From treatment to prevention of bleeds: what more evidence do we need?

In this edition of Haemophilia, Dr. Poonnoose and colleagues publish the results of the MUSFIH study 1, a large international collaboration including 10 haemophilia centres from nine developing countries. They were able to follow a well-defined group of haemophilia patients over a 5-year period, comparing joint outcomes as assessed with both the radiological Pettersson score and functional scores. Their objective was to investigate whether episodic treatment with different CFC dosages could prevent joint arthropathy. A total of 255 children with severe haemophilia A were enrolled. Their median age and range at the start of the study were 10 and 5–15 years, respectively. During the 5-year period, 52 patients were lost to follow-up and 39 started prophylaxis. The data of the 164 patients who used episodic treatment during the full 5-year period were analysed. Depending on the country, the variation in CFC dosage used was large. The median yearly usage was 662 IU kg−1, the interquartile (IQ) range 280–1437. The median annual joint bleeding rate was 10, with an IQ range of 5–17. This rate increased with age: for five-year-old children it was five and for 10-year-old children nine, increasing to 11 bleeds per year for children older than 15 years. At the start of the study, the majority of the children already had arthropathy. Only 20% had a zero Pettersson score, decreasing to 6.4% after 5 years. There was a direct correlation between bleeding rate and joint deterioration: The children with the highest bleeding rates had the most affected joints and the greatest deterioration of joint function, as assessed with both the Petterson score and the activity scores. The MUSFIH study underscores the fact that young children have less bleeds than older children. This lower bleeding rate has often been a reason to delay the start of prophylaxis. This study demonstrates excellently that episodic treatment cannot prevent joint deterioration. In contrast, low-dose prophylaxis can already be effective with yearly CFC dosages as low as 1000 IU kg−1. In Germany, in the seventies, Schimpf elegantly proved that 12 IU kg−1 given three times weekly could prevent bleeds, while twice weekly 18 IU kg−1 or once weekly 36 IU kg−1 was not effective 2. Later, the Swedish regimen of 20-40 IU kg−1 three times weekly has become the leading regimen; and despite it was proven to prevent joint arthropathy effectively, the high costs for life-long high-dose treatment have prohibited it to be introduced on a large scale 3. Now that the MUSFIH study confirms that episodic treatment, independent of the dosage, cannot prevent joint deterioration, prevention of bleeds by regular CFC administration should become the cornerstone of treatment. Decades of experience with prophylaxis in children with severe haemophilia in Europe have demonstrated the effectiveness of this approach 4-6. Yet, the long delay between the onset of bleeds and obvious arthropathy, as well as fear for regular infusions and for problems with central catheters, has led to much debate about the right age to start prophylaxis. The Swedish, who started prophylaxis already in the late fifties, were the first to stress the importance of starting prophylaxis early. Joint damage can only be completely prevented with prophylaxis from the age of 2–3 years 7, 8. As for the dosage to be given, in a key study comparing the high-dose Swedish regimen and the intermediate-dose Dutch regimen in adults followed for more than 24 years, was shown that both groups had an excellent overall outcome with similar social participation and quality of life 9. The Swedish patients had a slightly better clinical outcome, but this came at the expense of 66% higher annual costs for the high-dose regimen 9. A longer follow-up of both groups investigating the same parameters is needed to show the outcomes for these patients in their fifties. Now products are plentiful, it is advocated to dose higher and try to reach trough levels of 3–5% 10. Clearly, the best way to optimize long-term outcome is the prevention of bleeding while allowing the children normal activities and sports, thus improving their condition without risking joint damage. Recently it was shown that even in Western Europe in the last decade, primary prophylaxis was only implemented in 80% of the children with severe haemophilia 11. A recent large US study in patients with severe, moderate and mild haemophilia born in four different periods showed that the disability gap between mild and severe haemophilia had not decreased. Despite better access to care, still more than one in three participants with severe haemophilia born after 1992 reported more than five bleeds in a 6-month period 12. Prophylaxis on a wider scale was only introduced in the Unites States after the Manco-Johnson study proved superiority of prophylaxis over episodic treatment with regard to the number of bleeds 13. These data confirm that in the United States, despite a high consumption of CFCs, joint