperative transfusion (ß = -6.09, p = 0.02). There was no difference in thromboembolic events or in-hospital death. Total blood bank costs were $4,949 for PCC and $3,677 for no PCC (p = 0.01). CONCLUSIONS: Although more costly, PCC reduced transfusion requirements and delayed sternal closure in heart transplant recipients bridged with LVAD, justifying its use over traditional warfarin reversal.

Real-World Analysis of Dispensed IUs of Coagulation Factor IX and Resultant Expenditures in Hemophilia B Patients Receiving Standard Half-Life Versus Extended Half-Life Products and Those Switching from Standard Half-Life to Extended Half-Life Products.

BACKGROUND: Hemophilia B requires replacement therapy with factor IX (FIX) coagulation products to treat and prevent bleeding episodes. A recently introduced extended half-life (EHL) recombinant FIX replacement product provided the opportunity to compare the amount of dispensed factor and expenditures for EHL treatment compared with a standard half-life (SHL) product. OBJECTIVE: To determine factor international units (IUs) dispensed and expenditures associated with switching from nonacog alfa, the most commonly used SHL replacement product, to eftrenonacog alfa, an EHL FIX replacement product. METHODS: Two U.S. claims databases were analyzed. A large national specialty pharmacy dispensation claims database was used to identify the number of IUs dispensed and monthly charges for all patients with hemophilia B from April 2015 to June 2016. Truven Health MarketScan Research Databases (January 2010-July 2016) were used to identify IUs and expenditures for patients with claims data for at least 3 months before and after switching from the SHL to the EHL product. Medians for IUs and expenditures are presented to accommodate for skewness of data distribution. RESULTS: The national specialty pharmacy database analysis included 296 patients with moderate or severe hemophilia B (233 on SHL; 94 on EHL). Median monthly factor dispensed was 11% lower (2,142 IU) in the EHL versus SHL cohort over the study period, while individual monthly reductions ranged from 32% to 47% (9,838 IU to 16,514 IU). Using the wholesale acquisition cost, the median per-patient monthly factor expenditures over the 15-month study period were 94% higher ($23,005) for the EHL than for the SHL product. Individual median monthly expenditure differences ranged from 15% ($6,562) to 49% ($19,624). In the Truven database, 14 patients switched from the SHL to the EHL product. The amount of factor dispensed was variable; in the 1-year period before and after the switch from the SHL to the EHL product, mean IUs dispensed decreased by 3,005 IU, while median IUs dispensed increased by 4,775 IU. Factor replacement expenditures were higher after switching from the SHL to the EHL product in each of the 3-month periods examined before versus after the switch. CONCLUSIONS: This analysis of real-world data showed that switching from the SHL to the EHL product was associated with higher expenditures. Increased expenditures noted in the first 3 months after switching may be related to initial stocking up of the EHL product, but expenditures were sustained throughout the 1-year period of data analysis. Further analysis of these findings with larger numbers of patients should be explored. DISCLOSURES: This study was sponsored by Pfizer. Pfizer employees were involved in the study design; the collection, analysis, and interpretation of data; the review of the manuscript; and the decision to submit for publication. All authors are employees of Pfizer. No author received an honorarium or other form of payment related to the development of this manuscript. All authors participated in the study design, data interpretation, and manuscript review and revisions and granted approval for the submission of the manuscript. Alvir, McDonald, and Tortella also participated in data analysis. Data from this paper were presented in part at the European Association for Haemophilia and Allied Disorders Annual Meeting, February 1-3, 2017, Paris, France; at the International Society for Pharmacoeconomics and Outcomes Research Annual Meeting, May 20-24, 2017, Boston, MA; and at the International Society on Thrombosis and Haemostasis Congress, July 8-13, 2017, Berlin, Germany.

Comparison of 3-Factor Versus 4-Factor Prothrombin Complex Concentrate With Regard to Warfarin Reversal, Blood Product Use, and Costs.

