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INTRODUCTION: Considering the advances in haemophilia management and treatment observed in the last decades, a new set of value-based outcome indicators is needed to assess the quality of care and the impact of these medical innovations. AIM: The Value-Based Healthcare in Haemophilia project aimed to define a set of clinical outcome indicators (COIs) and patient-reported outcome indicators (PROIs) to assess quality of care in haemophilia in high-income countries with a value-based approach to inform and guide the decision-making process. METHODS: A Value-based healthcare approach based on the available literature, current guidelines and the involvement of a multidisciplinary group of experts was applied to generate a set of indicators to assess the quality of care of haemophilia. RESULTS: A final list of three COIs and five PROIs was created and validated. The identified COIs focus on two domains: musculoskeletal health and function, and safety. The identified PROIs cover five domains: bleeding frequency, pain, mobility and physical activities, Health-Related Quality of Life and satisfaction. Finally, two composite outcomes, one based on COIs, and one based on PROIs, were proposed as synthetic outcome indicators of quality of care. CONCLUSION: The presented standard set of health outcome indicators provides the basis for harmonised longitudinal and cross-sectional monitoring and comparison. The implementation of this value-based approach would enable a more robust assessment of quality of care in haemophilia, within a framework of continuous treatment improvements with potential added value for patients. Moreover, proposed COIs and PROIs should be reviewed and updated routinely.
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Hemofilia A , Humanos , Hemofilia A/tratamiento farmacológico , Calidad de Vida , Estudios Transversales , Atención Médica Basada en Valor , Evaluación de Resultado en la Atención de SaludRESUMEN
Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.
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Resistencia a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Infecciones por VIH/genética , Hemofilia A/genética , Adulto , Variaciones en el Número de Copia de ADN , Epistasis Genética , Factor VIII/uso terapéutico , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad , Seropositividad para VIH/genética , Heterocigoto , Homocigoto , Humanos , Modelos Logísticos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Receptores CCR5/genética , Receptores CCR5/metabolismoRESUMEN
BACKGROUND: Patients with severe hemophilia A and factor VIII inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Effective strategies to prevent bleeding in such patients have not yet been established. METHODS: We enrolled patients with hemophilia A who were older than 2 years of age, had high-titer inhibitors, and used concentrates known as bypassing agents for bleeding in a prospective, randomized, crossover study comparing 6 months of anti-inhibitor coagulant complex (AICC), infused prophylactically at a target dose of 85 U per kilogram of body weight (±15%) on 3 nonconsecutive days per week, with 6 months of on-demand therapy (AICC at a target dose of 85 U per kilogram [±15%] used for bleeding episodes). The two treatment periods were separated by a 3-month washout period, during which patients received on-demand therapy for bleeding. The primary outcome was the number of bleeding episodes during each 6-month treatment period. RESULTS: Thirty-four patients underwent randomization; 26 patients completed both treatment periods and could be evaluated per protocol for the efficacy analysis. As compared with on-demand therapy, prophylaxis was associated with a 62% reduction in all bleeding episodes (P<0.001), a 61% reduction in hemarthroses (P<0.001), and a 72% reduction in target-joint bleeding (≥3 hemarthroses in a single joint during a 6-month treatment period) (P<0.001). Thirty-three randomly assigned patients received at least one infusion of the study drug and were evaluated for safety. One patient had an allergic reaction to the study drug. CONCLUSIONS: AICC prophylaxis at the dosage evaluated significantly and safely decreased the frequency of joint and other bleeding events in patients with severe hemophilia A and factor VIII inhibitors. (Funded by Baxter BioScience; Pro-FEIBA ClinicalTrials.gov number, NCT00221195.).
