Variability of treatment modalities and intensity in patients with severe haemophilia A on prophylaxis: Results from the Italian national registry.

BACKGROUND: A shift from a standard to a personalized prophylaxis has been increasingly adopted in patients with severe haemophilia A (SHA). This approach has raised the likelihood of a significant variability in the prophylactic approaches and the relative Factor VIII (FVIII) consumptions. The aim of our study was to assess the treatment variability of SHA patients without inhibitors and on prophylaxis regimen in Italy. MATERIAL AND METHODS: Data reported in the National Registry of Congenital Coagulopathies (NRCC) were analysed to assess treatment distribution within SHA patients without inhibitors, focussing on FVIII consumption in 2017, associated with prophylaxis regimen. The analysis was stratified based on age groups and Italian regions to describe the variability of FVIII consumption in Italy. RESULTS: In 2017, the Registry reported the therapeutic plans of 1068 SHA patients without inhibitors on prophylaxis. The mean (95% CI) individual consumption ranges from 123 127 IU (99 736-146 518) in the age group 0-6 years to 345 000 IU (336 000-354 000) in the age group >20 years. A significant FVIII consumption variability was identified within the adult population. Regions with less than 50 patients reported the higher variability in mean FVIII consumption per patient-year within the different age groups. Similar difference in FVIII consumption variability was reported also in the age groups comparing "low," "middle" and "high" patient volume regions. DISCUSSION: A reliable estimation of FVIII consumption for patients' treatment is necessary to manage and plan the appropriate budget and keep treatment's costs affordable. However, without the implementation of a methodology aiming to assess the overall value produced by these FVIII consumptions, the scenario will keep driven by FVIII consumptions, its costs and the budget available. An effort by haemophilic community, haemophilia treatment centres and institutions is required to develop and share this cultural shift in improving haemophilia management and assessment.

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.

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.

Pharmacokinetic analysis of anti-hemophilic factor in the obese patient.

Standard dosing for individuals with hemophilia A is based on body weight such that 50 IU kg(-1) is defined as a 100% dose, or one attaining 1.00 IU mL(-1) factor VIII (FVIII) clotting activity. No guidelines exist, however, for individuals with hemophilia who are obese, body mass index (BMI) ≥ 30, who may actually be 'over'-treated based on higher in vivo recovery based on higher weight. Alternative treatment guidelines are needed for such patients. To determine FVIII pharmacokinetics we retrospectively collected data during ideal-body-weight dosing from six obese (BMI ≥ 30) hemophilia A patients cared for at the Hemophilia Center of Western PA, for prophylaxis or surgery. The pharmacokinetic data from six subjects undergoing ideal-body-weight dosing with recombinant FVIII indicate peak levels and half-life comparable to standard 50 IU kg(-1) dosing. The mean peak FVIII:C was 1.00 IU dL(-1) and the mean FVIII:C half-life was 10.14 h. IBW-dosing resulted in an average 48.9% reduction in factor use per patient over a 3-month period, for an annualized savings of $133,000 per patient. Ideal-body-weight dosing of recombinant FVIII in obese patients with hemophilia A results in comparable pharmacokinetics, including peak and half-life, with comparable hemostatic efficacy for prophylaxis and surgical treatment, at a significant reduction in factor use and cost. Future studies are needed to confirm these findings in individuals with other congenital bleeding disorders and in children.

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.

Hemostatic treatment using factor VIII concentrates for neutralizing high-responding inhibitors prior to CVAD insertion for immune-tolerance induction therapy.

We have utilized high-dose factor VIII (FVIII) concentrates in 4 hemophilia A patients with inhibitors prior to surgery for the insertion of a central venous access device. In total, 3 patients out of 4 had high responding inhibitors. Dosing algorithms for this type of therapy have not been previously validated and established. We devised an effective formula to calculate the initial dose required to neutralize the inhibitors, although some of the patients demonstrated a lower recovery of FVIII than expected. An anamnestic inhibitor response was evident in 3 cases, but overall our strategy provided a reliable hemostatic effect for at least 4 days after surgery. In addition, our protocol appeared to be more cost-effective than FVIII bypass therapy. The financial saving in 1 case for the initial 3 days was estimated to be approximately US$49 122. Our results demonstrated that high-dose FVIII therapy provided clinically effective and economically viable results even in high responders.

