Prophylaxis versus Episodic Treatment to Prevent Joint Disease in Boys with Severe Hemophilia

Cornell University, Итак, New York, United States
New England Journal of Medicine (Impact Factor: 55.87). 08/2007; 357(6):535-44. DOI: 10.1056/NEJMoa067659
Source: PubMed


Effective ways to prevent arthropathy in severe hemophilia are unknown.
We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI).
Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups.
Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. ( number, NCT00207597 [].).

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Available from: Leonard A Valentino, Sep 02, 2014
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    • "In particular , infusions could be injected either on-demand or on regular basis (prophylaxis). According to the scientific literature , prophylaxis is the first choice therapy, especially for children with severe haemophilia A [8]. "
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    ABSTRACT: Objectives: Haemophilia A is a congenital disorder of coagulation that mainly affects males and causes a considerable use of resources, especially when hemophilic patients are treated with prophylaxis. The aim of the present review was to discuss and appraise the methodological aspects and results of published economic evaluations of haemophilia A treatments in the last decade. Methods: The literature search, performed by consulting four engines, covered studies published between 2002 and 2014. Full economic evaluations published in English language were identified and included in the review. A quality assessment of the studies was also carried out based on Drummond's checklist. Results: After careful evaluations of the identified records, 5 studies were reviewed. Primary and secondary prophylaxis resulted cost-effective compared to on-demand therapy: the ICER of primary prophylaxis ranged from € 40.236 to € 59.315/QALY gained, while the ICER of secondary prophylaxis was € 40.229/QALY gained. Furthermore, 60% were high quality and 40% were medium quality studies. Conclusions: The review underlines the cost-effectiveness of prophylaxis versus on-demand treatment and the different methodological approaches applied. Further economic evaluations are required with models that reflect the clinical reality and consumption of resources in each country.
    Full-text · Article · Jan 2015
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    • "When untreated, patients with severe hemophilia B have a short life expectancy of approximately 25 years, but over the past several decades, the clinical management for hemophilia B has improved dramatically.2,3 Factor replacement therapy has reduced the morbidity and mortality of hemophilia B through reduction in the frequency of bleeding episodes and improvement in the quality of life.4,5 However, while individuals with hemophilia B have nearly normal life expectancy compared to individuals with normal coagulation, deaths still occur at higher rates due to bleeding episodes.6 "
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    ABSTRACT: Hemophilia B is an X-linked genetic disease caused by mutation of the gene for coagulation protein factor IX (FIX), with an incidence of approximately once every 30,000 male births in all populations and ethnic groups. When severe, the disease leads to spontaneous life threatening bleeding episodes. When untreated, most patients die from bleeding complications before 25 years of age. Current therapy requires frequent intravenous infusions of therapeutic recombinant or plasma-derived protein concentrates containing FIX. Most patients administer the infusions at home every few days, and must limit their physical activities to avoid abnormal bleeding when the FIX activity levels are below normal. After completing the pivotal Phase III clinical trial, a new therapeutic FIX preparation that has been engineered for an extended half-life in circulation, received regulatory approval in March 2014 in Canada and the US. This new FIX represents a major therapeutic advance for patients with hemophilia B. The half-life is prolonged due to fusion of the native FIX molecule with the normal constant region of immunoglobulin G. This fusion molecule then follows the normal immunoglobulin recirculation pathways through endothelial cells, resulting in prolonged times in circulation. In the clinical trials, over 150 patients successfully used eftrenonacog alfa regularly for more than 1 year to prevent spontaneous bleeding, to successfully treat any bleeding episodes, and to provide effective coagulation for major surgery. All infusions were well tolerated and effective, with no inhibitors detected and no safety concerns. This promising therapy should allow patients to use fewer infusions to maintain appropriate FIX activity levels in all clinical settings.
    Full-text · Article · Aug 2014 · Patient Preference and Adherence
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    • "Hemophilia A and B are congenital bleeding disorders caused by mutations in the genes coding for coagulation factor VIII (FVIII) and factor IX (FIX).1 Severe hemophilia, characterized by the complete plasma deficiency of these coagulation factors (less than 1%), is epitomized by limb- or life-threatening clinical manifestations such as hemarthrosis, soft-tissue hematomas, retroperitoneal, intracerebral, and excessive post-surgical hemorrhages. Recurrent joint bleeding and soft-tissue hematomas may cause severe arthropathy, muscle contractures, and pseudotumors, leading to chronic pain and disability that often warrant major orthopedic surgery.1 Prophylaxis of bleeds, involving the regular infusion of plasma-derived or recombinant pharmaceutical products containing the deficient coagulation factor, is the mainstay of hemophilia care, made evidence-based by the results of two randomized clinical trials that showed the capacity of this therapeutic approach to avoid arthropathy.2,3 However, the practical adoption and implementation of prophylaxis is inconvenient, because the most widely used therapeutic regimens involve repeated intravenous infusions of the deficient coagulation factors FVIII or FIX in order to maintain plasma trough levels at or above 1%.4 "
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    ABSTRACT: Prophylaxis with regular infusions of factor VIII (FVIII)- or factor IX (FIX)- containing products is the mainstay of modern hemophilia care. However, this therapeutic regimen is inconvenient, requiring repeated intravenous injections from childhood. Approaches meant to prolong the half-life of FVIII and FIX in plasma have been developed in order to improve the feasibility and acceptability of replacement therapy, extending protection from bleeding, reducing infusion frequency and hence the need for venous access devices in young children. Several strategies have been implemented to enhance the pharmacokinetics of clotting factors, including conjugation with polyethylene glycol and the production by genetic engineering of fusion proteins containing the coagulation factors linked to a long-lived plasma protein such as albumin or the Fc fragment of immunoglobulin (Ig)G. The latter technology is one of the most promising, since the prolongation of FVIII and FIX half-life is obtained by exploiting the physiological binding of the Fc domain to the neonatal Fc receptor. Fc fusion monomers have been obtained with both recombinant FVIII (rFVIIIFc) and FIX (rFIXFc), and data from preclinical and clinical studies showed improved pharmacokinetics for both factors, which are produced in human embryonic kidney (HEK) 293 cells, thus ensuring full human post-translational modifications. In Phase I/IIa studies, rFVIIIFc and rFIXFc showed 1.5-1.7 fold and 3.0-4.0 fold longer elimination half-life, respectively. Similar data have been obtained in the Phase III clinical studies with rFVIIIFc and rFIX-Fc published recently. Both drugs were satisfactorily safe, particularly with respect to immunogenicity, and no serious adverse event was observed.
    Full-text · Article · Mar 2014 · Drug Design, Development and Therapy
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