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Factores de Coagulación Sanguínea/administración & dosificación , Hemofilia A/tratamiento farmacológico , Hemorragia/prevención & control , Adolescente , Adulto , Anciano , Factores de Coagulación Sanguínea/efectos adversos , Niño , Preescolar , Estudios Cruzados , Esquema de Medicación , Factor VIII/administración & dosificación , Factor VIII/antagonistas & inhibidores , Femenino , Hemofilia A/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estadísticas no Paramétricas , Adulto JovenRESUMEN
Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs. Enabling therapeutics development from unused plasma fractionation intermediates would therefore constitute a substantial innovation. To this objective, we characterized the proteome of unused plasma fractionation intermediates and prioritized proteins for their potential as new candidate therapies for human disease. We selected ceruloplasmin, a plasma ferroxidase, as a potential therapy for aceruloplasminemia, an adult-onset ultra-rare neurological disease caused by iron accumulation as a result of ceruloplasmin mutations. Intraperitoneally administered ceruloplasmin, purified from an unused plasma fractionation intermediate, was able to prevent neurological, hepatic and hematological phenotypes in ceruloplasmin-deficient mice. These data demonstrate the feasibility of transforming industrial waste plasma fraction into a raw material for manufacturing of new candidate proteins for replacement therapies, optimizing plasma use and reducing waste generation.
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Ceruloplasmina , Trastornos del Metabolismo del Hierro , Enfermedades Neurodegenerativas , Proteoma , Adulto , Humanos , Animales , Ratones , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Proteoma/metabolismo , Enfermedades Raras , Residuos IndustrialesRESUMEN
Two bypassing agents are currently available to circumvent the need for factor FVIII in hemophilia A patients with inhibitors: the activated prothrombin complex FEIBA VH and recombinant activated factor VII (NovoSeven. Both products are highly effective in controlling bleeding in the presence of inhibitory alloantibodies, yet their hemostatic efficacy can be unpredictable. As the results of the FEIBA NovoSeven( Comparative (FENOC) study illustrate, patients may respond better to one bypassing agent than the other. Furthermore, guidelines from an expert panel reflect that responsiveness to bypassing therapy may change from one bleed to the next in the same patient and even from hour to hour during the course of a single bleeding event. These findings underscore the need to have both bypassing products available to treat bleeding episodes in inhibitor patients, to frequently evaluate the efficacy of hemostasis during the course of a bleeding event, and to switch products early if the response to treatment is unsatisfactory.
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Factores de Coagulación Sanguínea/administración & dosificación , Factor VIIa/administración & dosificación , Hemofilia A/tratamiento farmacológico , Inhibidores de Factor de Coagulación Sanguínea/inmunología , Esquema de Medicación , Quimioterapia Combinada , Factor VIII/inmunología , Hemorragia/tratamiento farmacológico , Humanos , Guías de Práctica Clínica como Asunto , Proteínas Recombinantes/administración & dosificaciónRESUMEN
BACKGROUND AND OBJECTIVE: Hepatitis C virus (HCV) infection is frequent in HIV-positive subjects. We evaluated the potential impact of HCV coinfection and other determinants on HIV disease progression in a cohort of long-term non-progressors (LTNPs). STUDY DESIGN: We studied immunological and virological factors in a cohort of 49 LTNPs, 23 of whom progressed during the follow-up (late progressors; LPs). RESULTS: HCV coinfection was detected in 19/26 LTNPs and 15/23 LPs. Univariate analysis showed that HIV viral load was associated with disease progression (P=0.04), and time-to-event analysis indicated that HCV genotype 1 significantly correlated with LTNP status (P=0.031). At multivariate analysis, HIV viremia at study entry remained independently associated with LTNP status (P=0.049). When the most represented genotypes (1 and 3a) were considered in the model, genotype 3a infection (P=0.034) and gender (P=0.035) emerged as independent variables related to HIV disease progression, whereas HIV viral load disappeared. CONCLUSIONS: In addition to HIV viremia, coinfection with different HCV genotypes and gender may affect LTNP status.
