ORIGINAL ARTICLE Prophylaxis therapy in paediatric patients with haemophilia: a survey of clinical management trends in Italy Giancarlo Castaman1,2, Angiola Rocino3, M. Gabriella Mazzucconi4, Ezio Zanon5, Fabio Gagliano6, Angelo C. Molinari7 Centre for Bleeding Disorders, Careggi University Hospital, Florence; 2Haemophilia and Thrombosis Centre, Department of Haematology, San Bortolo Hospital, Vicenza; 3Haemophilia and Thrombosis Centre, San Giovanni Bosco Hospital, Naples; 4Department of Cellular Biotechnology and Haematology, La Sapienza University, Rome; 5Department of Cardiologic, Thoracic and Vascular Sciences, Haemophilia Center-University of Padua; 6 Reference Centre for Paediatric Haemostasis and Thrombosis, G. Di Cristina Hospital, Palermo; 7Thrombosis and Haemostasis Unit, Haemophilia Treatment Centre, Giannina Gaslini Children's Hospital, Genoa, Italy 1
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Background. Although current treatment guidelines recommend prophylaxis in paediatric patients with haemophilia, specific indications for and barriers to the prescription of prophylaxis in the paediatric haemophiliac population have not been established. The aim of this web-based survey of clinicians at Haemophilia Treatment Centres in Italy was to identify factors for and against the initiation of prophylactic coagulation factor replacement therapy in paediatric patients with haemophilia. Materials and methods. A literature search was conducted to identify factors to include in the survey. Seventeen clinicians from Italian Haemophilia Centres were invited to complete the webbased survey and to rank factors in favour of and those that acted as barriers to prophylaxis in terms of "importance" and "influence" on a numerical scale (0=not important to 100=very important). Any factors for which there was a large discrepancy in results from the survey were further "ranked" by clinicians at an interactive question and answer session at a symposium. Results. A total of 13 web surveys were returned; the most highly scored factors favouring prophylaxis were "bleeding frequency", "bleeding severity" and "presence of target joints", and the most highly scored barriers were "parents' acceptance", "venous access" and "compliance to therapy". Other important factors favouring prophylaxis were "severity of coagulation defect" and "orthopaedic score". Discussion. This survey gives helpful clinician-derived information for people treating haemophiliacs in Italy, to help the treatment-providers orient themselves better regarding the prescription of prophylaxis for paediatric patients.
Introduction
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Keywords: haemophilia, prophylaxis, paediatrics, clinical management, factor VIII.
Haemophilia is an inherited, life-long bleeding disorder caused by deficiencies of factor VIII (FVIII) or factor IX (FIX) and, in its severe form, is characterised by recurrent bleeding into joints and soft tissues1. Crippling arthropathy, chronic pain, the need for orthopaedic surgery, disability and comorbidities (e.g. liver disease), which can have a negative impact on a patient's quality of life, are the most feared consequences of inadequate treatment of these bleeding episodes1,2. Nowadays, the primary aim of the management of patients with haemophilia is to treat and prevent bleeding by replacing the deficient clotting factor3. Patients with moderate or mild disease usually receive on-demand therapy with coagulation factor concentrates or desmopressin, but it is recommended that those with
severe disease are given prophylactic factor replacement therapy with FVIII or FIX concentrate4. Prophylactic therapy results in change from severe to moderate or mild haemophilia5 and has been shown to be superior to on-demand treatment with regards to reducing jointor life-threatening bleeds, limiting the development of arthropathy and improving quality of life5-11. Furthermore, the initiation of prophylaxis at an early age (i.e. before 3 years of age) is associated with better long-term outcomes in patients with severe haemophilia12. The prophylactic treatment of children with haemophilia is associated with a number of challenges. Patients' compliance with treatment often declines in the transition from childhood to adolescence and the support from parents, peers and caregivers is critical to improve adherence to treatment programmes13. Additionally, the
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Castaman G et al
Phase 1A: identification of factors Factors were identified within the plenary session of the GILP group on the basis of a literature search and the group members' clinical experience, and used to design the survey as described by Astermark and Colleagues in 201015. Consequently, identified factors were ranked by 13 members of the group for "importance" (i.e. how relevant it is considered in the literature) and "influence" (i.e. to what extent it affects his/her personal choice to administer prophylaxis) on a six-point scale where 0 = not important/no influence on choice to administer prophylaxis and 5 = very important/greatly influences choice to administer prophylaxis. Each of these factors was subsequently judged to be "for" or "against" the initiation of prophylaxis during the survey, based on the clinical experience of the participating members of the group. The factors were then classified into two groups (i.e. indications for and barriers to prophylaxis) based on score results.
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burden that is placed on parents with regards to disease management can be stressful and problematic, which emphasises the need for healthcare services to provide easy access to appropriate support14. Another challenge to treating children with haemophilia is the formation of alloantibodies (inhibitors) to FVIII or FIX, which is a significant treatment-related complication of haemophilia replacement therapy that occurs mainly at a young age (median age ≤3 years) in about 30% of patients with severe haemophilia A3,4. Immune tolerance induction (ITI) can be used to eradicate the inhibitors, and in order to prevent or treat bleeds either during or outside ITI, patients can be treated with bypassing agents such as recombinant factor VIIa (Novoseven; NovoNordisk A/S, Bagsvaerd, Denmark) or activated prothrombin complex concentrates (FEIBA; Baxter AG, Wien, Austria)4. The European Haemophilia Treatment Standardisation Board (EHTSB) recommends that prophylaxis for the prevention of bleeding should be provided to all children with haemophilia, since it also seems to exert a favourable immunological effect to promote immune tolerance15. Although haemophilia treatment guidelines generally recommend the use of prophylaxis, there is limited guidance on how to decide whether a patient should receive prophylaxis or not3,16,17. Physician surveys are useful tools to determine current standards of practice in haemophilia treatment18, especially if there is disparity between guideline recommendations and current practice19. A web-based survey was, therefore, conducted in various Italian Haemophilia Treatment Centres to identify current trends in the clinical management of haemophilia, as well as barriers to initiating prophylaxis, in paediatric patients with haemophilia. In so doing, this study aims to provide clinicians with an expert opinion-based rationale on whether or not to prescribe prophylaxis to their paediatric patients.
Study design Factors promoting the initiation of haemophilia prophylaxis and factors presenting an obstacle to the initiation of prophylaxis were identified through a literature review. The literature search was performed according to the method described by Berntorp and colleagues in 201110, but focused on prophylaxis in various clinical settings and ranges of age. A web-based survey of the Gruppo Italiano Lavoro sulla Profilassi emofilica (GILP) was then conducted among 17 Italian haematologists asking them to rank the importance of these factors identified from the literature review in the management of paediatric patients with haemophilia. Paediatric patients were stratified into four age groups: 0 to 2 years; >2 to 6 years; >6 to 12 years; and >12 to 18 years.
