This page contains a Flash digital edition of a book.
Haemophilia


Recombinant Factor VIIa Concentrate versus Plasma-derived Concentrates for the Treatment of Acute Bleeding Episodes in Persons with Haemophilia and Inhibitors


Emanuela Marchesini,1 Domenico Prisco2 and Alfonso Iorio3


1. Fellow, Haemophilia Centre, Perugia University; 2. Professor and Chair, Atherothrombotic Disease Unit, Department of Internal Medicine, University of Florence; 3. Associate Professor, Health Information Research Unit, Department of Clinical Epidemiology and Biostatistics, McMaster University


Abstract


The development of inhibitors remains the most challenging complication of treatment in persons with haemophilia, resulting in increased morbidity and a significant economic burden. The ultimate goal of treatment in patients with inhibitors is immune tolerance induction (ITI) therapy; however, during the induction phase of ITI, when ITI fails and where ITI is not affordable, the treatment of bleeding becomes a crucial issue. Recombinant activated factor VII (rFVIIa) and activated prothrombin complex concentrate (aPCC) have been developed to bypass the inhibitor antibody effect and have been tested in several randomised controlled trials, including two crossover head-to-head comparisons. Two systematic reviews of the literature have appraised and synthesised the available evidence. The recombinant drug seems to provide a more favourable benefit–risk ratio and may be easily administered as a single front-loaded bolus, making it a good candidate for the role of first-line treatment for bleeding in patients with inhibitors. Aggressive treatment of acute bleeds should be considered, including the use of higher and repeated-dose regimens until complete resolution of the bleed.


Keywords Haemophilia, inhibitors, bypassing agents, acute bleeding


Disclosure: Emanuela Marchesini has no conflicts of interest to declare. Domenico Prisco received fees for giving talks and for serving on advisory boards for Bayer and GSK. Alfonso Iorio received fees for giving talks and for serving on national and international advisory boards for NovoNordisk and Baxter. Received: 16 November 2010 Accepted: 15 March 2011 Citation: European Oncology & Haematology, 2011;7(2):140–2 Correspondence: Alfonso Iorio, Health Information Research Unit, Department of Clinical Epidemiology and Biostatistics, CRL-140, McMaster University, 1280 Main Street West, Hamilton, ON, Canada, L8S 4K1. E: iorioa@mcmaster.ca


Persons with haemophilia (PWH) experience spontaneous or trauma- related bleedings, most commonly joint bleeds, which progressively lead to swelling, limitation of movement, cartilage destruction and haemophilic arthropathy.1


Regular replacement therapy with clotting


factor concentrates significantly improves the quality of life in PWH, dramatically reducing the bleeding rate and preserving the joint health status.2,3


Inhibitors can be


The development of inhibitors remains the most challenging complication of treatment in PWH, resulting in increased morbidity and a significant economic burden.4


classified as high- or low-responding according to a cut-off level of 5 Bethesda units (BU). The likelihood of developing inhibitors is highest during the first 50 exposure days (EDs) to clotting factor, and searching for inhibitors every three to five EDs for the first 20 EDs and monthly until 50 EDs is recommended for early detection.5 Many low-level inhibitors will disappear spontaneously (transient inhibitors),6


while others persist, sometimes at very high titre, making standard replacement treatment with factor VIII (FVIII) ineffective. The prevalence of inhibitors has been found to be 5–7% in all severities7 of haemophilia A and up to 30% in patients with severe haemophilia.8 In patients with severe haemophilia B the prevalence of inhibitors is around 3%.8


The ultimate goal of treatment in patients with inhibitors is immune tolerance induction (ITI); however, during the induction phase of ITI,


140


when ITI fails and where ITI is not affordable, the treatment of bleeding becomes a relevant objective. The goals in the treatment of bleeding episodes are to relieve pain and to prevent, or at least slow down, the progression towards arthropathy caused by recurrent bleeding into the joint. Aggressive treatment of acute bleeds should be considered, including the use of higher and repeated-dose regimens until complete resolution of the bleed.9,10


For patients with high-responding, high-titre inhibitors and acute bleeding, bypassing agents – recombinant activated factor VII (rFVIIa) and plasma-derived activated prothrombin complex concentrate (aPCC) – are the gold standard.7,8


The use of bypassing


agents in the management of patients with inhibitors in different European countries has recently been assessed by Astermark et al.11 who ran a survey among investigators from 22 large haemophilia centres participating in the European Haemophilia Therapy Standardisation Board (EHTSB) network. The centres collectively followed 381 haemophilia patients with inhibitors to FVIII (349 patients) or factor IX (FIX) (32 patients), of whom 72% had high- responding inhibitors. In 10 of the centres high-dose FVIII/FIX was used as the first option for low-responding inhibitor patients. rFVIIa was routinely used in all centres for both children and adults at a dosage ranging from 90 to 250μg/kg every two to four hours. aPCC was used in 85 and 40% of the centres in adults with


© TOUCH BRIEFINGS 2011


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68