Understanding the evolution of coverage policies for prophylaxis treatments of hemophilia A without inhibitors: a payer Delphi panel.

BACKGROUND: The landscape for hemophilia A prophylaxis is rapidly expanding from factor VIII replacement therapy to include novel treatments such as nonfactor replacement therapies that may enhance coagulation (e.g., emicizumab) or inhibit anticoagulant pathways (e.g., fitusiran and concizumab). For payers, this expansion presents challenges in balancing well-established treatments with new options that cost more and have lesser known real-world safety and efficacy. OBJECTIVE: To evaluate likely coverage practices for hemophilia A prophylaxis therapies among U.S. payers given evolving real-world data on safety and efficacy. METHODS: A 3-round modified Delphi process was conducted with representatives of U.S. commercial health plans who had considerable expertise in managing populations of patients with hemophilia. Round 1 consisted of an online questionnaire; round 2 involved an online discussion about the aggregated results from round 1; and round 3 allowed participants to revise their responses from round 1 based on insights gained during round 2. Questions elicited ratings, rankings, and estimates on access restrictions based on given safety and efficacy information for hemophilia A prophylaxis therapies. Consensus was reached if ≥ 74% of panelists (14 of 19) were within 1 SD of the median group estimate during round 3. RESULTS: 19 Payers participated in the research. Among them, 94% dealt with commercial insurance, 94% with Medicare, and 81% with Medicaid; 79% had spent ≥ 5 years in their current role. Panelists reported limited access restrictions on hemophilia A prophylaxis therapies; the most common restrictions were prior authorization (n = 16, 84%) and quantity level limits (n = 13, 67%). Tiering and step therapy were reported by 7 respondents (39%). Respondents agreed that there was an 80% median likelihood that ≥ 9 additional patients with any safety event (e.g., thrombotic event, death) per year would trigger access restrictions, with the median likelihood of restrictions increasing to 95% for another ≥ 10 patients with safety events per year. Respondents also agreed that > 5 thrombotic events requiring treatment per patient per year would have a 98% median likelihood of leading to access restrictions and that ≥ 5 years of real-world safety and efficacy data would be highly likely (95% median likelihood) to affect coverage decisions. Noncoverage was highly unlikely (ranked fifth or sixth of 6 by 14 respondents), as was no restriction-coverage parity (ranked sixth of 6 by 10 respondents). All else being equal, cost continues to affect access policies, with respondents agreeing that a 13%-30% difference in net cost may lead to preferred formulary treatment for a drug with superior efficacy and noninferior safety, inferior efficacy and noninferior safety, or noninferior efficacy and inferior safety. CONCLUSIONS: Payers prefer treatments with well-understood efficacy, safety, and cost over newer treatments with uncertain long-term effects. Relatively unrestricted access to legacy and new hemophilia A prophylaxis will likely continue unless additional real-world safety concerns or major cost differences emerge. DISCLOSURES: Financial support for this study was provided by Takeda Pharmaceutical Company, which was involved in study concept and design. Graf, Tuly, Harley, and Pednekar are employees of PRECISIONheor, a research consultancy to the health and life sciences industries that was contracted by Takeda to conduct this study and write the manuscript. Batt served as a consultant on this project through PRECISIONheor.

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.

Model of Short- and Long-Term Outcomes of Emicizumab Prophylaxis Treatment for Persons with Hemophilia A.