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Infecciones por VIH/complicaciones , Sobrevivientes de VIH a Largo Plazo , Hepatitis C/complicaciones , Adulto , Recuento de Linfocito CD4 , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , VIH/fisiología , Infecciones por VIH/inmunología , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , Hepacivirus/genética , Hepacivirus/inmunología , Hepacivirus/aislamiento & purificación , Hepacivirus/fisiología , Hepatitis C/inmunología , Hepatitis C/virología , Humanos , MasculinoRESUMEN
Anti-inhibitor coagulant complex (AICC), an activated prothrombin complex concentrate, has been available for the treatment of patients with inhibitors since 1977, and thromboembolic events (TEEs) have been reported after infusion of AICC in patients with congenital or acquired hemophilia. With the aim of estimating the TEE incidence rate (IR) related to AICC exposure in these patients, a systematic review of the literature was carried out in Medline, according to PRISMA guidelines, from inception date to March 2017. The IR of TEEs was estimated through a meta-analytic approach by using a generalized linear mixed model based on a Poisson distribution. Thirty-nine studies were included (1980-2016). Overall, 46 TEEs were reported; of these, 13 were reported as disseminated intravascular coagulations, 11 as myocardial infarctions, and 3 as thrombotic cerebrovascular accidents. The pooled TEE IR was 2.87 (95% confidence interval [CI], 0.32-25.40) per 100 000 AICC infusions (5.42 in retrospective studies [95% CI, 0.92-31.82]; 1.09 in prospective studies [95% CI, 0.01-238.77]). The TEE rate was 5.09 (95% CI, 0.01-1795.60) per 100 000 AICC infusions administered on demand, whereas no TEEs were reported with prophylaxis. Interestingly, the estimated IR in patients with congenital hemophilia was <0.01 per 100 000 infusions. These findings provide robust evidence of safety of AICC over almost 40 years of published studies.
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: Recent cohort studies showed differences in inhibitor incidence in previously untreated patients (PUPs) with haemophilia A treated with recombinant factor VIII (rFVIII) concentrates. We carried out a systematic literature search and meta-analysis for all randomized clinical trials and observational studies published from 1 January 1988 to 31 August 2015, to assess the incidence of inhibitor development and the relationship with rFVIII product used in PUPs and minimally treated patients (MTPs, ≤5 previous exposure days), with severe haemophilia. The primary outcome measure was development of all inhibitors and high-titre inhibitors. We computed pooled meta-analytic estimates according to the rFVIII product used with the inverse-variance method, assuming a fixed, or a random-effects model if significant between-studies heterogeneity was present. Out of 781 articles, 16 published between 1998 and 2015 were included in the meta-analysis, involving a total of 2094 haemophilia A PUPs or MTPs. The pooled estimate of all inhibitors was 0.27 (95% confidence interval 0.23-0.31). No significant difference in pooled inhibitor incidence across products was found (Pâ=â0.72). Meta-analysis of studies reporting inhibitor hazard ratios with different rFVIII products, adjusted to different risk factors, showed that PUPs/MTPs treated with Advate had a pooled inhibitor hazard ratio estimate of 0.63 (95% confidence interval 0.48-0.83) as compared with Kogenate FS. The overall inhibitor incidence in PUPs/MTPs was 27%. Differences between products were found considering hazard ratios in which potential confounders were taken into account.
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Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Hemofilia A/inmunología , Formación de Anticuerpos , Factor VIII/inmunología , Humanos , Incidencia , Proteínas Recombinantes/uso terapéuticoRESUMEN
: The objective of this study was to assess the cost-effectiveness of pharmacokinetic-driven prophylaxis in severe haemophilia A patients. A microsimulation model was developed to evaluate the cost-effectiveness of pharmacokinetic-driven prophylaxis vs. standard prophylaxis and estimate cost, annual joint bleed rate (AJBR), and incremental cost-effectiveness ratio over a 1-year time horizon for a hypothetical population of 10â000 severe haemophilia A patients. A dose of 30âIU/kg per 48âh was assumed for standard prophylaxis. Pharmacokinetic prophylaxis was individually adjusted to maintain trough levels at least 1 and 5âIU/dl or less. AJBR was estimated on the relationship between factor VIII (FVIII) levels and bleeding rate reported in the literature. Sensitivity analyses were performed to assess the stability of the model and the reliability of results. The FVIII dose was reduced in the 27.8% of patients with a trough level more than 5âIU/dl on standard prophylaxis, with a negligible impact on AJBR (+0.1 bleed/year). The FVIII dose was increased in the 10.6% of patients with trough levels less than 1âIU/dl on standard prophylaxis, with a significant reduction of AJBR (-1.9 bleeds/year). On average, overall, pharmacokinetic-driven prophylaxis was shown to decrease the AJBR from 1.012 to 0.845 with a slight reduction of the infusion dose of 0.36âIU/kg, with total saving of 5â197&OV0556; per patient-year. Pharmacokinetic-driven prophylaxis was preferable (i.e. more effective and less costly) compared with standard prophylaxis, with savings of 31â205&OV0556; per bleed avoided. Pharmacokinetic-driven prophylaxis, accounting for patients' individual pharmacokinetic variability, appears to be a promising strategy to improve outcomes with efficient use of available resources in severe haemophilia A patients.