Phase 2: revision and recommendations For those factors for which a large discrepancy remained in the results from phase 1B (i.e. when the median score assigned by participants differed by more than 1), a further "ranking" (and scoring) was performed during an interactive question and answer session (using audience response keypads) as part of a medical meeting. Participants comprised over 50 haematologists, paediatricians and transfusion specialists involved in haemophilia treatment throughout Italy, who convened to discuss the merits of the content and interpretation (e.g. to balance the importance of each factor against feasibility). Wherever necessary, questions from the survey were rephrased to help with reaching a final agreement.
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Materials and methods
Phase 1B: administration and analysis Participants were asked to complete the survey by filling in an Excel document sent by email. After a plenary session, the GILP group was split into subgroups with a specific focus on prophylactic treatment of paediatric, adult or surgical patients. In the GILP paediatric group, Italian haemophilia treatment providers were asked to rank the factors (from 0 to 5) and score them in terms of "importance" and "influence" (from 0=not important/no influence to 100=very important/greatly influences). This allowed the identification of factors for or against prophylaxis, i.e. the indications for prophylaxis initiation, the barriers (potential obstacles) to prophylaxis and the degree of agreement/disagreement on the findings within the GILP paediatric group. Factors for which no agreement was reached were subjected to reconsideration through discussion amongst the participants of this survey as described in phase 2 of the study.
Blood Transfus 2015; 13: 631-8 DOI 10.2450/2015.0333-14 632 All rights reserved - For personal use only No other uses without permission
Haemophilia prophylaxis in paediatric patients
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Results
Results of phase 1B: survey responses The five most highly scored factors indicating the initiation of prophylaxis in paediatric patients according to age subgroup are listed in Table I. Overall, "bleeding frequency", "bleeding severity" and "severity of coagulation defect" were the most highly scored indications for prophylaxis in the subgroup aged 6 to 18 years of age (Table II).
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Statistical analysis The completed sections of all returned surveys (including completed sections of incomplete surveys) were included in the analysis; the incomplete sections of surveys were excluded from the analysis. Surveys were collected by email, thus the results were not provided anonymously. Minimum, maximum, median (interquartile range) and mean scores were calculated based on rankings made by the clinicians. Given the wide variability in data, ≥75% consensus among responders during phases 1 and 2 were defined as a significant majority.
psychological barriers; compliance to therapy; venous access; quality of life; orthopaedic score; presence of target joints (i.e. repeated haemorrhagic events in the same joint); sport and play activity; previous prophylaxis; type of occupation; planned orthopaedic surgery; type of hobbies; previous orthopaedic surgery (the latter four criteria were added for the group 12 to 18 years old). Overall, "bleeding frequency", "bleeding severity" and "presence of target joints" were ranked by haematologists as having the most "importance" and "influence" when deciding whether to prescribe prophylaxis in paediatric patients (Figure 1A-D).
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Data collection procedures From among all Italian Haemophilia Centres in existence at the start of the study (n=48), 15 of the major Italian Centres were selected and 17 clinicians from the GILP group, all also caring for patients below the age of 18, were recruited to receive the survey (i.e. those with more experience and with the largest number of patients), which was sent to the head of each Centre. This meant that the survey was able to cover approximately 70% of Italian haemophilia treatment providers.
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Survey respondents Phase 1 During phase 1, a total of 17 clinicians (15 haematologists; 2 paediatricians) from 15 Haemophilia Treatment Centres across regional locations in Italy were invited to participate in the survey. Overall, 13 of the 17 participants responded to and returned the complete surveys. The estimated proportion of haemophilia patients considered by the participants of the survey was approximately 70% of the Italian haemophilia population.
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Phase 2 During phase 2, the 17 participants in the survey and an additional 50 haematologists and transfusion specialists from a total of 48 Centres convened to discuss the merits of the content and interpretation of the results. Overall, a total of 45 participants completed the interactive session (i.e. not all participants responded to every question). Results of phase 1A: identification of factors The following factors indicating initiation of prophylaxis and those considered to be barriers or "contraindications" to prophylaxis in paediatric patients were identified and included in the survey: bleeding frequency; bleeding severity; severity of coagulation defect; high-risk genetic mutation for inhibitor development; intensive treatment at the beginning of infusion history; family history of inhibitors; lively behaviour of child; parents' acceptance; social and cultural level of parents; geographical, cultural and
Results of the phase 2 interactive session Overall, nine factors were associated with a large discrepancy in results from phase 1B; these were formulated as specific questions, and results of the audience voting on these questions during the symposium are listed in Table III. Both factors influencing the choice of establishing prophylaxis in paediatric patients (≥50% consensus) and factors that represent a barrier to the use of prophylaxis in paediatric patients (≥50% consensus) according to age subgroups are listed in Table III. An additional question was posed asking symposium participants if they agreed that prophylaxis with a bypassing agent should be prescribed for paediatric patients with high-titre inhibitors and most agreed (30/44 =68%) (Table III).
Discussion This is the largest survey conducted among Italian clinicians to identify factors that are considered to be
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Figure 1 A-B - Ranking decisional factors that were considered "important" and had "influence" in therapeutic choice in paediatric patients aged: A) 0-2 years, and B) >2-6 years.
important and influential in the decision of whether or not to prescribe prophylaxis in paediatric patients with haemophilia. Several factors favouring the initiation of prophylaxis in paediatric patients were identified, including "bleeding frequency", "bleeding severity", "presence of target joints", "severity of coagulation defect" and "orthopaedic score". On the other hand, factors that were considered to act as barriers to prophylaxis in paediatric patients with haemophilia included "parents' acceptance", "venous access", "compliance to therapy" and "geographical, cultural and psychological barriers". The results of this survey may provide useful insight
into clinician beliefs and practice patterns regarding the use of prophylactic therapy for paediatric patients with haemophilia in Italy. Many international haemophilia treatment guidelines recommend prophylaxis in children with haemophilia3,13,16. However, they do not provide specific guidance on the indications or "contraindications" (barriers) to prophylaxis in paediatric patients. UK guidelines for patients with severe haemophilia A state that prophylaxis should be initiated by the second joint bleed or significant tissue bleed16, and the World Federation of Haemophilia (WFH) defines primary prophylaxis as treatment initiated in the Blood Transfus 2015; 13: 631-8 DOI 10.2450/2015.0333-14
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Figure 1 C-D - Ranking decisional factors that were considered "important" and had "influence" in therapeutic choice in paediatric patients aged: C) >6-12 years, and D) >12-18 years.
