Spanish Consensus Guidelines on prophylaxis with bypassing agents in patients with haemophilia and inhibitors

Maria Fernanda López-Fernández; Carmen Altisent Roca; Maria Teresa Álvarez-Román; Mariana Isabel Canaro Hirnyk; Maria Eva Mingot-Castellano; Víctor Jiménez-Yuste; Ana Rosa Cid Haro; Rosario Pérez-Garrido; Carmen Sedano Balbas

doi:10.1160/TH15-07-0568

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(05): 872-895
DOI: 10.1160/TH15-07-0568

Consensus Paper

Schattauer GmbH

Spanish Consensus Guidelines on prophylaxis with bypassing agents in patients with haemophilia and inhibitors

Maria Fernanda López-Fernández

¹Complejo Hospitalario Universitario A Coruña, Haematology, A Coruña, Spain

,

Carmen Altisent Roca

²Hospital Universitario Vall d’Hebron, Haemophilia Unit, Barcelona, Spain

,

Maria Teresa Álvarez-Román

³Hospital Universitario La Paz, Thrombosis and Haemostasis, Madrid, Spain

,

Mariana Isabel Canaro Hirnyk

⁴Hospital Universitario Son Espases, Haematology, Palma de Mallorca, Spain

,

Maria Eva Mingot-Castellano

⁵Hospital Regional Universitario de Málaga, Haematology, Málaga, Spain

,

Víctor Jiménez-Yuste

³Hospital Universitario La Paz, Thrombosis and Haemostasis, Madrid, Spain

,

Ana Rosa Cid Haro

⁶Hospital Universitario La Fe, Thrombosis and Haemostasis, Valencia, Spain

,

Rosario Pérez-Garrido

⁷Hospital Universitario Virgen del Rocío, Haemophilia Unit, Sevilla, Spain

,

Carmen Sedano Balbas

⁸Hospital Universitario Marqués de Valdecilla, Haematology, Cantabria, Spain

› Author Affiliations

Abstract

Summary

Prophylaxis with the blood clotting factor, factor VIII (FVIII) is ineffective for individuals with haemophilia A and high-titre inhibitors to FVIII. Prophylaxis with the FVIII bypassing agents activated prothrombin complex concentrates (aPCC; FEIBA^® Baxalta) or recombinant activated factor VII (rFVIIa; Novo-Seven^®, Novo Nordisk) may be an effective alternative. It was our aim to develop evidence -and expert opinion- based guidelines for prophylactic therapy for patients with high-titre inhibitors to FVIII. A panel of nine Spanish haematologists undertook a systematic review of the literature to develop consensusbased guidance. Particular consideration was given to prophylaxis in patients prior to undergoing immune tolerance induction (ITI) (a process of continued exposure to FVIII that can restore sensitivity for some patients), during the ITI period and for those not undergoing ITI or for whom ITI had failed. These guidelines offer guidance for clinicians in deciding which patients might benefit from prophylaxis with FVIII bypassing agents, the most appropriate agents in various clinical settings related to ITI, doses and dosing regimens and how best to monitor the efficacy of prophylaxis. The paper includes recommendations on when to interrupt or stop prophylaxis and special safety concerns during prophylaxis. These consensus guidelines offer the most comprehensive evaluation of the clinical evidence base to date and should be of considerable benefit to clinicians facing the challenge of managing patients with severe haemophilia A with high-titre FVIII inhibitors.