BACKGROUND: Hemophilia A (HA) can result in bleeding events because of low or absent clotting factor VIII (FVIII). Prophylactic treatment for severe HA includes replacement FVIII infusions and emicizumab, a bispecific factor IXa- and factor X-directed antibody. OBJECTIVE: To develop an economic model to predict the short- and long-term clinical and economic outcomes of prophylaxis with emicizumab versus short-acting recombinant FVIII among persons with HA in the United States. METHODS: A Markov model was developed to compare clinical outcomes and costs of emicizumab versus FVIII prophylaxis among persons with severe HA from U.S. payer and societal perspectives. Patients started prophylaxis at age 1 year in the base case. Mutually exclusive health states considered were "no arthropathy," "arthropathy," "surgery," and "death." Serious adverse events, breakthrough bleeds, and inhibitor development were simulated throughout the modeled time horizon. In addition to the prophylaxis drug costs, patients could incur other direct costs related to breakthrough bleeds treatment, serious adverse events, development of inhibitors, arthropathy, and orthopedic surgery. Indirect costs associated with productivity loss (i.e., missed work or disabilities) were applied for adults. Model inputs were obtained from the HAVEN 3 trial, published literature, and expert opinion. The model used a lifetime horizon, and results for 1 year and 5 years were also reported. Deterministic sensitivity analyses and scenario analyses were conducted to assess robustness of the model. RESULTS: Over a lifetime horizon, the cumulative number of all treated bleeds and joint bleeds avoided on emicizumab versus FVIII prophylaxis were 278.2 and 151.7, respectively. Correspondingly, arthropathy (mean age at onset: 12.9 vs. 5.4 years) and FVIII inhibitor development (mean age at development: 13.9 vs. 1.1 years) were delayed. Total direct and indirect costs were lower for emicizumab versus FVIII prophylaxis for all modeled time horizons ($97,159 vs. $331,610 at 1 year; $603,146 vs. $1,459,496 at 5 years; and $15,238,072 vs. $22,820,281 over a lifetime horizon). The sensitivity analyses indicated that clinical outcomes were sensitive to efficacy inputs, while economic outcomes were driven by the discount rate, dosing schedules, and treatments after inhibitor development. Results for moderate to severe patients were consistent with findings in the severe HA population. CONCLUSIONS: The model suggests that emicizumab prophylaxis confers additional clinical benefits, resulting in a lower number of bleeding events and delayed onset of arthropathy and inhibitor development across all time assessment horizons. Compared with short-acting recombinant FVIII, emicizumab prophylaxis leads to superior patient outcomes and cost savings from U.S. payer and societal perspectives. DISCLOSURES: Funding for this study was provided by Genentech. Raimundo and Patel are employees of Genentech and own stock or stock options. Zhou, Han, Ji, Fang, Zhong, and Betts are employees of Analysis Group, which received consultancy fees from Genentech for conducting this study. Mahajerin received consultancy fees from Genentech for work on this study. Portions of this research were presented as a poster at the 2018 American Society of Hematology Conference; December 1-4, 2018; San Diego, CA.

Low Dose Prophylaxis vis-a-vis on-Demand Treatment Strategies for Hemophilia: A Cost Effective and Disability Attenuating Approach.

AIM: To assess effect of low dose prophylaxis in hemophilics in terms of bleeding, joint function, QoL and cost-effectiveness. METHODS: Analytic study done during one year among 70 adult hemophilics. In observation period (12 weeks), on-demand factor and during prophylaxis (12 weeks), low dose factor was given (Factor VIII 10 IU/KgBW biweekly for haemophilia A and Factor IX 20 IU/KgBW weekly for haemophilia B). Clinical joint assessment was done by Gilbert score and improvement by WFH definitions. RESULTS: Bleed reduced by 68.99% in moderate hemophilics (40 v/s 129) and 64.86% in severe hemophilics (26 v/s74) (p<0.05). During observation in moderate hemophilics, joint, soft tissue and mucosal bleeds occurred in frequency of 120, 1 and 8. This was reduced to 39 joint bleeds, 1 soft tissue bleed and no mucosal bleed during prophylaxis. In severe hemophilics, 70 joint, 2 soft tissue bleeds and 2 mucosal bleeds occurred during observation which reduced to 26 joint bleeds without soft tissue/mucosal bleed in prophylaxis. Bleeding episodes decreased by 65.79% in joints, 66.67% in soft tissues, 100% mucosal bleeds. After prophylaxis one joints (0.61 %) showed good improvement in joint function, thirty (18.18 %) joints showed moderate improvement and ninety two joints (55.76 %) showed mild improvement in joint function. Hospitalization reduced by 60.34% (163 v/s 411) and absenteeism by 53.73% (279 v/s 603). Factors consumption reduced by 12.33 % during prophylaxis period. CONCLUSION: The low dose prophylaxis strategy significantly decreased the subsequent episodes of total bleeds including joint bleeds and improved the joint function as well as quality of life.

