Haemophilia (2015), 21, 430–435
DOI: 10.1111/hae.12731
REVIEW ARTICLE
Assessments of outcome in haemophilia – what is the added value of QoL tools? H. M. VAN DEN BERG,* B. M. FELDMAN,†‡ K. FISCHER,*§ V. BLANCHETTE,¶** P . P O O N N O O S E † † and A . S R I V A S T A V A ‡ ‡ *Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; †Division of Rheumatology, The Hospital for Sick Children; ‡Departments of Paediatrics, Medicine, and the Institute of Health Policy, Management and Evaluation University of Toronto, Toronto, ON, Canada; §Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands; ¶Division of Haematology/Oncology, The Hospital for Sick Children; **Department of Paediatrics, University of Toronto, Toronto, ON, Canada; ††Department of Orthopaedics, Christian Medical College; and ‡‡Department of Haematology, Christian Medical College, Vellore, India
Introduction: Access to treatment and especially to long-term regular replacement treatment with clotting factor concentrates (prophylaxis) have caused dramatic contrasts in the clinical picture between haemophilia populations. An individual patient with severe haemophilia age 20 years can have normal joints or can be severely crippled and unable to work. Assessment of outcome in a standardized way has therefore become essential. Aim: Discuss the relevance and utility of the different outcome assessment tools in patient groups with different access to treatment. Methods: In the last decade new outcome assessment tools specific for haemophilia have been developed that measure all aspects of health according to the International Classification of Functioning, Disability and Health (ICF) model. These tools are directed at assessing the clinical and radiological status of joints as well as overall functioning, such as participation and psychosocial aspects, evaluating overall health-related quality of life (HRQOL). For deciding which tools to use in clinical practice or research, one needs to consider the specific context with regard to disease burden, healthcare environment and socioeconomic background of the patients being evaluated. Conclusion: Prospective systematic assessment of outcome in haemophilia and related bleeding disorders is important. Based upon recent literature a critical appraisal of outcome tools is described. Keywords: haemophilia, health-related quality of life, haemophilia health joint score, outcome assessment
Introduction In the last decades, major advances have been made in the treatment of patients with severe haemophilia. With access to modern haemophilia treatment and primary prophylaxis with clotting factor concentrates (CFC), most bleedings can be prevented. From a crippling disease with a life expectancy of about 20 years, haemophilia has turned into a condition for which normal life expectancy has become feasible. Patients with severe haemophilia who have been treated with prophylaxis from early childhood onwards Correspondence: H. M. van den Berg, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands Tel.: +31887568189; fax: +31887568099; e-mail: [email protected] Accepted after revision 25 April 2015 430
are now adults with academic achievements and sports participation comparable to their peers [1–3]. While the importance of comprehensive care in the management of haemophilia patients can never be underestimated, the main contribution to the improved outcome is the access to sufficient amounts of CFC, appropriately administered. Doses of 15– 40 IU kg 1 two to three times per week, started in early childhood, can prevent bleeding and arthropathy [1–3]. Although very effective as a treatment, the lifelong need for this costly therapy has hampered its wider introduction. This becomes particularly important considering that more than 95% of the cost of treatment in haemophilia is related to CFCs [4]. There is a great need to collect data on the longterm outcome of different regimens and to support optimally cost-effective regimens for CFC replacement, relevant and acceptable to all stakeholders in any healthcare system. In addition, the introduction of © 2015 John Wiley & Sons Ltd
ASSESSMENTS OF OUTCOME IN HAEMOPHILIA
new CFCs has led to a large number of clinical trials to assess their safety and effectiveness. Standardized outcome assessment is important in both situations from the perspective of all stakeholders – treating physicians, patients and health care payers. In this article, we discuss the relevance and utility of the different tools available for outcome assessment in haemophilia.
Assessment of outcome of musculoskeletal disease To allow comparison between diseases, the WHO has adopted the ICF model for the assessment of outcomes. The primary purpose of the International Classification of Functioning, Disability and Health (ICF) as a classification system is to capture the components of health. The ICF manual includes a new model of human functioning and disability to reflect current views of the interactive relationship between health conditions and social and environmental contextual factors (Fig. 1). In the previous WHO model (ICD 10), major emphasis was on the handicap, while the new ICF model recognizes the impact of a disorder on an individual’s functioning and capacity to engage fully in their lives. This means that not only the physical disability is considered, but also the environmental and personal factors that have an impact on the patient’s daily life [5]. This new ICF model was adapted for use in children in 2007 [6].
