A comparison between on-demand usage of rFVIIa vs prophylaxis use of emicizumab in high titer inhibitory hemophilia A patients in Iran: A cost-utility analysis.

BACKGROUND: Hemophilia A (HA) is an inherited X-linked bleeding disease with costly treatment, especially for high titer inhibitory patients. Emicizumab, a new humanized bispecific antibody, has been approved for use to prevent or reduce the frequency of bleeding episodes in HA patients with inhibitors. This study evaluated the cost-utility of emicizumab prophylaxis (EP) in comparison with recombinant factor VII activated on-demand treatment in HA patients with inhibitors. METHODS: A life-time Markov model with payer and societal perspectives was developed in different age groups with different annual bleeding rates (ABR). Efficacy of treatments were extracted from HAVEN trials. Utilities were retrieved from published evidence. Costs were calculated based on Iran food and drug administration official website, national tariff book for medical services and hospital data. One-way deterministic sensitivity analysis was performed. RESULTS: EP was dominant choice in comparison with on-demand administration of recombinant factor VII activated in all age groups with ABR 20 and 25, and it remained dominant in patients with age 2 and age 12 at start point with ABR 16 and 17. The reported incremental cost-effectiveness ratio for the group with ABR 18 at the age 20, was 12,936 United States Dollars which is lower than the acceptable threshold of cost-effectiveness in Iran (1-3 gross domestic product per capita) and EP can be considered as cost-effective choice in this scenario. CONCLUSION: EP was found to be a dominant and cost-effective choice for Iranian HA patients with factor VIII inhibitors with ABR 18 and above with considerable cost saving.

Antithrombotic and hemostatic stewardship: evaluation of clinical outcomes and adverse events of recombinant factor VIIa (Novoseven®) utilization at a large academic medical center.

BACKGROUND: Recombinant factor VIIa (rFVIIa) (Novoseven®) is utilized for the reversal of anticoagulation-associated bleeding and refractory bleeding in cardiac surgery. In August 2015, rFVIIa was transferred from the blood bank to the pharmacy at New York University (NYU) Langone Health. Concordantly, an off-label dosing guideline was developed. The objective of this study was to describe utilization and cost of rFVIIa and assess compliance to our dosing guideline. METHODS: We performed a retrospective, observational review of rFVIIa administrations post-implementation of an off-label dosing guideline. All patients who received rFVIIa between September 2015 and June 2017 were evaluated. For each rFVIIa administration, anticoagulation and laboratory values, indications for use, dosing, ordering and administration times, concomitant blood products, and adverse events were collected. Adverse events included venous thromboembolism, stroke, myocardial infarction, and death due to systemic embolism and mortality. The primary endpoint was the utilization of rFVIIa in accordance with the off-label dosing guideline. Secondary endpoints included hemostatic efficacy of rFVIIa, adverse events, blood products administered, and cost-effectiveness of rFVIIa transition to pharmacy. RESULTS: A total of 63 patients [pediatric (n = 6), adult (n = 57)] received rFVIIa, with the majority of use for refractory bleeding after cardiac surgery. The utilization of rVIIa decreased after development of the off-label dosing guideline and transition from blood bank to pharmacy. The total incidence of thromboembolic events within 30 days was 19.6%; 17.6% arterial and 2% venous; 70% of patients with an adverse event were over 70 years of age. Use of rFVIIa reduced the median number of units of blood products administered. CONCLUSION: Administration of rFVIIa for cardiac surgery appears to be effective for hemostasis. Transitioning rFVIIa from the blood bank to pharmacy and implementation of a dosing guideline appears to have reduced utilization. Patients receiving rFVIIa should be monitored for thromboembolic events. Elderly patients may be at higher risk for thromboembolic events.

aPCC vs. rFVIIa for the treatment of bleeding in patients with acquired haemophilia - a cost-effectiveness model.