Budget impact analysis of the use of extended half-life recombinant factor VIII (efmoroctocog alfa) for the treatment of congenital haemophilia a: the Italian National Health System perspective.

BACKGROUND: Congenital haemophilia A (HA) is a rare, inherited, life-long bleeding disorder characterised by prolonged or spontaneous bleeding due to the lack of clotting factor VIII (FVIII) in the body. Treatment for HA involves FVIII replacement therapy and poses great economic burden to National Health Systems and to society. Availability of novel products as extended half-life clotting factor products might change treatment approches and their economic evaluation is essential for an informed treatment choice. Accordingly the objective of the present work is to analyse the economic impact of using efmoroctocog alfa (recombinant factor VIII-Fc fusion protein, rFVIIIFc) for the treatment of children and adults with severe congenital haemophilia A (HA). METHODS: A budget impact analysis was performed to estimate the economic impact of the introduction of rFVIIIFc in the market-mix of products for the treatment of HA. The analysis condidered a 3-year time horizon and the Italian National Health System (INHS) perspective. The model estimated drug costs associated with the treatment of HA in the current scenario - representing the marketplace forecast for the time period of interest assuming that rFVIIFc is not introduced - and a new scenario, assuming that rFVIIIFc is available in the market. The size of the target population was calculated using epidemiological national data. Univariate one-way sensitivity analyses and scenario analyses were performed. RESULTS: Overall 3-year costs of treating the HA population in the current scenario were 555,277,691 Euro for the INHS. With the introduction of rFVIIIFc, the costs were reduced to 541,897,466 Euro suggesting potential savings to the INHS of 13,380,255 Euro. Results were consistent at variation of most of the model's parameters; only in case of lower dosage of conventional products and higher dosage of rFVIIIFc, costs for the INHS increased, in both cases, of about 20 million Euro. CONCLUSIONS: The use of rFVIIIFc for the treatment of HA has been recently approved by the Italian Medicines Agency (AIFA) and this is the first study estimating the financial impact of this new therapeutic alternative in the Italian context. The analysis suggests that rFVIIIFc use does not result in higher expenditure for the INHS.

The Therapeutic Effect of Pancreatic Kininogenase on Treatment of Diabetic Peripheral Neuropathy in Patients with Type 2 Diabetes.

Background: To determine the therapeutic efficacy and cost-effective of pancreatic kininogenase (PKase) on treatment of diabetic peripheral neuropathy (DPN) compared with Prostaglandin E1 (PGE1) in patients with type 2 diabetes. Methods: 104 patients with DPN receiving standard glucose control therapy were randomly assigned into 3 groups: Group-A received PKase treatment, Group-B received PGE1 treatment, and Group-C received only standard glucose control therapy. Michigan neuropathy screening instrument (MNSI) score, neurophysiology examination, and nerve conduction velocity were measured. Results: Standard glucose control therapy significantly reduced hyperglycemia to a similar level in all groups. Questionnaire grading and neurophysiology examination both indicated that no significant difference was found at the end of treatment between Groups -A and -B. Except for the ulnar nerve sensory conduction velocity that was significantly improved in Group-B, the remaining nerve conduction velocity (regardless of sensory or motor nerve conduction velocities) was improved to a similar level in Groups -A and -B. Group-A had significantly reduced questionnaire grading and better improvement in motor nerve conduction velocity of the common peroneal nerve, ulnar nerve, and sensory nerve conduction velocity of the sural nerve as compared with Group-C. However, the medical cost of PKase was only 18.9% of that of PGE1 during one course of treatment. Conclusions: PKase has the similar therapeutic efficacy as PGE1 on treatment of DPN in patients with type 2 diabetes. However, the medical cost of PKase is one fifth of that of PGE1. Thus, PKase is a cost-effective drug for treatment of DPN.