outcome of the youngest group is still abnormal in the majority of the patients. Although data regarding the age at the start of prophylaxis were not presented, it seems likely that most patients only started after the occurrence of joint bleeds. A Canadian tailored prophylaxis study attempted to reduce the number of infusions at the time of introduction of prophylaxis. Patients started with 50 IU kg−1 once weekly, the frequency only being increased after breakthrough joint bleeds 14. However, the 5-year follow-up revealed that the clinical score nevertheless showed joint deterioration 15. Last year the ISTH did a clear recommendation on when and how to start prophylaxis. Based on all the available evidence, the advice is to start after the first joint bleed with once weekly infusions and to preferably increase the frequency until full dosage within 6 months 16. Although the onset of joint bleeding varies widely, in a cohort of over 900 children with severe haemophilia the median age was show to be as low as 1.7 years 17. Parents should be informed that longer delay of prophylaxis leads to bleeds that could have been prevented. As there are no additional parameters that can discriminate between patients with better and worse outcomes, it seems contradictory to leave children with severe haemophilia without preventive therapy for many years during a period that they are at high risk for developing joint bleeds, as well as other serious bleeds, such as intracranial haemorrhage 18. Another reason to start early is that animal models have shown that young cartilage is more vulnerable than mature cartilage 19. The results of the MUSFIH study make clear that the use of prophylaxis needs reconsideration, even in countries with cost restraints. Despite lower costs of episodic treatment in the short term, its ineffectiveness to prevent joint damage should make it obsolete in any country that has access to a regular supply of CFC. Especially in young children, low-dose prophylaxis with annual dosing of 1000–2000 IU kg−1 can make a dramatic change; and dosages of 10–15 IU kg−1 two to three times weekly can prevent 80% of the bleeds 20. Modelling of the most cost-effective outcome has resulted in a regimen based on life-long treatment with 1000–1500 IU kg−1 per year 21. With gene therapy within reach, a brighter future for these children is achievable, and this should be our goal 22, 23. Although fear for inhibitors is another reason delaying the introduction of primary prophylaxis, observational cohort studies have demonstrated that prophylaxis may contrarily prevent inhibitor development 17, 24, 25. Furthermore, many studies confirm that it is intensive treatment that increases inhibitor risk 17, 26. Patients who are not on prophylaxis are likely to start with intensive treatment because of a large bleeding, which may promote the development of inhibitors. Animal studies have demonstrated that inhibitors are more likely to occur during bleeds 27. The focus of haemophilia treatment has been mostly on the safety of products and far less on the implementation of best practices. With current knowledge, all patients with severe haemophilia should get the benefit of preventing bleeds and leading a normal life. Within this field, the World Federation of Haemophilia has a pivotal role. The WFH treatment guidelines are currently updated and they are expected to underscore that prophylaxis is the only acceptable treatment regimen for severe haemophilia 28. Thanks to the support of many companies, the humanitarian aid programme of the WFH supporting this concept was able to extend its reach. Currently, low-dose prophylaxis is offered to children in many developing countries 29. Clinical studies collecting data beyond marketing authorization are very important to improve our knowledge and to support advocacy of better CFC use with governments. The WFH has recently introduced an important initiative to harmonize data collection worldwide and deliver an infrastructure for collaboration: the World Bleeding Registry 30. Haemophilia has now reached beyond PK measurements and entered the era of precision medicine, aiming at improving physical activity, risk profiles and joint status. To measure the effect of different treatment regimens on joint disease, long-term outcome studies should structurally use both joint assessment and PRO related tools. While randomized controlled trials have proven the short-term beneficial effect of prophylaxis on bleeding, observational studies are better equipped to study long-term benefits 26. Haemophilia studies in different parts of the world, such as the MUSFIH study, are needed to determine the long-term outcome of various regimens under different circumstances, including new treatment options and gene therapy. H.M.v.d.B. has received unrestricted research support from CSL Behring, Novo Nordisk, Sobi, Biogen, Wyeth, Baxter, and Bayer; speakers fees from NovoNordisk, Biotest, Baxter; and review board fees for the Bayer Hemophilia Awards Program.

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