Immune tolerance induction in patients with haemophilia a and inhibitors: effectiveness and cost analysis in an European Cohort (The ITER Study).

INTRODUCTION: Although immune tolerance induction (ITI) is considered the first choice treatment to eradicate inhibitors in haemophilia A patients, little is known about outcomes determinants and cost magnitude. AIM AND METHODS: A retrospective, multicentre study was conducted to assess the relationship between ITI outcome, clinical and treatment characteristics and cost of ITI treatment in haemophilia A patients. Data from 12 months before inhibitor diagnosis to 12 months after ITI completion were collected. Treatment cost was calculated in the third-party perspective and expressed as mean € per patient-month. Cox regression models were used to identify predictors of better outcome and the time taken to achieve tolerance. RESULTS: Seventy-one patients, aged 0.4-41 years (median: 3.8 years) at ITI start, were enrolled. Undetectable inhibitor was achieved in 84.5% of patients and inhibitor eradication with normal factor VIII (FVIII) pharmacokinetics in 74.2%. Median time to successful tolerance was 10.7 months (range 2.0-90.0 months). Peak inhibitor level on ITI was a significant predictor of ITI success. Breakthrough bleeding event incidence during ITI was associated with time to success. The mean cost of treatment for the time period between inhibitor diagnosis and ITI start was €3188 per patient-month (92.1% for bypassing agents), and €60 078 during ITI (76.8% for FVIII use in ITI). CONCLUSION: Immune tolerance induction in this patient cohort was successful in 84.5% of patients with a mean cost of €60 000 per patient-month. This high cost is dwarfed by comparison with the prospect of lifelong care of an inhibitor patient, in addition to gains in life expectancy and health-related quality of life.

Health-related quality of life assessment in haemophilia patients on prophylaxis therapy: a systematic review of results from prospective clinical trials.

INTRODUCTION: Prophylaxis is effective in reducing the number of bleeding episodes in patients with severe or moderately severe haemophilia A and B, including those with inhibitors. However, data, predominantly from observational studies, suggest more equivocal effects on health-related quality of life (HRQoL). AIM: To examine the impact of prophylaxis on HRQoL from prospective clinical trials. METHODS: We performed a systematic literature review of clinical trials evaluating the efficacy of prophylaxis with factor VIII, FIX or bypassing agents. Trials assessing HRQoL via validated instruments were selected and summarized. RESULTS: Thirteen trials (haemophilia A [n = 8]; haemophilia B [n = 2]; inhibitors [n = 3]) met all inclusion criteria. HRQoL instruments included the EQ-5D, SF-36, Haem-QoL-A, Haem-A-QoL, Haemo-QoL and CHO-KLAT. Improvements in HRQoL following prophylaxis were observed with the EQ-VAS, SF-36 and haemophilia-specific instruments in adult patients and were associated with reduced pain, fewer restrictions in physical activities and better general health. Prophylaxis led to statistically significant or clinically meaningful HRQoL improvement in six trials and non-significant improvement in four trials; two trials found no improvement and one reported no data. Despite study differences, consistent trends suggested that patients previously treated solely on-demand and those who experienced marked reductions in the frequency of bleeding with prophylaxis had a greater improvement in HRQoL. CONCLUSION: Contrary to findings of observational studies, the results from the majority of prospective trials using validated instruments showed positive trends for improved HRQoL with prophylaxis in adults.

Tertiary prophylaxis in adults: is there a rationale?

There is lack of evidence-based recommendations or clear-cut consensus regarding the clinical and economic utility of regular prophylaxis started in adulthood, with the aim of keeping the clinical situation from getting worse by prevention of further bleeds contributing to increasing musculo-skeletal or other morbidity in haemophilia. Such a prophylaxis program has been shown in relatively small cohorts to be effective in reducing bleeding occurrence, with a variable effect on the joint status, but with significantly higher factor consumption and consequently higher costs than on-demand therapy. There has been no attempt to identify subsets of patients who may benefit from "tertiary" prophylaxis more than others, for example, due to their bleeding phenotype and/or requirements for product issued on-demand or to identify the dosage that provides the optimal balance of clinical benefit and cost effectiveness. This article reviews the published literature on prophylaxis started beyond the age of 18 years, the barriers to the uptake of prophylaxis programs particularly in adults and highlights areas in need of further research.