The case for wider use of recombinant factor VIII concentrates.

The introduction of clotting factor concentrates led to major advances in hemophilia care. Rather than simply providing an alternative to plasma-derived concentrates, the introduction in the 1990s of recombinant concentrates added value to replacement therapy particularly with respect to prophylaxis and immune-tolerance induction. While the safety of plasma-derived concentrates has improved considerably, these concentrates may still pose an infectious risk through as-yet unknown pathogens and poor impurity constituent characterization. Recombinant concentrates are increasingly used because of their benefits in pathogen safety, convenience and the potential for unfettered supply. Yet worldwide they remain accessible only to a limited number of patients due to fear of the potential for inhibitor development, overestimation of their costs and underestimation of their benefits. This article reviews the characteristics and properties of recombinant FVIII concentrates to help physicians and patient representatives promote the right of access of patients to the safest products.

Revisiting the cost-effectiveness of primary prophylaxis with clotting factor for the treatment of severe haemophilia A.

Severe haemophilia A is a lifelong condition that requires treatment with exogenous clotting factor. While primary prophylaxis is the clinically preferred method of delivering treatment, its provision is costly. A 2002 evaluation of primary prophylaxis suggested an incremental cost-effectiveness of approximately 50,000 pounds per additional quality-adjusted life-year (QALY). However, since this time, preferable evaluative methods have been developed and means of assessing the value of future research also now exist. Thus, the primary aims of this study were to update a previously published cost-effectiveness analysis of primary prophylaxis vs. treating on-demand in terms of methods and to estimate the value of undertaking further primary research. The base case incremental cost-effectiveness ratio was shown to be approximately 37,000 pounds, 10,000 pounds lower than the value published in 2002. The main reason for this difference was the use of different structural assumptions and methods to fit the various model parameters. At a willingness to pay per additional QALY threshold of 30,000 pounds, the probability prophylaxis is cost-effective was 13%. However, this increased to over 90% when alternative structural assumptions were employed, such as the rate at which future QALYs are discounted. The value of further research to increase the precision of this newly calculated cost-effectiveness estimate was high at a threshold willingness to pay values of 30,000- 40,000 pounds per QALY, particularly for the utilities associated with the health states. Thus, there is considerable value in conducting further primary research related to economic aspects of primary prophylaxis.

Epidemiological survey of haemophiliacs with inhibitors in France: orthopaedic status, quality of life and cost--the 'Statut Orthopédique des Patients Hémophiles' avec Inhibiteur study.

The physical condition of severe haemophilia and the impact of advances in replacement therapy have been much studied, but little work has been done on patients who developed inhibitors. The 'Statut Orthopédique des Patients Hémophiles avec Inhibiteur' study was conducted in France in order to assess the orthopaedic status and quality of life of such patients, and the cost of their medical management. Fifty haemophiliacs aged 12-63 years with a history of high-responder inhibitors were included. Clinical assessment showed that only 12% of the patients had a nil pain score and 2% a nil clinical score, as per Gilbert scale. The mean clinical score was significantly higher in patients over 35 years of age than in younger ones. However, younger patients appeared to have a more impaired orthopaedic status than young haemophiliacs without inhibitors of similar age in previous published cohorts. Surprisingly, older haemophiliacs tended to have the best mental quality of life, contrasting with their highly impaired orthopaedic condition and physical quality of life. The mean cost of clinical resources consumed during the year preceding enrolment was Euro 268 999, 99% of which was related to clotting factor. Marked between-patient differences in cost were noted. Our study suggests that the management of haemophiliacs with inhibitors should be improved in order to prevent haemophilic arthropathy to an extent similar to that of patients without inhibitors. Cost-benefit assessment of any therapeutic strategy should always be combined with quality-of-life evaluation.

Recombinant activated factor VII use in critically ill infants with active hemorrhage.