BACKGROUND: Acquired haemophilia A (AHA) is an autoimmune bleeding disorder with significant morbidity and mortality. Bleeding AHA patients with high titre inhibitors can be treated with either activated prothrombin complex concentrate (aPCC) or recombinant activated factor VII (rFVIIa). Given that both replacement therapies have inherent benefits and limitations, a cost-effectiveness analysis (CEA) was performed in this population to compare rFVIIa with aPCC. METHODS: In high-titered AHA patients with bleeding treated with either aPCC or rFVIIa, during a 5-day study period, a Markov model was developed such that these patients were transitioned into four different health states: (1) continuous bleeding, (2) thrombosis, (3) stop bleeding and (4) death, with states (2), (3) and (4) modelled as absorbing states. Model parameters, including probabilities, health utility index and costs, were gathered from the medical literature, except for the costs of aPCC and rFVIIa, which were obtained from our institutional data. RESULTS: During the 5-day period, the total treatment cost of rFVIIa was substantially more than the cost of aPCC ($13 635 vs. $1741). The average quality-adjusted life days (QALDs) gained for rFVIIa were slightly lower compared to aPCC (4·08 vs. 4·09). Overall, aPCC prevailed over rFVIIa. Sensitivity analysis confirmed the robustness of the model across tested ranges of all input variables. CONCLUSION: In high-titered AHA patients with bleeding, aPCC is a cost-effective treatment option when compared to rFVIIa. Thus, aPCC may be considered in these patients, if available, and provided there is no clinical contraindication.

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.

Managing the Rising Costs and High Drug Expenditures in Critical Care Pharmacy Practice.

Pharmaceutical costs for patients in the intensive care unit (ICU) constitute a large portion of hospital drug budgets. Unfortunately, prices for medications commonly used in the ICU are on the rise for a variety of reasons. In particular, the U.S. Food and Drug Administration's Unapproved Drugs Initiative, generic manufacturers cornering the marketplace, drug shortages, and regulatory device changes are major drivers of pharmaceutical price escalation affecting costs in the ICU. Furthermore, traditional high acquisition cost items still pose challenges to controlling costs. To offer strategies to mitigate the rising costs of pharmaceuticals in the ICU setting, we searched the PubMed/Medline and International Pharmaceutical Abstracts databases and other related sources to identify published cost-saving protocols concerning specific medications that are affected by rising prices or have traditional high acquisition costs. In the absence of specific protocols, we offer possible cost-saving initiatives based on published literature regarding specific agents or based on our own diverse set of experiences. Finally, we review suggested clinical and operational activities at an institutional level to address these rising drug costs in the ICU setting.

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.

Impact on postoperative bleeding and cost of recombinant activated factor VII in patients undergoing heart transplantation.

BACKGROUND: Cardiac transplantation can be complicated by refractory hemorrhage particularly in cases where explantation of a ventricular assist device is necessary. Recombinant activated factor VII (rFVIIa) has been used to treat refractory bleeding in cardiac surgery patients, but little information is available on its efficacy or cost in heart transplant patients. METHODS: Patients who had orthotopic heart transplantation between January 2009 and December 2014 at a single center were reviewed. Postoperative bleeding and the total costs of hemostatic therapies were compared between patients who received rFVIIa and those who did not. Propensity scores were created and used to control for the likelihood of receiving rFVIIa in order to reduce bias in our risk estimates. RESULTS: Seventy-six patients underwent heart transplantation during the study period. Twenty-one patients (27.6%) received rFVIIa for refractory intraoperative bleeding. There was no difference in postoperative red blood cell transfusion, chest tube output, or surgical re-exploration between patients who received rFVIIa and those who did not, even after adjusting with the propensity score (P = 0.94, P = 0.60, and P = 0.10, respectively). The total cost for hemostatic therapies was significantly higher in the rFVIIa group (median $10,819 vs. $1,985; P < 0.0001). Subgroup analysis of patients who underwent redo-sternotomy with left ventricular assist device explantation did not show any benefit for rFVIIa either. CONCLUSIONS: In this relatively small cohort, rFVIIa use was not associated with decreased postoperative bleeding in patients undergoing heart transplantation; however, it led to significantly higher cost.