Haemophilia care in Europe: the ESCHQoL study.

The aim of this study was to determine the clinical conditions of patients with haemophilia within Europe as recommended by the European Commission. In this multicentre, cross-sectional, ambispective study, conducted within 21 European countries patients' clinical data were collected, amongst others haemophilia type, severity, treatment pattern, use of factor products, bleeding, orthopaedic joint scores and infections. A total of 1400 patients, 84.3% with haemophilia A and 15.7% with haemophilia B were enrolled by 42 centres between 2004 and 2006. Thereof, 417 were children (30.0%) and 983 were adults (70.0%). About 70% of patients had severe factor deficiency (<1%). More than half of the adults were carriers of chronic infections (12.6% HIV, 55.8% HCV), compared to only 3.8% children (no HIV, 2.9% HCV). Patients were grouped according to per capita amount of clotting factor used in patients' region of residence in 2005: region 1: >5 IU; region 2: 2-5 IU; region 3: <2 IU. Paediatric and adult patients in region 3 had median numbers of three and eight joint bleeds, respectively, with worse joint scores compared to region 1 with zero and one bleed. Prophylactic therapy was used in only 31.3% children and 8.9% adults with severe haemophilia in region 3 compared to 93.7% and 54.1%, respectively, in region 1. Statistical analysis revealed that residence in areas with low factor consumption/availability is the most prominent risk factor for joint disease. Access of European patients with haemophilia to optimal care with safe factor VIII concentrates is limited and depends on the region of residence.

Haemophilia prophylaxis: how can we justify the costs?

Severe haemophilia results in increased mortality and poorer quality of life. Factor prophylaxis leads to a more normal life, but is very costly; most of the cost is due to the high cost of replacement factor. Despite its high cost, factor prophylaxis has been adopted throughout the developed world--even in different health care systems. We argue that there are at least five possible reasons why societies may value factor prophylaxis despite its cost: (i) it is directed towards an inherited disease, (ii) the treatment is largely directed towards children, (iii) the disease is rare and the overall cost to society is small, (iv) the treatment is preventative, and v) the high cost is largely the result of providing safe products. In an era of rising health care costs, there is a strong research agenda to establish the factors that determine the value of expensive therapies for rare diseases like haemophilia.

Understanding FVIII/VWF complex--report from a symposium of XXIX WFH meeting 2010.

von Willebrand factor (VWF) has the capacity to form a complex with factor VIII (FVIII) which may modulate the immunogenicity of FVIII. It has been proposed that a significant fraction of recombinant FVIII (rFVIII) is unable to bind VWF. In an experimental model studied at the McMaster University in Canada, this VWF-unbound rFVIII fraction showed no coagulant function. Sulphation of FVIII tyrosine (Tyr) 1680 has been reported as essential for the interaction with VWF. In a study performed at the Grifols and CNS-CSIC in Spain, Tyr1680 sulphation was observed to be incomplete in rFVIII and complete in plasma-derived FVIII (pdFVIII). This could explain the incapability of some rFVIII molecules to bind VWF. Experience with immune tolerance induction (ITI) at the Bonn Haemophilia Centre indicates that only eradication of FVIII inhibitors allows safe haemostasis control and the option of prophylactic treatment. Various clinical trials were planned to evaluate the clinical role VWF-containing FVIII concentrates (FVIII/VWF). RES.I.ST (an acronym for REScue Immunotolerance STudy) is an international, prospective study aimed at assessing whether FVIII/VWF can induce ITI in high-risk haemophilia patients (RES.I.ST naïve) and whether patients who previously failed ITI with FVIII alone can be rescued with FVIII/VWF (RES.I.ST experienced). Enrolment started in November 2009. In the FAIReSt.Will (Fanhdi and Alphanate Italian Retrospective Study in Willebrand disease) study, 120 von Willebrand disease (VWD) patients treated with Fanhdi(®) or Alphanate(®) were retrospectively analysed. Efficacy was excellent and no side effects were reported. The ongoing PRO.Will study is a prospective, multicenter trial aimed at assessing the efficacy, safety and pharmacoeconomics of secondary long-term prophylaxis in patients with severe inherited VWD.

