Emily Oliovecchio

Mortality and causes of death in Italian persons with haemophilia, 1990–2007

Summary.  Although a number of studies have analysed so far the causes of death and the life expectancy in haemophilic populations, no investigations have been conducted among Italian haemophilia centres. Thus, the aim of this study was to investigate mortality, causes of deaths, life expectancy and co‐morbidities in Italian persons with haemophilia (PWH). Data pertaining to a total of 443 PWH who died between 1980 and 2007 were retrospectively collected in the 30 centres who are members of the Italian Association of Haemophilia Centres that chose to participate. The mortality rate ratio standardized to the male Italian population (SMR) was reduced during the periods 1990–1999 and 2000–2007 such that during the latter, death rate overlapped that of the general population (SMR 1990–1999: 1.98 95% CI 1.54–2.51; SMR 2000–2007: 1.08 95% CI 0.83–1.40). Similarly, life expectancy in the whole haemophilic population increased in the same period (71.2 years in 2000–2007 vs. 64.0 in 1990–1999), approaching that of the general male population. While human immunodeficiency virus infection was the main cause of death (45%), 13% of deaths were caused by hepatitis C‐associated complications. The results of this retrospective study show that in Italian PWH improvements in the quality of treatment and global medical care provided by specialized haemophilia centres resulted in a significantly increased life expectancy.

Italian Registry of Haemophilia and Allied Disorders. Objectives, methodology and data analysis.

Summary.  National haemophilia registries are powerful instruments to support health care and research. A national registry was established in Italy by the Ministry of Health until 1999. Since 2003 the Italian Association of Haemophilia Centres (AICE) started a new programme aiming at building up the Italian Registry of Haemophilia and Allied Disorders. The AICE identified an expert panel to steer the registry. A computer software to assist patient management was developed and all the AICE‐affiliated haemophilia treatment centres (HTC) were prompted to adopt it. Twice a year a predefined set of anonymized data is centralized and merged into a national database. Duplicated entries are managed through a confidentiality sparing mechanism. The database covers sociodemographic, clinical, laboratory and treatment data. A subset of data are shared with the Ministry of Health (Istituto Superiore di Sanità,ISS).Overall, data were collected six times by 43 of 49 HTC; 41 centres updated their patients’ records up to December 2006. The database contains 6632 unique records, 442 of them referring to dead patients. Database growth and missing data clearance showed a constantly positive trend over time. The database has collected records of the following alive patients – haemophilia A: 1364 severe, 398 moderate and 935 mild; haemophilia B: 231 severe, 138 moderate and 204 mild; von Willebrand’s disease: 1208 type 1, 346 type 2 and 96 type 3. Inhibitor patients were 296 (of which 194 high responders and 65 low responders).The Italian registry run by AICE adds to the list of the available national haemophilia registries and is intended to establish treatment guidelines and foster research projects in Italy.

Management of Inherited von Willebrand Disease in Italy: Results from the Retrospective Study on 1234 Patients

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to quantitative and/or qualitative defects of von Willebrand factor (VWF). Despite the improved knowledge of the disease, detailed data on VWD types requiring specific treatments have not been reported thus far. To determine the number and types of VWD requiring therapy with desmopressin (DDAVP) and/or VWF/FVIII concentrates in Italy, a national registry on VWD (RENAWI) was organized. Only 16 of 48 centers included VWD in the RENAWI with diagnoses performed locally. Patients with uncertain results were retested by two expert laboratories using multimeric analysis and mutations of the VWF gene. A total of 1234 of 1529 (81%) cases satisfied the inclusion criteria and could be classified as VWD1 (63%), VWD2A (7%), VWD2B (6%), VWD2M (18%), VWD2N (1%), and VWD3 (5%). VWD types were also confirmed by DNA analyses and occur in young adults (83%), mainly in women (58%). Mucosal bleedings (32 to 57%) are more frequent than hematomas (13%) or hemarthrosis (6%). Most patients were exposed to an infusion trial with desmopressin (DDAVP) and found responsive with the following rates: VWD1 (69%), VWD2A (26%), VWD2M (29%), and VWD2N (71%). However, DDAVP was not always used to manage bleeding in all responsive patients and VWF/FVIII concentrates were given instead of or together with DDAVP in VWD1 (30%), VWD2A (84%), VWD2B (62%), VWD2M (63%), VWD2N (30%), and VWD3 (91%). Data of the RENAWI showed that correct VWD identification and classification might be difficult in many Italian centers. Therefore, evidence-based studies should be organized only in well-characterized patients tested by laboratories that are expert in the clinical, laboratory, and molecular markers of VWD.

