Recommendations for assessment, monitoring and follow-up of patients with haemophilia

1. Recommendations for assessment, monitoring and follow-up of patients with haemophilia P. de Moerloose, K. Fischer, T. Lambert, J. Windyga, A. Batorova, G. Lavigne, A. Rocino, J. Astermark and C. Hermans a subgroup of the European Haemophilia Standardisation Board (EHTSB) Haemophilia 2011 in press

2. The European Haemophilia Therapy Standardisation Board (EHTSB) • Founded in 2003 • Independent Group of 24 Haemophilia Centre Directors and a pharmacoeconomist from 14 countries in Western and Central Europe • Almost 12,000 patients with bleeding disorders are followed • Represents approximately 15% of the European severe patient population • Supported and facilitated by Baxter BioScience Europe

3. Oslo The EHTSB Centres Hamburg Amsterdam Porto Montpellier Lecce

4. Background • Clinical follow-up of pwh has become more complex as a result of the introduction of new treatment strategies, the presence of co-morbidities related to haemophilia or ageing as well as the emergence of new tools to evaluate the medical and social consequences of haemophilia • Many countries that are starting to establish care for haemophilia patients do not have standard protocols to ensure the proper management of haemophilia. Some country-specific guidelines for the diagnosis and treatment of haemophilia have been published. However, there is no current consensus at a European level, particularly to cover the follow-up of patients.

5. Aim of this work The European Haemophilia Therapy Standardisation Board (EHTSB) therefore has sought to provide practicalconsensus recommendationsto ensure the quality of care and follow-up of PWH

6. Methods • In the absence of formal studies, the present approach was to assess what information was available from the literature and, combining this with the clinical experience of the Board, to establish recommendations as a result of a series of consensus meetings of the EHTSB • We describe the parameters and information that should be documented and tests, examinations and interventions required for optimal follow-up of PWH

7. 11 domains were identified • Demographics and history as baseline information • Current status • Treatment • Inhibitor status • Bleeding • Joint status and pain • Comorbidities • Dental Care • Physical Activities • Social Participation • Quality of Life For each domain the main parameters to be captured and monitored as well as the relevant tools were detailed

8. Table 1: Parameters recorded for baseline information Date of birth Gender Body weight Ethnicity Blood group Family history of Haemophilia Inhibitors Diagnosis Haemophilia type and severity Genetics Inhibitor status Age at: Diagnosis First bleeding symptom (specify date, type and location of bleed) First joint bleed (specify site, reason) First treatment (specify type of treatment) Start of prophylaxis History of blood transfusion products other than factor concentrates

9. Comments for demographics and history at baseline information A family history of haemophilia and known carrier status of the mother would identify at-risk babies before delivery. If the maternal carrier status is not known, or the baby has a spontaneous mutation, the diagnosis might not be made until some days, months or even years after birth. In this baseline information, because the diagnosis could have been missed previously, it is important to record all bleeds before diagnosis and how (if) they have been treated.

10. Table 2: Current status Clinical Assessment Date of update Complaints Drugs Alcohol and smoking Major Events Major bleeding Surgery (orthopaedics and others), hospitalisations Family history New cases New inhibitors Identification of carriers Vaccinations General physical status including weight, height, blood pressure Blood coagulation assessment Factor VIII or IX levels for mild/moderate patients Recovery, half-life study, DDAVP response (if appropriate)

11. Comments Patients with severe haemophilia should be assessed at least once per year; mild and moderate patients can be reviewed less frequently. The patient should document all bleeds and the reason for these. Trough levels(last dose of factor infused as well as time from the last infusion has to be collected for correct interpretation) should be part of the regular follow-up visits and done together with inhibitor testing if breakthrough bleeds start to occur.