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 computer-based model to assess costs associated with the use of factor VIII and factor IX one-stage and chromogenic activity assays.

BACKGROUND: Measurement of coagulation factor factor VIII (FVIII) and factor IX (FIX) activity can be associated with a high level of variability using one-stage assays based on activated partial thromboplastin time (APTT). Chromogenic assays show less variability, but are less commonly used in clinical laboratories. In addition, one-stage assay accuracy using certain reagent and instrument combinations is compromised by some modified recombinant factor concentrates. Reluctance among some in the hematology laboratory community to adopt the use of chromogenic assays may be partly attributable to lack of familiarity and perceived higher associated costs. OBJECTIVES: To identify and characterize key cost parameters associated with one-stage APTT and chromogenic assays for FVIII and FIX activity using a computer-based cost analysis model. METHODS: A cost model for FVIII and FIX chromogenic assays relative to APTT assays was generated using assumptions derived from interviews with hematologists and laboratory scientists, common clinical laboratory practise, manufacturer list prices and assay kit configurations. RESULTS: Key factors that contribute to costs are factor-deficient plasma and kit reagents for one-stage and chromogenic assays, respectively. The stability of chromogenic assay kit reagents also limits the cost efficiency compared with APTT testing. Costs for chromogenic assays might be reduced by 50-75% using batch testing, aliquoting and freezing of kit reagents. CONCLUSIONS: Both batch testing and aliquoting of chromogenic kit reagents might improve cost efficiency for FVIII and FIX chromogenic assays, but would require validation. Laboratory validation and regulatory approval as well as education and training in the use of chromogenic assays might facilitate wider adoption by clinical laboratories.

Treatment-related knowledge and skills of patients with haemophilia and their informal caregivers.

BACKGROUND: Replacement therapy in haemophilia plays an important role in the effective management of this rare bleeding disorder and requires a high level of knowledge and practical skills. OBJECTIVE: To evaluate and to compare the knowledge and skills about the medicines and their management among people with haemophilia treated with clotting factor concentrates, and their informal caregivers. SETTING: Eight Hospital Pharmacies working closely with Haemophilia Care Centres in France. Method In this cross-sectional and multi-centre study, 26-item questionnaire was specifically developed to assess the knowledge and skills. Face-to-face interviews using a questionnaire were conducted with patients and caregivers. MAIN OUTCOME MEASURE: Level of knowledge and skills about disease, treatment and medication management. Results This study included 80 patients and 55 caregivers. Although most interviewees had basic knowledge of the treatment, only 43.7 % knew the effect of clotting factor concentrates on the haemostasis process. Similarly, only 12.7 % of the patients and 30.9 % of the caregivers referred to inhibitors as adverse effects. Despite intensive training for home treatment, 55.7 % reported difficulties with reconstitution or injection. The knowledge required for the responsible management of their medications had not been totally acquired: only 17 participants were indeed familiar with the medication storage conditions; 29 patients and 9 caregivers had already experienced an emergency which they had to treat with no medicine available at home; and 47.4 % of participants had already thrown away an unused drug vial. CONCLUSION: This study shows the need of a regular update and to renew awareness of haemophilia treatment specificities among these populations. The identified needs suggest that we should more invest in educational techniques or therapeutic education programs more focused on medication management.

Costs and utilization of treatment in patients with hemophilia.