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Análisis Costo-Beneficio , Hemofilia A/economía , Farmacocinética , Premedicación/métodos , Factor VIII/administración & dosificación , Factor VIII/economía , Hemartrosis/economía , Hemartrosis/prevención & control , Hemofilia A/tratamiento farmacológico , Humanos , Premedicación/economíaAsunto(s)
Factor IX , Factor VIII , Hemofilia A , Hemofilia B , Factor IX/administración & dosificación , Factor IX/economía , Factor VIII/administración & dosificación , Factor VIII/economía , Femenino , Hemofilia A/economía , Hemofilia A/prevención & control , Hemofilia B/economía , Hemofilia B/prevención & control , Humanos , Italia , Masculino , Encuestas y CuestionariosRESUMEN
Hemophilia is a rare bleeding disorder associated with spontaneous and post-traumatic bleeding. Each hemophilia patient requires a personalized approach to episodic or prophylactic treatment, but self-management can be challenging for patients, and avoidable bleeding may occur. Patient-tailored care may provide more effective prevention of bleeding, which in turn, may decrease the likelihood of arthropathy and associated chronic pain, missed time from school or work, and progressive loss of mobility. A strategy is presented here aiming to reduce or eliminate bleeding altogether through a holistic approach based on individual patient characteristics. In an environment of budget constraints, this approach would link procurement to patient outcome, adding incentives for all stakeholders to strive for optimal care and, ultimately, a bleed-free world.
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Hemofilia A/terapia , Hemorragia/prevención & control , Modelos Teóricos , Evaluación de Resultado en la Atención de Salud , Presupuestos , Hemofilia A/economía , Hemofilia A/fisiopatología , Hemorragia/etiología , Salud Holística , Humanos , Medicina de Precisión , Autocuidado/métodosRESUMEN
This prospective, Post-Authorization Safety Surveillance (PASS) study was carried out in patients with hemophilia A or B and inhibitors treated with FEIBA for 1 year to collect real-world data on safety and effectiveness of FEIBA. The study followed a cohort design and did not make stipulations on treatment or observation schedule, as it was designed to observe routine medical practices based on physicians' treatment decisions, including whether patients received on-demand or prophylaxis with FEIBA. The attending physician maintained documentation, including medical records, laboratory reports, adverse event reports, and so on and a subject diary was used. Eighty-one patients were treated with FEIBA at 40 sites in 10 countries over a 4-year period. Sixty-nine patients (85.2%) had hemophilia A, two had (2.5%) hemophilia B, and ten (12.3%) had acquired hemophilia A. At baseline 45 patients (55.6%) were prescribed prophylaxis and 36 (44.6%) on-demand treatment. This study was novel in following safety and effectiveness in 'real world' on-demand and prophylactic use of FEIBA, and was able to collect data in these rare patients under routine clinical practice.
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Factores de Coagulación Sanguínea/uso terapéutico , Coagulantes/uso terapéutico , Hemofilia A/tratamiento farmacológico , Hemofilia B/tratamiento farmacológico , Hemorragia/prevención & control , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Hemofilia A/sangre , Hemofilia B/sangre , Hemorragia/sangre , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Estudios ProspectivosRESUMEN
Prophylaxis is considered optimal care for patients with severe hemophilia to prevent bleeding, including hemarthroses, which may cause arthropathy with chronic pain, occupational impairment and progressive loss of mobility. Questions remain regarding the optimal delivery of prophylaxis including how to individualize prophylaxis and optimize outcomes for each patient. Designing a prophylactic regimen for severe hemophilia must account for each patient's unique disease course, bleeding pattern, presence/absence of joint damage, pharmacokinetic profile, level of physical activity and adherence to treatment. Standard weight-based prophylaxis regimens and regimens optimized by bleeding phenotype (i.e., patients are 'allowed' to bleed to dose optimization) fail to prevent complications in many patients. Pharmacokinetic-guided dosing enables precise adjustment of dosing level and frequency to maintain adequate hemostatic levels and prevent bleeding. Optimal outcomes, such as reducing or eliminating hemorrhages, preventing or minimizing joint damage, and improving quality of life, can be achieved through an individualized care approach.
