Oਉਇਉਁ Aਔਉਃਅ The social burden and quality of life of patients with haemophilia in Italy Yllka Kodra 1, Marianna Cavazza 2, Arrigo Schieppati 3, Marta De Santis 1, Patrizio Armeni 2, Romano Arcieri4, Gabriele Calizzani5, Giovanni Fattore2, Lamberto Manzoli6, Lorenzo Mantovani6, Domenica Taruscio1 1
Italian National Centre for Rare Diseases, National Institute of Health, Rome; 2Centre for Research on Health and Social Care Management (CERGAS) Bocconi University, Milan; 3Clinical Research Centre for Rare Disease, Mario Negri Institute, Ranica and Department of Medicine, Rare Disease Unit, Papa Giovanni XXIII Hospital, Bergamo; 4Italian Federation of Haemophilia Societies, Rome; 5National Blood Centre, National Institute of Health, Rome; 6Italian Federation of Haemophilia Societies, Medical Council, Rome, Italy
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Background. In Italy, the project on the social burden and quality of life (QoL) of patients with haemophilia investigates costs from a society perspective and provides an overview of their quality of life. Moreover, as life expectancy increased in recent years along with new treatment strategies implemented in the last decades, it analyses trends of costs other than drugs simulating impacts during patient whole life. Material and methods. We ran a web-based cross-sectional survey supported by the Italian Federation of Haemophilia Societies in recruiting patients with haemophilia and their caregivers. We developed a questionnaire to collect information on demographic characteristics, healthcare and social services consumption, formal and informal care utilisation, productivity loss and quality of life. In particular, quality of life was assessed through the EuroQoL tool. Last, we applied the illness cost method from a society perspective. Results. On average, quality of life is worse in adult patients compared to child and caregivers: more than 75% of adult patients declare physical problems, 43% of adult patients and 54% of their parents have anxiety problems. Assuming a society perspective, the estimated mean annual total cost per patient in 2012 is 117,732 €. Drugs represent 92% of total costs. Focusing on costs other than drugs, each additional point of EuroQoL tool implies a costs' reduction of 279 €. The impact of age varies across age groups: each added year implies a total decrease of costs up to 46.6 years old. Afterwards, every additional year increases costs. Discussion. Quality of life of patients with haemophilia and their caregivers improved and it influences positively on consumed resources and on their contribution to the social-economic system. Costs other than drugs for patients with haemophilia follow the same trends of general population.
Introduction
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Keywords: quality of life, cost of illness, haemophilia.
Haemophilias are a group of inherited bleeding disorders caused by an X-chromosome linked deficiency in coagulation factors VIII (FVIII) (in haemophilia A) or IX (FIX) (in haemophilia B). The disorders are rare affecting approximately 1 in 10,000 births1. The prevalence in Italy, according to the most recent report (2012) of the Italian Association of Haemophilia Centres that operates a national registry, consists of 3,690 patients with haemophilia A and 750 with haemophilia B2,3. The use of factor replacements has significantly decreased the mortality and morbidity of patients with haemophilia: life expectancy has increased from 40 years old in the 1960s to 60-70 years today4,5. Quality of life (QoL) has become an important measure of the health improvements in haemophilic patients brought about by therapeutic progress in this field, although it
remains significantly poorer as compared with QoL of general population6,7. Specifically, QoL is viewed as a measure of the outcome of care for individuals with haemophilia that can inform disease management and policy decision making8. It is not known, however, whether changes in QoL can have an impact on costs trend in the case of haemophilia9. Last, while there are several studies on QoL in haemophilia10-12, there have been very few on caregivers QoL13-15. On the other hand, the diffusion of new treatment strategies, based not only on factor replacement therapy, but also on a switch from the on demand to prophylaxis treatment, has also an economic impact. Actually, it requires a dramatic increase of economic resources' consumption by a small portion of the population affected by a rare condition and therefore the third-payers interest on this disease is also increased.
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participate. The survey was anonymous, as the patients were contacted by their patient organisation and their responses, without any identification data, were sent directly to the researchers. The fieldwork was carried out between March 2012 and October 2012. The questionnaires were administrated by e-mail through patient organisations and patients were asked to provide information on demographic characteristics, consumed healthcare and non healthcare resources related to the disease and QoL information in the six months preceding the enrolment (12 months for hospital admissions).