12. Table 3:Treatmentinformation Replacement therapy: Concentrate type On-demand: Dosing (IU/infusion) Prophylaxis: Date/age of start/stop Dosing (IU/infusion) Frequency Timing of infusions Who carries out the infusion Examine log-book: Dose and time of each infusion / reason Batch number Annual consumption Other haemostatic treatments (DDAVP, antifibrinolytic agents) Treatment in case of hospitalisations Other medications (analgesics, anti-inflammatories and for co-morbidities)

13. Comments A treatment log-book is recommended. The cumulative number of exposure days and the annual consumption are important parameters and should be extracted from the log-book. It is important to note not only regular doses and their frequency but also extra doses and for what reason. If a central venous line is used (and if it is removed) this should also be recorded.

14. Table 4: Recommended screening frequency for inhibitors in patients with severe haemophilia A Initial screening Every 5 exposure days (EDs) until 20 EDs After 21 EDs, every 10 EDs until 50 EDs At least 2 x times a year until 150 EDs Follow-up screening Annually thereafter Whenever clinically indicated Before and after surgery Before and after a switch of products If positive, repeat and check recovery of concentrates

15. Comments domain 4 Inhibitor assay should ideally be performed after a washout period of 72 hours. We recommend performing inhibitor testing 5-7 days prior to surgery to allow full laboratory assessment and repeat testing if necessary. Although not clearly evidence-based, it recommended that inhibitor testing after surgery is delayed for 3-5 weeks, unless there is a clinical suspicion of inhibitor development.

16. Comments (next) For patients who switch concentrate, the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHDCO) has recommended that an inhibitor test has to be performed at least twice in the 6 months after the switch. Moreover UKHCDO recommends that inhibitor screening for severe haemophilia patients should be performed indefinitely because there appears to be a risk of inhibitor development throughout life and this risk may be increased after the age of 50.

17. Inhibitor incidence by age in UK, 1990-2009: 2528 patients, follow-up 12 yrs, 351 new inhibitors Hay et al. Blood 2011;117:6367

18. Domain 4. Recommended screening frequency for inhibitors in patients with mildhaemophilia and haemophilia B In patients with mild haemophilia, inhibitors may arise after treatment with concentrates and inhibitors should be checked accordingly Mauser-Bunschoten et al. Haemophilia 2011; in press In the absence of specific recommendations for HB we recommend following the schedule for haemophilia A.

19. Domain 5. Information on bleeding episodes Bleeding pattern is the key parameter to evaluate efficacy of treatment strategy and any changes in bleeding frequency or severity should be thoroughly investigated and treatment modified as necessary

20. Table 5: Information on bleeding episodes Haemarthrosis Number of episodes Time, location and reason Type of treatment (dose, number and interval)* Response to treatment Other major bleeds Number, type Time, location and reason Treatment and response to treatment Minor bleeds Number, type Time, location and reason Treatment and response to treatment

21. Our group recently published recommendations concerning treatment of acute haemarthrosis which reflected the literature, current practice and the clinical experience of the European Haemophilia Therapy Standardisation Board. Hermans C, de Moerloose P, Fischer K et al. Haemophilia 2011 May;17(3):383-92.

22. Table 6: Musculoskeletal and pain assessment Function at least once a year for severe patients Haemophilia Joint Health Score (HJHS) Range of motion (ROM) Imaging If clinically indicated consider further investigations using imaging (ultrasonography, MRI, X-rays) Pain, at every visit. If present: Intensity (0-10 ) Average duration per day Frequency (5 point scale) Localisation/involved joints Analgesic: type and consumption

23. Domain 6. Assessment of joint health status • There are several validated clinical or image-based scores. When using a scoring system, it is important to select one that is relevant to the age of the patient. • Example ROM: Soucie et al. Haemophilia 2011;17:500 • Formerly, the orthopaedic joint score designed by Gilbert was most widely used. However, the recently developed Haemophilia Joint Health Score, or HJHS, scoring system is more sensitive to early changes and can be used for both children and adults.