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.

[Quality of life of young patients with haemophilia in Europe]. / Lebensqualität von jungen Patienten mit Hämophilie in Europa.

Haemophilia, an inherited x-linked bleeding disorder, is a rare disease with comparable prevalence worldwide, which leads to early disability if untreated, and which, if treated via substitution of blood clotting factor, is associated with high treatment costs. Recent research has focused on bio-psychosocial consequences of treatment from the patient's perspective, in order to identify new treatment approaches, to quantify the patient benefit, and to compare haemophilia care across countries. For this, generic and disease-specific instruments have been developed and are currently being used in studies. The present paper describes clinical aspects of haemophilia as well as the assessment of quality of life and proceeds to introduce two recent studies on quality of life of children and adolescents with haemophilia in Europe. The HAEMO-QoL study investigated the quality of life of 339 children with haemophilia age 4 and above from six European countries. A total of 1,424 patients from 21 European countries participated in the ESCHQoL study, among these were 444 children aged 4 and above years. In both studies clinical data, information about health care and psychosocial determinants such as coping, life satisfaction and social support were assessed. Significant differences in quality of life between countries were found. Psychosocial determinants were associated with quality of life. Current analyses suggest that important determinants for quality of life are availability of factor concentrate from the clinical side and social support from the psychosocial side. The difference in quality of life across countries is a future major health-political challenge.

European principles of haemophilia care.

As the management of haemophilia is complex, it is essential that those with the disorder should have ready access to a range of services provided by a multidisciplinary team of specialists. This document sets out the principles of comprehensive haemophilia care in Europe. Within each country there should be a national organization which oversees the provision of specialist Comprehensive Care Centres that provide the entire spectrum of clinical and laboratory services. Depending upon the size and geographical distribution of the population, a network of smaller haemophilia centres may also be necessary. There should be arrangements for the supply of safe clotting factor concentrates which can also be used in home treatment and prophylaxis programmes. A national register of patients is recommended along with collection of treatment statistics. As comprehensive haemophilia care is multidisciplinary by nature, the need for education and research programmes for all staff members is emphasized: Members of the Interdisciplinary Working Group not represented in the list of authors are mentioned in Section 4 of this document.

Recommendations for reporting economic evaluations of haemophilia prophylaxis: a nominal groups consensus statement on behalf of the Economics Expert Working Group of The International Prophylaxis Study Group.

BACKGROUND: The need for clearly reported studies evaluating the cost of prophylaxis and its overall outcomes has been recommended from previous literature. OBJECTIVES: To establish minimal ''core standards'' that can be followed when conducting and reporting economic evaluations of hemophilia prophylaxis. METHODS: Ten members of the IPSG Economic Analysis Working Group participated in a consensus process using the Nominal Groups Technique (NGT). The following topics relating to the economic analysis of prophylaxis studies were addressed; Whose perspective should be taken? Which is the best methodological approach? Is micro- or macro-costing the best costing strategy? What information must be presented about costs and outcomes in order to facilitate local and international interpretation? RESULTS: The group suggests studies on the economic impact of prophylaxis should be viewed from a societal perspective and be reported using a Cost Utility Analysis (CUA) (with consideration of also reporting Cost Benefit Analysis [CBA]). All costs that exceed $500 should be used to measure the costs of prophylaxis (macro strategy) including items such as clotting factor costs, hospitalizations, surgical procedures, productivity loss and number of days lost from school or work. Generic and disease specific quality of lífe and utility measures should be used to report the outcomes of the study. CONCLUSIONS: The IPSG has suggested minimal core standards to be applied to the reporting of economic evaluations of hemophilia prophylaxis. Standardized reporting will facilitate the comparison of studies and will allow for more rational policy decisions and treatment choices.

Quality of life assessment in clinical practice in haemophilia treatment.

