Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study

Annarita Tagliaferri; Giulio Feola; Angelo Claudio Molinari; Cristina Santoro; Gianna Franca Rivolta; Dorina Bianca Cultrera; Fabio Gagliano; Ezio Zanon; Maria Elisa Mancuso; Lelia Valdrè; Luciana Mameli; Susanna Amoresano; Prasad Mathew; Antonio Coppola; for the POTTER Study Group

doi:10.1160/TH14-05-0407

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2015; 114(01): 35-45
DOI: 10.1160/TH14-05-0407

Coagulation and Fibrinolysis

Schattauer GmbH

Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study

Annarita Tagliaferri

¹Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy

,

Giulio Feola

²Immunohematology and Hemophilia Center, S. Luca Hospital, Vallo della Lucania, Italy

,

Angelo Claudio Molinari

³Thrombosis and Hemostasis Unit, Giannina Gaslini Children’s Hospital, Genoa, Italy

,

Cristina Santoro

⁴Hematology, Department of Cellular Biotechnology and Haematology, Sapienza University of Rome, Rome, Italy

,

Gianna Franca Rivolta

¹Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy

,

Dorina Bianca Cultrera

⁵Hemophilia Center, Hematology, Ferrarotto Hospital, Policlinico Vittorio Emanuele University Hospital, Catania, Italy

,

Fabio Gagliano

⁶Hemophilia Center, G. Di Cristina Children’s Hospital, Palermo, Italy

,

Ezio Zanon

⁷Hemophilia Center, Second Chair of Internal Medicine, University of Padua, Padua, Italy

,

Maria Elisa Mancuso

³Thrombosis and Hemostasis Unit, Giannina Gaslini Children’s Hospital, Genoa, Italy

,

Lelia Valdrè

⁹Angiology and Coagulation Disease Unit, Bologna, Italy

,

Luciana Mameli

¹⁰Thrombosis and Hemostasis Unit, SS Annunziata Hospital, Sassari, Italy

,

Susanna Amoresano

¹¹Bayer HealthCare, Milan, Italy

,

Prasad Mathew

¹²Bayer HealthCare, Whippany, NJ, and University of New Mexico, Albuquerque, NM, USA

,

Antonio Coppola

¹³Regional Reference Centre for Coagulation Disorders, Federico II University Hospital, Naples, Italy

,

for the POTTER Study Group

› Author Affiliations

Abstract

Summary

Rigorous evidence is lacking on long-term outcomes of factor VIII (FVIII) prophylaxis initiated in adolescent or adult patients with severe haemophilia A. The prospective, open-label Prophylaxis versus On-demand Therapy Through Economic Report (POTTER) study (Clinical-Trials.gov NCT01159587) compared long-term late secondary prophylaxis (recombinant FVIII-FS 20–30 IU/kg thrice weekly) with on-demand treatment in patients aged 12 to 55 years with severe haemophilia A. The annual number of joint bleeding episodes (primary endpoint), total bleeding episodes, orthopaedic and radiologic (Pettersson) scores, health-related quality of life (HRQoL), pharmacoeconomic impact, and safety were evaluated over a > 5-year period (2004–2010). Fifty-eight patients were enrolled at 11 centres in Italy; 53 (27 prophylaxis, 26 on demand) were evaluated and stratified into 2 age subgroups (12–25 and 26–55 years). Patients receiving prophylaxis experienced a significantly lower number of joint bleeding episodes vs the on–demand group (annualised bleeding rate, 1.97 vs 16.80 and 2.46 vs 16.71 in younger and older patients, respectively; p=0.0043). Results were similar for total bleeding episodes. Prophylaxis was associated with significantly fewer target joints (p< 0.001), better orthopaedic (p=0.0019) and Pettersson (p=0.0177) scores, better HRQoL, and fewer days of everyday activities lost (p< 0.0001) but required significantly higher FVIII product consumption. The POTTER study is the first prospective, controlled trial documenting long-term benefits of late secondary prophylaxis in adolescents and adults with severe haemophilia A. The benefits of reduced bleeding frequency, improved joint status, and HRQoL may offset the higher FVIII consumption and costs.

Keywords

Bleeding - health-related quality of life - haemophilia - haemophilic arthropathy - prophylaxis