Outcome assessment in haemophilia Body functions and structures Annual bleeding rate (ABR). With bleeding into joints as the predominant manifestation of severe disease, the rate of joint bleeding has long been considered a direct and immediate measure of not only the severity of disease but also of the effectiveness of the therapy
431
being administered. It also served as a useful surrogate marker of long-term joint damage. However, it must be recognized that there is considerable heterogeneity in both reported bleeding rates and the association of bleeding with joint damage [7]. Consensus definitions on joint and muscle bleeding have recently been proposed by the factor VIII and IX Subcommittee of the SSC of the ISTH. The definitions drafted after extensive discussions with patients and taking into consideration the different contexts in which they occur [8]. Bringing accuracy to the measurement is very important to judge the immediate effectiveness of the therapeutic protocol. Given the lack of precision in the assessment of joint bleeds, the measurement should preferably be based on actual observations over a period of at least 12 months. Musculoskeletal status. Joint status was initially assessed at the level of the individual joints (ICF body structure & functions), using a clinical physical examination joint score (Gilbert score) and a radiological score (Pettersson score) described in the 1980s [9,10]. The former never had its measurement properties evaluated and the latter did not include the early soft tissue and cartilage component changes that are detected before bone changes become visible. With clinical emphasis shifting to detection of early musculoskeletal changes for those on regular replacement therapy, there was a clear need for tools that were more sensitive to such changes in order to compare the outcome of different treatment strategies in patient cohorts. Such a score is the Haemophilia Joint Health Score developed by the International Prophylaxis Study Group [11,12]. This is an improvement of the Gilbert score because it takes into account early changes in joints in young children. While plain X-ray has been used since the 1980s to evaluate advanced osteocartilage abnormalities in joints, MRI and ultrasound have been introduced more recently to assess early soft tissue changes [13,14]. Though cumbersome and expenHealth condition (disorder or disease)
Body functions and structures
Fig. 1. Interactions between the components of the International Classification of Functioning, Disability, and Health [6].
© 2015 John Wiley & Sons Ltd
Activity
Environmental factors
Participation
Personal factors
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sive, MRI is the most sensitive and comprehensive method to detect early changes in cartilage and bone. Ultrasound is also very good in detecting soft tissue changes such as synovial hypertrophy and vascularity. Both tools await assessment of their suitability and usefulness in outcome studies and clinical practice.
Activity and participation In addition to the evaluation of joints, there was also a need to investigate the ability of the individual patient to perform physical activities. Two disease-specific instruments were introduced, the Haemophilia Activities List (HAL) and the Functional Independence Score in Haemophilia (FISH) [15,16]. Both instruments measure the specific problems a patient encounters in daily life due to haemophilia. While the HAL is self-administered and covers a wider range of activities, the FISH is based on assessment of simulated performance of activities of daily living by the patient in the clinic and therefore errs towards a functional test For the HAL, a pediatric version (pedhal) was developed as well [17]. For the individual patient, scoring of activities and participation is very important and it likely best measures the impact of the disease on his physical functioning. Further work is needed to adapt these outcome measures for wider use across the spectrum of musculoskeletal diseases and socioeconomic background. Specifically, attention needs to be paid to the ceiling effect of the FISH in patients with mild joint abnormalities and the need for cultural adaptation of certain domains in the HAL [16,17]. The significant point to note is that all these instruments provide data that clearly relate to the disease process and can help to make individual therapeutic decisions.
Overall outcome assessment: health-related quality of life Over the past decade, several health-related quality of life (HRQoL) instruments were introduced into haemophilia. Much focus has been put on the development of age and disease-specific instruments for haemophilia children, including the Haemo-Qol [18] and the CHO-KLAT [19]. To have age-specific instruments is important in haemophilia and allows for comparison of the impact of disease over time. These instruments have been translated and validated in several languages. For adult patients, generic HRQoL instruments such as SF36 and, more recently, EQ-5D have been used most frequently [20,21], although disease-specific HRQoL questionnaires have been developed as well [22,23]. Health-related quality of life tools provide an overview of the different dimensions in the ICF model of health as applied to the life of a person with haemo-
Haemophilia (2015), 21, 430--435
philia. However, most often they cannot provide specific insight into the possible causes of the problems in changes of quality of life. For example, poor scores may be due to social or economic factors unrelated to specific disease management, just as improved scores may be related to acceptance of the compromised musculoskeletal functions rather than specific improvement of the musculoskeletal status. Although these results may be meaningful for the individual patient, they need to be supplemented with information obtained from other instruments to understand to which extent changes are caused by the disease.