The modern management of haemophilia has greatly influenced not only survival of patients, their clinical symptoms and orthopaedic outcome but also their perceived quality of life (QoL). QoL measures recently became an essential part of clinical trials being one of the most important patient-rated outcomes (PROs). Moreover, QoL assessment is essential in pharmacoeconomics. In clinical trials, not only clinical outcomes but also the so-called PROs and health-economic outcomes are included. Different types of economic evaluations may be conducted in order to describe the economic burden of a disease condition, to determine the cost of care and to assess and evaluate alternative treatments in terms of both costs and effects as well as benefits and outcomes with the aim of optimizing the use of resources. For these evaluations, the following analyses are performed: descriptive cost of illness study, incremental cost-effectiveness analysis, incremental cost-utility analysis and incremental cost-benefit analysis. By contrast, PROs are derived from direct patient reports and they allow to evaluate the impact of a disease and its treatment on patients' well-being and functioning. PROs include health-related quality of life, patient preferences/utilities, treatment satisfaction and other PROs such as functional assessment, etc. Choosing a QoL measure, study- and instrument-related aspects have to be taken into account. Finally, QoL assessment will become a part of the regular clinical assessment of persons with haemophilia, in order to provide trustworthy data of perceived well-being to be compared over time and in order to assess treatment efficacy and quality of care.

Consensus perspectives on prophylactic therapy for haemophilia: summary statement.

Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long-term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality-of-life assessment instruments, and cost-benefit analyses.

Clinical outcomes and resource utilization associated with haemophilia care in Europe.

We conducted a multicentre, cross- sectional study of 1042 haemophilia subjects across Europe to compare various health outcomes associated with on-demand vs. prophylactic factor-substitution therapy. Demographic, medical history, and healthcare resource utilization data were analysed along with the number of bleeding events over the past 6 months. Treatment-cost data were also examined to provide preliminary information for future economic studies. A logistic regression analysis, controlling for other statistically significant covariates, showed that patients treated on demand were 3.4 times more likely to have had a joint bleed over the previous 6 months than those treated with prophylaxis. Multiple regression analyses further confirmed these findings, because on-demand subjects had, on average, 5.15 more joint bleeds over the reporting period than patients treated with prophylaxis. Notably, these findings were even more dramatic for younger haemophilia patients when our study sample was stratified by age. Due to the high cost of factor replacement, healthcare costs were significantly higher for subjects treated prophylactically. While hospital costs for prophylaxis subjects were, on average, lower, statistically significant cost savings for prophylactic subjects were not noted. These results suggest that clinicians and health policy decision-makers should consider the advantages of prophylactic therapy for haemophilia patients in formulating treatment protocols and allocating health resources.

Quality-of-life differences between prophylactic and on-demand factor replacement therapy in European haemophilia patients.

The European Study on the Clinical Outcomes and Resource Utilization associated with Haemophilia Care was designed to compare various health outcomes associated with on-demand and prophylactic factor substitution methods in European haemophilia patients. While the primary objective of this research is to conduct an economic analysis, an important component of this study is to evaluate quality-of-life differences that may exist between patients who utilize these two styles of therapy. Quality-of-life research has emerged as a primary measure of health outcomes because it allows the augmentation of traditional clinical indicators of health with data gathered from the patient's perspective. A total of 1033 haemophilia patients from 16 European haemophilia treatment centres were enrolled in this study. The SF-36, a multidimensional quality-of-life instrument, was administered to all participants. This instrument measures eight health-related quality-of-life dimensions: physical functioning, physical role limitations, bodily pain, general health, vitality, social functioning, emotional role limitations, and mental health. All haemophilia subjects enrolled in the study scored significantly lower than the population normative means in the three physical dimensions and in the general health dimension. HIV-negative haemophiliac subjects differed significantly by factor substitution type in a multivariate analysis examining all eight health dimensions. Univariate analyses testing each dimension separately indicated that patients treated prophylactically reported significantly less bodily pain, better general health, and scored significantly higher in the physical functioning, mental health, and social functioning dimensions. While these results suggest that health-related quality-of-life may be better for haemophilia patients treated prophylactically, future prospective studies that gather periodic quality-of-life data over time should be conducted.