A Budget Impact Model of Hemophilia Bypassing Agent Prophylaxis Relative to Recombinant Factor VIIa On-Demand.

BACKGROUND: Hemophilia patients use factor-clotting concentrates (factor VIII for hemophilia A and factor IX for hemophilia B) for improved blood clotting. These products are used to prevent or stop bleeding episodes. However, some hemophilia patients develop inhibitors (i.e., the patient's immune system develops antibodies against these factor concentrates). Hence, these patients do not respond well to the factor concentrates. A majority of hemophilia patients with inhibitors are managed on-demand with the following bypassing agents: recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC). The recently published U.S. registries Dosing Observational Study in Hemophilia (DOSE) and Hemostasis and Thrombosis Research Society (HTRS) reported higher rFVIIa on-demand use for bleed management than previously described. OBJECTIVE: To estimate aPCC and rFVIIa prophylaxis costs relative to rFVIIa on-demand treatment cost based on rFVIIa doses reported in U.S. registries. METHODS: A literature-based cost model was developed assuming a base case on-demand annual bleed rate (ABR) of 28.7 per inhibitor patient, which was taken from a randomized phase 3 clinical trial. The doses for rFVIIa on-demand were taken from the median dose per bleed reported by the DOSE and HTRS registries. Model inputs for aPCC and rFVIIa prophylaxis (i.e., dosing and efficacy) were derived from respective randomized clinical trials. Cost analysis was from the U.S. payer perspective, and only direct drug costs were considered. The drug cost was based on the Medicare Part B 2014 average sale price (ASP). Two-way sensitivity and threshold analyses were performed by simultaneously varying on-demand ABR, prophylaxis efficacy, and unit drug cost. In addition to studying relative costs associated with on-demand and prophylaxis treatments, relative cost per bleeding episode avoided were also calculated for aPCC and rFVIIa prophylaxis treatments. The prophylaxis efficacy reported in the trials were used to determine the number of bleeding episodes avoided. RESULTS: Based on the median on-demand dose of 695 mcg per kg per bleed, reported by the DOSE registry, the annual rFVIIa on-demand cost was $34,009 per kg of body weight. The annual rFVIIa on-demand cost was $22,020 per kg of body weight when the median dose of 450 mcg per kg per bleed reported by the HTRS registry was considered. The annual cost rose to $38,461 per kg of body weight when the rFVIIa on-demand dose of 786 mcg per kg per bleed among patients infusing an initial dose ≥ 250 mcg per kg was considered. The aPCC (85 units per kg per every other day) and rFVIIa (90 mcg per kg per every day) annual prophylaxis costs were $26,536 and $60,700, respectively. Also, aPCC and rFVIIa prophyaxis treatments were estimated to prevent a total of 20.8 and 12.9 annual bleeding episodes, respectively. When compared with the on-demand dose of 695 mcg per kg per bleed (DOSE registry), the annual aPCC and rFVIIa prophylaxis costs were 21.9% lower and 78.4% higher, respectively. Additionally, aPCC prophylaxis saved $360 per kg for each bleeding episode avoided. rFVIIa prophylaxis cost $2,066 per kg for each bleeding episode avoided. Compared with the on-demand dose of 450 mcg per kg per bleed (HTRS registry), aPCC and rFVIIa prophylaxis costs were 20.5% and 174.9% higher, respectively. In this case, aPCC and rFVIIa prophylaxis treatment costs were $217 per kg and $2,995 per kg, respectively, for each bleeding episode avoided. aPCC and rFVIIa prophylaxis costs were 31.0% lower and 57.8% higher, respectively, when compared with the rFVIIa on-demand dose of 786 mcg per kg per bleed, among patients infusing an initial dose ≥ 250 mcg per kg (HTRS registry). In this case, aPCC prophylaxis saved $573 per kg for each bleeding episode avoided, while rFVIIa prophylaxis costs $1,724 per kg for each bleeding episode avoided. Results of the 2-way sensitivity analyses were robust in the majority of the scenarios considered. CONCLUSIONS: aPCC prophylaxis may be cost saving for managing hemophilia patients with inhibitors who bleed frequently and infuse significant quantities of rFVIIa on-demand.