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Costs' materials and methods To measure the burden of haemophilia, we have applied the cost of illness approach from a society perspective25. Therefore, both direct and indirect costs were included, and a bottom-up approach was used for their calculation: we valued the average unit cost of each set of resources consumed by enrolled patients. Direct costs include health and non-healthcare resources directly consumed by the surveyed Italian patients with type A and type B haemophilia in 2012. Direct health care costs include drugs, outpatient and inpatient care, and all range of primary care services. As far as their data source, we used services' fees because Italy does not have a national healthcare services' costs data set and we could not run specific costs' survey. However, we applied region Lombardy's fees as this region has updated nearly regularly its tariff set, surveying its providers' costs26. Moreover, as far as drugs, we have considered Italian Medicines Agency 's drugs national formulary, reducing by 30% the price of drugs distributed only by hospitals once they bought them through tenders. Considering the co-payment of drugs and outpatient care, we estimated a national average of regional fees. Last, according to the following strategy, we estimated the healthcare services fees out of Italian National Health Service (INHS), paid out of pocket by patients: we selected a small and a big town in Northern, Centre and Southern Italy and then we ran a pricing market analysis. Direct non healthcare costs comprise socialhealthcare and social services managed at city-council level: the resulting high fragmentation of these services' provision has led us to implement again the above described strategy to collect information on this setting without national or regional standards. This cost's set includes not only the formal care (i.e. provided by contracted professionals), but also the informal care provided by relatives and friends. We have applied the proxy good approach to value these resources, then we have considered if he/she did not provide these services, he/she would need to be replaced by another person who could provide the necessary care, applying the average
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In particular, it is an example of the socioeconomic impact of biotechnology in rare diseases16. Hence, the scientific literature considering economic aspects has focused mainly on the cost-effectiveness of prophylaxis vs on-demand treatment in patients with a severe haemophilia17,18 or with inhibitors19. A further set of manuscripts implements a cost of illness approach on haemophilia in different countries and in some cases the economic and the social burden of this disease is included20-23. Moreover, amongst the latter ones, only one study21 have addressed in some way the relationship between age and QoL on one side, and costs on the other side. This is, actually, a new perspective arisen from the life expectancy increase in these last years. In the early 2000s, seminal contributions concerning the Italian context provided direct healthcare costs evaluation for patients with haemophilia complicated by inhibitors in the Cost of Care Inhibitors Study16 and the first estimation of the QoL of patients without inhibitors in the Cost of Care of Hemophilia Study24. The Burden and Health-Related Quality of Life in Patients with Rare Diseases - BURQoL-RD Study was a 3 year project under the 2nd Programme of Community Action in the Field of Public Health, that commenced in April 2010 and was promoted by the Directorate General Health and Consumers of European Commission. The main aim of BURQoL-RD was to generate a model to quantify the socio-economic costs and QoL of both patients and caregivers, for up to 10 rare diseases (RD) in different European countries. According to this goal, the evaluation of the economic and social impact of haemophilias has been one of the objects of BURQoL-RD Study. Therefore, the BURQoL-RD Study on haemophilia in Italy investigates costs of this disease from a society perspective (using a cost of illness approach) for the first time and it provides an update of this group of patients' QoL. Moreover, considering the increase of life expectancy occurring in these last years, it analyses the impact of this trend on costs other than drug, simulating the whole life cycle. Last, as the expensive switch of treatment strategies implemented in the last decade has provided an increased QoL, we are going to test this improvement's impact on costs other than drugs.
Materials and methods We conducted a web-based cross-sectional study. The target sample were Italian patients diagnosed with haemophilia A and B and their caregivers. Cases were recruited from the Italian Federation of Haemophilia Societies (Federazione delle Associazioni Emofilici,FedEmo, www.fedemo.it). All patients and caregivers were informed about the study objectives and data confidentially, and were asked to indicate their understanding of the study conditions and agreement to
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organisations, no sample size calculation was performed. For cost analysis we used means and central tendency parameters, generally expressed as mean cost per patient per year, because this parameter can be easily used for policy maker. We reported the standard deviations as a variability measure. Costs were stratified according to their categories. Descriptive analyses were applied also to define health status measurements variables and QoL separately for adult, children and caregivers. It was convenient to reclassify the EQ-5D-5L and EQ-5D-Y-3L levels into 'no problems' (i.e. level 1) and "problems" (i.e. levels 2 to 5 for EQ-5D-5L and level 2 to 3 for EQ-5D-Y-3L). For categorical measures, statistical significance was determined by using chi-squared test. The one-way analysis of variance (ANOVA) was used to determine whether there were any significant differences between the means of two or more independent (unrelated) groups. Intra class correlation between ranked (ordinal) data, such as EQ-5D, was determined by means of Spearman's correlation coefficients (correlations >r=0.4 were considered relevant). A multiple linear regression was ran in order to assess the relationship between the patients' total costs without drugs (dependent variable) and patients' age and EQ-5D. We tested a possible non-linear (quadratic) relationship for both independent variables and we controlled for drugs costs and age of diagnosis. Moreover, based on estimation results, we ran a two-way simulation analysis to evaluate the joint impact of every pair of age and EQ-5D on costs, all other things being equal. We let both independent variables to range between 0 and 100 in order to capture every possible combination of the two, also including out-of-sample values. Descriptive analyses were performed using SPSS version 21.0 software. Regression analysis and two-way simulation analysis were performed using Stata, release 12. Statistical significance was set up at pF=0.0000; Root MSE=6682.3; F(6, 61)=7.56; R-squared=0.3102
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Figure 1 - Trend of costs other than drugs correlated to QoL and age.