BACKGROUND: Although hemophilia has a potentially high economic impact, there are no published estimates of healthcare costs for this disease in Portugal. The aim of this study was to evaluate costs of treatment and hospital utilization among patients with hemophilia A and B, with and without inhibitors, over a 3-year period in a Portuguese Comprehensive Care Hemophilia Centre. This is the first study on the financial impact of healthcare costs in patients with hemophilia in Portugal. METHODS: This retrospective, observational study identified patients diagnosed with hemophilia A and B using medical and pharmacy electronic medical records and data from Centro Hospitalar São João, between January 2011 and December 2013. Patients with inhibitors were all high responders (>5 Bethesda Units [BU]). Severity was classified as mild, moderate or severe based on clotting factor levels. Two main outcomes were measured: (1) cost associated with hospital pharmacy claims (clotting factor) and (2) number of hospital visits/hospitalization. RESULTS: A cohort of 103 patients were identified: 72 (69.9 %) with hemophilia A and 31 (30.1 %) with hemophilia B. Among these, five individuals were classified as patients with inhibitors (four with hemophilia A and one with hemophilia B). From the cohort of hemophilia A patients, 36 individuals (35.0 %) were identified as having severe disease; 20 (19.4 %) moderate; and 16 (15.5 %) mild. In the cohort of hemophilia B patients, 14 (13.6 %) were identified as having severe disease; 14 (13.6 %) moderate; and three (2.9 %) mild. The total mean aggregate cost per year (including clotting factor and hospital utilization) for patients with severe hemophilia B was €112,469, compared with €793 for mild hemophilia A. Clotting factor concentrate amounted for 90 % of total cost in severe cases and hospital utilization was also higher in these cases. CONCLUSIONS: Hemophilia treatment is expensive, particularly for patients with severe disease and especially if they develop inhibitors to replacement clotting factors. In our study, severe hemophilia is associated with greater annual total costs in both types of hemophilia (A = €77,587 and B = € 112,469). Patients with inhibitors have costs 3.3 times higher than patients without inhibitors. Age was not associated with significantly greater total costs (clotting factor and hospital visits/hospitalizations).

[Prophylactic factor substitution in severe haemophilia A. Economic assessment in adult patients]. / Prophylaktische Faktorsubstitution bei schwerer Hämophilie A. Ökonomische Bewertung erwachsener Patienten.

UNLABELLED: Prophylaxis in adults can be necessary and reasonable for clinical reasons. The aim was to evaluate from an economic viewpoint prophylactic factor VIII substitution in adult patients with haemophilia in Germany. PATIENTS, METHODS: A decision model (time frame: one year; perspective: statutory health insurance; reference patient (RP) and 2 patient profiles) was developed. Calculations are based on data from a structured literature search and a pharmacovigilance study: therapy switch on-demand/prophylaxis (OD/Proph). RESULTS: RP: 45 years, 20 bleeds p.a. OD, 16 bleeds avoided with 8.5 I.U./kg/d Proph, additional cost Euro 141,113 p.a.; profile 1: 50 years, 55 bleeds p.a. OD, factor consumption per bleed 20 I.U./kg higher than RP, 39 bleeds avoided with 8.5 I.U./kg/d Proph, additional cost Euro 19,134 p.a.; profile 2: 60 years, 35 bleeds p.a. OD, factor consumption per bleed 40-80 I.U./kg higher than RP, 34 bleeds avoided with 11 I.U./kg/d Proph, cost reduction Euro 660 p.a. CONCLUSIONS: Prophylactic factor VIII substitution in adult haemophilia patients is depending on the individual clinical situation not only clinically but also economically reasonable. To evaluate this effects in the future comprehensively, longitudinal real-life data from patient-centered care are needed including clinical outcomes, quality of life and adherence.

Using value-of-information methods when the disease is rare and the treatment is expensive--the example of hemophilia A.

BACKGROUND: Hemophilia A is a rare, sex-linked genetic disorder treated with intravenous administration of factor VIII (FVIII) to prevent bleeding; however, approaches vary across and within countries. Value-of-information (VOI) methods identify situations in which the cost-benefit evidence is sufficient to adopt one treatment strategy over another; when the evidence is insufficient, VOI methods provide the optimal sample size for additional research. OBJECTIVE: The objective of the study was to use VOI methods in a cost-benefit decision context to evaluate the current evidence in support of using (1) alternate day prophylaxis (AP), (2) tailored prophylaxis (TP) or (3) on-demand treatment (OD) with FVIII to prevent arthropathy in children with severe hemophilia A. METHODS: To apply VOI methods, several parameters such as incidence, time horizon for the decision, costs, and threshold values to avoid MRI-detected joint damage or arthropathy were defined. Two baseline threshold values of willingness to pay for avoiding arthropathy--$200,000 and $400,000--were selected for comparing the treatment strategies. RESULTS: For threshold values < $200,000, OD had a higher expected net benefit than either prophylaxis strategy, and the evidence was sufficient for its adoption. For threshold values > $400,000 prophylaxis strategies had higher expected net benefit; however, a new trial with 38 patients per arm was needed to compare AP and TP, yielding an expected net gain of over $17 million. In sensitivity analyses, the results were robust to assumptions regarding discount rate, trial fixed and variable costs, enrollment fraction, and the time horizon. CONCLUSIONS: In rare diseases, evidence is often scarce and insufficient for decision making. In considering the funding of new research and patient reimbursement in rare diseases, VOI methodology may provide more relevant determinations of the value and costs of additional research, compared to standard frequentist methods.

