Healthcare expenditures for males with haemophilia and employer-sponsored insurance in the United States, 2008.

Although hemophilia has a potentially high economic impact, published estimates of health care costs for Americans with hemophilia are sparse and non-specific as to the non-bleeding complications of the disease. The objective of this study is to estimate average annual health care expenditures for people with hemophilia covered by employer-sponsored insurance, stratified according to the influence of age, type of hemophilia [A (factor VIII deficiency) versus B (factor IX)], presence of neutralizing alloantibody inhibitors and exposure to blood-borne viral infections. Data from the MarketScan Commercial and Medicare Research Databases were used for the period 2002-2008 to identify cases of hemophilia and to estimate mean and median medical expenditures during 2008. A total of 1,164 males with hemophilia were identified with continuous enrollment during 2008, 933 with hemophilia A and 231 with hemophilia B. Mean health care expenditures were $155,136 [median $73,548]. Mean costs for 30 (3%) males with an inhibitor were 5 times higher than for males without an inhibitor, approximately $697,000 [median $330,835] and $144,000 [median $73,321], respectively. Clotting factor concentrate accounted for 70%-82% of total costs. Average costs for 207 adults with HCV or HIV infection were 1.5 times higher than those for adults without infection. Hemophilia treatment is costly, particularly for individuals with neutralizing alloantibody inhibitors who require bypassing agents. Efforts to understand the cause of inhibitors are needed so that prevention strategies can be implemented and the excess costs resulting from this serious complication of hemophilia care can be avoided.

Immune tolerance induction therapy for patients with hemophilia A and FVIII inhibitors particularly using low-dose regimens.

BACKGROUND: Inhibitory antibodies against infused clotting factor VIII concentrates (FVIII) developed in 20-30% of patients with hemophilia A. Bypass therapy may control the bleeds in patients with FVIII inhibitors, however, immune tolerance induction (ITI) therapy is the only proven modality for eradicating FVIII inhibitors. Since the cost of high-dose (200 IU/kg) ITI is extremely expansive, we conducted this study to identify whether low-dose ITI can be an alternative strategy besides high-dose ITI or bypass therapy. PROCEDURE: Patients with hemophilia A and FVIII inhibitors treated by ITI in Kaohsiung Medical University Hospital from January 2000 to January 2010 were enrolled. Regimens of ITI therapy included high-dose (100 IU/kg) and low-dose (30-50 IU/kg). RESULTS: High-dose ITI therapy for two high responders (HRs) and low-dose ITI therapy for three HRs and all low responders (LRs) were performed. Complete tolerance was achieved in 2 HRs with high-dose regimen, and in one HR and 19 LRs with low-dose regimens. We administered low-dose ITI combined with immune suppressants treatment for one of the patient with extremely high FVIII inhibitor titers and the inhibitor level markedly declined and no spontaneous bleeding episode was noticed during the treatment period. CONCLUSIONS: The outcome of ITI in our study was satisfactory without clinically significant complications. Low-dose ITI regimens can effectively treat patients with high responder inhibitors, including one patient with extremely high inhibitor levels over 700 BU. Low-dose ITI may be an alternative modality for FVIII inhibitors management, especially in countries with limited resources.

Cost of care of haemophilia with inhibitors.

In Western countries, the treatment of patients with inhibitors is presently the most challenging and serious issue in haemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the healthcare of patients in this setting. Being designed to address questions of resource allocation and effectiveness, decision models are the golden standard to reliably assess the overall economic implications of haemophilia with inhibitors in terms of mortality, bleeding-related morbidity, and severity of arthropathy. However, presently, most data analyses stem from retrospective short-term evaluations, that only allow for the analysis of direct health costs. In the setting of chronic diseases, the cost-utility analysis, that takes into account the beneficial effects of a given treatment/healthcare intervention in terms of health-related quality of life, is likely to be the most appropriate approach. To calculate net benefits, the quality adjusted life year, that significantly reflects such health gain, has to be compared with specific economic impacts. Differences in data sources, in medical practice and/or in healthcare systems and costs, imply that most current pharmacoeconomic analyses are confined to a narrow healthcare payer perspective. Long-term/lifetime prospective or observational studies, devoted to a careful definition of when to start a treatment; of regimens (dose and type of product) to employ, and of inhibitor population (children/adults, low-responding/high responding inhibitors) to study, are thus urgently needed to allow for newer insights, based on reliable data sources into resource allocation, effectiveness and cost-utility analysis in the treatment of haemophiliacs with inhibitors.

Concomitant infusion of low doses of rFVIIa and FEIBA in haemophilia patients with inhibitors.