Assessment of outcomes – a context-specific approach To document outcomes among patient groups with severe haemophilia, their disease status as well as environmental context and the purpose of the assessment need to be taken into account. Patients with severe haemophilia may be divided into three groups: Group 1. Haemophilia patients who have benefited from primary and secondary prophylaxis from early childhood onwards and with minimal bleeding; Group 2. Patients on tertiary prophylaxis but with significant arthropathy [8]; Group 3. Patients with limited access to clotting factor products receiving episodic replacement therapy and continuing to have frequent bleeds. Among patients in Group 1, the ABR cannot be used as a short-term outcome because of the effectiveness of prophylaxis. For those who have very infrequent bleeds on prophylaxis and a near normal musculoskeletal status, further improvements can only be achieved by more convenience in accessing health care or easier administration of CFCs. There is no or only limited/minimal anatomic construct of disease in these patients, or in other words, no or very limited symptoms or signs of disease. The quality of life of these patients is excellent and similar to their peers [4]. Long-term outcomes should be evaluated by radiological instruments that are able to assess soft-tissue changes, combined with assessment of the ability to participate in physical, academic and vocational activities similar to their peers. Additional measurement of HRQoL is more likely to reflect the socioeconomic or psychosocial situation as opposed to the impact of the disease. Group 2 includes patients who have had haemarthrosis and some joint damage before starting prophylaxis; in this group, short-term outcome measured by bleeding frequencies may also pose problems, as it is very difficult to improve on low bleeding rates. Moreover, patients with one or more abnormal joints may judge new treatment regimens by the effect on pain reduction rather than on a reduction in number of
© 2015 John Wiley & Sons Ltd
ASSESSMENTS OF OUTCOME IN HAEMOPHILIA
bleedings. To reliably assess changes in bleeding pattern, follow-up of the effect of prophylaxis should be more than 1 year. Assessment of limitations in activities may pick up changes, but imaging is expected to detect the results of previous bleeding only. While HRQoL measures may provide an overall assessment of their life and health, assessment of the domains of ‘body functions and structures’ and ‘activity and participation’ is still needed to make therapeutic decisions. Group 3 includes patients who have had no or limited access to treatment and generally have severe arthropathy already in early adulthood. In this group, the short-term outcome as determined by bleeding frequency can be measured. A reduction in ABR may be reported as a huge improvement in HRQoL. Should that be taken as an indicator of the current, new therapeutic agent in the clinical trial or rather the effect of any treatment? Clinical trials recruit patients from all over the world and the number of reported bleed preinclusion is often not standardized, which has an impact on the reporting of efficacy. Moreover, access to treatment, the care and attention to the participant involved in such studies could already lead to reporting better HRQoL scores regardless of the actual improvement of musculoskeletal status or the treatment.
Discussion Over the last three decades, the focus of haemophilia care has shifted from on demand therapy to early prophylactic replacement therapy. Documenting outcome of replacement therapy has become very important in different contexts, including adjusting treatment for individual patients, justification of costs and the evaluation of efficacy and costs of new concentrates. Overall, a steep increase in clotting factor consumption has been recorded in the developed world [24]. Limited long-term data are available underlining the cost–benefit ratio of the increase in consumption. Even in Sweden which is considered the place where the concept of prophylaxis is born, the cost-effectiveness of prophylaxis has been challenged [25]. While attempts must continue to reduce ABR to near zero, it is also necessary to know the effect of a few bleeds on overall long-term joint outcome in individual patients. In this context, an interesting study was performed that linked in children the ICF parameters with HRQoL and found that the level of restriction as well as barriers was higher than the level of impairments [26]. Older children, children receiving on-demand treatment and children with severe haemophilia tended to have more problems compared with younger children, children receiving prophylaxis treatment and children with mild to moderate haemophilia. © 2015 John Wiley & Sons Ltd
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Using items from quality-of-life instruments with the International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY) as a frame of reference proved to be a useful approach for the assessment of health and functioning in children with haemophilia [6]. The newly developed outcome assessment tools are extremely useful for the coverage of different aspects of the ICF model and for the assessment of health, disability and functioning. The problem today is not the availability of suitable instruments, but the lack of awareness in both patients and physicians to implement these tools and document outcome of treatment regimens over time in order to collect these data. Two important contexts can be conceptualized for the applications of the new tools – first, the response on an individual patient with haemophilia on the therapeutic regimen being administered with existing or new haemostasis agents; and secondly, to compare outcome of two different cohorts of patients with haemophilia treated with different therapeutic protocols. For the individual patient, it is critical that ABR be kept as low as possible and the impact of whatever bleeds occur be assessed with sensitive instruments that can document early joint changes and the ability to perform activities of daily living, work and leisure and to participate in social activities. The outcomes can then be used for therapeutic interventions to improve