Download PDF
Semin Thromb Hemost 2016; 42(05): 533-540
DOI: 10.1055/s-0036-1579639
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Is Continuous Low-Dose Prophylaxis Superior to On-Demand Treatment for Patients with Hemophilia?

Jerzy Windyga
1   Department of Disorders of Hemostasis and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
› Author Affiliations
Further Information

Publication History

Publication Date:
20 April 2016 (online)

    Permissions and Reprints

Abstract

Long-term (or continuous) prophylaxis is generally accepted as the best form of treatment for patients with severe hemophilia A and B. Results of recent prospective, randomized clinical trials, as well as observational studies performed in the last decades, have provided strong and convincing evidence that continuous prophylaxis leads to reduction in the number of bleeding episodes, better joint status and improved health-related quality of life as compared with on-demand (or episodic) treatment. Nevertheless, many questions regarding long-term prophylaxis still remain open, for instance: when should prophylaxis be started (before or after the first joint bleeding), what is the optimal dosage to replace the missing factor, when should discontinuation of long-term prophylaxis be considered, what is the best way to measure the outcome of prophylaxis, etc. Moreover, there are numerous obstacles to widespread use of prophylactic therapy. The most challenging seem to be adequate venous access (particularly in younger patients) and patients' adherence. The crucial barrier to long-term prophylaxis is, however, the remarkably high cost of clotting factor concentrates. For most countries high-dose or intermediate-dose prophylaxis regimens are not affordable due to lack of economic resources. So, is continuous prophylaxis reserved exclusively for wealthy societies? Fortunately, there is an increasing body of evidence to suggest that low-dose prophylaxis offers significant benefits over on-demand treatment with comparable amounts of factor concentrate (and much lower amounts if compared with intermediate or high-dose prophylaxis regimens). The aim of this article is to discuss the clinical and economical aspects of continuous prophylaxis in hemophilia with emphasis on the low-dose regimens.