24. Hemophilia joint health score • Swelling • Duration (swelling) • Muscle atrophy • Axial alignment • Crepitus on motion • Flexion loss • Extension loss • Instability • Joint pain • Strength • Gait • Joint total • Global gait score Hilliard et al. Haemophilia 2006;12:518

25. Hemophilia joint health score Swelling 0 = no swelling 1 = mild 2 = moderate 3 = severe Duration 0 = no swelling or <6 months 1 = >6 months Muscle atrophy 0 = none 1 = mild 2 = severe Axial alignment ……

26. Domain 6. Assessment of joint health status • The need for physiotherapy and/or education about physical activity should also be evaluated in close collaboration with physiotherapist or specialist in rehabilitation medicine. • To help evaluate the efficacy of prophylaxis, imaging of the six major joints (knees, ankles and elbows) should be considered, usually at 4-5 year intervals starting at the age of 8 or before if clinically indicated. These images may be scored using the additive score developed by Pettersson et al or the progressive score of Arnold and Hilgartner. • MRI scoring systems have recently been developed, but have not been used routinely. Ultrasound evaluation of joint status is currently being studied by international groups.

27. Pettersson score Radiologic change finding Score (points) Osteoporosis Absent = 0 Present = 1 Enlarged epiphysis Absent = 0 Present = 1 Irregular subchondral surface Absent = 0 Partially involved = 1 Totally involved = 2 Narrowing of joint space Absent = 0 Joint space >1mm = 1 Joint space <1mm = 2 Subchondral cyst formation Absent = 0 1 cyst = 1 >1 cyst = 2 Erosions of joint margins Absent = 0 Present = 1 Gross incongruence of articulating bone ends Absent = 0 Slight = 1 Pronounced = 2 Deformity (angulation and/or displacement between articulating bones) Absent = 0 Slight = 1 Pronounced = 2 Acta Paediatr Scand 1981;70:565

29. Lundin et al. Haemophilia 2005;11:109

30. Jelbert et al. Clin Radiol 2009;64:1119

31. Domain 6. Assessment of pain • There are a number of pain scales that range in complexity for a simple visual analogue scale (VAS) to detailed questionnaires. The selection of an appropriate tool is dependent on the clinical circumstances (e.g. routine monitoring of the patient or as part of a clinical trial) as well as time and facilities available. • Pain intensity is rated usually from 0 “no pain” to 10 “worst pain possible”. Frequency is rated on a five-point scale, where 1 = never and 5 = daily.

32. Domain 7. Screening of co-morbidities • PWH are living longer, which means that the inevitable increase in other health problems including CV disease, neoplasms etc. so it is important to carry appropriate screenings for risk factors. • The following tests are a reminder of the range of screening that should be considered. Who carries it out is not critical as long as a record is kept centrally.

33. Table 7: Screening of haemophilia specific co-morbidities (mainly in adult patients) Blood count (Hb, white cells, platelets) Blood coagulation tests (PT, aPTT, fibrinogen, factors if necessary) Iron status Viral screening (according to vaccination status) Hepatitis HIV Where positive, follow-up with further tests and refer to specialist Liver/kidney function Other tests if clinically indicated

34. Domain 8. Dental care • Routine examinations and dental care does not require raising the factor level, but adequate coverage is required prior to, and possibly after, more intensive treatments (deep cleaning, removal of heavy plaque/tartar). • Therefore it is essential that patients/parents appreciate the value of a preventative approach to dental problems and try to ensure that dental check-up are carried out at least on a annual basis. • Where aggressive treatment or dental surgery is required the events and any medication used to provide haemostatic cover should be documented to maintain a comprehensive patient record.

35. Domain 9. Physical Activities • A goal of management of PWH is to allow them to pursue an active lifestyle. The Haemophilia Activities List (HAL) is a haemophilia-specific self assessment questionnaire designed to evaluate and monitor patients’ perceived functional health status. The questionnaire seems to be a useful tool to identify problem activities for PWH. • It is also important to record patient’s occupation and to record and monitor patients’ participation in sports.