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project provides data on drugs consumption and their valorisation, however information on patients' severity and the related treatment plans are not available, restricting the possible interpretation of drugs' data. Secondly, the core of the treatment strategy's change is the switch from on-demand to prophylaxis based treatment along with new drugs' use: this substitution may imply that the patient's consumption of drugs does not change for long whiles, making drugs' cost no more a fully variable cost over time. Last, even if costs other than drugs represent a small quota of total costs, they have been poorly investigated up to now and their analysis allows to enlighten relevant aspects with respect to the trends we are addressing. The first evidence to consider is the positive impact of new treatment's strategies on patients' QoL: this is a consolidated evidence in both type A and B haemophilia30,31 even if it implies a relevant increase of costs and the debate on the related cost-effectiveness, usually in a third-payer perspective, is still open32. Hence, as we have in hand both direct and indirect costs of this Italian patients' sample, we have tested the impact of a possible QoL improvement on this set of costs, excluding the drug ones: this is a step towards estimating how much the new drugs' greater costs are
offset by a decrease of other costs' items33,34. The result is that every EQ-5D point added implies a quota of decreased total costs other than drugs: therefore, an improved QoL has an impact not only on the patient's life, but also on consumed healthcare and non healthcare resources related to the disease by these patients and on their capacity to contribute positively to the socialeconomic system where they live. The second evidence concerns the increased life expectancy that also Italian haemophilic population has experienced2. Specific guidelines and clinical pathways to manage the comorbidities, complications and management aspects are needed now that haemophiliac patients' are getting older35-37. However, it seems that poor attention has been paid to the impact on costs of this aging process. Hence, we have found a significant relationship between age and total costs other than drugs and moreover we have simulated the trend of this set of costs over the patients' whole life cycle. The main finding is that costs other than drugs for haemophilic population follow the same trend of the general population38 or people with diabetes39: costs are at their highest level in the very first years of life and then they decrease up to the age of nearly 46 years old when they start to increase again. Moreover, we have
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loss of productivity of informal carers that has to be considered. Finally, the ageing of haemophilic population beyond previous life expectancy limits is posing new challenges to the health care systems requiring planning of resources and health care provisions.
Funding and resources This deliverable arises from the project "Social Economic Burden and Health Related Quality of Life in Patients with Rare Diseases in Europe" which has received funding under the 2 nd Programme of Community Action in the Field of Public Health. The Authors declare no conflict of interest.
References
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Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Treatment Guidelines Working Group on Behalf of The World Federation Of Haemophilia. Guidelines for the management of haemophilia. Haemophilia 2013; 19: e1-47. Abbonizio A, Giampaolo A, Arcieri R, et al. Registro Nazionale delle Coagulopatie Congenite. Rapporto 2011. Rapporti ISTISAN 2012; 55/12: iii, p 63. Italian Association of Haemophilia Centres (AICE). Individuals with Factor VIII Deficiency and Individuals with Factor IX Deficiency. Data Summaries 2012 Dec. Available at: http://www.aiceonline.it/emocard/summaries.htm. Accessed on 20/01/2014. von Mackensen S, Gringeri A, Siboni SM,et al. Health-related quality of life and psychological well-being in elderly patients with haemophilia. Haemophilia 2012; 18: 345-52. Tagliaferri A, Rivolta GF, Iorio A, et al. Mortality and causes of death in Italian persons with haemophilia, 1990-2007. Haemophilia 2010; 16: 437-46. 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. Gringeri A, Mantovani LG, Scalone L, et al. for the COCIS Study Group. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood 2003; 102: 2358-63. Naraine VS, Risebrough NA, Oh P, et al. Health-related quality-of-life treatments for severe haemophilia: utility measurements using the Standard Gamble technique. Haemophilia 2002; 8: 112-120. Franchini M, Mannucci PM. Co-morbidities and quality of life in elderly persons with haemophilia. Br J Haematol. 2010; 148: 522-33. Gringeri A, von Mackensen S, Auerswald G, et al. Health status and health-related quality of life of children with haemophilia from six West European countries. Haemophilia 2004; 10 (Suppl 1): 26-33. Pollak E, Mühlan H, von Mackensen S, et al. The Haemo-QoL Index: developing a short measure for health-related quality of life assessment in children and adolescents with haemophilia. Haemophilia 2006; 12: 384-92. Szende A, Schramm W, Flood E, et al. Health-related quality of life assessment in adult haemophilia patients: a systematic review and evaluation of instruments. Haemophilia 2003; 9: 678-87. Beeton K, Neal D, Watson T, Lee CA. Parents of children with haemophilia - a transforming experience. Haemophilia 2007; 13: 570-9.
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identified the main driver of costs other than drugs according to the population age: as far as children, the most relevant item of cost is the informal care provided by parents and their related productivity loss that it had never been estimated previously in Italy. In adults, the driver is not only hospitalisation, but also specialist visits including a significant quota of cardiology, dentist and ophthalmologist visits, and these results are consistent with the literature above mentioned. Although this study provides valuable insights into the QoL and the costs of patients with haemophilia and their caregivers, there are some limitations that warrant mention. Both the sample and the recruitment process limit the external validity of the study. A limit of this study is the costs' data source. As far as healthcare services provided by INHS, we have valued them by tariffs which are a costs' proxy, however we have selected the Region Lombardy's ones as they are the most regularly updated according to costs' surveyed at providers. A further problem has been to identify the fees of services provided out of INHS coverage: unfortunately, there are not updated price lists determined by professionals associations and then we resorted to a sort of market survey. A similar difficulty has risen about the social services supplied by the city councils and possibly by Local Healthcare Units when an healthcare expertise is required: the fragmentation level prevents to provide any national or regional average. Therefore, we have implemented a spot survey considering the geographical variability and the size of the city council involved. A further drawback of the study is that the disease severity and treatment were not recorded, limiting our ability for additional stratification by variables of interest. We categorize participants only in terms of disability level. Considering the low level of disability, probably our sample reflects a more motivated and less disabled patient/caregiver population. As BURQoL-RD project comprised other RDs and aimed to possible comparison with general population, to measure the QoL we did not use disease specific instruments for haemophilia.