Full Text

References

References
1 Coppola A, Tagliaferri A, Di Capua M. et al. Prophylaxis in children with hemophilia: evidence-based achievements, old and new challenges. Semin Thromb Hemost 2012; 38: 79-94.
2 Nilsson IM, Berntorp E, Lofqvist T. et al. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232: 25-32.
3 Berntorp E, Boulyjenkov V, Brettler D. et al. Modern treatment of haemophilia. Bull World Health Organ 1995; 73: 691-701.
4 Gringeri A, Lundin B, Mackensen SV. et al. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 09: 700-710.
5 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: 535-544.
6 Srivastava A, Brewer AK, Mauser-Bunschoten EP. et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19: e1-e47.
7 Coppola A, Franchini M, Tagliaferri A. Prophylaxis in people with haemophilia. Thromb Haemost 2009; 101: 674-681.
8 Gringeri A, Lambert T, Street A. et al. Tertiary prophylaxis in adults: is there a rationale?. Haemophilia 2012; 18: 722-728.
9 Miners AH, Sabin CA, Tolley KH. et al. Assessing the effectiveness and cost-effectiveness of prophylaxis against bleeding in patients with severe haemophilia and severe von Willebrand’s disease. J Intern Med 1998; 244: 515-522.
10 Fischer K, van Dijk K, van den Berg HM. Late prophylaxis for severe hemophilia: effects of prophylaxis started in adulthood (abstract). J Thromb Haemost 2005; 03: OR205.
11 Tagliaferri A, Rivolta GF, Rossetti G. et al. Experience of secondary prophylaxis in 20 adolescent and adult Italian hemophiliacs. Thromb Haemost 2006; 96: 542-543.
12 Tagliaferri A, Franchini M, Coppola A. et al. Effects of secondary prophylaxis started in adolescent and adult haemophiliacs. Haemophilia 2008; 14: 945-951.
13 Collins P, Faradji A, Morfini M. et al. Efficacy and safety of secondary prophylactic vs. on-demand sucrose-formulated recombinant factor VIII treatment in adults with severe hemophilia A: results from a 13-month crossover study. J Thromb Haemost 2010; 08: 83-89.
14 Valentino LA, Mamonov V, Hellmann A. et al. A randomized comparison of two prophylaxis regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A management. J Thromb Haemost 2012; 10: 359-367.
15 Manco-Johnson MJ, Kempton CL, Reding MT. et al. Randomized, controlled, parallel-group trial of routine prophylaxis versus on-demand treatment with rFVIII-FS in adults with severe hemophilia A (SPINART). J Thromb Haemost 2013; 11: 1119-1127.
16 Santagostino E, Mannucci PM, Bianchi Bonomi A. Guidelines on replacement therapy for haemophilia and inherited coagulation disorders in Italy. Haemophilia 2000; 06: 1-10.
17 Gilbert MS. Prophylaxis: musculoskeletal evaluation. Semin Hematol 1993; 30: 3-6.
18 Pettersson H, Ahlberg A, Nilsson IM. A radiologic classification of hemophilic arthropathy. Clin Orthop Relat Res 1980; 149: 153-159.
19 Gringeri A, Von Mackensen S. Quality of life in haemophilia. Haemophilia 2008; 14: 19-25.
20 Rentz A, Flood E, Altisent C. et al. Cross-cultural development and psychometric evaluation of a patient-reported health-related quality of life questionnaire for adults with haemophilia. Haemophilia 2008; 14: 1023-1034.
21 Fischer K, van der Bom JG, Molho P. et al. Prophylactic versus on-demand treatment strategies for severe haemophilia: a comparison of costs and long-term outcome. Haemophilia 2002; 08: 745-752.
22 Schramm W, Royal S, Kroner B. et al. Clinical outcomes and resource utilization associated with haemophilia care in Europe. Haemophilia 2002; 08: 33-43.
23 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 2102; 88: 329-335.
24 Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group. J Intern Med 1994; 236: 391-399.
25 Lindvall K, Von Mackensen S, Berntorp E. Quality of life in adult patients with haemophilia--a single centre experience from Sweden. Haemophilia 2012; 18: 527-531.
26 Richards M, Altisent C, Batorova A. et al. Should prophylaxis be used in adolescent and adult patients with severe haemophilia? An European survey of practice and outcome data. Haemophilia 2007; 13: 473-479.
27 Walsh CE, Valentino LA. Factor VIII prophylaxis for adult patients with severe haemophilia A: results of a US survey of attitudes and practices. Haemophilia 2009; 15: 1014-1021.
28 van Dijk K, Fischer K, van der Bom JG. et al. Can long-term prophylaxis for severe haemophilia be stopped in adulthood? Results from Denmark and the Netherlands. Br J Haematol 2005; 130: 107-112.
29 De Moerloose P, Urbancik W, Van Den Berg HM. et al. A survey of adherence to haemophilia therapy in six European countries: results and recommendations. Haemophilia 2008; 14: 931-938.
30 Valentino LA. Controversies regarding the prophylactic management of adults with severe haemophilia A. Haemophilia 2009; 15: 5-18 quiz 19–22.
31 Lofqvist T, Nilsson IM, Berntorp E. et al. Haemophilia prophylaxis in young patients--a long-term follow-up. J Intern Med 1997; 241: 395-400.
32 Coppola A, Santoro C, Franchini M. et al. Emerging issues on comprehensive hemophilia care: preventing, identifying and monitoring age-related comorbidities. Semin Thromb Hemost 2013; 39: 794-802.
33 Miners A. Revisiting the cost-effectiveness of primary prophylaxis with clotting factor for the treatment of severe haemophilia A. Haemophilia 2009; 15: 881-887.
34 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: 743-752.
35 Bjorkman S, Folkesson A, Jonsson S. Pharmacokinetics and dose requirements of factor VIII over the age range 3–74 years: a population analysis based on 50 patients with long-term prophylactic treatment for haemophilia A. Eur J Clin Pharmacol 2009; 65: 989-998.
36 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: 738-743.