36. Haemophilia Activities List (HAL-2), 42 items, 10 minutes • Lying/sitting/kneeling/standing • Functions of the legs • Functions of the arms • Use of transportation • Self-care • Household tasks • Leisure activities and sport van Genderen et al. Haemophilia 2004;10:565 PedHal. Groen et al. Haemophilia 2010;16:281

37. Table 8. Items to record about Physical Activities Haemophilia Activities List (HAL) once a year Occupation Risk factors for bleeding or joint damage Limitations of current condition on type of work undertaken Sports activities/hobbies Which sports Frequency Any regimen of concentrate use before sports

38. Domain 10. Social participation PWH and their families may find that their condition impacts on the time they can participate in education and employment. The impact of haemophilia on their social participation needs to be documented to enable the healthcare team to identify potential problems and instigate supportive measures.

39. Domain 10. Social participation Specific tools to record aspects relevant to this domain are not available yet, even though data relating to many aspects of social participation have been collected for economic evaluations from a societal perspective. Some studies have used the Impact on Participation and Autonomy (IPA) participation assessment tool in haemophilia patients, but only in the process of validating an activity questionnaire.

40. IPA, five domains • Autonomy indoors (7 items) • Family role (7 items) • Autonomy outdoors (5 items) • Social activities (6 items) • Work and educational opportunities (6) Cardol et al. Arch Phys Med Rehabil 2002;83:1524

41. Table 9. Items to record about Social participation • Marital Status • Offspring • Education • Employment status • Disability Allowance • Days lost from work or school • since last visit • total days lost annually to assess overall impact on patient • Involvement in a patient organisation • Participation to self-injection courses

42. Domain 11. Quality of Life • QOL measures can help patients and clinicians to decide between different treatments, to monitor treatment success from the patients’ perspective; increasingly they are being used to support funding and re-imbursement for drugs. • For example the National institute for Clinical Excellence (NICE) recommends that health benefits should be valued in terms of gains in quality adjusted life years (QALYS) • In order to be able to compare different disease conditions NICE advises using a generic measure of QOL, and it prefers the EQ-5D.

43. EQ-5D-3L Mobility I have no problems in walking about I have some problems in walking about I am confined to bed Self-Care I have no problems with self-care I have some problems washing or dressing myself I am unable to wash or dress myself Usual Activities (e.g. work, study, housework, family or leisure activities) I have no problems with performing my usual activities I have some problems with performing my usual activities I am unable to perform my usual activities Pain/Discomfort I have no pain or discomfort I have moderate pain or discomfort I have extreme pain or discomfort Anxiety/Depression I am not anxious or depressed I am moderately anxious or depressed I am extremely anxious or depressed

44. Visual analog scale The EQ-VAS records the respondent’s self-rated health on a vertical, visual analog scale where the endpoints are labelled: « Best imaginable health state » and « Worst imaginable health state ». This information is used as a quantitative measure of health outcome.

45. Domain 11. Quality of Life The EQ-5D is simple, short and allows comparisons between different medical conditions. However, the EQ-5D is a very general instrument and has been criticised on the basis that it was developed in healthy people, asking them to imagine a poor health state. So for some circumstances a more haemophilia and age specific tool such as the one published by many authorsmay be desirable.

46. Domain 11. Haemophilia specific QoL Remor et al. Haemophilia 2004;10:30 Arranz et al. Haemophilia 2004;10:376 Pollak et al. Haemophilia 2006;12:384 Young et al. Pediatr Blood Cancer 2006;47:305

47. General comments The rarity of haemophilia as a disease, combined with the complexity of its management, requires that patients are evaluated by specialised haemophilia centres in close collaboration with other specialists. The recommendations are written from the perspective of the haemophilia doctor/caregiver/treater who wants to provide state-of-the-art/complete follow-up of his/her patients. Although there is a continual effort to improve care of patients with haemophilia, these recommendations will need updating in the future to take account of new developments.

48. Conclusion • Adopting these recommendations should help the individual care of patients; at the national and international level it should also help to shape a new approach by working towards a more standardised outcome assessment • This should have implications for data collection, improvements in treatment evaluation, and optimising resources

49. Choukran li estikbalikom