Cryoprecipitate therapy.

Cryoprecipitate, originally developed as a therapy for patients with antihaemophilic factor deficiency, or haemophilia A, has been in use for almost 50 yr. However, cryoprecipitate is no longer administered according to its original purpose, and is now most commonly used to replenish fibrinogen levels in patients with acquired coagulopathy, such as in clinical settings with haemorrhage including cardiac surgery, trauma, liver transplantation (LT), or obstetric haemorrhage. Cryoprecipitate is a pooled product that does not undergo pathogen inactivation, and its administration has been associated with a number of adverse events, particularly transmission of blood-borne pathogens and transfusion-related acute lung injury. As a result of these safety concerns, along with emerging availability of alternative fibrinogen preparations, cryoprecipitate has been withdrawn from use in a number of European countries. Compared with the plasma from which it is prepared, cryoprecipitate contains a high concentration of coagulation factor VIII, coagulation factor XIII, and fibrinogen. Cryoprecipitate is usually licensed by regulatory authorities for the treatment of hypofibrinogenaemia, and recommended for supplementation when plasma fibrinogen levels decrease below 1 g litre(-1); however, this threshold is empiric and is not based on solid clinical evidence. Consequently, there is uncertainty over the appropriate dosing and optimal administration of cryoprecipitate, with some guidelines from professional societies to guide clinical practice. Randomized, controlled trials are needed to determine the clinical efficacy of cryoprecipitate, compared with the efficacy of alternative preparations. These trials will allow the development of evidence-based guidelines in order to inform physicians and guide clinical practice.

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.

Management of patients with long-term inhibitors: is immune tolerance an underestimated life-long solution?

Immune tolerance induction (ITI) is recognized as the first choice treatment in haemophilic patients with inhibitors, with the aim of restoring safe and effective standard factor VIII replacement and, particularly, prophylaxis in children. For the latter, literature data and clinical practice support the optimal cost utility ratio of ITI. Indeed, the high success rate, the low incidence of inhibitor recurrence after successful ITI and the possibility of preventing joint deterioration, enable one to predict a considerable long-term reduction of costs in the majority of treated patients. Therefore, in spite of high costs and open issues about optimal regimens, ITI is actually attempted in virtually all children with inhibitors. Few patients with long-standing inhibitors presently undergo ITI, particularly in the case of severe bleeding tendency. In this setting, uncertainties concerning management are amplified by the paucity of literature data and psychological reluctance by both patients and treaters due to the perceived poor prognosis and the demanding treatment (also in terms of costs). However, clinical data suggest that the role of age at ITI start and of time interval from inhibitor diagnosis, as predictors of ITI outcome, should be considered in a larger framework of proposed and more established prognostic factors. Moreover, optimising ITI management, particularly with respect to inhibitor titre at ITI start and avoidance of adverse events or interruption of treatment, may also contribute to improve outcomes. Although the economic constraints of the present era significantly affect resources for such a high-cost treatment, the individual cost-utility ratio (bleeding tendency and risk of fatal bleeding, arthropathy and need for orthopaedic surgery, comorbidities, quality of life) should be assessed carefully to determine whether ITI is a suitable option and thus not preclude adults from the opportunity of inhibitor eradication.

Economic evaluations of prophylaxis with clotting factor for people with severe haemophilia: why do the results vary so much?