absence of joint disease and started before the second clinically evident large joint bleed and age 3 years3. The clinicians in the current survey agreed that "bleeding frequency", "bleeding severity" and "presence of target joints" were the most important factors influencing the initiation of prophylaxis in paediatric patients with haemophilia. Previous studies have shown that early initiation of prophylaxis is associated with improvements in long-term outcomes, including reductions in joint bleeds and the development of chronic arthropathy5,7,12, which has had an impact on the prescription of prophylaxis by clinicians treating paediatric patients. Indeed, a recent
survey20 of healthcare professionals in the USA indicated an increase in the prescription of prophylaxis for children with haemophilia since the publication of the Joint Outcome Study7. To date, there are limited European survey data on clinical management trends in paediatric patients with haemophilia. However, results of the current survey are in broad agreement with those of other surveys of current practice and attitudes in the management of paediatric and adult patients with haemophilia21,22. A survey of prophylaxis use in male paediatric patients with haemophilia from North American Treatment
Blood Transfus 2015; 13: 631-8 DOI 10.2450/2015.0333-14 635 All rights reserved - For personal use only No other uses without permission
Castaman G et al Table I - The five most highly-scored factors favouring prophylaxis in paediatric patients with haemophilia according to age subgroup.
Table II - The five most highly-scored factors as barriers to prophylaxis in paediatric patients with haemophilia according to age subgroup.
Categories
Categories
Age >12-18 years
97
95
Bleeding severity
97
96
Severity of coagulation defect
95
90
High risk genetic mutation
83
60
Intensive treatment at the beginning of transfusional history
83
76
Bleeding severity
99
98
Bleeding frequency
99
98
Presence of target joints
97
91
Age 0-2 years
Age >2-6 years
Quartile 1
Parents' acceptance
89
59
Venous access
85
70
Compliance to therapy
78
57
Social and cultural level of parents
75
38
Geographical, cultural and psychological barriers
70
50
Venous access
96
90
Parents' acceptance
94
78
Compliance to therapy
88
78
Geographical, cultural and psychological barriers
80
75
Social and cultural level of parents
75
63
Compliance to therapy
80
69
Venous access
78
61
Geographical, cultural and psychological barriers
75
67
94
90
Orthopaedic score
86
80
Bleeding severity
99
98
Bleeding frequency
98
96
Presence of target joints
96
90
Orthopaedic score
93
84
Severity of coagulation defect
90
86
Bleeding frequency
98
96
Parents' acceptance
73
60
Bleeding severity
97
97
96
95
Social and cultural level of parents
65
54
94
89
Compliance to therapy
76
53
92
86
Geographical, cultural and psychological barriers
65
38
Presence of target joints Orthopaedic score Quality of life
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Severity of coagulation defect
Age >6-12 years
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Age >6-12 years
Bleeding frequency
Score† Median
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Age >2-6 years
Quartile 1
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Age 0-2 years
Score† Median
Age >12-18 years
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†Factors favourable to prophylaxis scored for importance and influence on a scale of 0 to 100, where 0=not important and 100=very important.
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Centres found that the major reason for initiating prophylaxis was a history or presence of joint bleeding22. Additionally, an update of a global survey (UK, USA, Canada, Sweden) of nurses at Haemophilia Treatment Centres on treatment practice patterns for children and adults with haemophilia A indicated that the most influential factors for initiating prophylaxis were bleeding history and target joint development (i.e. the development of arthropathy in target joints)22. Other important factors included patients' adherence, adequacy of family commitment, adequacy of venous access, disease severity and level of patients' activity22. In the current survey, "bleeding frequency", "bleeding severity" and "presence of target joints" were among the most highly scored factors favouring prophylaxis in paediatric patients with haemophilia (Table I). However, "venous access" was included in the current Italian survey as a barrier to prophylaxis (Table II). Interestingly, the current study did not identify the presence of inhibitors as an indication or "contraindication" to prophylaxis in paediatric patients
Occupation type
63
34
Venous access
61
40
Parents' acceptance
52
28
† Factors non favourable to prophylaxis (i.e. barriers) scored for importance and influence on a scale of 0 to 100, where 0=not important and 100=very important.
with haemophilia, although "family history of inhibitors" was identified as a factor favouring the initiation of prophylaxis (data not shown). Inhibitor formation to FVIII or FIX is a severe treatment-related complication in haemophilia which often develops at an early age (≤3 years) in patients with severe haemophilia A3, and both the EHTSB and recent consensus guidelines recommend prophylaxis with bypassing agents (e.g. FVIII inhibitor bypassing activity [FEIBA] concentrate) in paediatric and adult patients with inhibitors 18,23 . Indeed, a retrospective survey of some European Haemophilia Centres (Italy, Germany, France, Spain, Switzerland and the Czech Republic) showed that prophylactic treatment with recombinant factor VIIa in paediatric and adult patients with severe haemophilia and inhibitors effectively reduced the number of bleeding episodes Blood Transfus 2015; 13: 631-8 DOI 10.2450/2015.0333-14
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Haemophilia prophylaxis in paediatric patients Table III - Factors for which there was a large discrepancy in results from phase 1B: audience responses to questions asked during an interactive session (total number of participants =45, although not all participants answered each question). Data are number of respondents for each category. Question
None
Low
Medium
Influence of living far away from the centre on the clinical decision to prescribe prophylaxis
13
20
11
Influence of the low cultural level of the child's parents on the clinical decision to prescribe prophylaxis
21
14
10
Influence of the parents' psychological difficulty to accept prophylaxis on the clinical decision to prescribe prophylaxis
12
24
9
Influence of low parents' acceptance on the clinical decision not to prescribe prophylaxis
0
11
22
Age >2-6 years
Influence of the presence of a genetic mutation associated with a high risk for developing inhibitors on the clinical decision to prescribe prophylaxis
11
10
19
Age >6-12 years
Influence of poor compliance to the prescribed prophylactic regimen on clinical decision to continue prophylaxis
5
22
13
Influence of a low perceived quality of life on the clinical decision to prescribe prophylaxis
3
4
16
Overall
Influence of a high orthopaedic score on the clinical decision to prescribe prophylaxis
1
1
9
Influence of sport and play activities and/or hobbies associated with a high haemorrhagic risk on the clinical decision to prescribe prophylaxis
1
10
12
Do you agree with the following statement: prophylaxis with a bypass agent is indicated for children with high-titre inhibitor
No: 3
Agree a little: 11
Agree: 24
experience due to the large number of patients, including those of paediatric age, being treated at the selected Centres. Questions from the survey referred only to "prophylaxis" and did not provide a clear definition of this term. As a result, an understanding of the clinical context of "prophylaxis" may differ between respondents of the survey and the study investigators.
