K. Fischer

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.

Phenotype of severe hemophilia A and plasma levels of risk factors for thrombosis

*Van Creveldkliniek, University Medical Center Utrecht, Utrecht; Julius Center for Health Sciences and Primary Care, University Medical CenterUtrecht, Utrecht; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden; §Department of Hematology, UniversityMedical Center Utrecht, Utrecht; and –Department of Pediatrics, Wilhelmina Childrens Hospital, University Medical Center Utrecht, Utrecht,the NetherlandsTo cite this article: van Dijk K, van der Bom JG, Fischer K, de Groot PG, van den Berg HM. Phenotype of severe hemophilia A and plasma levels ofrisk factors for thrombosis. J Thromb Haemost 2007; 5: 1062–4.

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

Summary.  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

Domain specificity of factor VIII inhibitors during immune tolerance induction in patients with haemophilia A

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.

Choosing outcome assessment tools in haemophilia care and research: a multidisciplinary perspective

Summary.  Introduction‐Frequent administration of high dosages factor VIII (FVIII), so‐called immune tolerance induction (ITI), provides an efficient strategy to eradicate inhibitory antibodies in patients with haemophilia A. At present, our knowledge on the characteristics of inhibitory antibodies in patients undergoing ITI is limited. Aim‐In this study we characterized the domain specificity of FVIII inhibitors in 11 haemophilia A patients during ITI. Results‐In three of six patients who were successfully tolerized, inhibitory antibodies were directed predominantly against the FVIII light chain. In two other patients within this group, a significant contribution of A2 antibodies was observed which did not change during treatment. In the sixth patient the relative contribution of A2 inhibitors declined which coincided with an increase in antilight chain antibodies. In four of five patients who failed ITI, A2 inhibitors were observed. In two patients the contribution of A2 inhibitors increased during treatment, while in two other patients the contribution of A2 inhibitor remained constant. The fifth patient had inhibitory antibodies predominantly directed against the FVIII light chain. Conclusion‐Overall, our findings revealed changes in domain specificity of FVIII antibodies in five of 11 patients analysed. Remarkably, antibodies exclusively directed towards the light chain of FVIII were predominantly observed in patients who were successfully tolerized.

Haemophilia prophylaxis: how can we justify the costs?

The implementation of early long‐term, regular clotting factor concentrate (CFC) replacement therapy (‘prophylaxis’) has made it possible to offer boys with haemophilia a near normal life. Many different regimens have reported favourable results, but the optimum treatment regimens have not been established and the cost of prophylaxis is very high. Both for optimizing treatment and reimbursement issues, there is a need to provide objective evidence of both short‐ and long‐term results and benefits of prophylactic regimens.

Do the SIPPET study results apply to the patients I treat

Summary.  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.

Promoting self‐management and adherence during prophylaxis: evidence‐based recommendations for haemophilia professionals

To the editor, We thank the investigators and participants of SIPPET (Survey of Inhibitors in Plasma-Products Exposed Toddlers) study [1] for their invaluable commitment to provide evidence for the improvement of care for haemophilia. While we do not question that in SIPPET, plasma-derived concentrates were associated with lower risk of developing inhibitors; we regret to see that incomplete reporting of the study precludes the adoption of study results in clinical practice. After establishing that the study results are valid (i.e. the two study arms were balanced, and results are unconfounded), each doctor has to evaluate the applicability of the study results, which includes similarity of the study population and treatment to those the doctor cares for. First question is why the baseline inhibitor risk was higher than previous reports [2,3] and if the SIPPET patients were really PUPs (Previously untreated patients). At 35.4%, the baseline inhibitor risk was higher than the 25% expected by the investigators in their protocol. How can this be explained? How is baseline inhibitor risk affected by the exposure of some patients to different blood products prior to enrolment to the study? The authors do not report in detail about this previous treatment, although it may have impact on results. We do not know, if the risk of inhibitors is the same for those, who were really PUPs, compared to those, who were treated with one unit of red blood cells concentrate and/or those, who received cryoprecipitate four times. Nor do we know if inhibitor risk was underestimated by the fact that not all patients were followed until 50 EDs. The second question is whether clinical management was really comparable between treatment arms and comparable to practice reflecting current guidelines in Europe and North America. The SIPPET reports that treatment was decided solely by the site investigators but insufficient information is provided about what that treatment was; neither if treatment was the same in both study arms. Especially, since not all centres included more than one patient, randomization may not have been successful in achieving comparable treatment between both arms. Moreover, randomization with a block size of two per centre, when not all consecutive patients were enrolled, poses a risk of selection bias (‘confounding by indication’). Treatment data provided also suggest that SIPPET patients started treatment later (median 20 months) and were treated less intensively (just 15% on standard prophylaxis and 7 EDs/year while treated on demand) than is current European/North American practice. It is well known that treatment intensity affects inhibitor risk [4], yet details of prophylaxis and dosing were not provided. The third question is whether data gathered mostly on first or second generation recombinant concentrates apply to third or fourth generation recombinant concentrates. Providing treatment details and presenting inhibitor rates according to treatment regimen/intensity (e.g. European/American vs. Eastern/African patients) and according to concentrate may allow assessment of generalizability. We hope that the authors will be able to provide this information to the haemophilia community.

Achievements, challenges and unmet needs for haemophilia patients with inhibitors

Throughout life, a patient with severe haemophilia is confronted with many treatment‐related challenges. Insight into self‐management and non‐adherence could improve the quality of care for these patients. The aim of this study was to provide an overview of the current evidence on self‐management and adherence to prophylaxis in haemophilia.

A consensus statement on clinical trials of bypassing agent prophylaxis in inhibitor patients

Over the past 20 years, there have been many advances in haemophilia treatment that have allowed patients to take greater control of their disease. However, the development of factor VIII (FVIII) inhibitors is the greatest complication of the disease and a challenge in the treatment of haemophilia making management of bleeding episodes difficult and surgical procedures very challenging. A meeting to discuss the unmet needs of haemophilia patients with inhibitors was held in Paris on 20 November 2014. Topics discussed were genetic and non‐genetic risk factors for the development of inhibitors, immunological aspects of inhibitor development, FVIII products and inhibitor development, generation and functional properties of engineered antigen‐specific T regulatory cells, suppression of immune responses to FVIII, prophylaxis in haemophilia patients with inhibitors, epitope mapping of FVIII inhibitors, current controversies in immune tolerance induction therapy, surgery in haemophilia patients with inhibitors and future perspectives for the treatment of haemophilia patients with inhibitors. A summary of the key points discussed is presented in this paper.