A number of studies examining the cost effectiveness of haemophilia prophylaxis have been published, but they report a wide range of results. The aim of this study was to explain why the results from existing economic evaluations of prophylaxis with clotting factor vary so much and to suggest areas of further research that will help to generate stronger economic evidence. Results from a previous systematic review were updated using a textword search of a number of electronic databases. Eleven economic evaluations were identified. They reported incremental cost-effectiveness ratios for prophylaxis ranging from 'cost saving and clinically beneficial' (i.e. 'dominant') to over €1 million per additional quality-adjusted life year (QALY) if prophylaxis replaces treatment following a bleed. A number of reasons are likely to explain this breadth of results, most notably differences in choice of time horizon, estimates of treatment effect, clotting factor unit cost, discount rates and definitions of prophylaxis. Although the existing cost-effectiveness literature for haemophilia prophylaxis appears to report a wide range of results, closer inspection suggests that differences are largely explained by a number of design features. Some are likely to reflect local economic conditions and should be expected. However, others, such as differences in the choice of appropriate time horizon, are more concerning as they reflect differences in opinion over appropriate methodology. A number of studies to help address these evidence gaps are suggested: however, it is also recommended that analysts continue to adhere to established conventions when conducting and reporting economic evaluations.

Models of prophylaxis.

Long-term, continuous prophylaxis for haemophilia began at a modest scale during the 1950s and 1960s in Sweden and The Netherlands. In the face of high cost and impediments to the performance of longitudinal, well-designed studies, it was decades before prophylaxis was considered to be the best practice in countries that could afford the cost. In 2007 and 2011, the only prospective randomized studies ever performed confirmed what large cohort studies in Europe had long since shown. Today, focus is on when to start prophylaxis, dosing and when/if to stop. Retrospective comparisons of the Swedish and Dutch cohorts, where different strategies have been used, indicate that a costly, high-dose regimen improves outcome, but not dramatically. A prospective comparison is now underway. Treatment, clinical outcome, clotting factor consumption and socioeconomic parameters will be compared between the two strategies. Results are expected to provide greater insight into the long-term consequences of the different prophylactic treatment strategies. The economic justification for prophylaxis has been addressed in several studies with varying results. While the majority (implicitly) suggest that prophylaxis is not cost effective at conventional willingness to pay for additional units in health thresholds, their results vary markedly. Closer inspection suggests that the primary reasons results differ include different definitions of prophylaxis, clotting factor price, discount rates, choice of outcome measures and time horizon.

Healthcare resource utilization among haemophilia A patients in the United States.

Advances in therapy have improved life expectancy and quality of life of patients with haemophilia A. Due to the chronic and complex management of this disease, particularly, the development of inhibitors, little is known about their health resource utilization in the real-life setting over time. The aim was to assess the distribution and trend of healthcare resource utilization among US haemophilia A patients with and without inhibitors. The MarketScan® Database, was queried to identify individuals with ≥1 year continuous enrolment, two medical diagnoses of haemophilia A and claims for factor VIII or bypassing agent (to infer inhibitor status) during 2001-2007. Haemophilia-related cost was estimated from inpatient, outpatient and pharmacy claims. Annual cost differences were assessed by age and over a 4-year period for those with continuous enrolment. Among 51 million covered lives, 1044 haemophilia patients were identified, of whom 981 (94%; mean age = 21.2 years) did not have an inhibitor. The median haemophilia-related cost for these patients was $63,935 per patient per year. When normalized by weight, annual cost was stable (no statistically significant differences) among 312 non-inhibitor patients (mean age = 21.8 years) with 4-year continuous data. While there was a wide distribution of haemophilia-related cost among the 63 individuals with an inhibitor (mean age = 15.4 years), only 0.6% of the total haemophilia patients had costs exceeding $1 million per patient per year. This study indicated that most haemophilia A patients were inhibitor-free with relatively stable annual costs over time. There was a wide distribution of haemophilia-related cost for inhibitor patients, while the proportion of patients who incurred extreme high cost was low.