Paul Giangrande

Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C

BACKGROUND Most people with haemophilia who were treated with blood products before the introduction of virus-inactivation procedures were infected with the hepatitis-C virus (HCV). However, there is little quantitative information about the long-term effects on mortality of such infection. METHODS We carried out a cohort study of mortality from liver cancer and liver disease in 4865 haemophilic men and boys in the UK. They were treated between 1969 and 1985 with blood products carrying a high risk of HCV infection, and were followed up from first recorded exposure to Jan 1, 1993. FINDINGS Based on death-certificate information, mortality was 16.7 times higher than in the general population for liver disease (95% CI 12.5-22.0; 51 deaths), and 5.6 times higher (1.8-13.0; five deaths) for liver cancer. For men and boys with severe haemophilia who were not infected with HIV-1, the cumulative risks of death from chronic or unspecified liver disease or from liver cancer in the 25 years since first recorded exposure to high HCV-risk products were 1.4% (0.7-3.0) at all ages, and 0.10% (0.01-0.7), 2.2% (0.8-6.1), and 14.3% (4.5-40.9) for those with first recorded exposure at ages under 25, 25-44, and 45 or older. For those with haemophilia and HIV-1 infection, the corresponding risks were 6.5% (4.5-9.5) at all ages, and 3.8% (2.1-6.8), 17.1% (10.0-28.5), and 18.7% (6.4-47.6) in the three age-groups. In those with severe haemophilia, age-standardised all-cause mortality was stable during 1969-84 but increased during 1985-92 in both HIV-1-infected and HIV-1-uninfected groups. Among those not infected with HIV-1, the increase in all-cause mortality resulted largely from deaths attributed to chronic or unspecified liver disease or liver cancer in men aged over 45. INTERPRETATION There is an emerging risk of mortality from liver disease and liver cancer in the UK haemophilia population in individuals both infected and uninfected with HIV-1, which probably results from infection with hepatitis C.

Consensus perspectives on prophylactic therapy for haemophilia: summary statement

Summary.  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.

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 patients 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.

Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders

Summary.  Background:  The European Network of Rare Bleeding Disorders (EN‐RBD) was established to bridge the gap between knowledge and practise in the care of patients with RBDs.

Enhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia B

Replacement therapy with factor IX (FIX) concentrates is the recommended treatment for patients with hemophilia B, an X-linked bleeding disorder occurring in 1:25,000 male births. N9-GP is a recombinant FIX molecule with a prolonged half-life which is obtained by site-directed glycoPEGylation where a 40-kDa polyethylene glycol molecule is attached to the activation peptide of FIX. This first human dose trial in patients with hemophilia B investigated the safety and pharmacokinetic properties of a single IV dose of N9-GP. Sixteen previously treated patients received one dose of their previous FIX product followed by one dose of N9-GP at the same dose level (25, 50, or 100 U/kg). None of the patients developed inhibitors. One patient developed transient hypersensitivity symptoms during administration of N9-GP and was excluded from pharmacokinetic analyses. In the remaining 15 patients, N9-GP was well-tolerated. The half-life was 93 hours, which was 5 times higher than the patients previous product. The incremental recovery of N9-GP was 94% and 20% higher compared with recombinant and plasma-derived products, respectively. These results indicate that N9-GP has the potential to reduce dosing frequency while providing effective treatment of bleeding episodes with a single dose. The trial was registered at www.clinicaltrials.gov as NCT00956345.

Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with haemophilia A

Summary.  To establish the pharmacokinetic profile of activated recombinant coagulation factor VII (rFVIIa; NovoSeven®) in children with haemophilia A, and to compare it with the pharmacokinetic profile in adults with haemophilia A.

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.

Haemophilia care in Europe - a survey of 35 countries.

A questionnaire was circulated in 2012 to national haemophilia patient organizations in Europe affiliated to the European Haemophilia Consortium (EHC) and the World Federation of Hemophilia (WFH) to seek information about the organization of haemophilia care and treatment available at a national level. The 35 responses received highlighted major differences in the availability of treatment and care. There was a wide range in factor VIII consumption with usage ranging from 0.20 IU per capita in Armenia to 8.56 IU per capita in Sweden (median: IU per capita). The decrease in health budgets in many countries was not matched by decreases in use of FVIII per capita. In the 19 countries that responded to the previous survey, there was a significant improvement in access to prophylaxis and home treatment.

Consensus protocol for the use of recombinant activated factor VII [eptacog alfa (activated); NovoSeven®] in elective orthopaedic surgery in haemophilic patients with inhibitors

Summary.  Patients with haemophilia complicated by inhibitors have a significant burden of joint disease, which is associated with a negative impact on their quality of life. Successful elective orthopaedic surgery can result in decreased bleed frequency into a new joint, less time spent in hospital, increased mobility and improved well being. This paper describes a new protocol for use of recombinant activated factor VII (rFVIIa) in elective orthopaedic surgery, based on a review of published data as well as the personal experience of a group of expert physicians. The protocol offers guidance on the planning of the surgery and preoperative testing as well as the bolus schedule for rFVIIa and advice on the concomitant use of antifibrinolytic agents and fibrin sealants. A total of 10 operations involving 13 procedures in eight patients in five comprehensive care centres have been undertaken until now using the protocol, which employs an initial bolus dose of rFVIIa in the range of 120–180 μg kg−1 to cover surgery. The clinical experience reported here encompasses all cases of elective orthopaedic surgery using rFVIIa as initial treatment carried out in the UK and Republic of Ireland over the last 2 years. In all cases, there was good control of haemostasis during surgery and the final outcome was rated as ‘excellent’ or ‘extremely satisfactory’ by the reporting clinicians. Although the initial cost of product to cover surgery such as arthroplasty is high, it needs to be borne in mind that this may be offset in subsequent years by savings resulting from avoidance of bleeding episodes in the affected joint.

Cost effectiveness of haemophilia treatment: a cross-national assessment.

The aim of this study was to assess the incremental cost effectiveness of on-demand versus prophylactic haemophilia therapy in Germany, Sweden, the United Kingdom and The Netherlands from the third-party payers’ perspective. Using a decision tree model, the cost effectiveness of on-demand versus prophylactic therapy was analysed by extrapolating data from the European Haemophilia Economic Study to a 1-year analytic time horizon. Five hundred and six patients with severe haemophilia A and B, without inhibitors and at least 14 years of age, were enrolled in this study. Patients treated prophylactically had fewer bleeds than patients treated on-demand. With prophylactic treatment, the incremental cost per avoided bleeding ranged from &U20AC;6650 for patients 30 years of age or younger in Germany to &U20AC;14 140 for patients over 30 years old in Sweden. If quality of life was taken into account, patients receiving prophylactic treatment had higher mean utilities than patients on on-demand therapy. The incremental effectiveness ratios in Germany were &U20AC;1.2 million per quality-adjusted life year gained for patients 30 years or younger and HIV-positive and &U20AC;2.2 million for patients 30 years or younger and HIV-negative. In the group aged over 30 years and HIV-positive the on-demand treatment strategy was dominant, whereas in the over 30 years/HIV-negative group the incremental cost-utility ratio was &U20AC;4.7 million per quality-adjusted life year. Based on our decision analysis, the use of prophylactic treatment was overall more effective than on-demand therapy in young haemophiliacs, but at extremely high cost.