outcome. On a group level, specific and sensitive assessment of the different aspects of long-term outcome will provide the best comparisons for effectiveness of treatment protocols. Recent RCTs comparing episodic and prophylactic CFC replacement therapies as well as the long-term comparison of outcome of routine treatment between Sweden and the Netherlands are examples thereof [3,4,27]. In both these contexts, therefore, data from clinimetric instruments that measure body structure, functions and activities can be used to both make individual therapeutic decisions and compare cohorts. What then can the assessment of HRQoL with a generic or disease-specific tool add to what is covered by the other measurements? As explained above, in different contexts of evaluation of replacement therapy, the data from HRQoL assessments may not contribute or give false impressions of major improvement. Considerations regarding the use of the different HRQoL and PRO outcome measures have been published [28,29]. In fact, used in inappropriate contexts, HRQoL can also lead to potentially harmful conclusions. The recent review of Buchbinder and Ragni [30], evaluating the existing data on the impact of prophylaxis on HRQoL, concluded that there was not enough data to proof that prophylaxis improves HRQoL. This unexpected conclusion can only have been drawn from the use of these instruments in inappropriate clinical settings. The conclusion of this study Haemophilia (2015), 21, 430--435
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was based on the fact that adult patients who started prophylaxis while already having arthropathy did not report an improved HRQoL [30]. This is not unexpected, since pain related to arthropathy does not improve in a short period and further improvement of HRQoL due to the effect of reduction in bleeding can only be expected after many years of follow-up. In any case, at a time when health care providers are obviously struggling to cope with the task of outcome assessment of any kind, a major consideration would be whether time and effort should be put in contextspecific instruments that provide data which can guide individual therapeutic decisions, or in complex HRQoL instruments that can be challenging to administer and do not provide specific data able to guide individual care. Obviously, HRQoL instruments cannot replace adequate collection of specific data on different aspects of the ICF model described above. An additional challenge in using HRQoL instruments is that they need validation for various sociocultural and economic factors at each translation. This adds to the challenges of using such instruments in a rare disease such as haemophilia, when patient populations from all over the world are to be evaluated and compared. It has been argued that HRQoL measurements are useful for comparisons of outcomes between diseases and could help when lobbying with health care payers. This presump-
References 1 Nilsson IM, Berntorp E, L€ ofqvist T, Pettersson H. Twenty-five years’ experience of prophylactic therapy in severe haemeophilia A and B. J Int Med 1992; 1: 25–32. 2 van den Berg HM, Fischer K, Mauser-Bunschoten EP et al. Long-term outcome of individualized prophylactic treatment of children with severe haemophilia. Br J Haematol 2001; 112: 561–5. 3 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. 4 Fischer K, Steen Carlsson K, Petrini P et al. Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s. Blood 2013; 122: 1129–36. 5 World Health Organization. International Classification of Functioning, Disability and Health (ICF). Geneva: WHO. Available at http://www.who.int/classifications/icf/en/. 2001. 6 World Health Organization. International Classification of Functioning, Disability and Health, Children and Youth Version. Geneva: WHO. Available at http:// www.who.int/classifications/icf/en/. 2007. 7 Fischer K, van Hout BA, van der Bom JG, Grobbee DE, van den Berg HM. Association between joint bleeds and Pettersson scores in severe haemophilia. Acta Radiol 2002; 43: 528–32.
Haemophilia (2015), 21, 430--435
tion could be true. Even then, such data will need to be combined with more specific data of assessment of musculoskeletal function to truly document the impact of the disease and the therapeutic interventions.
Conclusion In conclusion, prospective systematic assessment of outcome of therapeutic interventions in haemophilia and related bleeding disorders is important. HTCs need to allocate resources to develop capacities to use appropriate tools that will provide relevant data. The usefulness or additional contribution of HRQoL data to those obtained by the more direct assessment of joint health, activities and participation is unclear at this time.
Author contributions H. Marijke van den Berg, Brian M. Feldman, Kathelijn Fischer, Victor Blanchette, Pradeep Poonnoose and Alok Srivastava conceptualized, discussed and co-authored the manuscript.
Disclosures The authors stated that they had no interests which might be perceived as posing a conflict or bias.
8 Blanchette VS, Key NS, Ljung LR, MancoJohnson MJ, van den Berg HM, Srivastava A; Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1935–9. 9 Gilbert MS. Prophylaxis: musculoskeletal evaluation. Semin Haematol 1993; 30: 3–6. 10 Pettersson H, Ahlberg A, Nilsson IM. A radiologic classification of hemophilic arthropathy. Clin Orthop Relat Res 1980; 149: 153–9. 11 Feldman BM, Funk SM, Bergstrom BM et al. Validation of a new pediatric joint scoring system from the International Hemophilia Prophylaxis Study Group: validity of the hemophilia joint health score. Arthritis Care Res (Hoboken) 2011; 63: 223–30. 12 Groen W, van der Net J, Bos K et al. Joint health and functional ability in children who receive intensive replacement therapy. Haemophilia 2011; 17: 783–90. 13 Lundin B, Pettersson H, Ljung R. A new magnetic resonance imaging scoring method for assessment of hameophilic arthropathy. Haemophilia 2004; 10: 383–9. 14 Keshava S, Gibikote S, Mohanta A, Doria AS. Refinement of a sonographic protocol for assessment of haemophilic arthropathy. Haemophilia 2009; 15: 1168–71. 15 Poonnoose PM, Thomas R, Keshava SN et al. Psychometric analysis of the functional independence score in haemophilia (FISH). Haemophilia 2007; 13: 620–6.
