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European Consensus for treatment of hemophilia
products for treatment. The first Kreuth meeting also dealt with the optimal use of the available products in hemo- philia therapy, emphasizing that the main priority was the safety of blood and blood products. Attention was also given to the need to guarantee an effective treatment, ensuring that all subjects with coagulation disorders can benefit from these lifesaving therapies.1
The following Kreuth meetings were periodically con- vened under the joint auspices of the Ludwig-Maximilian University of Munich (LMU), the Paul Ehrlich Institute (PEI), and the Council of Europe through its European Directorate for the Quality of Medicines and Healthcare (EDQM), under the aegis of the European Committee on Blood Transfusion (CD-P-TS). The latter institution pro- vides resolutions that are non-binding but that are still strong indications for member states. The second Kreuth meeting in 2009 was attended by 110 transfusion medi- cine experts, hemophilia clinicians and regulatory author- ity representatives from 38 countries. New recommenda- tions were provided regarding the best clinical practice on hemophilia, home treatment, genetic counselling and equal treatment across European member states.2
The following two meetings in 2013 and 2016 focused on the optimal use of coagulation factors and provided the opportunity to review trends in the use of factor concen- trates.3,4 A total of 12 recommendations were made in 2016, dealing with national protocols or guidelines for the management of aging patients with hemophilia, the min- imum utilization of FVIII and FIX concentrates in each country, treatment for hepatitis C with direct-acting antiviral agents, genotype analysis for all patients with severe hemophilia, access to bypassing agents and immune tolerance for those with inhibitors, individualiza- tion of treatment regimens with extended half-life prod- ucts and the attainment of the highest possible rate of bleeding prevention by increasing the trough plasma fac- tor levels. The recommendations emerging from the 2013 and 2016 Kreuth meetings were subsequently incorporat- ed by the EDQM into proposals for resolutions adopted by the Committee of Ministers of the Council of Europe, with the objective of increasing their visibility and provid- ing official support. The 2017 Resolution [Resolution CM/Res(2017)43 on principles concerning hemophilia therapies]5 listed 17 principles.
The 2019 meeting was the most recent opportunity for the official delegates nominated by 26 Council of Europe members and observer states, along with members from the academia, the European Hemophilia Consortium (EHC) and the European Medicines Agency (EMA), to review trends in the use of standard half-life coagulation factor concentrates, but also of the new extended half-life products and non-replacement therapies.
Methodology
The “Wildbad Kreuth Initiative V – Optimal Treatment of hemophilia symposium” that took place in June 2019 involved clinicians, regulators and patient organizations from 26 European countries.
The participants were experts invited by the Scientific Programme Committee, as well as delegates appointed by the Council of Europe (CoE) Member States on the invita- tion of the EDQM, plus delegates from the patient organ- izations, the European Hemophilia Consortium (EHC)
and World Federation of Hemophilia (WFH), and the European Medicines Agency (EMA). Several of the partic- ipating experts are active members of the European Association for Hemophilia and Allied Disorders (EAHAD) or other scientific societies. Industry representa- tives had the opportunity to participate in the open ses- sions, but were excluded from the discussion and formu- lation of the recommendations.
The topics of the symposium were defined by the Scientific Committee on the basis of the results and rec- ommendations of the previous symposia and the latest developments in the field of therapies for hemophilia. During the subsequent open plenary sessions, the invited experts presented an overview of the current state-of-the- art on hemophilia therapy in Europe and treatment progress on the topics predefined by the Scientific Committee. Their solid scientific background and in- depth knowledge of the particular situation of hemophilia treatment in their own countries enabled the chosen dele- gates taking part to elaborate the recommendations to be presented to the Health Authorities of the CoE Member States.
The experts met in three different working groups to discuss and develop the new recommendations. Each working group was responsible for one of the following areas of discussion:
- clinical evaluation of hemophilia therapy;
- collection of data on hemophilia therapy;
- methodological aspects of hemophilia therapy.
Each working group prepared an interim report which
was then discussed with the general assembly. If the report received full and unanimous consensus, it would then go forward for final approval. Based on the final report, this manuscript was prepared and circulated among all participants of all three working groups. Literature research was based on articles published in peer reviewed journals. Medline and PubMed were also searched for all articles published in English in the last ten years. Furthermore, data were extracted from the abstracts of the more recent international congresses.
Recommendation 1
Prophylactic treatment should be available to all hemophilia patients, with or without inhibitors, and access to physiotherapy should be provided.
Prophylaxis in hemophilia is considered the standard of care to prevent joint bleeding and related arthropathy, with the objective of preserving a normal musculoskeletal function. Manco-Johnson established the superiority of prophylactic versus on-demand therapy in a randomized clinical trial in 2007.6 Primary prophylaxis in hemophilia should start at a very young age (≤2 years of age) before joint disease develops, and usually requires coagulation factor infusions 2-3 times per week, whereas secondary prophylaxis begins after the onset of joint disease.7 There are many prophylactic schedules, although the optimum dosing regimen is still to be defined. Prophylaxis with standard half-life coagulation factor products is usually given at a dose of 25-40 IU/kg 2-3 times per week,7,8 whereas with the extended half-life products, prophylaxis regimens with intervals of 3-5 days in hemophilia A and once every 7-14 days in hemophilia B can be effectively implemented.9-11
Currently, the availability of a non-replacement therapy administered subcutaneously such as emicizumab makes
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