Impact of an innovative blood factor stewardship program on drug expense and patient care.

PURPOSE: An innovative pharmacist-led program to improve prescribing, dosing, and monitoring of clotting factor therapy within a large health system is described. SUMMARY: In an initiative to optimize patient outcomes and control costs associated with the use of clotting factor concentrates, the pharmacy department at University of North Carolina Medical Center (UNCMC) led the development of a "factor stewardship program" in collaboration with UNCMC hematologists. Key steps in program development and implementation included (1) selection of one formulary product within each clotting factor class, (2) establishment of guidelines on blood factor prescribing, order review, compounding, and administration, and (3) initial and ongoing education of pharmacy, nursing, and medical staff. As part of the program, a designated pharmacist rounds with hematologists daily, recommending treatment plan modifications and dosage adjustments as appropriate. Now in its fifth year, the stewardship program has enabled consistent pharmacist oversight of all aspects of clotting factor use and enhanced transitions-of-care coordination. Through optimization of product selection, dosing regimens, and infusion frequencies, the number of blood factor doses in fiscal year 2013 was reduced by 45% from the prior year despite a 22% increase in the volume of treated patients; in patients with hemophilia A, re-admissions due to bleeding episodes have declined. During the four-year period ending in July 2014, estimated cost savings attributable to the stewardship program exceeded $4 million annually. CONCLUSION: Implementation of the UNCMC stewardship program has led to improved outcomes in patients receiving clotting factor concentrates, with significant institutional cost savings.

Cost-utility analysis of an adjunctive recombinant activated factor VIIa for on-demand treatment of bleeding episodes in dengue haemorrhagic fever.

The present study aimed to assess the cost-utility analysis of using an adjunctive recombinant activated factor VIIa (rFVIIa) in children for controlling life-threatening bleeding in dengue haemorrhagic fever (DHF)/dengue shock syndrome (DSS). We constructed a decision-tree model, comparing a standard care and the use of an additional adjuvant rFVIIa for controlling life-threatening bleeding in children with DHF/DSS. Cost and utility benefit were estimated from the societal perspective. The outcome measure was cost per quality-adjusted life years (QALYs). Overall, treatment with adjuvant rFVIIa gained QALYs, but the total cost was higher. The incremental cost-utility ratio for the introduction of adjuvant rFVIIa was $4241.27 per additional QALY. Sensitivity analyses showed the utility value assigned for calculation of QALY was the most sensitive parameter. We concluded that despite high cost, there is a role for rFVIIa in the treatment of life-threatening bleeding in patients with DHF/DSS.

Costs and utilization of hemophilia A and B patients with and without inhibitors.