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Conclusions The BURQoL study on Italian haemophilic patients provides the first estimation of total costs in the society's perspective that can be of value to policy-makers. The QoL increase in haemophilic patients implies both a life's improvement and a decrease in the overall costs other than drugs: even if we do not have yet evidence that the new drugs' increased costs may be offset by the other costs' reduction, the drugs' costs extent over the total ones suggests that only a partial offset might be possible. A second evidence concerns the charge's level of informal care supplied to haemophilic children and the related
10)
11)
12) 13)
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29) Badia X, Roset M, Herdman M, Kind P. A comparison of United Kingdom and Spanish general population time tradeoff values for EQ-5D health states. Med Decis Making. 2001; 21: 7-16. 30) Gringeri A, Leissinger C, Cortesi PA, et al. Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study. Haemophilia 2013; 19: 736-43. 31) Windyga J, Indyga VW, Lin J, et al. Improvement in healthrelated quality of life with recombinant factor IX prophylaxis in severe or moderately. Haemophilia 2013; 20: 1-7. 32) Farrugia A, Cassar J, Kimber K et al. Treatment for life for severe haemophilia A. A cost-utility model for prophylaxis vs. on-demand treatment. Haemophilia 2013; 19: e228-38. 33) Lichtenberg FR. Effects of New Drugs on Overall Health Spending: Frank Lichtenberg responds. Health Aff (Millwood). 2007; 26: 887-90. 34) Santerre RE. National and international tests of the new drug cost offset theory. Southern Economic Journal 2011; 77: 1033-43. 35) Mannucci PM, Schutgens REG, Santagostino E, MauserBunschoten EP. How I treat age-related morbidities in elderly persons with hemophilia. Blood 2009; 114: 5256-63. 36) Konkle BA. The aging patient with hemophilia. Am J Hematol. 2012; 87 (Suppl 1): S27-32. 37) Philipp C. The aging patient with hemophilia: complications, comorbidities, and management issues. Hematology Am Soc Hematol Educ Program. 2010; 2010: 191-6. 38) Ministry of Economy and Finance. Tendenze di medio lungo periodo del sistema pensionistico e socio-sanitario 2013. Ragioneria Generale dello Stato 2013 May; Rapporto n. 14. Available at:http://www.rgs.mef.gov.it/VERSIONE-I/Attivit-i/Spesa-soci/Attivita_di_previsione_RGS/2013. Accessed on 30/01/2014. 39) Diabetes American Association. Economic Costs of Diabetes in the U.S. in 2012. Diabetes Care. 2013; 36: 1033-46.
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14) Wiedebusch S, Pollmann H, Siegmund B, Muthny FA. Quality of life, psychosocial strains and coping in parents of children with haemophilia. Haemophilia 2008; 14: 1014-22. 15) Shaw D, Riley GA. The impact on parents of developments in the care of children with bleeding disorders. Haemophilia 2008; 14: 65-7. 16) Gringeri A, Mantovani LG, Scalone L, et al. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood. 2003; 102: 2358-63. 17) Miners AH, Sabin CA, Tolley KH, et al. Cost-utility analysis of primary prophylaxis versus treatment on-demand for individuals with severe haemophilia. Pharmacoeconomics 2002; 20: 759-74. 18) Steen Carlsson K, Höjgård S, Glomstein A, et al. On-demand vs. prophylactic treatment for severe haemophilia in Norway and Sweden: differences in treatment characteristics and outcome. Haemophilia 2003; 9: 555-66. 19) Odeyemi IAO, Guest JF. Modelling the economic impact of recombinant activated factor VII compared and activated prothrombin-complex concentrate in the home treatment of a mild to moderate bleed in adults with inhibitors to clotting factors VIII and IX at a comprehensive care centre in the UK. Journal of Medical Economics 2002; 5: 119-33. 20) Auerswald G, Von Depka Prondzinski M, Ehlken B, et al. Treatment patterns and cost-of-illness of severe haemophilia in patients with inhibitors in Germany. Haemophilia 2004; 10: 499-508. 21) Globe DR, Curtis RG, Koerper MA, HUGS Steering Committee. Utilization of care in haemophilia: a resourcebased method for cost analysis from the Haemophilia Utilization Group Study (HUGS). Haemophilia 2004; 10 (Suppl 1): 63-70. 22) Nerich V, Tissot E, Faradji A, et al. Cost-of-illness study of severe haemophilia A and B in five French haemophilia treatment centres. Pharm World Sci 2008; 30: 287-92. 23) Johnson K, Zheng Yi K. Costs of Care in Hemophilia and Possible Implications of Health Care Reform. ASH Education Book. December 10, 2011; vol. 2011 no. 1: 413-8. 24) Scalone L, Gringeri A, Von Mackensen S, et al. Quality o of life in haemophilic patients without inhibitors: the COCHE Study. Value in Health 2005; 8: A14. 25) Tarricone R. Cost-of-illness analysis: What room in health economics? Health Policy 2006; 77: 51-63. 26) Bartoli S, Cantù E. Le analisi dei costi per la determinazione delle tariffe: esperienze regionali a confronto. In: Cantù E. editor. Rapporto OASI 2009. L'aziendalizzazione della sanità in Italia. Milan: Egea; 2009; 221-48. 27) Van der Berg B, Brouwe B, Koopmanschap M. Economic valuation of informal care: an overview of methods and application. Eur J Health Ec 2004; 5: 36-45. 28) Drummond M, Sculpher MJ, Torrance GW, et al. Methods for economic Evaluation of Health Care Programmes 3th ed. Oxford University Press, Oxford 2005.