Keywords

Prophylaxis - bypassing agents - haemophilia - inhibitors - guidelines

Full Text

References

References
1 Nilsson IM. et al. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. J Intern Med 1992; 232: 25-32.
2 Manco-Johnson MJ. et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535-544.
3 Morfini M. et al. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia 2007; 13: 606-612.
4 Coppola A. et al. Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: Towards evidence-based approaches. Br J Haematol 2010; 150: 515-528.
5 DiMichele DM. Immune tolerance: a synopsis of the international experience. Haemophilia 1998; 4: 568-573.
6 Hay CRM, DiMichele DM. The principal results of the International Immune Tolerance Study: A randomized dose comparison. Blood 2012; 119: 1335-1344.
7 Abshire TC, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors. J Thromb Haemost 2004; 2: 899-909.
8 DiMichele DM, Négrier C. A retrospective postlicensure survey of FEIBA efficacy and safety. Haemophilia 2006; 12: 352-362.
9 Leissinger CA. Prevention of bleeds in hemophilia patients with inhibitors: Emerging data and clinical direction. Am J Hematol 2004; 77: 187-193.
10 Gringeri A. 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: 736-743.
11 Soucie JM. et al. Joint range-of-motion limitations among young males with hemophilia: prevalence and risk factors. Blood 2004; 103: 2467-2473.
12 Brackmann HH, Gormsen J. Massive factor-VIII infusion in haemophiliac with factor-VIII inhibitor, high responder. Lancet 1977; 2: 933.
13 Brackmann HH. et al. Immune tolerance for the treatment of factor VIII inhibitors--twenty years’ “bonn protocol”. Vox Sang 1996; 70 (Suppl. 01) 30-35.
14 Leissinger CA. et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med 2011; 365: 1684-1692.
15 Antunes SV. et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia 2014; 20: 65-72.
16 Konkle BA. et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost 2007; 5: 1904-1913.
17 Valentino LA. Assessing the benefits of FEIBA prophylaxis in haemophilia patients with inhibitors. Haemophilia 2010; 16: 263-271.
18 Young G. et al. PRO-PACT: Retrospective observational study on the prophylactic use of recombinant factor VIIa in hemophilia patients with inhibitors. Thromb Res 2012; 130: 864-870.
19 Young G. et al. When should prophylaxis therapy in inhibitor patients be considered?. Haemophilia 2011; 17: 849-857.
20 Teitel JM, Sholzberg M. Current status and future prospects for the prophylactic management of hemophilia patients with inhibitor antibodies. Blood Rev 2013; 27: 103-109.
21 Valentino LA. et al. The application of bypassing-agent prophylaxis in haemophilia A patients with inhibitors: A meeting report. Haemophilia 2009; 15: 959-965.
22 Perry D. et al. FEIBA prophylaxis in haemophilia patients: A clinical update and treatment recommendations. Haemophilia 2010; 16: 80-89.
23 Astermark J. et al. Current European practice in immune tolerance induction therapy in patients with haemophilia and inhibitors. Haemophilia 2006; 12: 363-371.
24 DiMichele DM. et al. International workshop on immune tolerance induction: consensus recommendations. Haemophilia 2007; 13 (Suppl. 01) 1-22.
25 Benson GM. et al. Immune tolerance induction in patients with severe hemophilia with inhibitors: Expert panel views and recommendations for clinical practice. Eur J Haematol 2012; 88: 371-379.
26 Lόpez-Fernández MF. et al. Effective prophylaxis with rFVIIa in young haemophiliacs with inhibitors using a schedule similar to FVIII prophylaxis in non-inhibitor patients. Health 2013; 5: 1151-1157.
27 Jimenez-Yuste V. et al. Primary prophylaxis” with rFVIIa in a patient with severe haemophilia A and inhibitor. Blood Coagul Fibrinolysis 2008; 19: 719-720.
28 Sedano C. et al. Retrospective evaluation of secondary episodic prophylaxis with rFVIIa in hemophilia patients with inhibitor. J Coagul Disord 2010; 2: 5-9.
29 Jimenez-Yuste V. et al. Prophylaxis in 10 patients with severe haemophilia A and inhibitor: Different approaches for different clinical situations. Haemophilia 2009; 15: 203-209.
30 Laffan M. et al. The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors Õ Organization. Haemophilia 2004; 10: 199-217.
31 DiMichele DM, Kroner BL. The North American Immune Tolerance Registry: practices, outcomes, outcome predictors. Thromb Haemost 2002; 87: 52-57.