Keywords

hemophilia - low-dose prophylaxis - on-demand therapy - costs
 

  • References

  • 1 Berntorp E, Shapiro AD. Modern haemophilia care. Lancet 2012; 379 (9824) 1447-1456
    CrossrefPubMedGoogle Scholar
  • 2 Srivastava A, Brewer AK, Mauser-Bunschoten EP , et al; Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013; 19: e1-e47
    CrossrefPubMedGoogle Scholar
  • 3 Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A ; Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12 (11) 1935-1939
    CrossrefPubMedGoogle Scholar
  • 4 Nilsson IM, Hedner U, Ahlberg A. Haemophilia prophylaxis in Sweden. Acta Paediatr Scand 1976; 65 (2) 129-135
    CrossrefPubMedGoogle Scholar
  • 5 Ramgren O. A clinical and medico-social study of haemophilia in Sweden. Acta Med Scand Suppl 1962; 379: 111-190
    PubMedGoogle Scholar
  • 6 Ahlberg A. Haemophilia in Sweden. VII. Incidence, treatment and prophylaxis of arthropathy and other musculo-skeletal manifestations of haemophilia A and B. Acta Orthop Scand Suppl 1965; (Suppl. 77) 77 , 3–132
    PubMedGoogle Scholar
  • 7 Van Creveld S. Prophylaxis of joint hemorrhages in hemophilia. Acta Haematol 1969; 41 (4) 206-214
    CrossrefPubMedGoogle Scholar
  • 8 Kasper CK, Dietrich SL, Rapaport SI. Hemophilia prophylaxis with factor VIII concentrate. Arch Intern Med 1970; 125 (6) 1004-1009
    CrossrefPubMedGoogle Scholar
  • 9 Nilsson IM, Berntorp E, Löfqvist T, Pettersson H. Twenty-five years' experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232 (1) 25-32
    CrossrefPubMedGoogle Scholar
  • 10 Aledort LM, Haschmeyer RH, Pettersson H ; The Orthopaedic Outcome Study Group. A longitudinal study of orthopaedic outcomes for severe factor-VIII-deficient haemophiliacs. J Intern Med 1994; 236 (4) 391-399
    CrossrefPubMedGoogle Scholar
  • 11 Coppola A, Tagliaferri A, Di Capua M, Franchini M. Prophylaxis in children with hemophilia: evidence-based achievements, old and new challenges. Semin Thromb Hemost 2012; 38 (1) 79-94
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 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 (6) 535-544
    CrossrefPubMedGoogle Scholar
  • 13 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 (4) 700-710
    CrossrefPubMedGoogle Scholar
  • 14 Manco-Johnson MJ, Kempton CL, Reding MT , et al. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost 2013; 11 (6) 1119-1127
    CrossrefPubMedGoogle Scholar
  • 15 Tagliaferri A, Feola G, Molinari AC , et al; POTTER Study Group. Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study. Thromb Haemost 2015; 114 (1) 35-45
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Santagostino E, Fasulo MR. Hemophilia a and hemophilia B: different types of diseases?. Semin Thromb Hemost 2013; 39 (7) 697-701
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 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 (4) 737-743
    CrossrefPubMedGoogle Scholar
  • 18 Nagel K, Walker I, Decker K, Chan AK, Pai MK. Comparing bleed frequency and factor concentrate use between haemophilia A and B patients. Haemophilia 2011; 17 (6) 872-874
    CrossrefPubMedGoogle Scholar
  • 19 Vyas S, Enockson C, Hernandez L, Valentino LA. Towards personalizing haemophilia care: using the Haemophilia Severity Score to assess 178 patients in a single institution. Haemophilia 2014; 20 (1) 9-14
    CrossrefPubMedGoogle Scholar
  • 20 Clausen N, Petrini P, Claeyssens-Donadel S, Gouw SC, Liesner R ; PedNet and Research of Determinants of Inhibitor development (RODIN) Study Group. Similar bleeding phenotype in young children with haemophilia A or B: a cohort study. Haemophilia 2014; 20 (6) 747-755
    CrossrefPubMedGoogle Scholar
  • 21 Ljung R, Gretenkort Andersson N. The current status of prophylactic replacement therapy in children and adults with haemophilia. Br J Haematol 2015; 169 (6) 777-786
    CrossrefPubMedGoogle Scholar
  • 22 Witmer C, Presley R, Kulkarni R, Soucie JM, Manno CS, Raffini L. Associations between intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients in the United States. Br J Haematol 2011; 152 (2) 211-216
    CrossrefPubMedGoogle Scholar
  • 23 Berntorp E, Boulyjenkov V, Brettler D , et al. Modern treatment of haemophilia. Bull World Health Organ 1995; 73 (5) 691-701
    PubMedGoogle Scholar
  • 24 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 (7) 1129-1136
    CrossrefPubMedGoogle Scholar
  • 25 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 (3) 561-565
    CrossrefPubMedGoogle Scholar
  • 26 Feldman BM, Pai M, Rivard GE , et al; Association of Hemophilia Clinic Directors of Canada Prophylaxis Study Group. 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 (6) 1228-1236