BACKGROUND: Prothrombin complex concentrates (PCCs) are drug products containing varying amounts of vitamin K-dependent coagulation factors II, VII, IX, and X. The evidence comparing 3-factor PCC (3-PCC) versus 4-factor PCC (4-PCC) for warfarin reversal is conflicting. It has been hypothesized that 3-PCC may be less effective than 4-PCC because of relatively lower factor VII content. STUDY QUESTION: The primary objective of this study was to compare international normalized ratio (INR) reversal between 3-PCC and 4-factor PCC (4-PCC) in warfarin-treated patients. The secondary objectives include comparing blood product use, total reversal costs, and cost-effectiveness between the groups. STUDY DESIGN: This was a retrospective cohort study conducted in 2 affiliated, academic institutions in the United States. Consecutive adult patients who received 3-PCC or 4-PCC for warfarin reversal were included. MEASURES AND OUTCOMES: The primary outcome was adequate INR reversal defined as a final INR ≤1.5. Secondary outcomes were the utilization of plasma, red blood cells and platelets, reversal costs, and the cost-effectiveness ratio. RESULTS: There were 89 patients who were included in the overall cohort (3-PCC = 57, 4-PCC = 32). Adequate INR reversal occurred less commonly with 3-PCC (45.6%) compared with 4-PCC (87.5%) (P < 0.001). There was no significant difference in the proportion of patients who received plasma (32% vs. 28%, P = 0.813), red blood cells (37% vs. 47%, P = 0.377), or platelets (16% vs. 28%, P = 0.180) between the 3-PCC and 4-PCC groups, respectively. The median reversal cost of 3-PCC ($3663) was lower than 4-PCC ($5105) (P = 0.001). The cost-effective ratio favored 4-PCC ($5105/87.5% = $5834) compared with 3-PCC ($3663/45.6% = $8033). CONCLUSIONS: Four-PCC was more effective than 3-PCC with regard to INR reversal in patients taking warfarin, but blood product use was similar. Although 4-PCC is associated with increased reversal costs, it may be cost-effective in terms of INR reversal.

Fixed dose 4-factor prothrombin complex concentrate for the emergent reversal of warfarin: a retrospective analysis.

Published literature suggests that a fixed-dose 4-factor prothrombin complex concentrate (4FPCC) may be efficacious in managing warfarin-associated hemorrhage, however the ideal dose is still unclear. The purpose of this evaluation was to determine the efficacy of fixed-dose 4FPCC in reducing the International Normalized Ratio (INR) to ≤ 1.5 among warfarin patients with need for urgent or emergent anticoagulation reversal. Starting October 2016, our institution changed from standard 4FPCC FDA-labeled dosing based on the patient's presenting INR and weight, to a fixed-dose of 1500 units for all patients requiring urgent or emergent warfarin reversal. We conducted a retrospective evaluation, after implementation, with the primary outcome being the proportion of patients who achieved an INR ≤ 1.5 with a single fixed-dose of 1500 units of 4FPCC. Secondary outcomes assessed included: medication turnaround times, attainment of target INR ≤ 2 or clinical hemostasis (as judged by the prescribing provider), use of rescue doses, thrombotic events, and cost savings. A total of 37 patients were included in the analysis. Almost 75% of patients achieved an INR ≤ 1.5 after a single fixed dose of 1500 units, and 100% of patients achieved an INR ≤ 2. The median pre- and post-dose INRs were 3.06 and 1.32 respectively. Based on this evaluation, the administration of a fixed dose of 1500 units 4FPCC, was shown to be effective in adequately reversing the INR in the majority of patients with minimal thrombotic risks.

Economic Burden of Illness among Persons with Hemophilia B from HUGS Vb: Examining the Association of Severity and Treatment Regimens with Costs and Annual Bleed Rates.

OBJECTIVES: To determine US societal burden of illness, including direct and indirect costs and annual bleed rate (ABR), for persons with hemophilia B (HB), a rare and debilitating genetic disorder, and to examine associations of hemophilia severity and treatment regimens with costs and ABR. METHODS: From 2009 to 2014, the Hemophilia Utilization Group Studies Part Vb collected prospective data from 10 US hemophilia treatment centers. Participants with HB completed initial surveys on sociodemographic characteristics, clinical characteristics, and treatment patterns. During the 2-year follow-up, participants reported bleeding episodes, work absenteeism, and caregiver time quarterly. These data were used to calculate ABR and indirect costs. Direct costs were calculated using 1-year clinical chart records and 2-year dispensing records. RESULTS: Of the 148 participants, 112 with complete medical records and one or more follow-up survey were included. Total mean annual per-person costs were $85,852 (median $20,160) for mild/moderate HB, $198,733 (median $147,891) for severe HB, and $140,240 (median $63,617) for all participants without inhibitors (P < 0.0001). Mean ABR for participants with severe HB on prophylaxis (5.5 ± 7.9 bleeds/y) was almost half that of those treated episodically. Clotting factor and indirect costs accounted for 85% and 9% of total costs, respectively. Compared with episodic treatment, prophylaxis use was associated with 2.5-fold higher clotting factor costs (P < 0.01), low but significantly more missed parental workdays (P < 0.0001) and clinician (P < 0.001) or nursing visits (P < 0.0001), less part-time employment and unemployment, and lower hospitalizations costs (P = 0.17) and ABR (P < 0.0001). CONCLUSIONS: HB is associated with high economic burden, primarily because of clotting factor costs. Nevertheless, prophylaxis treatment leads to clinical benefits and may reduce other nonfactor costs.