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Hemofilia A/tratamiento farmacológico , Hemartrosis , Humanos , Medicina de PrecisiónRESUMEN
Immunological abnormalities have been reported in haemophiliacs. Although infections with HIV, hepatitis and other viruses may contribute to these abnormalities, immune defects are detectable also in HIV seronegative haemophiliacs. It is likely that chronic exposure to extraneous proteins in clotting factor concentrates (CFCs) may play a role in immunomodulation, but the underlying mechanisms remain unclear. The results of the present paper show that: a) soluble HLA class I (sHLA-I), soluble Fas-ligand (sFas-L) and transforming growth factor beta 1 (TGF-beta1) are detectable in plasma derived but not in recombinant CFCs; b) the level of sHLA-I and sFas-L is proportional to the grade of CFCs purity whereas TGF-beta1 showed very variable levels; c) soluble molecules detected in CFCs exert immunomodulatory effects in vitro like apoptosis induction in Jurkat cells and inhibition of mixed lymphocyte reaction response, antigen-specific lymphocyte cytotoxic activity and neutrophil chemotaxis.
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Factores de Coagulación Sanguínea/aislamiento & purificación , Contaminación de Medicamentos , Antígenos HLA/análisis , Terapia de Inmunosupresión , Linfocitos/efectos de los fármacos , Glicoproteínas de Membrana/análisis , Neutrófilos/efectos de los fármacos , Factor de Crecimiento Transformador beta/análisis , Apoptosis/efectos de los fármacos , Factores de Coagulación Sanguínea/genética , Factores de Coagulación Sanguínea/uso terapéutico , Quimiotaxis de Leucocito/efectos de los fármacos , Pruebas Inmunológicas de Citotoxicidad , Proteína Ligando Fas , Antígenos HLA/sangre , Antígenos HLA/farmacología , Hemofilia A/sangre , Hemofilia A/tratamiento farmacológico , Hemofilia A/inmunología , Humanos , Células Jurkat/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Linfocitos/fisiología , Glicoproteínas de Membrana/sangre , Glicoproteínas de Membrana/farmacología , N-Formilmetionina Leucil-Fenilalanina/farmacología , Neutrófilos/fisiología , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/uso terapéutico , Estallido Respiratorio/efectos de los fármacos , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Factor de Crecimiento Transformador beta/sangre , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta1RESUMEN
On demand treatment of bleeding episodes is still the main approach to hemophilia care of patients of any age. Prompt infusion of coagulation factor concentrate in the home setting allows treatment of hemorrhages at early onset, reducing the incidence of complications and improving the quality of life. Nevertheless, the technological evolution and progressive improvement in the safety of therapeutic products have changed the management of the disease, particularly in children. The current availability of safer concentrates has drastically reduced the risk of transmission of blood-borne infections. Innovative approaches, such as early primary prophylaxis and immune tolerance induction, have become feasible and their introduction represents a major advance in the achievement of the main therapeutic goals: control of the bleeding diathesis and elimination of inhibitors. Prophylactic regimens have been shown to be effective in preventing the occurrence not only of joint bleeding but also of arthropathy when started early in children with severe hemophilia. Inhibitor development still represents the main complication of hemophilia treatment, making concentrate administration ineffective. Immune tolerance induction by daily infusion of coagulation factor concentrate was shown to eradicate the inhibitors in 63 to 83% of patients. These intensive treatment regimens are administered at home to very young children and create the problem of adequate venous access. Subcutaneous venous ports have been used in patients with hemophilia if peripheral veins could not be frequently accessed; however, the risk of infection is an important limit to their use.
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Hemofilia A/terapia , Profilaxis Antibiótica/métodos , Factores de Coagulación Sanguínea/uso terapéutico , Niño , Hemofilia A/inmunología , Hemofilia A/fisiopatología , Humanos , AutoadministraciónRESUMEN
This paper focuses on the benefits of prophylaxis, compared with on-demand therapy, in achieving long-term treatment goals in hemophilia patients. While primary treatment goals are to prevent joint damage and improve quality of life, other issues such as treatment costs-balanced against improvements in health status and direct and indirect costs of hemophilic arthropathy-need to be considered. The ESPRIT study (Evaluation Study on Prophylaxis: a Randomized Italian Trial), a 10-year trial comparing on-demand and prophylactic treatment in terms of efficacy, safety, and cost, is discussed. Early results support findings from other studies regarding the benefits of prophylaxis. Prospective pharmacoeconomic evaluations are needed to help define optimal treatment programs for patients with hemophilia A and B.