OBJECTIVE: To evaluate the health system costs among patients with hemophilia A and B with and without inhibitors over 5 years. METHODS: This was a retrospective, observational study utilizing medical and pharmacy electronic medical records and administrative encounters/claims data tracking US patients between 2006-2011. Patients with diagnosis codes for hemophilia A and B were identified. Patients with inhibitors were characterized by utilization of bypassing agents activated prothrombin complex concentrate or factor VIIa on two or more distinct dates. Severity was classified as mild, moderate, or severe based on laboratory tests of clotting factor. RESULTS: There were 160 hemophilia A patients and 54 hemophilia B patients identified. From this group, seven were designated as patients with inhibitors (five with hemophilia A and two with hemophilia B). Hemophilia A patients without inhibitors reported 65 (41.9%) as being severe, 19 (12.3%) as moderate, and 71 (45.8%) as mild. Hemophilia B patients without inhibitors reported nine (17.3%) had severe, 13 (25.0%) had moderate, and 30 (57.7%) had mild hemophilia. All patients with inhibitors had been hospitalized in the previous 5 years compared to 64 (41.3%) with hemophilia A without inhibitors and 22 (42.3%) with hemophilia B without inhibitors. The median aggregate cost per year (including factor and health resource use) was $325,780 for patients with inhibitors compared to $98,334 for hemophilia A patients without inhibitors and $23,265 for hemophilia B patients without inhibitors. CONCLUSIONS: The results suggest that, while the frequency of inhibitors within the hemophilia cohort was low, there was a higher frequency of hospitalizations, and the associated median aggregate costs per year were 3-fold higher than those patients without inhibitors. In contrast, hemophilia B patients experience less severe disease and account for lower aggregate yearly costs compared to either patients with hemophilia A or patients with inhibitors.

Cost-Effectiveness Analysis of Plasma Versus Recombinant Factor VIIa for Placing Intracranial Pressure Monitors in Pretransplant Patients With Acute Liver Failure.

Both plasma- and recombinant activated factor VII (rFVIIa)-based algorithms can be used to correct coagulopathy in preliver transplant patients with acute liver failure requiring intracranial pressure monitor (ICPM) placement. A decision model was created to compare the cost-effectiveness of these methods. A 70-kg patient could receive either 1 round of plasma followed by coagulation testing or 2 units of plasma and 40 µg/kg rFVIIa. Intracranial pressure monitor is placed without coagulation testing after rFVIIa administration. In the plasma algorithm, the probability of ICPM placement was estimated based on expected international normalized ratio (INR) after plasma administration. Risks of rFVIIa thrombosis and transfusion reactions were also included. The model was run for patients with INRs ranging from 2 to 6 with concomitant adjustments to model parameters. The model supported the initial use of rFVIIa for ICPM placement as a cost-effective treatment when INR ≥2 (with incremental cost-effectiveness ratio of at most US$7088.02).

Economic evaluation of rFVIIa high initial dose compared to rFVIIa standard initial dose in patients with haemophilia with inhibitors using the Czech HemoRec registry.

INTRODUCTION: In the treatment of bleeds in haemophilia patients with inhibitors, a high initial dose of recombinant Factor VIIa (rFVIIa) provides at least equal efficacy and a similar safety profile to a standard initial dose. However, no pharmacoeconomic comparison between these dosing regimens has previously been performed. Here, we assess the pharmacoeconomics of high (>120 µg/kg) versus standard (≤120 µg/kg) initial rFVIIa dose in inhibitor patients and the impact of time to treatment initiation on costs and outcomes. METHODS: In a retrospective analysis, observational data on bleed characteristics, rFVIIa treatment, hospitalizations and outcomes were extracted from the Czech Republic HemoRec registry. Crude comparisons and generalized linear regression modelling (GLM; correcting for patient differences) were performed to compare costs and outcomes between the high and standard initial dosing groups. RESULTS: Of 314 rFVIIa-treated bleeding episodes (12 inhibitor patients), most were spontaneous joint bleeds and 67.5% were treated with a high initial dose. In the crude comparison, high initial rFVIIa dosing was associated with a lower mean number of doses needed to achieve haemostasis compared with standard dosing (p<0.001), but higher total dose and costs (p ≤ 0.008). However, regression analyses revealed that high initial dose was associated with similar costs (p=0.891) and a shorter time to bleeding resolution (p=0.014). Increasing time to treatment initiation increased both time to bleeding resolution and total costs. CONCLUSION: Compared with a standard dose, a high initial rFVIIa dose may improve treatment outcomes without increasing costs. Early treatment initiation may reduce treatment costs.

