Costs of treatment of haemophilia A in Italy: comparison of the use of plasma-derived and recombinant FVIII using a discrete event simulation (DES) model

Mario Eandi, Lorenzo Pradelli, Massimiliano Povero



OBJECTIVE: To simulate haemophilia A (HA) real-life management and compare the cost of different treatment strategies, both with plasma-derived and recombinant factor VIII (pdFVIII and rFVIII, respectively), from the perspective of the Italian NHS.
METHODS: A discrete event (micro-)simulation (DES) model was developed to reproduce every possible HA patient clinical pathway: on-demand (OD) treatment of bleeding, continuous or discontinuous prophylaxis (PRO) with FVIII, inhibitors-tolerance-induction treatment (ITI), surgery in case of severe disability. Patient characteristics, treatment indications and disease evolution were modeled basing on data available in clinical literature in order to represent the actual state of art of HA management. In addition to the baseline scenario, reproducing current HA management, alternative strategies were simulated to explore the impact on the cost borne by the Italian NHS for these patients. Only differential direct sanitary costs were considered in the simulation, with a 3.5% discount rate.
RESULTS: Baseline scenario results show difference between patients treated with pdFVIII and those treated with rFVIII: mean lifetime HA patient management cost was estimated at € 1,332,373 with pdFVIII treatment, compared with € 2,013,222 for rFVIII. The saving is due mainly to the lower acquisition cost of pdFVIII. Total medical costs are strongly and positively correlated with HA severity: cost per patient increases from € 86,269 (mild HA) to € 1,509,231 (severe HA) for patients treated with pdFVIII and from € 147,900 to € 2,621,540 in patients treated with rFVIII. All analyses conducted in the study lead to the conclusion that the use of pdFVIII is much less expensive than rFVIII, but therapeutically equivalent.
CONCLUSION: Management of HA patients is complex and difficult to optimize; although involving a limited number of patients, lifetime management costs for the Italian NHS are extremely high. The main advantage of this model lies in the capability of estimating the economic impact of different strategic choices and economic/regulatory constraints.