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and improved patients' compliance and quality of life24. The current survey appears to provide decisional support among Italian clinicians for prophylaxis in paediatric patients with haemophilia. However, the mean number of FVIII concentrate units used per capita is lower than in other EU countries despite primary prophylaxis being provided as standard therapy to children with haemophilia in Italy25. Furthermore, an analysis of epidemiological, diagnostic and therapeutic data from an Italian Regional Haemophilia Centre showed that prophylaxis in children or adults was used less often than on-demand treatment, especially in patients with severe haemophilia26. "Compliance to therapy", "venous access" and "parents' acceptance" were the most important barriers to prophylaxis in the current survey. These results confirm those from a global survey, which reported similar barriers to prophylaxis, including poor adherence, inadequate family commitment and venous access22. In the current survey, "parents' acceptance" was most important in paediatric patients aged 0-2 years, which is to be expected since younger patients are more reliant on the support and care of their parents. Poor adherence is a major issue that can decrease the efficacy of prophylactic treatment, and previous surveys conducted in the USA also found poor adherence to be a barrier to prescribing prophylaxis in paediatric patients with haemophilia20,27. The results of the current survey should be considered against its limitations. The data may be subject to selection bias due to the small number of Centres that completed the survey. However, we feel that the opinion captured in this survey is based on extensive clinical
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Age >12-18 years
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Age group Age 0-2 years
Conclusions The achievement of effective prophylaxis in paediatric patients with haemophilia is an on-going challenge. This study provides a useful clinician-derived perspective on the management of haemophilia, helping to identify patients who should be given prophylaxis as well as barriers to successful initiation of prophylactic treatment in paediatric patients, in Italy.
Authorship contributions GC wrote the initial draft of the manuscript. All the Authors read, reviewed and approved the final draft of the paper.
Disclosure of conflicts of interest The GILP study was sponsored by Baxter. GC has received fees for lectures from Baxter, CSL Behring, Kedrion and NovoNordisk. AR has attended advisory board meetings of Baxter, NovoNordisk and Pfizer, acted as a paid consultant for Bayer, CSL Behring, NovoNordisk and Pfizer and received fees as a speaker in meetings organised by Baxter, Bayer, CSL Behring, NovoNordisk and Pfizer. MGM served in a speaker
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Barr RD, Saleh M, Furlong W, et al. Health status and healthrelated quality of life associated with hemophilia. Am J Hematol 2002; 71: 152-60. Klamroth R, Pollmann H, Hermans C, et al. The relative burden of haemophilia A and the impact of target joint development on health-related quality of life: results from the ADVATE Post-Authorization Safety Surveillance (PASS) study. Haemophilia 2011; 17: 412-21. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19: e1-47. Fijnvandraat K, Cnossen MH, Leebeek FW, Peters M. Diagnosis and management of haemophilia. BMJ 2012; 344: e2707. Gringeri A, Lundin B, von Mackensen S, et al. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9: 700-10. Fischer K, van der Bom JG, Molho P, et al. Prophylactic versus on-demand treatment strategies for severe haemophilia: a comparison of costs and long-term outcome. Haemophilia 2002; 8: 745-52. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535-44. Tagliaferri A, Franchini M, Coppola A, et al. Effects of secondary prophylaxis started in adolescent and adult haemophiliacs. Haemophilia 2008; 14: 945-51. Collins P, Faradji A, Morfini M, et al. Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-month crossover study. J Thromb Haemost 2010; 8: 83-9. Berntorp E, Collins P, D'Oiron R, et al. Identifying nonresponsive bleeding episodes in patients with haemophilia and inhibitors: a consensus definition. Haemophilia 2011; 17: e202-10. Witmer C, Presley R, Kulkarni R, et al. Associations between intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients in the United States. Br J Haematol 2011; 152: 211-6. Astermark J, Petrini P, Tengborn L, et al. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol 1999; 105: 1109-13. Petrini P, Seuser A. Haemophilia care in adolescents-compliance and lifestyle issues. Haemophilia 2009; 15 (Suppl 1): 15-9. Shaw D, Riley GA. The impact on parents of developments in the care of children with bleeding disorders. Haemophilia 2008; 14: 65-7. Astermark J, Altisent C, Batorova A, et al. Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report. Haemophilia 2010; 16: 747-66.
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References
16) Richards M, Williams M, Chalmers E, et al. A United Kingdom Haemophilia Centre Doctors' Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A. Br J Haematol 2010; 149: 498-507. 17) National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (Revised November 2011), 2012. Available at: http://www.hemophilia.org/NHFWeb/Resource/ StaticPages/menu0/menu5/menu57/masac190.pdf. Accessed on 10/11/2014. 18) Astermark J, Rocino A, Von Depka M, et al. Current use of by-passing agents in Europe in the management of acute bleeds in patients with haemophilia and inhibitors. Haemophilia 2007; 13: 38-45. 19) Ragni MV, Fogarty PJ, Josephson NC, et al. Survey of current prophylaxis practices and bleeding characteristics of children with severe haemophilia A in US haemophilia treatment centres. Haemophilia 2012; 18: 63-8. 20) Thornburg CD, Carpenter S, Zappa S, et al. Current prescription of prophylactic factor infusions and perceived adherence for children and adolescents with haemophilia: a survey of haemophilia healthcare professionals in the United States. Haemophilia 2012; 18: 568-74. 21) Blanchette VS, McCready M, Achonu C, et al. A survey of factor prophylaxis in boys with haemophilia followed in North American haemophilia treatment centres. Haemophilia 2003; 9 (Suppl 1): 19-26. 22) Khair K, Lawrence K, Butler R, et al. Assessment of treatment practice patterns for severe hemophilia A: a global nurse perspective. Acta Haematol 2008; 119: 115-23. 23) Perry D, Berntorp E, Tait C, et al. FEIBA prophylaxis in haemophilia patients: a clinical update and treatment recommendations. Haemophilia 2010; 16: 80-9. 24) Morfini M, Auerswald G, Kobelt RA, et al. Prophylactic treatment of haemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Haemophilia Centres. Haemophilia 2007; 13: 502-7. 25) European Haemophilia Consortium. EHC country fact sheet: Italy. 2012. Available at: http://www.ehc.eu/fileadmin/ about_EHC/members/fact_sheet/Italy-EN.pdf. Accessed on 10/11/2014. 26) Dragani A, Malizia R, Iuliani O, et al. Inherited bleeding disorders: results from the Italian Regional Haemophilia Centre of Pescara. Blood Transfus 2008; 6: 136-42. 27) Thornburg CD. Physicians' perceptions of adherence to prophylactic clotting factor infusions. Haemophilia 2008; 14: 25-9.
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bureau for Amgen, Bayer, Glaxo, Pfizer and Shire and in an advisory board and speaker bureau for Baxter and NovoNordisk. EZ has acted as a paid consultant and has received fees as a speaker in the frame of scientific symposia organised by Baxter, Bayer, Grifols and NovoNordisk. ACM acted as speaker for Bayer and as an advisory board member for Baxter, Bayer and Pfizer.