16 van Genderen FR, van Meeteren NL, van der Bom JG et al. Functional consequences of haemophilia in adults: the development of the Haemophilia Activities List. Haemophilia 2004; 10: 565–71. 17 Groen WG, van der Net J, Helders PJ et al. Development and preliminary testing of a Paediatric Version of the Haemophilia Activities List (pedhal). Haemophilia 2010; 16: 281–9. 18 Von Mackensen S, Bullinger M; HaemoQoL Group. Development and testing of an instrument to assess the Quality of Life of Children with Haemophilia in Europe (Haemo-QoL). Haemophilia 2004; 10(Suppl. 1): 17–25. 19 Young NL, Bradley CS, Blanchette V et al. Development of a health-related quality of life measure for boys with haemophilia: the Canadian Haemophilia Outcomes—Kids Life Assessment Tool (CHOKLAT). Haemophilia 2004; 10(Suppl. 1): 34–43. 20 Ware JE Jr, Sherbourne CD. The MOS 36item short-form health survey (SF-36). Conceptual framework and item selection. Med Care 1992; 30: 473–83. 21 Stolk EA, Busschbach JJ. Validity and feasibility of the use of condition-specific outcome measures in economic evaluation. Qual Life Res 2003; 12: 363–71. 22 Arranz P, Remor E, Quintana M, Villar A, Dıaz JL, Moreno M. Development of a new disease-specific quality-of-life questionnaire to adults living with haemophilia. Haemophilia 2004; 10: 376–82.
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ASSESSMENTS OF OUTCOME IN HAEMOPHILIA 23 Remor E, Young NL, Von Mackensen S, Lopatina EG. Disease-specific quality-of-life measurement tools for haemophilia patients. Haemophilia 2004; 10(Suppl. 4): 30–4. 24 O’Mahony B, Noone D, Giangrande PL, Prihodova L. Haemophilia care in Europe – a survey of 35 countries. Haemophilia 2013; 19: e239–47. 25 Khawaji M, Astermark J, Berntorp E. Lifelong prophylaxis in a large cohort of adult patients with severe haemophilia: a beneficial effect on orthopaedic outcome and quality of life. Eur J Haematol 2012; 88: 329–35. 26 Krasuska M, Riva S, Fava L, Von Mackensen S, Bullinger M. Linking quality-of-life measures using the International Classifica-
© 2015 John Wiley & Sons Ltd
tion of Functioning, Disability and Health and the International Classification of Functioning, Disability and Health-Children and Youth Version in chronic health conditions: the example of young people with hemophilia. Am J Phys Med Rehabil 2012; 91(13 Suppl 1): S74–83. 27 Gringeri A, Lundin B, Von Mackensen S, Mantovani L, Mannucci PM; ESPRIT Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9: 700–10. 28 European Medicine Agency. Reflection paper on the regulatory guidance for the use of health-related quality of life (HRQL) measures in the evaluation of medicinal
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products; EMEA/CHMP/EWP139391/ 2004. London: EMA, 2004 www.emea.eu. int. 29 Food and Drug Administration. Guidance for Industry. Patient-reported outcome measures: use in medical product development to support labeling claims. Silver Spring, MD: FDA, 2009 www.fda. gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM 193282.pdf . 30 Buchbinder D, Ragni MV. What is the role of prophylaxis in the improvement of health-related quality of life of patients with hemophilia? Hematology Am Soc Hematol Educ Program 2013; 2013: 52–5.
Haemophilia (2015), 21, 430--435
DOI: 10.1111/hae.12731
REVIEW ARTICLE
Assessments of outcome in haemophilia – what is the added value of QoL tools? H. M. VAN DEN BERG,* B. M. FELDMAN,†‡ K. FISCHER,*§ V. BLANCHETTE,¶** P . P O O N N O O S E † † and A . S R I V A S T A V A ‡ ‡ *Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; †Division of Rheumatology, The Hospital for Sick Children; ‡Departments of Paediatrics, Medicine, and the Institute of Health Policy, Management and Evaluation University of Toronto, Toronto, ON, Canada; §Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands; ¶Division of Haematology/Oncology, The Hospital for Sick Children; **Department of Paediatrics, University of Toronto, Toronto, ON, Canada; ††Department of Orthopaedics, Christian Medical College; and ‡‡Department of Haematology, Christian Medical College, Vellore, India
Introduction: Access to treatment and especially to long-term regular replacement treatment with clotting factor concentrates (prophylaxis) have caused dramatic contrasts in the clinical picture between haemophilia populations. An individual patient with severe haemophilia age 20 years can have normal joints or can be severely crippled and unable to work. Assessment of outcome in a standardized way has therefore become essential. Aim: Discuss the relevance and utility of the different outcome assessment tools in patient groups with different access to treatment. Methods: In the last decade new outcome assessment tools specific for haemophilia have been developed that measure all aspects of health according to the International Classification of Functioning, Disability and Health (ICF) model. These tools are directed at assessing the clinical and radiological status of joints as well as overall functioning, such as participation and psychosocial aspects, evaluating overall health-related quality of life (HRQOL). For deciding which tools to use in clinical practice or research, one needs to consider the specific context with regard to disease burden, healthcare environment and socioeconomic background of the patients being evaluated. Conclusion: Prospective systematic assessment of outcome in haemophilia and related bleeding disorders is important. Based upon recent literature a critical appraisal of outcome tools is described. Keywords: haemophilia, health-related quality of life, haemophilia health joint score, outcome assessment