Haemophilia A; Factor VIII; DES model simulation; Cost minimization

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  • Mannucci PM. Back to the future: a recent history of haemophilia treatment. Haemophilia 2008; 14 Suppl 3: 10-8;
  • Srivastava A, Brewer AK, Mauser-Bunschoten EP, et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19: e1-47;
  • Mannucci PM. Hemophilia: treatment options in the twenty-first century. J Thromb Haemost 2003; 1: 1349-55;
  • Darby SC, Kan SW, Spooner RJ, et al. Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV. Blood 2007; 110: 815-25;
  • Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003; 9: 418-35;
  • Astermark J, Altisent C, Batorova A, et al. Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report. Haemophilia 2010; 16: 747-66;
  • Paisley S, Wight J, Currie E, et al. The management of inhibitors in haemophilia A: introduction and systematic review of current practice. Haemophilia 2003; 9: 405-17;
  • Mannucci PM, Abshire T, Dimichele D, et al. Inhibitor development, immune tolerance and prophylaxis in haemophilia A--the need for an evidence-based approach. Haemophilia 2006; 12: 429-34;
  • Mannucci PM. Clinical evaluation of viral safety of coagulation factor VIII and IX concentrates. Vox Sang 1993; 64: 197-203;
  • Makris M, Calizzani G, Fischer K, et al. EUHASS: The European Haemophilia Safety Surveillance system. Thromb Res 2011; 127 Suppl 2: S22-5;
  • Ofosu FA, Freedman J, Semple JW. Plasma-derived biological medicines used to promote haemostasis. Thrombosis and haemostasis 2008; 99: 851-62
  • Franchini M. Plasma-derived versus recombinant Factor VIII concentrates for the treatment of haemophilia A: recombinant is better. Blood Transfus 2010; 8: 292-6
  • Mannucci PM. Plasma-derived versus recombinant factor VIII concentrates for the treatment of haemophilia A: plasma-derived is better. Blood Transfus 2010; 8: 288-91
  • Mannucci PM, Mancuso ME, Santagostino E. How we choose factor VIII to treat hemophilia. Blood 2012; 119: 4108-14;
  • Gouw SC, van der Bom JG, Auerswald G, et al. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007; 109: 4693-7;
  • Gouw SC, van der Bom JG, Ljung R, et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med 2013; 368: 231-9;
  • Mannucci PM, Gringeri A, Peyvandi F, et al. Factor VIII products and inhibitor development: the SIPPET study (survey of inhibitors in plasma-product exposed toddlers). Haemophilia 2007; 13 Suppl 5: 65-8;
  • Aronstam A, Arblaster PG, Rainsford SG, et al. Prophylaxis in haemophilia: a double-blind controlled trial. Br J Haematol 1976; 33: 81-90;
  • Astermark J, Petrini P, Tengborn L, et al. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol 1999; 105: 1109-13;
  • Fischer K, van der Bom JG, Mauser-Bunschoten EP, et al. The effects of postponing prophylactic treatment on long-term outcome in patients with severe hemophilia. Blood 2002; 99: 2337-41;
  • Feldman BM, Pai M, Rivard GE, et al. Tailored prophylaxis in severe hemophilia A: interim results from the first 5 years of the Canadian Hemophilia Primary Prophylaxis Study. J Thromb Haemost 2006; 4: 1228-36;
  • 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;
  • Gringeri A, Lundin B, von Mackensen S, et al. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9: 700-10;
  • Fischer K, van der Bom JG, Mauser-Bunschoten EP, et al. Changes in treatment strategies for severe haemophilia over the last 3 decades: effects on clotting factor consumption and arthropathy. Haemophilia 2001; 7: 446-52;
  • Petrini P. What factors should influence the dosage and interval of prophylactic treatment in patients with severe haemophilia A and B? Haemophilia 2001; 7: 99-102;
  • Manco-Johnson M. Comparing prophylaxis with episodic treatment in haemophilia A: implications for clinical practice. Haemophilia 2007; 13 Suppl 2: 4-9;
  • Fischer K, Van Der Bom JG, Prejs R, et al. Discontinuation of prophylactic therapy in severe haemophilia: incidence and effects on outcome. Haemophilia 2001; 7: 544-50;
  • Hay CR. Prophylaxis in adults with haemophilia. Haemophilia 2007; 13 Suppl 2: 10-5;
  • Fischer K. Can we consider discontinuing primary prophylaxis in adults with severe haemophilia? Haemophilia 2008; 14 Suppl 4: 10;
  • Mannucci PM, Palhares de Miranda PA. International survey of attitudes towards secondary prophylaxis with recombinant factor VIIa in haemophilia A patients with inhibitors. Haemophilia 2009; 15: 345-7;
  • Teitel J, Berntorp E, Dolan G, et al. A consensus statement on clinical trials of bypassing agent prophylaxis in inhibitor patients. Haemophilia 2011; 17: 516-21;
  • Szucs TD, Offner A, Kroner B, et al. Resource utilisation in haemophiliacs treated in Europe: results from the European Study on Socioeconomic Aspects of Haemophilia Care. The European Socioeconomic Study Group. Haemophilia 1998; 4: 498-501;
  • 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;
  • Stonebraker JS, Amand RE, Nagle AJ. A country-by-country comparison of FVIII concentrate consumption and economic capacity for the global haemophilia community. Haemophilia 2003; 9: 245-50;
  • Globe DR, Curtis RG, Koerper MA. Utilization of care in haemophilia: a resource-based method for cost analysis from the Haemophilia Utilization Group Study (HUGS). Haemophilia 2004; 10 Suppl 1: 63-70;