Arrived: 23 December 2014 - Revision accepted: 18 February 2015 Correspondence: Giancarlo Castaman Center for Bleeding Disorders Careggi University Hospital Largo Brambilla 3 50134 Florence, Italy e-mail: [email protected]
Blood Transfus 2015; 13: 631-8 DOI 10.2450/2015.0333-14 638 All rights reserved - For personal use only No other uses without permission
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Background. Although current treatment guidelines recommend prophylaxis in paediatric patients with haemophilia, specific indications for and barriers to the prescription of prophylaxis in the paediatric haemophiliac population have not been established. The aim of this web-based survey of clinicians at Haemophilia Treatment Centres in Italy was to identify factors for and against the initiation of prophylactic coagulation factor replacement therapy in paediatric patients with haemophilia. Materials and methods. A literature search was conducted to identify factors to include in the survey. Seventeen clinicians from Italian Haemophilia Centres were invited to complete the webbased survey and to rank factors in favour of and those that acted as barriers to prophylaxis in terms of "importance" and "influence" on a numerical scale (0=not important to 100=very important). Any factors for which there was a large discrepancy in results from the survey were further "ranked" by clinicians at an interactive question and answer session at a symposium. Results. A total of 13 web surveys were returned; the most highly scored factors favouring prophylaxis were "bleeding frequency", "bleeding severity" and "presence of target joints", and the most highly scored barriers were "parents' acceptance", "venous access" and "compliance to therapy". Other important factors favouring prophylaxis were "severity of coagulation defect" and "orthopaedic score". Discussion. This survey gives helpful clinician-derived information for people treating haemophiliacs in Italy, to help the treatment-providers orient themselves better regarding the prescription of prophylaxis for paediatric patients.
Introduction
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Keywords: haemophilia, prophylaxis, paediatrics, clinical management, factor VIII.
Haemophilia is an inherited, life-long bleeding disorder caused by deficiencies of factor VIII (FVIII) or factor IX (FIX) and, in its severe form, is characterised by recurrent bleeding into joints and soft tissues1. Crippling arthropathy, chronic pain, the need for orthopaedic surgery, disability and comorbidities (e.g. liver disease), which can have a negative impact on a patient's quality of life, are the most feared consequences of inadequate treatment of these bleeding episodes1,2. Nowadays, the primary aim of the management of patients with haemophilia is to treat and prevent bleeding by replacing the deficient clotting factor3. Patients with moderate or mild disease usually receive on-demand therapy with coagulation factor concentrates or desmopressin, but it is recommended that those with
severe disease are given prophylactic factor replacement therapy with FVIII or FIX concentrate4. Prophylactic therapy results in change from severe to moderate or mild haemophilia5 and has been shown to be superior to on-demand treatment with regards to reducing jointor life-threatening bleeds, limiting the development of arthropathy and improving quality of life5-11. Furthermore, the initiation of prophylaxis at an early age (i.e. before 3 years of age) is associated with better long-term outcomes in patients with severe haemophilia12. The prophylactic treatment of children with haemophilia is associated with a number of challenges. Patients' compliance with treatment often declines in the transition from childhood to adolescence and the support from parents, peers and caregivers is critical to improve adherence to treatment programmes13. Additionally, the
Blood Transfus 2015; 13: 631-8 DOI 10.2450/2015.0333-14 © SIMTI Servizi Srl
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Castaman G et al
Phase 1A: identification of factors Factors were identified within the plenary session of the GILP group on the basis of a literature search and the group members' clinical experience, and used to design the survey as described by Astermark and Colleagues in 201015. Consequently, identified factors were ranked by 13 members of the group for "importance" (i.e. how relevant it is considered in the literature) and "influence" (i.e. to what extent it affects his/her personal choice to administer prophylaxis) on a six-point scale where 0 = not important/no influence on choice to administer prophylaxis and 5 = very important/greatly influences choice to administer prophylaxis. Each of these factors was subsequently judged to be "for" or "against" the initiation of prophylaxis during the survey, based on the clinical experience of the participating members of the group. The factors were then classified into two groups (i.e. indications for and barriers to prophylaxis) based on score results.
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burden that is placed on parents with regards to disease management can be stressful and problematic, which emphasises the need for healthcare services to provide easy access to appropriate support14. Another challenge to treating children with haemophilia is the formation of alloantibodies (inhibitors) to FVIII or FIX, which is a significant treatment-related complication of haemophilia replacement therapy that occurs mainly at a young age (median age ≤3 years) in about 30% of patients with severe haemophilia A3,4. Immune tolerance induction (ITI) can be used to eradicate the inhibitors, and in order to prevent or treat bleeds either during or outside ITI, patients can be treated with bypassing agents such as recombinant factor VIIa (Novoseven; NovoNordisk A/S, Bagsvaerd, Denmark) or activated prothrombin complex concentrates (FEIBA; Baxter AG, Wien, Austria)4. The European Haemophilia Treatment Standardisation Board (EHTSB) recommends that prophylaxis for the prevention of bleeding should be provided to all children with haemophilia, since it also seems to exert a favourable immunological effect to promote immune tolerance15. Although haemophilia treatment guidelines generally recommend the use of prophylaxis, there is limited guidance on how to decide whether a patient should receive prophylaxis or not3,16,17. Physician surveys are useful tools to determine current standards of practice in haemophilia treatment18, especially if there is disparity between guideline recommendations and current practice19. A web-based survey was, therefore, conducted in various Italian Haemophilia Treatment Centres to identify current trends in the clinical management of haemophilia, as well as barriers to initiating prophylaxis, in paediatric patients with haemophilia. In so doing, this study aims to provide clinicians with an expert opinion-based rationale on whether or not to prescribe prophylaxis to their paediatric patients.
Study design Factors promoting the initiation of haemophilia prophylaxis and factors presenting an obstacle to the initiation of prophylaxis were identified through a literature review. The literature search was performed according to the method described by Berntorp and colleagues in 201110, but focused on prophylaxis in various clinical settings and ranges of age. A web-based survey of the Gruppo Italiano Lavoro sulla Profilassi emofilica (GILP) was then conducted among 17 Italian haematologists asking them to rank the importance of these factors identified from the literature review in the management of paediatric patients with haemophilia. Paediatric patients were stratified into four age groups: 0 to 2 years; >2 to 6 years; >6 to 12 years; and >12 to 18 years.
Phase 2: revision and recommendations For those factors for which a large discrepancy remained in the results from phase 1B (i.e. when the median score assigned by participants differed by more than 1), a further "ranking" (and scoring) was performed during an interactive question and answer session (using audience response keypads) as part of a medical meeting. Participants comprised over 50 haematologists, paediatricians and transfusion specialists involved in haemophilia treatment throughout Italy, who convened to discuss the merits of the content and interpretation (e.g. to balance the importance of each factor against feasibility). Wherever necessary, questions from the survey were rephrased to help with reaching a final agreement.
