Elsevier

Blood Reviews

Volume 23, Issue 6, November 2009, Pages 267-274
Blood Reviews

REVIEW
Prophylactic therapy in haemophilia

https://doi.org/10.1016/j.blre.2009.08.001Get rights and content

Summary

Clinical experience since decades and numerous retro- and, recently, also prospective studies clearly demonstrate that prophylactic treatment, albeit much more expensive, is superior to on-demand treatment regardless if outcome focus on number of joint- or life-threatening bleeds or arthropathy, evaluated by X-ray or MRI, or quality of life measured by general or hemophilia specific instruments. Optimal prophylactic treatment should be started early (primary prophylaxis) but various opinions exist on the dose and dose interval, depending on the objective of treatment in the individual patient which in turn is usually dependent on the resources in the health care system. Secondary prophylaxis, started later in childhood or in adults is beneficial but less cost-effective. This review covers proof of concept of primary prophylaxis in children and secondary prophylaxis in adults, comparisons between prophylaxis and on demand treatment as well as outcome measurers, health economics and future trends of prophylactic treatment of hemophilia.

Section snippets

Introduction and definitions

Haemophilia A and B are hereditary, X-chromosomal recessive disorders caused by deficiency or absence of coagulation factors VIII (FVIII) or IX (FIX) in the blood. Depending on the concentration of FVIII or FIX coagulant activity in blood, the disorders may be classified as severe (<1% of normal activity), moderate (1–4%) or mild (5–25%). Haemophilic arthropathy due to repeated joint bleeds is the major cause of morbidity in individuals with haemophilia. In patients with the severe form of the

Experience and evidence for prophylactic treatment

Prophylaxis was pioneered for haemophilia A in the late 1950s and in haemophilia B in the early 70s in Sweden by Nilsson and colleagues.[7], [8], [9] At the time, factor VIII (FVIII) was not always available in sufficient amounts and the doses given were small compared with today’s norms. Moreover, many patients who received prophylaxis had already developed arthropathy prior to prophylaxis initiation. Despite these limitations, Nilsson et al.7 reported the most comprehensive experience of

Prophylaxis vs. on-demand treatment

The studies during the first decades of prophylactic treatment were cohort studies followed longitudinally for many years. These long-term experiences of prophylactic treatment from Sweden and The Netherlands did not compare prophylaxis with on-demand treatment. A few larger studies have had the aim to compare prophylactic regimens with on-demand studies. In 1994, Aledort et al. published results of a 6-year uncontrolled, longitudinal study of various dosage regimens in patients with severe

Different models for prophylactic treatment

The focus of discussion has switched from prophylactic treatment vs. on demand treatment to the optimal mode of the prophylactic regimen. However, the optimal mode depends on the aim of the prophylactic treatment (Fig. 1). The optimal mode differs if the objective is to keep an acceptable joint function for a sedentary daily life or the objective is to achieve nearly normal hemostasis that allows an active leisure life including sport activities. Opinions vary widely between countries and

Prophylaxis and life-threatening bleeds

The outcome of prophylactic treatment has usually been focused on joint outcome. The early experiences with prophylaxis showed that the large improvement of joint function came when patients were given FVIII or FIX on a regular basis, despite that at the time it was given at long intervals.7 Further refinement can then be achieved by more frequent dosing and higher doses. When discussing the optimal prophylactic regimen one has to include an estimation of the risk of other serious or

How to measure the outcome of prophylactic treatment?

Prophylactic treatment of haemophilia is expensive and it is important to optimise it in the individual patient using different outcome measurers. Evaluation of the number of total and joint haemorrhages is probably the easiest measure but is dependent on reliable co-operation of the patient or parents. As commented above, subclinical joint bleeds may cause significant osteochondral changes on MRI and there is an obvious need of objective outcome measurers.

The most widely used methods for

Prophylaxis and inhibitors

Another aspect of early treatment being currently discussed, is whether the mode of administration, regular prophylactic treatment or on demand has an impact on inhibitor development. In 2005, Morado66 analysed the inhibitor incidence in 50 children with hemophilia and its relationship with mutations, type of clotting factor used and treatment modality. Thirty-eight out of 50 were treated with rFVIII and the remaining 12 with pdFVIII. Twenty children had mutations associated with high risk for

Stopping or starting prophylaxis in adults?

The WHO and WFH have recommended that prophylactic treatment should be life-long. However, opinions vary also on this topic as can illustrated by a survey of the treatment regimens at 21 European centres treating 5000 patients.73 The survey concluded that there is an absence of consensus on the management of patients with severe haemophilia, as they pass through adolescence and young adulthood, but that aggregate outcome data suggest a significant proportion of patients in the 18–22 years age

Prophylaxis and economy

The cost of concentrates usually account for more than 90% of the costs of hemophilia treatment. Since prophylactic treatment will consume more concentrate than on demand it will be more expensive not at least in short time follow-up. However, comparison of economics between the treatment modalities is very difficult since it has to be based on long(life)-time follow-up and include parameters such as QoL. Attempts have been made to assess the economics of prophylaxis in Germany and Europe[80],

Conflicts of interest

The author has obtained research grants or fees for consultancy/presentations from Bayer, Baxter, NovoNordisk and Octapharma.

Acknowledgement

The author is supported by grants (ALF) from Lund University and Region of Skåne, Sweden.

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