Abshire T, Kenet G. Recombinant factor VIIa: review of efficacy, dosing regimens and safety in patients with congenital and acquired factor VIII or IX inhibitors

Emory University, Atlanta, Georgia, United States
Journal of Thrombosis and Haemostasis (Impact Factor: 5.72). 07/2004; 2(6):899-909. DOI: 10.1111/j.1538-7836.2004.00759.x
Source: PubMed


Recombinant factor (rF)VIIa has been available to clinicians since 1996 and has an excellent safety record after almost three-quarters of a million doses have been administered. This paper will review the current clinical experience with rFVIIa dosing in acquired and congenital hemophilia with inhibitors and chronicle all spontaneous and clinical trial reports of thrombotic adverse events as of April 2003. Standard dosing of rFVIIa (90 micro g kg(-1)) allows binding of FVIIa to the surface of an activated platelet and can directly activate factor X in the absence of tissue factor. Experience with bolus dosing suggests that higher dosing (>200 micro g kg(-1)) may be more efficacious in treating hemophilia patients. Clinical trials are ongoing to validate this observation. Continuous infusion dosing may be efficacious for major surgery but high infusion rates (50 micro g kg(-1) h(-1)) might be needed. The relationship between dose of rFVIIa, amount of thrombin generated and measurable FVIIa level is still not known and perhaps newer testing which measures thrombin generation might be more advantageous. Relatively few thrombotic events have been associated with rFVIIa. Known factors predisposing to thrombosis were present in 20 of the 25 (80%) hemophilia patients who were reported spontaneously or who developed a thrombosis during a clinical trial. Additionally, thrombotic events have not increased despite a growing experience with higher dosing of rFVIIa.