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Materials and methods
Phase 1B: administration and analysis Participants were asked to complete the survey by filling in an Excel document sent by email. After a plenary session, the GILP group was split into subgroups with a specific focus on prophylactic treatment of paediatric, adult or surgical patients. In the GILP paediatric group, Italian haemophilia treatment providers were asked to rank the factors (from 0 to 5) and score them in terms of "importance" and "influence" (from 0=not important/no influence to 100=very important/greatly influences). This allowed the identification of factors for or against prophylaxis, i.e. the indications for prophylaxis initiation, the barriers (potential obstacles) to prophylaxis and the degree of agreement/disagreement on the findings within the GILP paediatric group. Factors for which no agreement was reached were subjected to reconsideration through discussion amongst the participants of this survey as described in phase 2 of the study.
Blood Transfus 2015; 13: 631-8 DOI 10.2450/2015.0333-14 632 All rights reserved - For personal use only No other uses without permission
Haemophilia prophylaxis in paediatric patients
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Results
Results of phase 1B: survey responses The five most highly scored factors indicating the initiation of prophylaxis in paediatric patients according to age subgroup are listed in Table I. Overall, "bleeding frequency", "bleeding severity" and "severity of coagulation defect" were the most highly scored indications for prophylaxis in the subgroup aged 6 to 18 years of age (Table II).
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Statistical analysis The completed sections of all returned surveys (including completed sections of incomplete surveys) were included in the analysis; the incomplete sections of surveys were excluded from the analysis. Surveys were collected by email, thus the results were not provided anonymously. Minimum, maximum, median (interquartile range) and mean scores were calculated based on rankings made by the clinicians. Given the wide variability in data, ≥75% consensus among responders during phases 1 and 2 were defined as a significant majority.
psychological barriers; compliance to therapy; venous access; quality of life; orthopaedic score; presence of target joints (i.e. repeated haemorrhagic events in the same joint); sport and play activity; previous prophylaxis; type of occupation; planned orthopaedic surgery; type of hobbies; previous orthopaedic surgery (the latter four criteria were added for the group 12 to 18 years old). Overall, "bleeding frequency", "bleeding severity" and "presence of target joints" were ranked by haematologists as having the most "importance" and "influence" when deciding whether to prescribe prophylaxis in paediatric patients (Figure 1A-D).
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Data collection procedures From among all Italian Haemophilia Centres in existence at the start of the study (n=48), 15 of the major Italian Centres were selected and 17 clinicians from the GILP group, all also caring for patients below the age of 18, were recruited to receive the survey (i.e. those with more experience and with the largest number of patients), which was sent to the head of each Centre. This meant that the survey was able to cover approximately 70% of Italian haemophilia treatment providers.
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Survey respondents Phase 1 During phase 1, a total of 17 clinicians (15 haematologists; 2 paediatricians) from 15 Haemophilia Treatment Centres across regional locations in Italy were invited to participate in the survey. Overall, 13 of the 17 participants responded to and returned the complete surveys. The estimated proportion of haemophilia patients considered by the participants of the survey was approximately 70% of the Italian haemophilia population.
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Phase 2 During phase 2, the 17 participants in the survey and an additional 50 haematologists and transfusion specialists from a total of 48 Centres convened to discuss the merits of the content and interpretation of the results. Overall, a total of 45 participants completed the interactive session (i.e. not all participants responded to every question). Results of phase 1A: identification of factors The following factors indicating initiation of prophylaxis and those considered to be barriers or "contraindications" to prophylaxis in paediatric patients were identified and included in the survey: bleeding frequency; bleeding severity; severity of coagulation defect; high-risk genetic mutation for inhibitor development; intensive treatment at the beginning of infusion history; family history of inhibitors; lively behaviour of child; parents' acceptance; social and cultural level of parents; geographical, cultural and
Results of the phase 2 interactive session Overall, nine factors were associated with a large discrepancy in results from phase 1B; these were formulated as specific questions, and results of the audience voting on these questions during the symposium are listed in Table III. Both factors influencing the choice of establishing prophylaxis in paediatric patients (≥50% consensus) and factors that represent a barrier to the use of prophylaxis in paediatric patients (≥50% consensus) according to age subgroups are listed in Table III. An additional question was posed asking symposium participants if they agreed that prophylaxis with a bypassing agent should be prescribed for paediatric patients with high-titre inhibitors and most agreed (30/44 =68%) (Table III).
Discussion This is the largest survey conducted among Italian clinicians to identify factors that are considered to be
Blood Transfus 2015; 13: 631-8 DOI 10.2450/2015.0333-14 633 All rights reserved - For personal use only No other uses without permission
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Figure 1 A-B - Ranking decisional factors that were considered "important" and had "influence" in therapeutic choice in paediatric patients aged: A) 0-2 years, and B) >2-6 years.
important and influential in the decision of whether or not to prescribe prophylaxis in paediatric patients with haemophilia. Several factors favouring the initiation of prophylaxis in paediatric patients were identified, including "bleeding frequency", "bleeding severity", "presence of target joints", "severity of coagulation defect" and "orthopaedic score". On the other hand, factors that were considered to act as barriers to prophylaxis in paediatric patients with haemophilia included "parents' acceptance", "venous access", "compliance to therapy" and "geographical, cultural and psychological barriers". The results of this survey may provide useful insight
into clinician beliefs and practice patterns regarding the use of prophylactic therapy for paediatric patients with haemophilia in Italy. Many international haemophilia treatment guidelines recommend prophylaxis in children with haemophilia3,13,16. However, they do not provide specific guidance on the indications or "contraindications" (barriers) to prophylaxis in paediatric patients. UK guidelines for patients with severe haemophilia A state that prophylaxis should be initiated by the second joint bleed or significant tissue bleed16, and the World Federation of Haemophilia (WFH) defines primary prophylaxis as treatment initiated in the Blood Transfus 2015; 13: 631-8 DOI 10.2450/2015.0333-14
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Figure 1 C-D - Ranking decisional factors that were considered "important" and had "influence" in therapeutic choice in paediatric patients aged: C) >6-12 years, and D) >12-18 years.
absence of joint disease and started before the second clinically evident large joint bleed and age 3 years3. The clinicians in the current survey agreed that "bleeding frequency", "bleeding severity" and "presence of target joints" were the most important factors influencing the initiation of prophylaxis in paediatric patients with haemophilia. Previous studies have shown that early initiation of prophylaxis is associated with improvements in long-term outcomes, including reductions in joint bleeds and the development of chronic arthropathy5,7,12, which has had an impact on the prescription of prophylaxis by clinicians treating paediatric patients. Indeed, a recent
survey20 of healthcare professionals in the USA indicated an increase in the prescription of prophylaxis for children with haemophilia since the publication of the Joint Outcome Study7. To date, there are limited European survey data on clinical management trends in paediatric patients with haemophilia. However, results of the current survey are in broad agreement with those of other surveys of current practice and attitudes in the management of paediatric and adult patients with haemophilia21,22. A survey of prophylaxis use in male paediatric patients with haemophilia from North American Treatment
Blood Transfus 2015; 13: 631-8 DOI 10.2450/2015.0333-14 635 All rights reserved - For personal use only No other uses without permission
Castaman G et al Table I - The five most highly-scored factors favouring prophylaxis in paediatric patients with haemophilia according to age subgroup.