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Hemofilia B/terapia , Calidad de Vida , Factor IX/economía , Factor IX/uso terapéutico , Hemofilia B/economía , Humanos , Premedicación/economía , Proteínas Recombinantes/economía , Proteínas Recombinantes/uso terapéutico , Resultado del TratamientoRESUMEN
INTRODUCTION: Haemophilia A is due to factor VIII (FVIII) deficiency. The main treatment is replacement therapy with FVIII concentrates. However, these concentrates carried a high risk of blood-borne viral infections and still have a high risk of inducing anti-FVIII inhibitors. AREAS COVERED: An overview of products available and therapeutic options for haemophilia A management in order to help in decision making. A literature search using Medline with the keywords: 'haemophilia', 'factor VIII', 'therapy', 'inhibitor', 'concentrate', 'bleeding', 'prophylaxis', 'on demand', 'plasma-derived', 'recombinant', 'coagulation factors', 'immunotolerance' was performed. The years 1960 - 2010 are included. EXPERT OPINION: Progress in management of patients with haemophilia A has allowed increased life expectancy and quality of life. There is evidence that prophylaxis prevents or, at least, slows down arthropathy development when started early in childhood. FVIII concentrates have achieved high levels of blood-borne pathogen safety. However, treatment is frequently complicated by development of FVIII-neutralizing inhibitors, which prevent control of bleeding and predispose to a high morbidity and mortality risk. Bypassing agents are effective in bleeding treatment in a high percentage of cases. Prophylaxis with bypassing agents and their use in combination are offering opportunities in management of inhibitor patients. More evidence is necessary to understand how to prevent and manage this complication.
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Factores de Coagulación Sanguínea/uso terapéutico , Hemofilia A/tratamiento farmacológico , Animales , HumanosRESUMEN
BACKGROUND: No evidence-based treatment guidelines are currently available for the treatment of problem bleedings in patients with hemophilia who develop clotting factor inhibitors. A treatment algorithm was developed previously to help providers optimize the approach to the treatment of this patient population. The algorithm provides the specific intervals between treatments; however, it does not specify dosing recommendations and does not offer insights into the likelihood of outcome improvements at each time interval. OBJECTIVE: To develop a model to analyze the impact on patient outcomes and costs of adhering to a current treatment algorithm for the 2 available clotting therapies to treat bleeding episodes in patients with hemophilia who develop clotting factor inhibitors. METHODS: A simulation model was developed using a modified Delphi method approach based on a consensus opinion of an expert panel. The model was used to analyze the impact of following the available treatment algorithm on patient outcomes and costs. Treatment patterns and the likelihood of a resolved bleeding episode associated with following the treatment algorithm (ie, adherence) were compared with not following the algorithm (ie, nonadherence). This model assumed 2 scenarios in which treatment was initiated with each of the 2 bypassing agents currently available, and clinical and economic outcomes were mapped for adhering to and not adhering to the consensus treatment algorithm. RESULTS: The simulation model shows that adhering to the treatment algorithm would result in 74.4% of patients improving at 72 hours compared with only 56.7% of patients when not adhering to the algorithm. According to this model, regardless of the bypassing agent used at initiation, adherence to the treatment algorithm would result in fewer patients requiring combined sequential therapy with the 2 bypassing agents for 3 days. In addition, using this analytic model, reducing the percentage of patients with hemophilia who required combined sequential therapy by 17.6% resulted in an average cost-savings of $16,305 per patient. CONCLUSION: Adherence to an algorithm in which treatment is altered at regular intervals based on a patient's clinical response has the potential to improve patient outcomes and reduce the number of nonresponsive patients requiring sequential therapy in patients with hemophilia who have clotting factor inhibitors and are experiencing problem bleeding episodes. >Adherence to the algorithm would also result in reduced costs to patients and payers.
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The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitor-bypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor VIIa (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (-11.4%-15.7%), P=.059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www.clinicaltrials.gov as #NCT00166309.