Bypass therapy assay testing as a strategy to reduce costs for treatment of haemophilia patients with inhibitors.

Published studies suggest that bypass therapy assay testing can be used to predict treatment response and dosing requirements for haemophilia patients with inhibitors. The aim of this study was to evaluate the costs of utilizing and not utilizing bypass therapy assay testing before treating mild-to-moderate bleeding episodes on-demand in haemophilia patients with inhibitors from a US third-party payer perspective. In our exploratory decision tree model, the average patient was assumed to be an adult weighing 75 kg. Based on existing head-to-head clinical trials, the efficacy of activated prothrombin complex (aPCC) and recombinant factor VIIa (rFVIIa) was assumed to be equivalent and based on expert opinion of the haematologist in our study it was conservatively assumed that assay testing improves the efficacy of both the bypassing agents by 10%. Probabilistic and one-way sensitivity analyses were used to determine the robustness of the results. Cost savings per bleeding episode were estimated at $6886 (95% CI = $4310-7978) for aPCC and $7647 (95% CI = $3134-10 388) for rFVIIa treatment. This translates in potential cost savings of 24.8% (95% CI = 15.5-28.8%) for aPCC use and 18.2% (95% CI = 8-24.7%) for rFVIIa use. Furthermore, if testing successfully predicts the optimum dose for concomitant therapy at the onset of bleeding, significant cost savings were observed compared with rFVIIa and aPCC therapies alone. Use of bypass therapy assay testing before treatment administration in haemophilia inhibitor patients can potentially reduce treatment costs significantly while optimizing dose and therapy response.

Timing of factor VIIa in liver transplantation impacts cost and clinical outcomes.

STUDY OBJECTIVE: To investigate the clinical and economic outcomes associated with the use of recombinant factor VIIa (rFVIIa) in perioperative liver transplantation (LT). DESIGN: Retrospective review. SETTING: Academic medical center. PATIENTS: A total of 63 adults who underwent LT between January 2000 and September 2008 and received rFVIIa prior to or during the procedure. Using a propensity-scoring method, these patients were matched in a 1:2 ratio with 120 controls. MEASUREMENTS AND MAIN RESULTS: Of the 473 patients who received any LT during the study period, 63 (13%) received rFVIIa and were matched with propensity score matched controls at a ratio of approximately 1:2. Of those who received rFVIIa, 27 (43%) received preemptive administration and 14 (22%) received intraoperative administration. (The remaining 22 patients received rFVIIa outside of a 12-hour window of time before or after surgery.) Clinical outcomes were similar between the preemptive and the control groups, although patients in the control group had a shorter length of stay in the intensive care unit (ICU) and incurred fewer expenses. Compared with both the preemptive and the control groups, patients who received rFVIIa intraoperatively required more blood products, longer stays in the ICU, and incurred higher costs. They also had poorer graft survival and decreased overall survival rates at 30 days and 1 year. CONCLUSION: Intraoperative administration of rFVIIa in LT was associated with higher blood product use, lower graft and patient survival rates, longer ICU stays, and higher overall costs compared with preemptive administration. The use of preemptive rFVIIa in select high-risk LT patients may prevent the development of poor clinical outcomes and may be more cost effective compared with intraoperative administration.

How we use recombinant activated Factor VII in patients with haemophilia A or B complicated by inhibitors. Working group of hematology experts from Australia and New Zealand, Melbourne, April 2011.