Patients with severe haemophilia A and an inhibitor may become refractory to FEIBA and/or recombinant factor VIIa (rFVIIa). Sequential therapy with both products has been reported in such patients. In this pilot study, we examined the safety and efficacy of combined rFVIIa and FEIBA therapy in patients with haemophilia A and inhibitors during bleeding episodes. We also tried to evaluate whether thrombin generation (TG), by various mixtures of these agents, can serve as a guide for tailoring therapy. TG was measured in plasma taken from eight haemophilia A patients. Increasing concentrations of rFVIIa, FEIBA or both were added ex vivo to the plasmas, and TG was induced by recalcification. Since low concentrations of rFVIIa and FEIBA had either an additive or a synergistic effect in all patients, the lowest combination, yielding TG comparable or lower than TG achieved with either FEIBA 100 U kg(-1) or rFVIIa 160 microg kg(-1) alone, was selected for the treatment of bleeding episodes. Five patients with a high titre of an inhibitor (8-1300 BU), including one previously refractory to infusions of rFVIIa at doses up to 400 microg kg(-1) X4 daily, were treated with combinations of 30-70 microg kg(-1) rFVIIa and 20-30 U kg(-1) FEIBA during a total number of 400 bleeding episodes with excellent haemostatic effect. No adverse events and no DIC were observed following these infusions. Concomitant infusion of low-dose rFVIIa and low-dose FEIBA, seems to be safe, efficacious and economical in patients refractory to rFVIIa and probably other haemophilia A patients with an inhibitor.

Patients', physicians', and pharmacists' preferences towards coagulation factor concentrates to treat haemophilia with inhibitors: results from the COHIBA Study.

Despite modern highly efficacious technologies, there is still a lack of consensus on how to optimally treat haemophilia patients with inhibitors. The aim of the study was to evaluate preferences towards the characteristics of different coagulation factor concentrates for haemophilia inhibitors patients, from the perspective of patients or their caregivers, haematologists and pharmacists. A discrete choice study was conducted. Potential products were described with eight selected characteristics: perceived viral safety, risk of anamnestic response, possibility of undergoing major surgery, frequency of infusions in prophylaxis, number of infusions to stop bleeding, time to stop bleeding, time to pain recovery and cost. Participants received 16 pairs of potential products and chose from each pair the option they considered better. Data were analysed with a random-effects conditional logistic model. Totally 1614 observations were obtained from 37 patients/caregivers, 39 physicians and 25 pharmacists from Italy. Cost was the most important characteristic to every group. For patients/caregivers, the next most important factors were: risk of anamnestic response, possibility of undergoing major surgery and perceived viral safety. For physicians, the next most important characteristics were: risk of anamnestic response, number of infusions to stop bleeding and possibility of undergoing major surgery. For pharmacists, the next most important factors were: time to stop bleeding, time to pain recovery and possibility of undergoing major surgery. Decisions on treatments must take into account patients clinical needs; however, preferences can also play an important role in the choice and success of treatments. The results of this study could, therefore, help decision-makers to optimize the overall benefits of treatments.

The benefits of prophylactic treatment with APCC in patients with haemophilia and high-titre inhibitors: a retrospective case series.

Prophylactic infusion of factor concentrates is a safe, effective intervention for preventing arthropathy in patients with haemophilia; on-demand treatment is insufficient to prevent the orthopaedic complications and subsequent haemophilic arthropathy that stem from recurrent joint haemorrhages. The usefulness of prophylaxis in haemophilia patients without inhibitors suggests that patients with haemophilia and inhibitors could derive similar benefits. In patients with haemophilia and high-titre (>5 BU mL(-1)) inhibitors, bleeding episodes are treated with bypassing agents such as activated prothrombin complex concentrates (APCCs) and recombinant activated factor VII (rFVIIa, NovoSeven; Novo Nordisk A/S, Bagsvaerd, Denmark). It is possible to administer bypassing therapy regularly to prevent haemorrhages, with the goal of limiting arthropathy and serious life- and limb-threatening bleeding. The data evaluating the efficacy and safety of this approach in patients with inhibitors are limited, consisting of results from one prospective trial and retrospective case reports. This report describes our experience with the prophylactic use of the APCC Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA; Baxter AG, Vienna, Austria). Data from patients at one treatment centre were retrospectively evaluated. Case records of six patients with haemophilia A or B and high-titre inhibitors were identified. When APCC was administered regularly, most patients exhibited a reduction in the numbers of haemorrhages, an improvement in orthopaedic status, and an improvement in quality of life. Prophylaxis with APCC can reduce haemorrhages and halt further joint deterioration in patients with haemophilia and inhibitors.

Home treatment with bypassing products in inhibitor patients: a 7.5-year experience.

The advantages of early treatment of bleeds include minimizing the damage caused by the haemorrhage as well as offering increased convenience and time saved for the patient. The objectives of this prospective, single-centre study were to evaluate the efficacy, safety and feasibility of long-term home treatment with bypassing product in inhibitor patients. Since May 2000, 10 haemophilia A patients with high-titre inhibitors have been included in the study. Nine patients were treated with activated prothrombin complex concentrate (aPCC; factor eight inhibitor bypassing activity, FEIBA; Baxter AG, Vienna, Austria) and one patient with both aPCC and recombinant activated factor VII (rFVIIa; NovoSeven; NovoNordisk A/S, Bagsvaerd, Denmark). A total of 1008 infusions of aPCC and 17 infusions of rFVIIa were given in a home treatment setting. The numbers include 448 infusions of aPCC and 10 infusions of rFVIIa given as prophylactic treatment. During the 7.5 years of follow-up, the patients experienced 431 bleeds. Five hundred and sixty infusions of aPCC and seven infusions of rFVIIa were given to treat these bleeds. Haemostasis was rated as effective in 88% (372/424) and partially effective in 10% (43/424) of the bleeds after a mean number of 1.3 injections. The number of treatments rated as effective was comparable for muscle (90%), joint (85%) and mucocutaneous (86%) bleeds. The safety of the treatment was very good. Only two mild adverse events were reported in total. No thrombotic adverse event has been observed. In conclusion, home treatment with bypassing agents in inhibitor patients is feasible, effective and safe in a long-term perspective.