32 Mariani G. et al. Immune tolerance in hemophilia-principal results from the International Registry. Report of the factor VIII and IX Subcommittee. Thromb Haemost 1994; 72: 155-158.
33 Teitel JM. et al. A consensus statement on clinical trials of bypassing agent prophylaxis in inhibitor patients. Haemophilia 2011; 17: 516-521.
34 Auerswald G, Morfini M. Prophylaxis with recombinant activated factor VII in hemophilia patients with inhibitors. J Coagul Disord 2010; 2: 1-8.
35 Brown SA. et al. How we use recombinant activated Factor VII in patients with haemophilia A or B complicated by inhibitors. Intern Med J 2012; 42: 1243-1250.
36 Carcao M, Lambert T. Prophylaxis in haemophilia with inhibitors: Update from international experience. Haemophilia 2010; 16 (Suppl. 02) 16-23.
37 Franchini M. et al. FEIBA versus NovoSeven in hemophilia patients with inhibitors. Semin. Thromb Hemost 2013; 39: 772-778.
38 Hedner U, Lee CA. First 20 years with recombinant FVIIa (NovoSeven). Haemophilia 2011; 17: 172-182.
39 Makris M. et al. How I treat inhibitors in haemophilia. Haemophilia 2012; 18 (Suppl. 04) 48-53.
40 Valentino LA. FEIBA prophylaxis for patients with haemophilia A and inhibitors [Abstract 22 PO 18]. Haemophilia 2004; 10 (Suppl. 03) 113-116.
41 Nanishi E. et al. Complete immunotolerance induction after FEIBA prophylaxis in a haemophilia A patient with high-titre inhibitor. Haemophilia 2012; 18: 75-77.
42 Valentino LA. The benefits of prophylactic treatment with APCC in patients with haemophilia and high-titre inhibitors: A retrospective case series. Haemophilia 2009; 15: 733-742.
43 Faradji A. et al. Late immune tolerance induction in an adult with severe haemophilia A and high-responder inhibitor: 1-year outcome. Haemophilia 2012; 18: 388-391.
44 Breen KA. et al. A single centre experience of prophylactic rFVIIa in paediatric patients with severe haemophilia and inhibitors. J Thromb Haemost. 2009 7. (suppl 2): Abstract PP-WE-615
45 Blatny J. et al. Prophylaxis with recombinant factor VIIa for the management of bleeding episodes during immune tolerance treatment in a boy with severe haemophilia A and high-response inhibitors. Haemophilia 2008; 14: 1140-1142.
46 Saxon BR. et al. Effective prophylaxis with daily recombinant factor VIIa (rFVIIa-Novoseven) in a child with high titre inhibitors and a target joint. Thromb Haemost 2001; 86: 1126-1127.
47 Henderson L. et al. FEIBA prophylaxis in children: A single-centre experience. Haemophilia 2012; 18 (Suppl. 02) 147.
48 Leissinger CA. et al. Prophylactic treatment with activated prothrombin complex concentrate (FEIBA) reduces the frequency of bleeding episodes in paediatric patients with haemophilia A and inhibitors. Haemophilia 2007; 13: 249-255.
49 Lambert T. et al. Secondary prophylaxis with activated prothrombin complex concentrates (APCC) reduces bleeding frequency in haemophilia A patients with inhibitors. In: the XXII Congress of the International Society on Thrombosis and Haemostasis July 16,2009. Boston, MA, USA. Poster PP-TH-593.
50 Cheng S. et al. FEIBA prophylaxis in hemophilia a patient with inhibitor decreases bleeding episodes, improves joint function and enhances quality of life. Haemophilia 2006; 12 (Suppl. 02) 17.
51 Kreuz W. et al. Factor VIII inhibitor bypass activity (FEIBA) for prophylaxis during immune tolerance induction (ITI) in patients with high-responding inhibitors. Blood 2000; 96: 266 Abstract 1141.
52 Kreuz W. et al. Immune tolerance therapy in paediatric haemophiliacs with factor VIII inhibitors: 14 years follow-up. Haemophilia 1995; 1: 9.
53 Ewing N. et al. Prophylaxis with FEIBA in paediatric patients with haemophilia A and inhibitors. Haemophilia 2015; 21: 358-364.
54 Escuriola-Ettingshausen C. et al. Long-term prophylaxis with FEIBA® in patients with high-responding inhibitors. J Thromb Haemost 2003 1. (supp1 1): Abstract P1628.
55 Kavakli K. et al. Activated prothrombin complex concentrate prophylaxis for haemophilia patients with inhibitors: importance of age; toddlers vs. young adults. Haemophilia 2015; 21 (Suppl. 02) 14-94 Abstract PP069.
56 Siegmund B. et al. Prophylactic treatment with FEIBA of a haemophilia A patient with inhibitor: What are the costs, what are the benefits?. Haemophilia 2005; 11: 638-641.
57 Smejkal P. et al. Prophylactic treatment with recombinant factor VIIa in patient with advanced haemophiliac arthropathy. J Thromb Haemost 2009 7. (suppl 2): Abstract PP-TH-612.