Introduction In the last decades, major advances have been made in the treatment of patients with severe haemophilia. With access to modern haemophilia treatment and primary prophylaxis with clotting factor concentrates (CFC), most bleedings can be prevented. From a crippling disease with a life expectancy of about 20 years, haemophilia has turned into a condition for which normal life expectancy has become feasible. Patients with severe haemophilia who have been treated with prophylaxis from early childhood onwards Correspondence: H. M. van den Berg, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands Tel.: +31887568189; fax: +31887568099; e-mail: [email protected] Accepted after revision 25 April 2015 430
are now adults with academic achievements and sports participation comparable to their peers [1–3]. While the importance of comprehensive care in the management of haemophilia patients can never be underestimated, the main contribution to the improved outcome is the access to sufficient amounts of CFC, appropriately administered. Doses of 15– 40 IU kg 1 two to three times per week, started in early childhood, can prevent bleeding and arthropathy [1–3]. Although very effective as a treatment, the lifelong need for this costly therapy has hampered its wider introduction. This becomes particularly important considering that more than 95% of the cost of treatment in haemophilia is related to CFCs [4]. There is a great need to collect data on the longterm outcome of different regimens and to support optimally cost-effective regimens for CFC replacement, relevant and acceptable to all stakeholders in any healthcare system. In addition, the introduction of © 2015 John Wiley & Sons Ltd
ASSESSMENTS OF OUTCOME IN HAEMOPHILIA
new CFCs has led to a large number of clinical trials to assess their safety and effectiveness. Standardized outcome assessment is important in both situations from the perspective of all stakeholders – treating physicians, patients and health care payers. In this article, we discuss the relevance and utility of the different tools available for outcome assessment in haemophilia.
Assessment of outcome of musculoskeletal disease To allow comparison between diseases, the WHO has adopted the ICF model for the assessment of outcomes. The primary purpose of the International Classification of Functioning, Disability and Health (ICF) as a classification system is to capture the components of health. The ICF manual includes a new model of human functioning and disability to reflect current views of the interactive relationship between health conditions and social and environmental contextual factors (Fig. 1). In the previous WHO model (ICD 10), major emphasis was on the handicap, while the new ICF model recognizes the impact of a disorder on an individual’s functioning and capacity to engage fully in their lives. This means that not only the physical disability is considered, but also the environmental and personal factors that have an impact on the patient’s daily life [5]. This new ICF model was adapted for use in children in 2007 [6].
Outcome assessment in haemophilia Body functions and structures Annual bleeding rate (ABR). With bleeding into joints as the predominant manifestation of severe disease, the rate of joint bleeding has long been considered a direct and immediate measure of not only the severity of disease but also of the effectiveness of the therapy
431
being administered. It also served as a useful surrogate marker of long-term joint damage. However, it must be recognized that there is considerable heterogeneity in both reported bleeding rates and the association of bleeding with joint damage [7]. Consensus definitions on joint and muscle bleeding have recently been proposed by the factor VIII and IX Subcommittee of the SSC of the ISTH. The definitions drafted after extensive discussions with patients and taking into consideration the different contexts in which they occur [8]. Bringing accuracy to the measurement is very important to judge the immediate effectiveness of the therapeutic protocol. Given the lack of precision in the assessment of joint bleeds, the measurement should preferably be based on actual observations over a period of at least 12 months. Musculoskeletal status. Joint status was initially assessed at the level of the individual joints (ICF body structure & functions), using a clinical physical examination joint score (Gilbert score) and a radiological score (Pettersson score) described in the 1980s [9,10]. The former never had its measurement properties evaluated and the latter did not include the early soft tissue and cartilage component changes that are detected before bone changes become visible. With clinical emphasis shifting to detection of early musculoskeletal changes for those on regular replacement therapy, there was a clear need for tools that were more sensitive to such changes in order to compare the outcome of different treatment strategies in patient cohorts. Such a score is the Haemophilia Joint Health Score developed by the International Prophylaxis Study Group [11,12]. This is an improvement of the Gilbert score because it takes into account early changes in joints in young children. While plain X-ray has been used since the 1980s to evaluate advanced osteocartilage abnormalities in joints, MRI and ultrasound have been introduced more recently to assess early soft tissue changes [13,14]. Though cumbersome and expenHealth condition (disorder or disease)
Body functions and structures
Fig. 1. Interactions between the components of the International Classification of Functioning, Disability, and Health [6].
© 2015 John Wiley & Sons Ltd
Activity
Environmental factors
Participation
Personal factors
Haemophilia (2015), 21, 430--435
432
H. M. VAN DEN BERG et al.
sive, MRI is the most sensitive and comprehensive method to detect early changes in cartilage and bone. Ultrasound is also very good in detecting soft tissue changes such as synovial hypertrophy and vascularity. Both tools await assessment of their suitability and usefulness in outcome studies and clinical practice.