Replacement therapy with recombinant factor IX. A multicentre evaluation of current dosing practices in Italy

BACKGROUND The in vivo recovery of recombinant factor IX (rFIX) is reported to be lower than that of plasma-derived products, with potential clinical implications for dosing. In clinical practice, a conversion (augmentation) factor is suggested to calculate the necessary doses of rFIX. The aim of this study was to assess the range of values for the conversion factor in usual clinical practice in Italy. MATERIALS AND METHODS The study was questionnaire-based and proposed to all Italian Haemophilia centres treating patients with haemophilia B. Age, weight, dosage used in the last effective infusion, treatment regimen (prophylaxis versus on-demand), human immunodeficiency virus (HIV) and hepatitis C virus (HCV) status, and years of previous therapy with rFIX were recorded for patients with severe haemophilia B treated with rFIX. Mean, standard deviation, median and range were calculated for demographic and treatment data for the overall population and for subgroups. The conversion factor for the theoretical dosage of 40 IU/Kg was calculated. RESULTS Among 207 patients with severe haemophilia B being followed in 24 centres, 138 (66.7%) were being treated with rFIX. The sample of 207 patients represents 83.1% of the population of Italian patients with severe haemophilia B. The age range of the studied patients was 0-72 years (mean, 24 years) and the weight range was 3-108 kg (mean, 60 kg). Nineteen patients (14.4%) were positive for HIV and 51 (42.9%) were positive for HCV. The mean dosage of rFIX was 44 IU/Kg, with no significant difference between those receiving the product as prophylaxis or on-demand. A reduction in dosage was observed with increasing age (0.23 IU/kg/year). The mean value for the conversion factor was 1.10 ± 0.36 (median 1.00, range 0.51-2.08), when estimated for the whole population. No effect of HIV and HCV status was found on the dose prescribed. No evident correlation was found with the underlying genetic mutation. DISCUSSION We found that dosing of rFIX in clinical practice is very close to that of plasma-derived FIX concentrates. As a consequence, dosing in the non-surgical setting should be started using the same criteria as those for plasma-derived FIX and treatment effectiveness verified on a clinical basis rather than relying on in vivo recovery assessments.

Current status of Italian Registries on inherited bleeding disorders.

Inherited bleeding disorders are a group of congenital coagulopathies resulting when deficiencies of the proteins responsible for coagulation, platelet function or fibrinolysis occur. Haemophilia A (HA, deficiency of factor VIII), Haemophilia B (HB, deficiency of factor IX) and von Willebrand Disease (vWD) are the most frequent, being >90% of all inherited bleeding disorders with a prevalence of 0.5, 0.1 and 1–5/10,000 respectively1–3. Other rare inherited bleeding disorders are represented by deficiencies of factor I, II, V, VII, X, XI, XII, XIII, combined V+VIII, combined vitamin K-dependent factors, with a general population prevalence between 1/500,000 and 1/2,000,0004. Inherited bleeding disorders require wide-ranging care and effective management within a multidisciplinary team setting. The modern treatments of inherited bleeding disorders are now remarkably effective, although expensive. In Italy the epidemiological data on inherited bleeding disorders derive from three registries: The Italian National Registry for Rare Diseases (RNMR); The National Registry of Congenital Coagulopathies (RNCC); The Haemophilia Database of the Italian Association of Haemophilia Centres (AICE). These registries differ in terms of organisation, purpose and data collection process. A general description and results for each registry is reported as follow.

Present and future challenges in the treatment of haemophilia: the patient’s perspective

Haemophilia is a rare bleeding disorder, caused by a mutation in the genes for factor VIII (Haemophilia A) and factor IX (Haemophilia B). Patients with severe haemophilia, with a factor plasma level of 1% or less, are affected by frequent episodes of spontaneous or excessive bleeding into joints and muscles. The current management of haemophilia is based on treatment with plasma-derived and recombinant factor VIII (FVIII) or factor IX products (FIX)1. Home treatment has shown to improve both life expectancy and quality of life of patients with haemophilia and other inherited coagulation disorders (PWH), with a reduction of musculoskeletal damage2.