58 Ohga S. et al. Successful self-infusion of activated prothrombin complex concentrate for prophylaxis in a child with a factor VIII inhibitor. Am J Hematol 2007; 82: 145-149.
59 Chuansumrit A. et al. Safety and efficacy of recombinant activated factor VII for long-term secondary prophylaxis in a haemophilia boy with high-titre inhibitors. Haemophilia 2013; 19: e182-e183.
60 Morfini M. et al. Prophylactic treatment of haemophilia patients with inhibitors: Clinical experience with recombinant factor VIIa in European Haemophilia Centres. Haemophilia 2007; 13: 502-507.
61 Martinez M. et al. Successful secondary prophilaxis in hemophilia with inhibitors using rFVIIa three times per week. Haemophilia 2012; 18 (Suppl. 03) 1.
62 Saxena K. et al. Long-term Clinical experience with FEIBA VH in Hemophilia Patients with Inhibitors [Abstract P0808]. In: XXth Congress of the International Society on Thrombosis and Haemostasis (ISTH), and 51st SSC Meeting 6–12 August 2005; Sydney, Australia.
63 Hilgartner MW. et al. Long-term FEIBA prophylaxis does not prevent progression of existing joint disease. Haemophilia 2003; 9: 261-268.
64 Ewing N. et al. Anamnesis in patients with hemophilia and inhibitors who receive activated prothrombin complex concentrates for prophylaxis. In: XXI Congress of the International Society on Thrombosis and Haemostasis (ISTH) July 6–12, 2007, Geneva, Switzerland.
65 Escuriola-Ettingshausen C, Kreuz W. Early long-term FEIBA prophylaxis in haemophilia A patients with inhibitor after failing immune tolerance induction: A prospective clinical case series. Haemophilia 2010; 16: 90-100.
66 Cermelj MA. et al. Prophylactic treatment with recombinant activated factor VII in paediatric patients with haemophilia and inhibitors. In: XXII ISTH Congress J Thromb Haemost 2009; 7 Abstract PP-WE-203.
67 Kajiwara M. et al. Two haemophilia patients with inhibitors who became ambulatory after physiotherapy under haemostatic cover with bypassing agents. Haemophilia 2013; 19: e301-e304.
68 Ewenstein B. et al. Evaluation of FEIBA for prophylaxis in patients with inhibitors. In: Haemophilia 2004 World Congress Oct 17–21 2004; Bangkok, Thailand: Baxter BioScience; 2004.
69 Novack A. et al. Safety and effectiveness of anti inhibitor coagulation complex (AICC) in routine clinical management: a post-authorization safety study (PASS). In: World Federation of Hemophilia (WFH) 2014 World Congress May 11–15 2014; Melbourne, Australia. Poster: P-M-045.
70 Stasyshyn O. et al. Prophylaxis with anti-inhibitor coagulant complex improves health-related quality of life in haemophilia patients with inhibitors: results from FEIBA NF Prophylaxis Study. Haemophilia 2014; 20: 644-650.
71 Hoots WK. et al. Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors. Haemophilia 2008; 14: 466-475.
72 Leissinger CA. et al. Joint disease and the potential for improved joint health in inhibitor patients who have a good response to APCC prophylaxis: data from the PROFEIBA study. Blood 2012; 120 Abstract PO-3374
73 Astermark J. et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood 2007; 109: 546-551.
74 Erhardtsen E. Pharmacokinetics of recombinant activated factor VII (rFVIIa). Semin Thromb Hemost 2000; 26: 385-391.
75 Santagostino E. et al. European Initiative to prevent joint damage in hemophilia children with inhibitors (ENJHOI) – a prospective study. Haemophilia 2010; 16 (Suppl. 04) 17.
76 World Federation of Hemophilia. Compedium of assessment tools. Resour. WFH. 2014 Available at http://www.wfh.org/en/page.aspx?pid=882 Accessed November 22, 2015.
77 Livnat T. et al. Combined administration of FVIII and rFVIIa improves haemostasis in haemophilia A patients with high-responding inhibitors--a thrombin generation-guided pilot study. Haemophilia 2013; 19: 782-789.
78 Luu H, Ewenstein B. FEIBA safety profile in multiple modes of clinical and home-therapy application. Haemophilia 2004; 10 (Suppl. 02) 10-16.
79 Negrier C. et al. Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors. French FEIBA Study Group. Factor Eight Bypassing Activity. Thromb Haemost 1997; 77: 1113-1119.
80 Hilgartner MW, Knatterud GL. The use of factor eight inhibitor by-passing activity (FEIBA immuno) product for treatment of bleeding episodes in hemophiliacs with inhibitors. Blood 1983; 61: 36-40.
81 Ewenstein BM. et al. Consensus recommendations for use of central venous access devices in haemophilia. Haemophilia 2004; 10: 629-648.