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.

Physiotherapy, rehabilitation and sports in countries with limited replacement coagulation factor supply.

It is well documented that physiotherapy and rehabilitation benefit people with haemophilia by strengthening the key muscle groups and protecting joints from the adverse effects of repeated haemorrhages. Rehabilitation, in conjunction with the availability of replacement coagulation factor products, has revolutionized approaches to the management of patients with haemophilia in developed countries and has led to a substantial decrease in both the morbidity and mortality rates among the haemophilic population. Modern treatment approaches have also enabled persons with haemophilia to participate in sporting activities along with their peers; however, these improvements in care have not been achieved in developing nations, where health-care resources and facilities are scarce and the supply of coagulation factor products is limited. This article attempts to address the following questions about the management of haemophilic patients in developing countries: Can physiotherapy, rehabilitation and sports prevent disabilities and preserve independence? Is participation in sports activities possible in developing countries? Do countries differ with regard to guidelines for participation in sports? Should we be encouraging participation in sports or allowing patients with haemophilia to do as they choose?

Assessing the costs for clinical care of patients with high-responding factor VIII and IX inhibitors.

The costs of haemophilia-related care and the impact of unusually expensive, or outlier, patients on these costs have been explored in numerous European, American and Canadian studies during the last decade. In particular, antibodies that neutralize infused factor VIII or IX (high-responding inhibitors) make treatment responses, and thereby costs, much less predictable. There is little debate that the health care costs of haemophilic patients with high-responding inhibitors are routinely higher and more variable than those of non-inhibitor patients. However, the extent to which this is attributable to the few outlier inhibitor patients whose expenditures tend to skew the data is not as clear. To compare the variation and range in health care expenditures among patients with inhibitors and those without, we reviewed data originally gathered during a 24-month period in 1995-1997 from a prospectively created cohort as part of a broader cost and utilization study conducted at a large haemophilia treatment centre. We conclude that although the use of outpatient factor replacement products was not significantly greater or more expensive among inhibitor patients, their hospital-related costs greatly increased overall expenditures. Among our study population, the overall costs associated with inhibitor patients are not only higher in absolute monetary terms, but also in terms of the degree of variation. This variation was demonstrated by: (i) the extremely wide range of costs over an extended timeframe among individual inhibitor patients when compared with those without inhibitors, and (ii) the much larger year-to-year variation in costs among the inhibitor group.

Inhibitor economics.

The majority of direct costs associated with caring for patients with hemophilia are attributed to replacement therapy with clotting factor concentrates (CFC). For patients who develop high-titer inhibitors, CFC are ineffective and bypassing therapy is used to achieve hemostasis, thus changing the direct costs associated with treatment. As bypassing agents are less predictably effective than CFC (often necessitating more frequent dosing) and are more costly on a per-unit basis, treatment costs for patients with inhibitors are usually much higher than those for patients without inhibitors. In addition, the immune tolerance induction protocols used to eradicate inhibitors are costly due to the frequent dosing of CFC over prolonged periods. It is estimated that the cost of hemostatic therapy for patients with inhibitors can be 2.5 times higher than the cost for patients without inhibitors. However, some studies have reported an outlier effect caused by a small percentage of inhibitor patients who require a disproportionate amount of treatment. These outliers magnify overall treatment costs, making cost assessments for hemostatic therapy less predictable in patients with inhibitors than in those without inhibitors.

Current opinion on inhibitor treatment options.

Inhibitor development in patients with hemophilia complicates hemostatic management. Currently, high doses of factor concentrates are used to override low-titer, low-responding inhibitors during acute bleeding episodes. Bypassing agents, such as the activated prothrombin complex concentrate (aPCC), Factor Eight Inhibitor Bypassing Activity, Anti-Inhibitor Coagulant Complex, Vapor Heated (FEIBA; Baxter AG, Vienna, Austria), and activated recombinant factor VII (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark), are commonly used to treat acute bleeding episodes in patients with high-titer, high-responding inhibitors, whereas long-term therapeutic options include inhibitor eradication using immune tolerance induction. Neither FEIBA nor rFVIIa can be monitored with a laboratory assay, making it difficult to establish optimal dosages. Comparative studies evaluating the efficacy of FEIBA and rFVIIa for bleed control have been sparse, prompting investigators to initiate crossover comparison studies to assess the efficacy and cost of aPCC and rFVIIa in the treatment of joint hemorrhages. Both the cost of therapy and the outcome of therapy will need to be considered in the development of future hemostatic agents for patients with inhibitors.