The management of bleeds in patients with haemophilia A or B complicated by inhibitors is complex. Recombinant activated Factor VII (rFVIIa; NovoSeven RT) is an established therapy in these patients. To develop a consensus-based guide on the practical usage of rFVIIa in haemophilia complicated by inhibitors, nine expert haemophilia specialists from Australia and New Zealand developed practice points on the usage of rFVIIa, based on their experience and supported by published data. Practice points were developed for 13 key topics: control of acute bleeding; prophylaxis; surgical prophylaxis; control of breakthrough bleeding during surgery or treatment of acute bleeds; paediatric use; use in elderly; intracranial haemorrhage; immune tolerance induction; difficult bleeds; clinical monitoring of therapy; laboratory monitoring of therapy; concomitant antifibrinolytic medication; practical dosing. Access to home therapy with rFVIIa is important in allowing patients to administer treatment early in bleed management. In adults, 90-120 µg/kg is the favoured starting dose in most settings. Initial dosing using 90-180 µg/kg is recommended for children due to the effect of age on the pharmacokinetics of rFVIIa. In the management of acute bleeds, 2-hourly dosing is appropriate until bleeding is controlled, with concomitant antifibrinolytic medication unless contraindicated. The practice points provide guidance on the usage of rFVIIa for all clinicians involved in the management of haemophilia complicated by inhibitors.

Intraoperative use of low-dose recombinant activated factor VII during thoracic aortic operations.

BACKGROUND: Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure. METHODS: Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 µg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison. RESULTS: Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 µg/kg (interquartile range [IQR], 16-43 µg/kg) rFVIIa given 51 minutes (42-67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p=0.05; international normalized ratio, 0.8 versus 1.2; p<0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p=0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups. CONCLUSIONS: Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach.

Economic analysis of recombinant activated factor VII versus plasma-derived activated prothrombin complex concentrate in mild to moderate bleeds: haemophilia registry data from the Czech Republic.

INTRODUCTION: Several studies suggest that recombinant activated factor VII (rFVIIa) is more cost-effective than plasma-derived activated prothrombin complex concentrate (pd-aPCC) in haemophilia with inhibitors. However, most do not consider differences between treated patients. This study compared the pharmacoeconomics of rFVIIa versus pd-aPCC treatment of mild to moderate bleeds in inhibitor patients, taking co-variables into account. METHODS: The HemoRec and HemIS registries capture exhaustive bleeding data in inhibitor patients in the Czech Republic. For each bleed, patient and bleed characteristics, treatment outcomes and bypassing agent use were retrospectively analysed, and direct costs of care per bleed calculated. Generalised Linear Model regression methods with cluster effect were employed to account for the possibility of several bleedings from the same patient. RESULTS: There were 108 and 53 mild to moderate bleeds in the rFVIIa and pd-aPCC groups, respectively. Although re-bleeding rates were similar in both groups, deeper analyses revealed significant differences in time to bleed resolution: 93.8% of bleeds treated with rFVIIa were resolved within ≤ 12 h, versus 60.4% with pd-aPCC (P < 0.001). Mean total cost/bleed was lower with rFVIIa (336,852 [median, 290,696] CZK; €12,760 [11,011]) than pd-aPCC (522,768 [341,310] CZK; €19,802 [12,928]) (P = 0.002). Results were maintained after controlling for potential co-variables (bleed nature, time to treatment, target joints). CONCLUSIONS: The lower total treatment costs per bleed with rFVIIa than pd-aPCC suggest that first-line rFVIIa is more cost-effective than pd-aPCC in mild to moderate bleeds. Time to bleed resolution was also significantly shorter with rFVIIa. These results were maintained when controlled for potential confounders.

No evidence or no alternative? Taking responsibility for off-label prescribing.

Recombinant activated factor VII (rFVIIa) is registered for patients with rare haematological disorders, but is used 'off-label' in many other situations, including intracranial haemorrhage, cardiac surgery, trauma, transplantation and prostatectomy. Lack of systematic evidence to support these off-label uses has not slowed the growth of off-label prescribing of rFVIIa. We use the case of rFVIIa to illustrate the issues raised by off-label prescribing, and the kind of impasse that can arise when views about evidence, expertise and clinical necessity are in conflict. We argue that clinicians, hospital drug committees and regulators all need to acknowledge the complexity of prescribing decisions, and ensure that decisions to prescribe off-label are sufficiently justified.