The scope and value of an anticoagulation stewardship program at a community teaching hospital.

To report the impact of an inpatient anticoagulation stewardship program at a community hospital to promote optimal anticoagulant use. The anticoagulation team (ACT) stewardship program consists of two clinical pharmacists and hematologists to provide oversight of anticoagulants, high cost reversal agents including prothrombin complex concentrate (PCC, Kcentra™), and heparin-induced thrombocytopenia (HIT) management. Intervention data and number of charts reviewed were collected. Average cost avoidance data was applied to ACT interventions to estimate cost savings. The PCC analysis was conducted via retrospective chart review during the pre-intervention period. Prospective monitoring continued in the post-intervention period to determine the percentage of PCC use within the institution's guidelines or approved by ACT or hematology. A total of 19,445 patient charts were reviewed, and 1930 (10%) contained stewardship opportunity. Of the interventions, 71% were provided to the medical service and 22% to surgical services with acceptance rates of 91 and 83%, respectively. Intervention cost-avoidance calculated to be $694,217. Regarding HIT interventions, 52% of interventions involved pharmacokinetic/pharmacodynamics optimization in 18 patients with suspected or confirmed HIT. Regarding PCC use, 55.8% of PCC orders were considered inappropriate in the pre-invention period versus 2.6% post-intervention. Appropriate PCC doses per month post-intervention were consistent with pre-intervention doses (7.67 vs. 6.73, respectively). The projected annual PCC cost savings is $385,473. The overall estimated financial impact of ACT is $799,690 saved. Implementation of an anticoagulation stewardship program reduced costs and improved clinical outcomes. It is also expected that anticoagulant optimization and provider education improved overall safety.

Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches.

The immune response to infused factor concentrates remains a major source of morbidity and mortality in the treatment of patients with hemophilia A and B. This review focuses on current treatment options and novel therapies currently in clinical trials. After a brief review of immune tolerance regimens, the focus of the discussion is on preventing bleeding in patients with hemophilia and inhibitors. Recombinant factor VIIa and activated prothrombin complex concentrates are the mainstays in treating bleeds in patients with inhibitors. Both agents have been shown to reduce bleeding episodes to a similar degree when infused prophylactically; however, individual patients may respond better to one agent over the other at any given time. The international immune tolerance trial revealed that a high-dose factor VIII regimen provided significantly better bleeding protection than the low-dose regimen. Given the high cost of treatment and the potential for a high-dose immune tolerance regimen to prevent bleeding in some patients, we discuss how we treat patients to maximize the prevention of bleeds while minimizing cost. Novel approaches to treatment of these patients are in development. These include agents that mimic factor VIII or augment thrombin generation by bypassing the inhibitor, as well as agents that inhibit the natural anticoagulants.

Point-of-care-based protocol with first-line therapy with coagulation factor concentrates is associated with decrease allogenic blood transfusion and costs in cardiovascular surgery: an Italian single-center experience.

BACKGROUND: Transfusion in patients having cardiac surgery has been associated with increased morbidity, mortality, and costs. This analysis assessed the impact of a rotational thromboelastometry (ROTEM®)- and functional platelet assessment (Multiplate®)-based protocol for bleeding management on perioperative outcomes and costs in patients undergoing cardiac surgery. METHODS: This retrospective analysis of the records of all patients who underwent cardiac surgery at the Hesperia Hospital, Modena, Italy, from December 2012 to December 2013 compared outcomes and costs of bleeding management for the two 6-month periods before/after introduction of the ROTEM- and Multiplate-based protocol. Descriptive and correlation analysis were performed as appropriate. Propensity score matching and its correlation analysis were performed. RESULTS: Data from 768 consecutive patients (mean age ~69 years, ~66% male) were included; 50.7% and 49.3% of patients had surgery before and after protocol introduction, respectively. Significantly fewer patients required transfusions of packed red blood cells after the protocol introduction over the 24 hours postsurgery (100 vs. 197 patients; P<0.001) and during ICU stay (134 vs. 221 patients; P<0.001). A significantly greater proportion of patients treated after protocol introduction received prothrombin complex concentrate (31 vs. 16; P<0.05) and fibrinogen concentrate (36 vs. 13; P<0.001). A significantly greater proportion of patients treated after protocol introduction had an ICU stay duration <48 hours (81.5% vs. 71.5%; P<0.001). ROTEM-based bleeding management was associated with a saving of €128,676.23 for the 379 patients undergoing surgery post-protocol introduction (€339.52 per patient). CONCLUSIONS: ROTEM-guided bleeding management in patients undergoing cardiac surgery was cost-effective and associated with an increase of administration of coagulation factor concentrates and a decrease of ICU length of stay.