Correspondence: Yllka Kodra Italian National Centre for Rare Diseases National Institute of Health Via Giano della Bella 34 00162 Rome, Italy e-mail: [email protected]
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Italian National Centre for Rare Diseases, National Institute of Health, Rome; 2Centre for Research on Health and Social Care Management (CERGAS) Bocconi University, Milan; 3Clinical Research Centre for Rare Disease, Mario Negri Institute, Ranica and Department of Medicine, Rare Disease Unit, Papa Giovanni XXIII Hospital, Bergamo; 4Italian Federation of Haemophilia Societies, Rome; 5National Blood Centre, National Institute of Health, Rome; 6Italian Federation of Haemophilia Societies, Medical Council, Rome, Italy
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Background. In Italy, the project on the social burden and quality of life (QoL) of patients with haemophilia investigates costs from a society perspective and provides an overview of their quality of life. Moreover, as life expectancy increased in recent years along with new treatment strategies implemented in the last decades, it analyses trends of costs other than drugs simulating impacts during patient whole life. Material and methods. We ran a web-based cross-sectional survey supported by the Italian Federation of Haemophilia Societies in recruiting patients with haemophilia and their caregivers. We developed a questionnaire to collect information on demographic characteristics, healthcare and social services consumption, formal and informal care utilisation, productivity loss and quality of life. In particular, quality of life was assessed through the EuroQoL tool. Last, we applied the illness cost method from a society perspective. Results. On average, quality of life is worse in adult patients compared to child and caregivers: more than 75% of adult patients declare physical problems, 43% of adult patients and 54% of their parents have anxiety problems. Assuming a society perspective, the estimated mean annual total cost per patient in 2012 is 117,732 €. Drugs represent 92% of total costs. Focusing on costs other than drugs, each additional point of EuroQoL tool implies a costs' reduction of 279 €. The impact of age varies across age groups: each added year implies a total decrease of costs up to 46.6 years old. Afterwards, every additional year increases costs. Discussion. Quality of life of patients with haemophilia and their caregivers improved and it influences positively on consumed resources and on their contribution to the social-economic system. Costs other than drugs for patients with haemophilia follow the same trends of general population.
Introduction
©
Keywords: quality of life, cost of illness, haemophilia.
Haemophilias are a group of inherited bleeding disorders caused by an X-chromosome linked deficiency in coagulation factors VIII (FVIII) (in haemophilia A) or IX (FIX) (in haemophilia B). The disorders are rare affecting approximately 1 in 10,000 births1. The prevalence in Italy, according to the most recent report (2012) of the Italian Association of Haemophilia Centres that operates a national registry, consists of 3,690 patients with haemophilia A and 750 with haemophilia B2,3. The use of factor replacements has significantly decreased the mortality and morbidity of patients with haemophilia: life expectancy has increased from 40 years old in the 1960s to 60-70 years today4,5. Quality of life (QoL) has become an important measure of the health improvements in haemophilic patients brought about by therapeutic progress in this field, although it
remains significantly poorer as compared with QoL of general population6,7. Specifically, QoL is viewed as a measure of the outcome of care for individuals with haemophilia that can inform disease management and policy decision making8. It is not known, however, whether changes in QoL can have an impact on costs trend in the case of haemophilia9. Last, while there are several studies on QoL in haemophilia10-12, there have been very few on caregivers QoL13-15. On the other hand, the diffusion of new treatment strategies, based not only on factor replacement therapy, but also on a switch from the on demand to prophylaxis treatment, has also an economic impact. Actually, it requires a dramatic increase of economic resources' consumption by a small portion of the population affected by a rare condition and therefore the third-payers interest on this disease is also increased.
Blood Transfus 2014; 12 Suppl 3: s567-75 DOI 10.2450/2014.0042-14s © SIMTI Servizi Srl
s567 All rights reserved - For personal use only No other uses without permission
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05/05/2014 12.59.10
Kodra Y et al
participate. The survey was anonymous, as the patients were contacted by their patient organisation and their responses, without any identification data, were sent directly to the researchers. The fieldwork was carried out between March 2012 and October 2012. The questionnaires were administrated by e-mail through patient organisations and patients were asked to provide information on demographic characteristics, consumed healthcare and non healthcare resources related to the disease and QoL information in the six months preceding the enrolment (12 months for hospital admissions).