Activity and participation In addition to the evaluation of joints, there was also a need to investigate the ability of the individual patient to perform physical activities. Two disease-specific instruments were introduced, the Haemophilia Activities List (HAL) and the Functional Independence Score in Haemophilia (FISH) [15,16]. Both instruments measure the specific problems a patient encounters in daily life due to haemophilia. While the HAL is self-administered and covers a wider range of activities, the FISH is based on assessment of simulated performance of activities of daily living by the patient in the clinic and therefore errs towards a functional test For the HAL, a pediatric version (pedhal) was developed as well [17]. For the individual patient, scoring of activities and participation is very important and it likely best measures the impact of the disease on his physical functioning. Further work is needed to adapt these outcome measures for wider use across the spectrum of musculoskeletal diseases and socioeconomic background. Specifically, attention needs to be paid to the ceiling effect of the FISH in patients with mild joint abnormalities and the need for cultural adaptation of certain domains in the HAL [16,17]. The significant point to note is that all these instruments provide data that clearly relate to the disease process and can help to make individual therapeutic decisions.
Overall outcome assessment: health-related quality of life Over the past decade, several health-related quality of life (HRQoL) instruments were introduced into haemophilia. Much focus has been put on the development of age and disease-specific instruments for haemophilia children, including the Haemo-Qol [18] and the CHO-KLAT [19]. To have age-specific instruments is important in haemophilia and allows for comparison of the impact of disease over time. These instruments have been translated and validated in several languages. For adult patients, generic HRQoL instruments such as SF36 and, more recently, EQ-5D have been used most frequently [20,21], although disease-specific HRQoL questionnaires have been developed as well [22,23]. Health-related quality of life tools provide an overview of the different dimensions in the ICF model of health as applied to the life of a person with haemo-
Haemophilia (2015), 21, 430--435
philia. However, most often they cannot provide specific insight into the possible causes of the problems in changes of quality of life. For example, poor scores may be due to social or economic factors unrelated to specific disease management, just as improved scores may be related to acceptance of the compromised musculoskeletal functions rather than specific improvement of the musculoskeletal status. Although these results may be meaningful for the individual patient, they need to be supplemented with information obtained from other instruments to understand to which extent changes are caused by the disease.
Assessment of outcomes – a context-specific approach To document outcomes among patient groups with severe haemophilia, their disease status as well as environmental context and the purpose of the assessment need to be taken into account. Patients with severe haemophilia may be divided into three groups: Group 1. Haemophilia patients who have benefited from primary and secondary prophylaxis from early childhood onwards and with minimal bleeding; Group 2. Patients on tertiary prophylaxis but with significant arthropathy [8]; Group 3. Patients with limited access to clotting factor products receiving episodic replacement therapy and continuing to have frequent bleeds. Among patients in Group 1, the ABR cannot be used as a short-term outcome because of the effectiveness of prophylaxis. For those who have very infrequent bleeds on prophylaxis and a near normal musculoskeletal status, further improvements can only be achieved by more convenience in accessing health care or easier administration of CFCs. There is no or only limited/minimal anatomic construct of disease in these patients, or in other words, no or very limited symptoms or signs of disease. The quality of life of these patients is excellent and similar to their peers [4]. Long-term outcomes should be evaluated by radiological instruments that are able to assess soft-tissue changes, combined with assessment of the ability to participate in physical, academic and vocational activities similar to their peers. Additional measurement of HRQoL is more likely to reflect the socioeconomic or psychosocial situation as opposed to the impact of the disease. Group 2 includes patients who have had haemarthrosis and some joint damage before starting prophylaxis; in this group, short-term outcome measured by bleeding frequencies may also pose problems, as it is very difficult to improve on low bleeding rates. Moreover, patients with one or more abnormal joints may judge new treatment regimens by the effect on pain reduction rather than on a reduction in number of
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bleedings. To reliably assess changes in bleeding pattern, follow-up of the effect of prophylaxis should be more than 1 year. Assessment of limitations in activities may pick up changes, but imaging is expected to detect the results of previous bleeding only. While HRQoL measures may provide an overall assessment of their life and health, assessment of the domains of ‘body functions and structures’ and ‘activity and participation’ is still needed to make therapeutic decisions. Group 3 includes patients who have had no or limited access to treatment and generally have severe arthropathy already in early adulthood. In this group, the short-term outcome as determined by bleeding frequency can be measured. A reduction in ABR may be reported as a huge improvement in HRQoL. Should that be taken as an indicator of the current, new therapeutic agent in the clinical trial or rather the effect of any treatment? Clinical trials recruit patients from all over the world and the number of reported bleed preinclusion is often not standardized, which has an impact on the reporting of efficacy. Moreover, access to treatment, the care and attention to the participant involved in such studies could already lead to reporting better HRQoL scores regardless of the actual improvement of musculoskeletal status or the treatment.