Italian Registries on Bleeding Disorders

To the Editor:We read with interest the review “The Growing Number of Hemophilia Registries: Quantity vs. Quality” by Keipert et al. on the current status of hemophilia registries in Europe. The authors discussed the diversity of the registries and underlined the importance of the harmonization to develop a pan-European strategy. The authors mentioned the Italian situation with some mistakes and inaccuracies, citing three different registries with no interoperability, that instead are strictly connected, so we need to supply an overview of these three tools. The correct data are reported in Table 1. The National Registry of Congenital Coagulopathies is a specific pathology registry, implemented at the National Institute of Health (ISS) and realized, in the current status, in stringent collaboration with the Italian Hemophilia Centers Association (AICE) and Patient’s Association (FedEmo). AICE is continuously monitoring and encouraging the participation of hemophilia treatment centers to data transmission, based on an electronic platform in which local physicians send data to the AICE database, shared with the ISS. AICE has identified ISS as the national organization in charge of the analysis and diffusion of the epidemiological data and the association itself utilizes the database as a research oriented instrument providing data for clinical studies. The National Registry of Congenital Coagulopathies supplies epidemiological data on the prevalence of the different congenital bleeding disorders in Italy, on therapy complications (infections and inhibitor antibodies), and on the needs of drugs for hemophilia treatment therapy. Data are published on the website of the ISS and through scientific publications. The Italian National Registry for Rare Diseases, established by law in 2001, is located at the National Centre for Rare Diseases of ISS. It collects data on 495 rare diseases, among which are congenital bleeding disorders. The person responsible for this registry is involved in several European projects (RD-Connect, EUCERD, and EPIRARE). Among the future directions of the Italian National Registry for Rare Diseases, there is the need to develop registries on specific rare diseases, to better understand their natural history, and, in this context, bleeding disorders are the subject of a collaboration with the National Registry of Congenital Coagulopathies. The Italian experience, aimed to the optimization of a national registry on bleeding disorders, can be considered adequate and can share reliable data at an international level. We agree with the value of a multinational registry, based on integration and harmonization of data, which should be the result of a network of different national registries, able to monitor and increase long-term safety of all the patients.

Rate and appropriateness of polypharmacy in older patients with hemophilia compared with age-matched controls

In older people, multiple chronic ailments lead to the intake of multiple medications (polypharmacy) that carry a number of negative consequences (adverse events, prescription and intake errors, poor adherence, higher mortality). Because ageing patients with haemophilia (PWHs) may be particularly at risk due to their pre‐existing multiple comorbidities (arthropathy, liver disease), we chose to analyse the pattern of chronic drug intake in a cohort of PWHs aged 60 years or more.

Definition of an organisational model for the prevention and reduction of health and social impacts of inherited bleeding disorders.

INTRODUCTION Due to the increase in life expectancy, patients with haemophilia and other inherited bleeding disorders are experiencing age-related comorbidities that present new challenges. In order to meet current and emerging needs, a model for healthcare pathways was developed through a project funded by the Italian Ministry of Health. The project aimed to prevent or reduce the social-health burden of the disease and its complications. MATERIAL AND METHODS The National Blood Centre appointed a panel of experts comprising clinicians, patients, National and Regional Health Authority representatives. Following an analysis of the scientific and regulatory references, the panel drafted a technical proposal containing recommendations for Regional Health Authorities, which has been formally submitted to the Ministry of Health. Finally, a set of indicators to monitor haemophilia care provision has been defined. RESULTS In the technical document, the panel of experts proposed the adoption of health policy recommendations summarised in areas, such as: multidisciplinary integrated approach for optimal healthcare provision; networking and protocols for emergency care; home therapy; registries/databases; replacement therapy supply and distribution; recruitment and training of experts in bleeding disorders. The recommendations became the content of proposal of agreement between the Government and the Regions. Monitoring and evaluation of haemophilia care through the set of established indicators was partially performed due to limited available data. CONCLUSIONS The project provided recommendations for the clinical and organisational management of patient with haemophilia. A particular concern was given to those areas that play a critical role in the comorbidities and complications prevention. Recommendations are expected to harmonise healthcare care delivery across regional networks and building the foundation for the national haemophilia network.

Uncovered needs in the management of inherited bleeding disorders in Italy.

Haemophilia is an X-linked bleeding disorder1 and is characterised by repeated bleeding, especially in joints. The current management of haemophilia is based on the replacement therapy with intravenous clotting factor and includes plasma-derived and recombinant factor concentrates2. The early treatment in pediatrics age has been recognised as an important determinant of better physical development3, and several studies have demonstrated that primary prophylaxis has a positive and significant impact on the quality of life and the prevention of arthropathy in haemophiliac children4,5. Also, home treatment has shown to improve both life expectancy and quality of life of patients with haemophilia6. The global treatment of haemophilia, however, requires a multidisciplinary team including haematologists, physicians, surgeons, orthopaedics and other specialists in several medical areas7. This level of clinical assistance is or can be guaranteed only in some countries, and this influences the life expectancy of haemophiliacs8. To ensure a high quality of haemophilia care, an appropriate health organisation and economic resources are necessary. The European Principles of Haemophilia Care (EPHC) were published in 20089. These Principles detail the standard of haemophilia care that should be achieved for an appropriate global care of persons with haemophilia (PWH). The aim of this review is to highlight uncovered needs of Italian haemophilia community, relative to the implementation of each of the EPHC.