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Costs' materials and methods To measure the burden of haemophilia, we have applied the cost of illness approach from a society perspective25. Therefore, both direct and indirect costs were included, and a bottom-up approach was used for their calculation: we valued the average unit cost of each set of resources consumed by enrolled patients. Direct costs include health and non-healthcare resources directly consumed by the surveyed Italian patients with type A and type B haemophilia in 2012. Direct health care costs include drugs, outpatient and inpatient care, and all range of primary care services. As far as their data source, we used services' fees because Italy does not have a national healthcare services' costs data set and we could not run specific costs' survey. However, we applied region Lombardy's fees as this region has updated nearly regularly its tariff set, surveying its providers' costs26. Moreover, as far as drugs, we have considered Italian Medicines Agency 's drugs national formulary, reducing by 30% the price of drugs distributed only by hospitals once they bought them through tenders. Considering the co-payment of drugs and outpatient care, we estimated a national average of regional fees. Last, according to the following strategy, we estimated the healthcare services fees out of Italian National Health Service (INHS), paid out of pocket by patients: we selected a small and a big town in Northern, Centre and Southern Italy and then we ran a pricing market analysis. Direct non healthcare costs comprise socialhealthcare and social services managed at city-council level: the resulting high fragmentation of these services' provision has led us to implement again the above described strategy to collect information on this setting without national or regional standards. This cost's set includes not only the formal care (i.e. provided by contracted professionals), but also the informal care provided by relatives and friends. We have applied the proxy good approach to value these resources, then we have considered if he/she did not provide these services, he/she would need to be replaced by another person who could provide the necessary care, applying the average
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In particular, it is an example of the socioeconomic impact of biotechnology in rare diseases16. Hence, the scientific literature considering economic aspects has focused mainly on the cost-effectiveness of prophylaxis vs on-demand treatment in patients with a severe haemophilia17,18 or with inhibitors19. A further set of manuscripts implements a cost of illness approach on haemophilia in different countries and in some cases the economic and the social burden of this disease is included20-23. Moreover, amongst the latter ones, only one study21 have addressed in some way the relationship between age and QoL on one side, and costs on the other side. This is, actually, a new perspective arisen from the life expectancy increase in these last years. In the early 2000s, seminal contributions concerning the Italian context provided direct healthcare costs evaluation for patients with haemophilia complicated by inhibitors in the Cost of Care Inhibitors Study16 and the first estimation of the QoL of patients without inhibitors in the Cost of Care of Hemophilia Study24. The Burden and Health-Related Quality of Life in Patients with Rare Diseases - BURQoL-RD Study was a 3 year project under the 2nd Programme of Community Action in the Field of Public Health, that commenced in April 2010 and was promoted by the Directorate General Health and Consumers of European Commission. The main aim of BURQoL-RD was to generate a model to quantify the socio-economic costs and QoL of both patients and caregivers, for up to 10 rare diseases (RD) in different European countries. According to this goal, the evaluation of the economic and social impact of haemophilias has been one of the objects of BURQoL-RD Study. Therefore, the BURQoL-RD Study on haemophilia in Italy investigates costs of this disease from a society perspective (using a cost of illness approach) for the first time and it provides an update of this group of patients' QoL. Moreover, considering the increase of life expectancy occurring in these last years, it analyses the impact of this trend on costs other than drug, simulating the whole life cycle. Last, as the expensive switch of treatment strategies implemented in the last decade has provided an increased QoL, we are going to test this improvement's impact on costs other than drugs.
Materials and methods We conducted a web-based cross-sectional study. The target sample were Italian patients diagnosed with haemophilia A and B and their caregivers. Cases were recruited from the Italian Federation of Haemophilia Societies (Federazione delle Associazioni Emofilici,FedEmo, www.fedemo.it). All patients and caregivers were informed about the study objectives and data confidentially, and were asked to indicate their understanding of the study conditions and agreement to
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organisations, no sample size calculation was performed. For cost analysis we used means and central tendency parameters, generally expressed as mean cost per patient per year, because this parameter can be easily used for policy maker. We reported the standard deviations as a variability measure. Costs were stratified according to their categories. Descriptive analyses were applied also to define health status measurements variables and QoL separately for adult, children and caregivers. It was convenient to reclassify the EQ-5D-5L and EQ-5D-Y-3L levels into 'no problems' (i.e. level 1) and "problems" (i.e. levels 2 to 5 for EQ-5D-5L and level 2 to 3 for EQ-5D-Y-3L). For categorical measures, statistical significance was determined by using chi-squared test. The one-way analysis of variance (ANOVA) was used to determine whether there were any significant differences between the means of two or more independent (unrelated) groups. Intra class correlation between ranked (ordinal) data, such as EQ-5D, was determined by means of Spearman's correlation coefficients (correlations >r=0.4 were considered relevant). A multiple linear regression was ran in order to assess the relationship between the patients' total costs without drugs (dependent variable) and patients' age and EQ-5D. We tested a possible non-linear (quadratic) relationship for both independent variables and we controlled for drugs costs and age of diagnosis. Moreover, based on estimation results, we ran a two-way simulation analysis to evaluate the joint impact of every pair of age and EQ-5D on costs, all other things being equal. We let both independent variables to range between 0 and 100 in order to capture every possible combination of the two, also including out-of-sample values. Descriptive analyses were performed using SPSS version 21.0 software. Regression analysis and two-way simulation analysis were performed using Stata, release 12. Statistical significance was set up at pF=0.0000; Root MSE=6682.3; F(6, 61)=7.56; R-squared=0.3102
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Figure 1 - Trend of costs other than drugs correlated to QoL and age.
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project provides data on drugs consumption and their valorisation, however information on patients' severity and the related treatment plans are not available, restricting the possible interpretation of drugs' data. Secondly, the core of the treatment strategy's change is the switch from on-demand to prophylaxis based treatment along with new drugs' use: this substitution may imply that the patient's consumption of drugs does not change for long whiles, making drugs' cost no more a fully variable cost over time. Last, even if costs other than drugs represent a small quota of total costs, they have been poorly investigated up to now and their analysis allows to enlighten relevant aspects with respect to the trends we are addressing. The first evidence to consider is the positive impact of new treatment's strategies on patients' QoL: this is a consolidated evidence in both type A and B haemophilia30,31 even if it implies a relevant increase of costs and the debate on the related cost-effectiveness, usually in a third-payer perspective, is still open32. Hence, as we have in hand both direct and indirect costs of this Italian patients' sample, we have tested the impact of a possible QoL improvement on this set of costs, excluding the drug ones: this is a step towards estimating how much the new drugs' greater costs are
offset by a decrease of other costs' items33,34. The result is that every EQ-5D point added implies a quota of decreased total costs other than drugs: therefore, an improved QoL has an impact not only on the patient's life, but also on consumed healthcare and non healthcare resources related to the disease by these patients and on their capacity to contribute positively to the socialeconomic system where they live. The second evidence concerns the increased life expectancy that also Italian haemophilic population has experienced2. Specific guidelines and clinical pathways to manage the comorbidities, complications and management aspects are needed now that haemophiliac patients' are getting older35-37. However, it seems that poor attention has been paid to the impact on costs of this aging process. Hence, we have found a significant relationship between age and total costs other than drugs and moreover we have simulated the trend of this set of costs over the patients' whole life cycle. The main finding is that costs other than drugs for haemophilic population follow the same trend of the general population38 or people with diabetes39: costs are at their highest level in the very first years of life and then they decrease up to the age of nearly 46 years old when they start to increase again. Moreover, we have
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loss of productivity of informal carers that has to be considered. Finally, the ageing of haemophilic population beyond previous life expectancy limits is posing new challenges to the health care systems requiring planning of resources and health care provisions.