INTRODUCTION: Recombinant activated factor VII (rFVIIa) is infrequently used off-label in infants despite a paucity of data in this population. We report a retrospective review of rFVIIa use in infants focusing on safety and efficacy. METHOD: Between 2002 and 2007, 32 critically ill nonhemophiliac infants less than 1 year old received rFVIIa at our institution. Indications of rFVIIa and post-rFVIIa venous thrombosis were reviewed. Transfusion requirements were calculated 8 hours before and after rFVIIa administration. RESULTS: Infants received on average 2 doses of rFVIIa at a mean dosage of 90 microg/kg. Active hemorrhage was the indication for rFVIIa in 24 infants, which included postoperative bleeding in 16 and nonsurgical bleeding in 8. The remaining 8 infants had preoperative coagulopathy. Thrombosis was noted in 4 infants (13%) and was not related to transfusion requirements, the number of doses, or dosage of rFVIIa. For infants who had active hemorrhage, rFVIIa was able to significantly reduce the requirements of packed red blood cells by 36.17 mL/kg (P < .005), platelets by 10.31 mL/kg (P < .01), and cryoprecipitates by 2.19 mL/kg (P < .05). CONCLUSION: This is the first large case series demonstrating the efficacy of rFVIIa in critically ill infants with active hemorrhage by reducing their transfusion requirements. Furthermore, venous thrombosis was not associated with increase in either the number of doses or dosage of rFVIIa.

Haemophilic arthropathy: the importance of the earliest haemarthroses and consequences for treatment.

In a case of massive bleeding, the possibility of puncturing the joint can be considered to reduce the total load of intra-articular blood, and thus the total load of iron which, in time, can be found in the synovium with devastating long-term effects. Subsequent initiation of prophylaxis, still very early in life, might be more beneficial for the preservation of joints. Thus, it might be argued that the initiation of primary prophylaxis should be based on joint haemorrhage history rather than age and, according to some authors, preferably after the bleed in a single joint. The high cost of recombinant factor VIII may make widespread acceptance of prophylaxis impractical. Thus, beneficial results should be balanced with cost considerations. In this balance of treatment cost and efficacy, it must be taken into account that improperly treated haemophilia patients make great demands on healthcare systems (in terms of costs) because of their need for additional treatments such as expensive joint replacement surgery. However, where resources are limited, it can be argued that prophylaxis may be stopped in adulthood, in a certain proportion of all adult patients, with acceptable consequences for orthopaedic outcome in the long term. By doing so, limited amounts of clotting factor can be used for young patients with optimal cost effectiveness.

Prophylaxis in adults with haemophilia.

The indications for and the efficacy of prophylaxis in adults with haemophilia remain controversial. It is unclear whether the benefits of secondary prophylaxis outweigh the costs, because adults with haemophilia usually already have established arthropathy. The objectives of secondary prophylaxis in this group are therefore more limited than the objectives of primary prophylaxis in children. It is also uncertain whether primary prophylaxis should stop or continue once adulthood is reached. Some individuals with near-normal joints may stop prophylaxis in early adulthood and then bleed infrequently. Others who stop prophylaxis begin to bleed frequently and suffer progressive arthropathy; these patients should probably have continued prophylaxis. There is no satisfactory method for selecting patients for continued prophylaxis. Adult prophylaxis is less well studied than prophylaxis in children. A few studies with a small number of patients suggest that adults treated with prophylaxis experienced fewer bleeding episodes, less pain and improved quality of life compared with those treated on demand. The mean annual cost of prophylaxis tends be substantially higher for adults than for children, largely owing to the high cost of clotting factor. Here we review the literature regarding the prophylactic treatment of adult patients with haemophilia A, including studies of the discontinuation of prophylaxis. These studies and others all show clinical benefit from prophylaxis in adulthood and suggest the possibility that optimized prophylaxis (e.g. tailoring an intermediate- or low-dose regimen in patients who bleed infrequently) may improve clinical outcome. The cost-effect argument is more difficult to sustain in adults compared with children; however, the cost of prophylaxis may be counterbalanced by indirect factors, such as days gained at work, reduced hospitalizations, reduced need for orthopaedic surgery and improved quality of life.

Current issues in prophylactic therapy for persons with hemophilia.

Factor VIII or IX replacement in a prophylactic manner is utilized for many patients with moderate to severe hemophilia A or B. Studies have shown it to be effective in reducing or preventing degenerative joint disease in many but not all patients. However, many unanswered questions still exist and optimization of this expensive treatment regimen is needed. This paper recounts the current products that are available for use and explores the literature regarding different treatment regimens. It explores age at initiation, dose, interval between infusions, joint health outcomes, barriers to compliance and age at discontinuation of prophylaxis. Individualized treatment is recommended. Collaborative efforts are needed to improve outcomes for all persons with hemophilia.