    CrossrefPubMedGoogle Scholar
  • 27 Astermark J, Petrini P, Tengborn L, Schulman S, Ljung R, Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol 1999; 105 (4) 1109-1113
    CrossrefPubMedGoogle Scholar
  • 28 Valentino LA, Mamonov V, Hellmann A , et al; Prophylaxis Study Group. 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 (3) 359-367
    CrossrefPubMedGoogle Scholar
  • 29 Santoro C, Baldacci E, Mercanti C, Mazzucconi MG. Tailored versus standard dose prophylaxis in children with hemophilia A. Semin Thromb Hemost 2013; 39 (7) 711-722
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Reininger AJ, Chehadeh HE. The principles of PK-tailored prophylaxis. Hamostaseologie 2013; 33 (Suppl. 01) S32-S35
    PubMedGoogle Scholar
  • 31 Collins PW, Fischer K, Morfini M, Blanchette VS, Björkman S ; International Prophylaxis Study Group Pharmacokinetics Expert Working Group. Implications of coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of haemophilia. Haemophilia 2011; 17 (1) 2-10
    CrossrefPubMedGoogle Scholar
  • 32 Giangrande P, Seitz R, Behr-Gross ME , et al. Kreuth III: European consensus proposals for treatment of haemophilia with coagulation factor concentrates. Haemophilia 2014; 20 (3) 322-325
    CrossrefPubMedGoogle Scholar
  • 33 De Kleijn P, Odent T, Berntorp E , et al. Differences between developed and developing countries in paediatric care in haemophilia. Haemophilia 2012; 18 (Suppl. 04) 94-100
    PubMedGoogle Scholar
  • 34 Srivastava A. Dose and response in haemophilia—optimization of factor replacement therapy. Br J Haematol 2004; 127 (1) 12-25
    CrossrefPubMedGoogle Scholar
  • 35 Blanchette VS. Prophylaxis in the haemophilia population. Haemophilia 2010; 16 (Suppl. 05) 181-188
    CrossrefPubMedGoogle Scholar
  • 36 Stonebraker JS, Brooker M, Amand RE, Farrugia A, Srivastava A. A study of reported factor VIII use around the world. Haemophilia 2010; 16 (1) 33-46
    CrossrefPubMedGoogle Scholar
  • 37 Srivastava A. Choice of factor concentrates for haemophilia: a developing world perspective. Haemophilia 2001; 7 (1) 117-122
    CrossrefPubMedGoogle Scholar
  • 38 Ozelo MC, Matta MA, Yang R. Meeting the challenges of haemophilia care and patient support in China and Brazil. Haemophilia 2012; 18 (Suppl. 05) 33-38
    CrossrefPubMedGoogle Scholar
  • 39 O'Mahony B, Noone D, Giangrande PL, Prihodova L. Haemophilia care in Europe - a survey of 35 countries. Haemophilia 2013; 19 (4) e239-e247
    CrossrefPubMedGoogle Scholar
  • 40 Srivastava A. Haemophilia care - beyond the treatment guidelines. Haemophilia 2014; 20 (Suppl. 04) 4-10
    PubMedGoogle Scholar
  • 41 Björkman S, Folkesson A, Jönsson 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 (10) 989-998
    CrossrefPubMedGoogle Scholar
  • 42 Collins PW, Björkman S, Fischer K , et al. Factor VIII requirement to maintain a target plasma level in the prophylactic treatment of severe hemophilia A: influences of variance in pharmacokinetics and treatment regimens. J Thromb Haemost 2010; 8 (2) 269-275
    CrossrefPubMedGoogle Scholar
  • 43 Lindvall K, Astermark J, Björkman S , et al. Daily dosing prophylaxis for haemophilia: a randomized crossover pilot study evaluating feasibility and efficacy. Haemophilia 2012; 18 (6) 855-859
    CrossrefPubMedGoogle Scholar
  • 44 Hermans C, Dolan G, Jennings I , et al. Managing Haemophilia for Life: 5th Haemophilia Global Summit. Eur J Haematol 2015; 95 (Suppl. 78) 1-25
    PubMedGoogle Scholar
  • 45 Wu R, Luke KH, Poon MC , et al. Low dose secondary prophylaxis reduces joint bleeding in severe and moderate haemophilic children: a pilot study in China. Haemophilia 2011; 17 (1) 70-74
    CrossrefPubMedGoogle Scholar
  • 46 Tang L, Wu R, Sun J , et al. Short-term low-dose secondary prophylaxis for severe/moderate haemophilia A children is beneficial to reduce bleed and improve daily activity, but there are obstacle in its execution: a multi-centre pilot study in China. Haemophilia 2013; 19 (1) 27-34
    CrossrefPubMedGoogle Scholar
  • 47 Celkan T, Ozdemir N. Reduced early prophylaxis of children with haemophilia in a developing country, Turkey. Haemophilia 2011; 17 (5) e840-e841
    PubMedGoogle Scholar
  • 48 Awidi A, Faouri S, Kiswani BA , et al. Haemophilia prophylaxis: a model and future directions in Jordan. Blood Transfus 2014; 12 (Suppl. 01) s343-s344
    PubMedGoogle Scholar
  • 49 Hacker MR, Geraghty S, Manco-Johnson M. Barriers to compliance with prophylaxis therapy in haemophilia. Haemophilia 2001; 7 (4) 392-396
    CrossrefPubMedGoogle Scholar