  • Knight C. Health economics of treating haemophilia A with inhibitors. Haemophilia 2005; 11 Suppl 1: 11-7;
  • Putnam KG, Bohn RL, Ewenstein BM, et al. A cost minimization model for the treatment of minor bleeding episodes in patients with haemophilia A and high-titre inhibitors. Haemophilia 2005; 11: 261-9;
  • Risebrough N, Oh P, Blanchette V, et al. Cost-utility analysis of Canadian tailored prophylaxis, primary prophylaxis and on-demand therapy in young children with severe haemophilia A. Haemophilia 2008; 14: 743-52;
  • Bonnet PO, Yoon BS, Wong WY, et al. Cost minimization analysis to compare activated prothrombin complex concentrate (APCC) and recombinant factor VIIa for haemophilia patients with inhibitors undergoing major orthopaedic surgeries. Haemophilia 2009; 15: 1083-9;
  • Odeyemi IA, Dano AM. Optimising immune tolerance induction strategies in the management of haemophilia patients with inhibitors: a cost-minimisation analysis. Curr Med Res Opin 2009; 25: 239-50;
  • Di Minno MN, Di Minno G, Di Capua M, Cerbone AM, Coppola A. Cost of care of haemophilia with inhibitors. Haemophilia. 2010; 16: e190-201;
  • Liou WS, Tu TC, Cheng SN, et al. Secondary prophylaxis treatment versus on-demand treatment for patients with severe haemophilia A: comparisons of cost and outcomes in Taiwan. Haemophilia 2011; 17: 45-54;
  • Fischer K, Pouw ME, Lewandowski D, et al. A modeling approach to evaluate long-term outcome of prophylactic and on demand treatment strategies for severe hemophilia A. Haematologica 2011; 96: 738-43;
  • Karnon J. Alternative decision modelling techniques for the evaluation of health care technologies: Markov processes versus discrete event simulation. Health Econ 2003; 12: 837-48;
  • Caro JJ. Pharmacoeconomic analyses using discrete event simulation. Pharmacoeconomics 2005; 23: 323-32;
  • Pradelli L, Iannazzo S, Zaniolo O, et al. Effectiveness and cost-effectiveness of supplemental glutamine dipeptide in total parenteral nutrition therapy for critically ill patients: a discrete event simulation model based on Italian data. Int J Technol Assess Health Care 2012; 28: 22-8;
  • Hay CR, Dimichele DM. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119: 1335-44;
  • 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;
  • Mejia-Carvajal C, Czapek EE, Valentino LA. Life expectancy in hemophilia outcome. J Thromb Haemost 2006; 4: 507-9;
  • Soucie JM, Nuss R, Evatt B, et al. Mortality among males with hemophilia: relations with source of medical care. The Hemophilia Surveillance System Project Investigators. Blood 2000; 96: 437-42
  • Reitter S, Waldhoer T, Vutuc C, et al. Survival in a cohort of patients with haemophilia at the haemophilia care center in Vienna, Austria, from 1983 to 2006. Haemophilia 2009; 15: 888-93;
  • Manco-Johnson MJ. Advances in the care and treatment of children with hemophilia. Adv Pediatr 2010; 57: 287-94;
  • Santagostino E, Mancuso ME, Tripodi A, et al. Severe hemophilia with mild bleeding phenotype: molecular characterization and global coagulation profile. J Thromb Haemost 2010; 8: 737-43;
  • Collins PW, Blanchette VS, Fischer K, et al. Break-through bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment for severe hemophilia A. J Thromb Haemost 2009; 7: 413-20;
  • den Uijl IE, Fischer K, Van Der Bom JG, et al. Analysis of low frequency bleeding data: the association of joint bleeds according to baseline FVIII activity levels. Haemophilia 2011; 17: 41-4;
  • Fischer K, Collins P, Bjorkman S, et al. Trends in bleeding patterns during prophylaxis for severe haemophilia: observations from a series of prospective clinical trials. Haemophilia 2011; 17: 433-8;
  • Stephensen D, Tait RC, Brodie N, et al. Changing patterns of bleeding in patients with severe haemophilia A. Haemophilia 2009; 15: 1210-4;
  • Kulkarni R, Soucie JM, Lusher J, et al. Sites of initial bleeding episodes, mode of delivery and age of diagnosis in babies with haemophilia diagnosed before the age of 2 years: a report from The Centers for Disease Control and Prevention’s (CDC) Universal Data Collection (UDC) project. Haemophilia 2009; 15: 1281-90;
  • van Dijk K, Fischer K, van der Bom JG, et al. Variability in clinical phenotype of severe haemophilia: the role of the first joint bleed. Haemophilia 2005; 11: 438-43;
  • van den Berg HM, De Groot PH, Fischer K. Phenotypic heterogeneity in severe hemophilia. J Thromb Haemost 2007; 5 Suppl 1: 151-6;
  • Knight C, Paisley S, Wight J, et al. Economic modelling of different treatment strategies for haemophilia A with high-responding inhibitors. Haemophilia 2003; 9: 521-40;
  • Teitel J, Berntorp E, Collins P, et al. A systematic approach to controlling problem bleeds in patients with severe congenital haemophilia A and high-titre inhibitors. Haemophilia 2007; 13: 256-63;
  • Stonebraker JS, Amand RE, Bauman MV, et al. Modelling haemophilia epidemiology and treatment modalities to estimate the unconstrained factor VIII demand. Haemophilia 2004; 10: 18-26;
  • Franchini M, Mannucci PM. Inhibitors of propagation of coagulation (factors VIII, IX and XI): a review of current therapeutic practice. British journal of clinical pharmacology 2011; 72: 553-62;


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