Funding and resources This deliverable arises from the project "Social Economic Burden and Health Related Quality of Life in Patients with Rare Diseases in Europe" which has received funding under the 2 nd Programme of Community Action in the Field of Public Health. The Authors declare no conflict of interest.
References
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Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Treatment Guidelines Working Group on Behalf of The World Federation Of Haemophilia. Guidelines for the management of haemophilia. Haemophilia 2013; 19: e1-47. Abbonizio A, Giampaolo A, Arcieri R, et al. Registro Nazionale delle Coagulopatie Congenite. Rapporto 2011. Rapporti ISTISAN 2012; 55/12: iii, p 63. Italian Association of Haemophilia Centres (AICE). Individuals with Factor VIII Deficiency and Individuals with Factor IX Deficiency. Data Summaries 2012 Dec. Available at: http://www.aiceonline.it/emocard/summaries.htm. Accessed on 20/01/2014. von Mackensen S, Gringeri A, Siboni SM,et al. Health-related quality of life and psychological well-being in elderly patients with haemophilia. Haemophilia 2012; 18: 345-52. Tagliaferri A, Rivolta GF, Iorio A, et al. Mortality and causes of death in Italian persons with haemophilia, 1990-2007. Haemophilia 2010; 16: 437-46. 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. Gringeri A, Mantovani LG, Scalone L, et al. for the COCIS Study Group. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood 2003; 102: 2358-63. Naraine VS, Risebrough NA, Oh P, et al. Health-related quality-of-life treatments for severe haemophilia: utility measurements using the Standard Gamble technique. Haemophilia 2002; 8: 112-120. Franchini M, Mannucci PM. Co-morbidities and quality of life in elderly persons with haemophilia. Br J Haematol. 2010; 148: 522-33. Gringeri A, von Mackensen S, Auerswald G, et al. Health status and health-related quality of life of children with haemophilia from six West European countries. Haemophilia 2004; 10 (Suppl 1): 26-33. Pollak E, Mühlan H, von Mackensen S, et al. The Haemo-QoL Index: developing a short measure for health-related quality of life assessment in children and adolescents with haemophilia. Haemophilia 2006; 12: 384-92. Szende A, Schramm W, Flood E, et al. Health-related quality of life assessment in adult haemophilia patients: a systematic review and evaluation of instruments. Haemophilia 2003; 9: 678-87. Beeton K, Neal D, Watson T, Lee CA. Parents of children with haemophilia - a transforming experience. Haemophilia 2007; 13: 570-9.
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identified the main driver of costs other than drugs according to the population age: as far as children, the most relevant item of cost is the informal care provided by parents and their related productivity loss that it had never been estimated previously in Italy. In adults, the driver is not only hospitalisation, but also specialist visits including a significant quota of cardiology, dentist and ophthalmologist visits, and these results are consistent with the literature above mentioned. Although this study provides valuable insights into the QoL and the costs of patients with haemophilia and their caregivers, there are some limitations that warrant mention. Both the sample and the recruitment process limit the external validity of the study. A limit of this study is the costs' data source. As far as healthcare services provided by INHS, we have valued them by tariffs which are a costs' proxy, however we have selected the Region Lombardy's ones as they are the most regularly updated according to costs' surveyed at providers. A further problem has been to identify the fees of services provided out of INHS coverage: unfortunately, there are not updated price lists determined by professionals associations and then we resorted to a sort of market survey. A similar difficulty has risen about the social services supplied by the city councils and possibly by Local Healthcare Units when an healthcare expertise is required: the fragmentation level prevents to provide any national or regional average. Therefore, we have implemented a spot survey considering the geographical variability and the size of the city council involved. A further drawback of the study is that the disease severity and treatment were not recorded, limiting our ability for additional stratification by variables of interest. We categorize participants only in terms of disability level. Considering the low level of disability, probably our sample reflects a more motivated and less disabled patient/caregiver population. As BURQoL-RD project comprised other RDs and aimed to possible comparison with general population, to measure the QoL we did not use disease specific instruments for haemophilia.