Table II - The five most highly-scored factors as barriers to prophylaxis in paediatric patients with haemophilia according to age subgroup.
Categories
Categories
Age >12-18 years
97
95
Bleeding severity
97
96
Severity of coagulation defect
95
90
High risk genetic mutation
83
60
Intensive treatment at the beginning of transfusional history
83
76
Bleeding severity
99
98
Bleeding frequency
99
98
Presence of target joints
97
91
Age 0-2 years
Age >2-6 years
Quartile 1
Parents' acceptance
89
59
Venous access
85
70
Compliance to therapy
78
57
Social and cultural level of parents
75
38
Geographical, cultural and psychological barriers
70
50
Venous access
96
90
Parents' acceptance
94
78
Compliance to therapy
88
78
Geographical, cultural and psychological barriers
80
75
Social and cultural level of parents
75
63
Compliance to therapy
80
69
Venous access
78
61
Geographical, cultural and psychological barriers
75
67
94
90
Orthopaedic score
86
80
Bleeding severity
99
98
Bleeding frequency
98
96
Presence of target joints
96
90
Orthopaedic score
93
84
Severity of coagulation defect
90
86
Bleeding frequency
98
96
Parents' acceptance
73
60
Bleeding severity
97
97
96
95
Social and cultural level of parents
65
54
94
89
Compliance to therapy
76
53
92
86
Geographical, cultural and psychological barriers
65
38
Presence of target joints Orthopaedic score Quality of life
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Severity of coagulation defect
Age >6-12 years
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Age >6-12 years
Bleeding frequency
Score† Median
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Age >2-6 years
Quartile 1
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Age 0-2 years
Score† Median
Age >12-18 years
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†Factors favourable to prophylaxis scored for importance and influence on a scale of 0 to 100, where 0=not important and 100=very important.
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Centres found that the major reason for initiating prophylaxis was a history or presence of joint bleeding22. Additionally, an update of a global survey (UK, USA, Canada, Sweden) of nurses at Haemophilia Treatment Centres on treatment practice patterns for children and adults with haemophilia A indicated that the most influential factors for initiating prophylaxis were bleeding history and target joint development (i.e. the development of arthropathy in target joints)22. Other important factors included patients' adherence, adequacy of family commitment, adequacy of venous access, disease severity and level of patients' activity22. In the current survey, "bleeding frequency", "bleeding severity" and "presence of target joints" were among the most highly scored factors favouring prophylaxis in paediatric patients with haemophilia (Table I). However, "venous access" was included in the current Italian survey as a barrier to prophylaxis (Table II). Interestingly, the current study did not identify the presence of inhibitors as an indication or "contraindication" to prophylaxis in paediatric patients
Occupation type
63
34
Venous access
61
40
Parents' acceptance
52
28
† Factors non favourable to prophylaxis (i.e. barriers) scored for importance and influence on a scale of 0 to 100, where 0=not important and 100=very important.
with haemophilia, although "family history of inhibitors" was identified as a factor favouring the initiation of prophylaxis (data not shown). Inhibitor formation to FVIII or FIX is a severe treatment-related complication in haemophilia which often develops at an early age (≤3 years) in patients with severe haemophilia A3, and both the EHTSB and recent consensus guidelines recommend prophylaxis with bypassing agents (e.g. FVIII inhibitor bypassing activity [FEIBA] concentrate) in paediatric and adult patients with inhibitors 18,23 . Indeed, a retrospective survey of some European Haemophilia Centres (Italy, Germany, France, Spain, Switzerland and the Czech Republic) showed that prophylactic treatment with recombinant factor VIIa in paediatric and adult patients with severe haemophilia and inhibitors effectively reduced the number of bleeding episodes Blood Transfus 2015; 13: 631-8 DOI 10.2450/2015.0333-14
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Haemophilia prophylaxis in paediatric patients Table III - Factors for which there was a large discrepancy in results from phase 1B: audience responses to questions asked during an interactive session (total number of participants =45, although not all participants answered each question). Data are number of respondents for each category. Question
None
Low
Medium
Influence of living far away from the centre on the clinical decision to prescribe prophylaxis
13
20
11
Influence of the low cultural level of the child's parents on the clinical decision to prescribe prophylaxis
21
14
10
Influence of the parents' psychological difficulty to accept prophylaxis on the clinical decision to prescribe prophylaxis
12
24
9
Influence of low parents' acceptance on the clinical decision not to prescribe prophylaxis
0
11
22
Age >2-6 years
Influence of the presence of a genetic mutation associated with a high risk for developing inhibitors on the clinical decision to prescribe prophylaxis
11
10
19
Age >6-12 years
Influence of poor compliance to the prescribed prophylactic regimen on clinical decision to continue prophylaxis
5
22
13
Influence of a low perceived quality of life on the clinical decision to prescribe prophylaxis
3
4
16
Overall
Influence of a high orthopaedic score on the clinical decision to prescribe prophylaxis
1
1
9
Influence of sport and play activities and/or hobbies associated with a high haemorrhagic risk on the clinical decision to prescribe prophylaxis
1
10
12
Do you agree with the following statement: prophylaxis with a bypass agent is indicated for children with high-titre inhibitor
No: 3
Agree a little: 11
Agree: 24
experience due to the large number of patients, including those of paediatric age, being treated at the selected Centres. Questions from the survey referred only to "prophylaxis" and did not provide a clear definition of this term. As a result, an understanding of the clinical context of "prophylaxis" may differ between respondents of the survey and the study investigators.