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    • "Briefly, in post-marketing sources (up to 31 December 2013), 13% of the events reported in rFVIIa-treated patients with AH were TEs: 50 patients had a total of 54 TEs; 19 of the 50 patients (38%) had a fatal outcome [29]. Clinical trials have reported three TEs associated with rFVIIa in patients with AH (fatal cerebrovascular thrombosis in a 55-year-old male; cerebrovascular accident, bilateral deep vein thrombosis and pulmonary embolism in an 81-year-old male; and DIC in a 56-year-old female) [30]. All cases of cerebrovascular thrombosis or DIC in the clinical trials are thought to have resulted from various combinations of age, comorbid conditions and concomitant treatment with factor concentrates or pd-aPCC. "
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    ABSTRACT: Acquired haemophilia (AH) is a rare, often severe bleeding disorder characterised by autoantibodies to coagulation factor VIII (FVIII). Observational studies offer crucial insight into the disease and its treatment. Recombinant activated factor VII (rFVIIa, eptacog alfa activated) was available on an emergency and compassionate use basis from 1988 to 1999 at sites in Europe and North America. In 1996, rFVIIa was approved in Europe for the treatment of AH; it was licensed for this indication in the United States in 2006. Recombinant activated FVII is approved for first-line treatment of bleeding episodes and prevention of bleeding in surgical/invasive procedures in patients with AH. This review provides an up-to-date summary of the haemostatic efficacy of rFVIIa in patients with AH, from the first emergency and compassionate use programmes, to patient registries and a post-marketing surveillance study. In acute bleeding episodes, rFVIIa provided high and consistent rates of control, and available data showed that acute bleed control rates were higher for first-line rFVIIa versus salvage rFVIIa. In surgical procedures, rFVIIa also provided high rates of control. In patients with AH, rFVIIa has a high rate of haemostatic efficacy in acute and surgical bleeding episodes. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jun 2015 · Blood reviews
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    • "rFVIIa was first approved in Europe in 1996. It has proved to be an effective and safe therapeutic agent for the management of bleeding in hemophiliac patients with inhibitors, with adverse thrombotic events occurring in less than 1% of patients.28 Data collected in a database demonstrated that rFVIIa dosed in a range of less than or equal to 200 μg/kg had a bleeding cessation rate of 84% compared with 97% for those receiving over 200 μg/kg. "
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    ABSTRACT: In developing countries, the treatment of hemophilia patients with inhibitors is presently the most challenging and serious issue in hemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the health care of patients in this setting. In the setting of chronic diseases, cost-utility analysis, which takes into account the beneficial effects of a given treatment/health care intervention in terms of health-related quality of life, is likely to be the most appropriate approach. The aim of this study was to assess the incremental cost-effectiveness ratios of immune tolerance induction (ITI) therapy with plasma-derived factor VIII concentrates versus on-demand treatment with recombinant-activated FVIIa (rFVIIa) in hemophilia A with high titer inhibitors from an Iranian Ministry of Health perspective. This study was based on the study of Knight et al, which evaluated the cost- effectiveness ratios of different treatments for hemophilia A with high-responding inhibitors. To adapt Knight et al's results to the Iranian context, a few clinical parameters were varied, and cost data were replaced with the corresponding Iranian estimates of resource use. The time horizon of the analysis was 10 years. One-way sensitivity analyses were performed, varying the cost of the clotting factor, the drug dose, and the administration frequency, to test the robustness of the analysis. Comparison of the incremental cost-effectiveness ratios between the three ITI protocols and the on-demand regimen with rFVIIa shows that all three ITI protocols dominate the on-demand regimen with rFVIIa. Between the ITI protocols the low-dose ITI protocol dominates both the Bonn ITI protocol and the Malmö ITI protocol and would be the preferred ITI protocol. All of the three ITI protocols dominate the on-demand strategy, as they have both a lower average lifetime cost and higher quality-adjusted life-years (QALYs) gained. The cost per QALY gained for the Bonn ITI protocol compared with the Malmö ITI protocol was $249,391.84. The cost per QALY gained for the Bonn ITI protocol compared with the low-dose ITI protocol was $842,307.69. The results of data derived from our study suggest that the low-dose ITI protocol may be a less expensive and/or more cost-effective option compared with on-demand first-line treatment with rFVIIa.
    Full-text · Article · Nov 2011 · ClinicoEconomics and Outcomes Research
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    • "Identified published reports on parallel use of aPCC ( FEIBA ) and r - FVIIa ( NovoSeven ) . Diagnosis Case ( s ) Age ( years ) , sex aPCC / r - FVIIa infusions Doses administered Complication Reference HA + inhibitor haematomas 1 2 2# Sequential 90 lg / kg r - FVIIa / 2 h 75 iu / kg aPCC / 12 h PE Rosenfeld et al ( 2002 ) HA + inhibitor 1 26 # Sequential 84 lg / kg r - FVIIa aPCC dose unknown AMI Abshire and Kenet ( 2004 ) Acquired HA 1 57 $ Sequential 20 – 48 lg / kg r - FVIIa aPCC dose unknown DVT + PE Abshire and Kenet ( 2004 ) Acquired HB 1 70 # Sequential r - FVIIa dose unknown aPCC dose unknown DIC Abshire and Kenet ( 2004 ) Acquired HA 1 55 # Sequential 80 lg / kg r - FVIIa aPCC dose unknown Cerebral thrombosis Abshire and Kenet ( 2004 ) Acquired HA 1 56 $ Sequential r - FVIIa dose unknown aPCC dose unknown DIC Abshire and Kenet ( 2004 ) "
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    ABSTRACT: In the absence of new outbreaks of transfusion-related infections, the occurrence of neutralizing antibodies currently remains the most prominent complication in haemophilia. Coagulation factor products that may circumvent the inadequate activation of factor X in classical haemophilia, often referred to as bypassing agents, have demonstrated a high degree of efficacy. A smaller number of patients have been described in whom either bypassing agent, or both, demonstrate diminished efficacy. In those cases, the use of both bypassing agents in parallel was attempted, either using simultaneous (combined) or alternating (sequential) infusion of the two drugs, reportedly with successful haemostasis. We speculated whether such treatment might cause thromboembolism. A thorough literature search disclosed 17 reports regarding the parallel use of bypassing agents in the same bleeding episode in 49 patients; reporting nine patients with acquired haemophilia and forty patients with congenital haemophilia with inhibitors. Notable incidences of thromboembolic manifestations were observed: in nine patients with acquired haemophilia, five and in 40 patients with congenital haemophilia five suffered from significant thrombotic complications, and overall four cases were fatal. Although efficacy of parallel treatment was reported excellent in most cases, thromboembolism is rare in haemophilia and parallel treatment with activated prothrombin complex concentrate and activated recombinant human factor VII appears to increase the risk of thrombosis in these patients.
    Full-text · Article · Sep 2011 · British Journal of Haematology
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