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Conclusions The BURQoL study on Italian haemophilic patients provides the first estimation of total costs in the society's perspective that can be of value to policy-makers. The QoL increase in haemophilic patients implies both a life's improvement and a decrease in the overall costs other than drugs: even if we do not have yet evidence that the new drugs' increased costs may be offset by the other costs' reduction, the drugs' costs extent over the total ones suggests that only a partial offset might be possible. A second evidence concerns the charge's level of informal care supplied to haemophilic children and the related
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29) Badia X, Roset M, Herdman M, Kind P. A comparison of United Kingdom and Spanish general population time tradeoff values for EQ-5D health states. Med Decis Making. 2001; 21: 7-16. 30) Gringeri A, Leissinger C, Cortesi PA, et al. Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study. Haemophilia 2013; 19: 736-43. 31) Windyga J, Indyga VW, Lin J, et al. Improvement in healthrelated quality of life with recombinant factor IX prophylaxis in severe or moderately. Haemophilia 2013; 20: 1-7. 32) Farrugia A, Cassar J, Kimber K et al. Treatment for life for severe haemophilia A. A cost-utility model for prophylaxis vs. on-demand treatment. Haemophilia 2013; 19: e228-38. 33) Lichtenberg FR. Effects of New Drugs on Overall Health Spending: Frank Lichtenberg responds. Health Aff (Millwood). 2007; 26: 887-90. 34) Santerre RE. National and international tests of the new drug cost offset theory. Southern Economic Journal 2011; 77: 1033-43. 35) Mannucci PM, Schutgens REG, Santagostino E, MauserBunschoten EP. How I treat age-related morbidities in elderly persons with hemophilia. Blood 2009; 114: 5256-63. 36) Konkle BA. The aging patient with hemophilia. Am J Hematol. 2012; 87 (Suppl 1): S27-32. 37) Philipp C. The aging patient with hemophilia: complications, comorbidities, and management issues. Hematology Am Soc Hematol Educ Program. 2010; 2010: 191-6. 38) Ministry of Economy and Finance. Tendenze di medio lungo periodo del sistema pensionistico e socio-sanitario 2013. Ragioneria Generale dello Stato 2013 May; Rapporto n. 14. Available at:http://www.rgs.mef.gov.it/VERSIONE-I/Attivit-i/Spesa-soci/Attivita_di_previsione_RGS/2013. Accessed on 30/01/2014. 39) Diabetes American Association. Economic Costs of Diabetes in the U.S. in 2012. Diabetes Care. 2013; 36: 1033-46.
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14) Wiedebusch S, Pollmann H, Siegmund B, Muthny FA. Quality of life, psychosocial strains and coping in parents of children with haemophilia. Haemophilia 2008; 14: 1014-22. 15) Shaw D, Riley GA. The impact on parents of developments in the care of children with bleeding disorders. Haemophilia 2008; 14: 65-7. 16) Gringeri A, Mantovani LG, Scalone L, et al. Cost of care and quality of life for patients with hemophilia complicated by inhibitors: the COCIS Study Group. Blood. 2003; 102: 2358-63. 17) Miners AH, Sabin CA, Tolley KH, et al. Cost-utility analysis of primary prophylaxis versus treatment on-demand for individuals with severe haemophilia. Pharmacoeconomics 2002; 20: 759-74. 18) Steen Carlsson K, Höjgård S, Glomstein A, et al. On-demand vs. prophylactic treatment for severe haemophilia in Norway and Sweden: differences in treatment characteristics and outcome. Haemophilia 2003; 9: 555-66. 19) Odeyemi IAO, Guest JF. Modelling the economic impact of recombinant activated factor VII compared and activated prothrombin-complex concentrate in the home treatment of a mild to moderate bleed in adults with inhibitors to clotting factors VIII and IX at a comprehensive care centre in the UK. Journal of Medical Economics 2002; 5: 119-33. 20) Auerswald G, Von Depka Prondzinski M, Ehlken B, et al. Treatment patterns and cost-of-illness of severe haemophilia in patients with inhibitors in Germany. Haemophilia 2004; 10: 499-508. 21) Globe DR, Curtis RG, Koerper MA, HUGS Steering Committee. Utilization of care in haemophilia: a resourcebased method for cost analysis from the Haemophilia Utilization Group Study (HUGS). Haemophilia 2004; 10 (Suppl 1): 63-70. 22) Nerich V, Tissot E, Faradji A, et al. Cost-of-illness study of severe haemophilia A and B in five French haemophilia treatment centres. Pharm World Sci 2008; 30: 287-92. 23) Johnson K, Zheng Yi K. Costs of Care in Hemophilia and Possible Implications of Health Care Reform. ASH Education Book. December 10, 2011; vol. 2011 no. 1: 413-8. 24) Scalone L, Gringeri A, Von Mackensen S, et al. Quality o of life in haemophilic patients without inhibitors: the COCHE Study. Value in Health 2005; 8: A14. 25) Tarricone R. Cost-of-illness analysis: What room in health economics? Health Policy 2006; 77: 51-63. 26) Bartoli S, Cantù E. Le analisi dei costi per la determinazione delle tariffe: esperienze regionali a confronto. In: Cantù E. editor. Rapporto OASI 2009. L'aziendalizzazione della sanità in Italia. Milan: Egea; 2009; 221-48. 27) Van der Berg B, Brouwe B, Koopmanschap M. Economic valuation of informal care: an overview of methods and application. Eur J Health Ec 2004; 5: 36-45. 28) Drummond M, Sculpher MJ, Torrance GW, et al. Methods for economic Evaluation of Health Care Programmes 3th ed. Oxford University Press, Oxford 2005.
Correspondence: Yllka Kodra Italian National Centre for Rare Diseases National Institute of Health Via Giano della Bella 34 00162 Rome, Italy e-mail: [email protected]
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