Discussion Over the last three decades, the focus of haemophilia care has shifted from on demand therapy to early prophylactic replacement therapy. Documenting outcome of replacement therapy has become very important in different contexts, including adjusting treatment for individual patients, justification of costs and the evaluation of efficacy and costs of new concentrates. Overall, a steep increase in clotting factor consumption has been recorded in the developed world [24]. Limited long-term data are available underlining the cost–benefit ratio of the increase in consumption. Even in Sweden which is considered the place where the concept of prophylaxis is born, the cost-effectiveness of prophylaxis has been challenged [25]. While attempts must continue to reduce ABR to near zero, it is also necessary to know the effect of a few bleeds on overall long-term joint outcome in individual patients. In this context, an interesting study was performed that linked in children the ICF parameters with HRQoL and found that the level of restriction as well as barriers was higher than the level of impairments [26]. Older children, children receiving on-demand treatment and children with severe haemophilia tended to have more problems compared with younger children, children receiving prophylaxis treatment and children with mild to moderate haemophilia. © 2015 John Wiley & Sons Ltd
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Using items from quality-of-life instruments with the International Classification of Functioning, Disability and Health for Children and Youth (ICF-CY) as a frame of reference proved to be a useful approach for the assessment of health and functioning in children with haemophilia [6]. The newly developed outcome assessment tools are extremely useful for the coverage of different aspects of the ICF model and for the assessment of health, disability and functioning. The problem today is not the availability of suitable instruments, but the lack of awareness in both patients and physicians to implement these tools and document outcome of treatment regimens over time in order to collect these data. Two important contexts can be conceptualized for the applications of the new tools – first, the response on an individual patient with haemophilia on the therapeutic regimen being administered with existing or new haemostasis agents; and secondly, to compare outcome of two different cohorts of patients with haemophilia treated with different therapeutic protocols. For the individual patient, it is critical that ABR be kept as low as possible and the impact of whatever bleeds occur be assessed with sensitive instruments that can document early joint changes and the ability to perform activities of daily living, work and leisure and to participate in social activities. The outcomes can then be used for therapeutic interventions to improve outcome. On a group level, specific and sensitive assessment of the different aspects of long-term outcome will provide the best comparisons for effectiveness of treatment protocols. Recent RCTs comparing episodic and prophylactic CFC replacement therapies as well as the long-term comparison of outcome of routine treatment between Sweden and the Netherlands are examples thereof [3,4,27]. In both these contexts, therefore, data from clinimetric instruments that measure body structure, functions and activities can be used to both make individual therapeutic decisions and compare cohorts. What then can the assessment of HRQoL with a generic or disease-specific tool add to what is covered by the other measurements? As explained above, in different contexts of evaluation of replacement therapy, the data from HRQoL assessments may not contribute or give false impressions of major improvement. Considerations regarding the use of the different HRQoL and PRO outcome measures have been published [28,29]. In fact, used in inappropriate contexts, HRQoL can also lead to potentially harmful conclusions. The recent review of Buchbinder and Ragni [30], evaluating the existing data on the impact of prophylaxis on HRQoL, concluded that there was not enough data to proof that prophylaxis improves HRQoL. This unexpected conclusion can only have been drawn from the use of these instruments in inappropriate clinical settings. The conclusion of this study Haemophilia (2015), 21, 430--435
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was based on the fact that adult patients who started prophylaxis while already having arthropathy did not report an improved HRQoL [30]. This is not unexpected, since pain related to arthropathy does not improve in a short period and further improvement of HRQoL due to the effect of reduction in bleeding can only be expected after many years of follow-up. In any case, at a time when health care providers are obviously struggling to cope with the task of outcome assessment of any kind, a major consideration would be whether time and effort should be put in contextspecific instruments that provide data which can guide individual therapeutic decisions, or in complex HRQoL instruments that can be challenging to administer and do not provide specific data able to guide individual care. Obviously, HRQoL instruments cannot replace adequate collection of specific data on different aspects of the ICF model described above. An additional challenge in using HRQoL instruments is that they need validation for various sociocultural and economic factors at each translation. This adds to the challenges of using such instruments in a rare disease such as haemophilia, when patient populations from all over the world are to be evaluated and compared. It has been argued that HRQoL measurements are useful for comparisons of outcomes between diseases and could help when lobbying with health care payers. This presump-
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Conclusion In conclusion, prospective systematic assessment of outcome of therapeutic interventions in haemophilia and related bleeding disorders is important. HTCs need to allocate resources to develop capacities to use appropriate tools that will provide relevant data. The usefulness or additional contribution of HRQoL data to those obtained by the more direct assessment of joint health, activities and participation is unclear at this time.
Author contributions H. Marijke van den Berg, Brian M. Feldman, Kathelijn Fischer, Victor Blanchette, Pradeep Poonnoose and Alok Srivastava conceptualized, discussed and co-authored the manuscript.
Disclosures The authors stated that they had no interests which might be perceived as posing a conflict or bias.
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