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and improved patients' compliance and quality of life24. The current survey appears to provide decisional support among Italian clinicians for prophylaxis in paediatric patients with haemophilia. However, the mean number of FVIII concentrate units used per capita is lower than in other EU countries despite primary prophylaxis being provided as standard therapy to children with haemophilia in Italy25. Furthermore, an analysis of epidemiological, diagnostic and therapeutic data from an Italian Regional Haemophilia Centre showed that prophylaxis in children or adults was used less often than on-demand treatment, especially in patients with severe haemophilia26. "Compliance to therapy", "venous access" and "parents' acceptance" were the most important barriers to prophylaxis in the current survey. These results confirm those from a global survey, which reported similar barriers to prophylaxis, including poor adherence, inadequate family commitment and venous access22. In the current survey, "parents' acceptance" was most important in paediatric patients aged 0-2 years, which is to be expected since younger patients are more reliant on the support and care of their parents. Poor adherence is a major issue that can decrease the efficacy of prophylactic treatment, and previous surveys conducted in the USA also found poor adherence to be a barrier to prescribing prophylaxis in paediatric patients with haemophilia20,27. The results of the current survey should be considered against its limitations. The data may be subject to selection bias due to the small number of Centres that completed the survey. However, we feel that the opinion captured in this survey is based on extensive clinical
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Age >12-18 years
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Age group Age 0-2 years
Conclusions The achievement of effective prophylaxis in paediatric patients with haemophilia is an on-going challenge. This study provides a useful clinician-derived perspective on the management of haemophilia, helping to identify patients who should be given prophylaxis as well as barriers to successful initiation of prophylactic treatment in paediatric patients, in Italy.
Authorship contributions GC wrote the initial draft of the manuscript. All the Authors read, reviewed and approved the final draft of the paper.
Disclosure of conflicts of interest The GILP study was sponsored by Baxter. GC has received fees for lectures from Baxter, CSL Behring, Kedrion and NovoNordisk. AR has attended advisory board meetings of Baxter, NovoNordisk and Pfizer, acted as a paid consultant for Bayer, CSL Behring, NovoNordisk and Pfizer and received fees as a speaker in meetings organised by Baxter, Bayer, CSL Behring, NovoNordisk and Pfizer. MGM served in a speaker
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Barr RD, Saleh M, Furlong W, et al. Health status and healthrelated quality of life associated with hemophilia. Am J Hematol 2002; 71: 152-60. Klamroth R, Pollmann H, Hermans C, et al. The relative burden of haemophilia A and the impact of target joint development on health-related quality of life: results from the ADVATE Post-Authorization Safety Surveillance (PASS) study. Haemophilia 2011; 17: 412-21. Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19: e1-47. Fijnvandraat K, Cnossen MH, Leebeek FW, Peters M. Diagnosis and management of haemophilia. BMJ 2012; 344: e2707. Gringeri A, Lundin B, von Mackensen S, et al. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9: 700-10. Fischer K, van der Bom JG, Molho P, et al. Prophylactic versus on-demand treatment strategies for severe haemophilia: a comparison of costs and long-term outcome. Haemophilia 2002; 8: 745-52. Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535-44. Tagliaferri A, Franchini M, Coppola A, et al. Effects of secondary prophylaxis started in adolescent and adult haemophiliacs. Haemophilia 2008; 14: 945-51. Collins P, Faradji A, Morfini M, et al. Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-month crossover study. J Thromb Haemost 2010; 8: 83-9. Berntorp E, Collins P, D'Oiron R, et al. Identifying nonresponsive bleeding episodes in patients with haemophilia and inhibitors: a consensus definition. Haemophilia 2011; 17: e202-10. Witmer C, Presley R, Kulkarni R, et al. Associations between intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients in the United States. Br J Haematol 2011; 152: 211-6. Astermark J, Petrini P, Tengborn L, et al. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol 1999; 105: 1109-13. Petrini P, Seuser A. Haemophilia care in adolescents-compliance and lifestyle issues. Haemophilia 2009; 15 (Suppl 1): 15-9. Shaw D, Riley GA. The impact on parents of developments in the care of children with bleeding disorders. Haemophilia 2008; 14: 65-7. Astermark J, Altisent C, Batorova A, et al. Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report. Haemophilia 2010; 16: 747-66.
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References
16) Richards M, Williams M, Chalmers E, et al. A United Kingdom Haemophilia Centre Doctors' Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A. Br J Haematol 2010; 149: 498-507. 17) National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders (Revised November 2011), 2012. Available at: http://www.hemophilia.org/NHFWeb/Resource/ StaticPages/menu0/menu5/menu57/masac190.pdf. Accessed on 10/11/2014. 18) Astermark J, Rocino A, Von Depka M, et al. Current use of by-passing agents in Europe in the management of acute bleeds in patients with haemophilia and inhibitors. Haemophilia 2007; 13: 38-45. 19) Ragni MV, Fogarty PJ, Josephson NC, et al. Survey of current prophylaxis practices and bleeding characteristics of children with severe haemophilia A in US haemophilia treatment centres. Haemophilia 2012; 18: 63-8. 20) Thornburg CD, Carpenter S, Zappa S, et al. Current prescription of prophylactic factor infusions and perceived adherence for children and adolescents with haemophilia: a survey of haemophilia healthcare professionals in the United States. Haemophilia 2012; 18: 568-74. 21) Blanchette VS, McCready M, Achonu C, et al. A survey of factor prophylaxis in boys with haemophilia followed in North American haemophilia treatment centres. Haemophilia 2003; 9 (Suppl 1): 19-26. 22) Khair K, Lawrence K, Butler R, et al. Assessment of treatment practice patterns for severe hemophilia A: a global nurse perspective. Acta Haematol 2008; 119: 115-23. 23) Perry D, Berntorp E, Tait C, et al. FEIBA prophylaxis in haemophilia patients: a clinical update and treatment recommendations. Haemophilia 2010; 16: 80-9. 24) Morfini M, Auerswald G, Kobelt RA, et al. Prophylactic treatment of haemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Haemophilia Centres. Haemophilia 2007; 13: 502-7. 25) European Haemophilia Consortium. EHC country fact sheet: Italy. 2012. Available at: http://www.ehc.eu/fileadmin/ about_EHC/members/fact_sheet/Italy-EN.pdf. Accessed on 10/11/2014. 26) Dragani A, Malizia R, Iuliani O, et al. Inherited bleeding disorders: results from the Italian Regional Haemophilia Centre of Pescara. Blood Transfus 2008; 6: 136-42. 27) Thornburg CD. Physicians' perceptions of adherence to prophylactic clotting factor infusions. Haemophilia 2008; 14: 25-9.
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bureau for Amgen, Bayer, Glaxo, Pfizer and Shire and in an advisory board and speaker bureau for Baxter and NovoNordisk. EZ has acted as a paid consultant and has received fees as a speaker in the frame of scientific symposia organised by Baxter, Bayer, Grifols and NovoNordisk. ACM acted as speaker for Bayer and as an advisory board member for Baxter, Bayer and Pfizer.
Arrived: 23 December 2014 - Revision accepted: 18 February 2015 Correspondence: Giancarlo Castaman Center for Bleeding Disorders Careggi University Hospital Largo Brambilla 3 50134 Florence, Italy e-mail: [email protected]
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