Systematic review and analysis of efficacy of recombinant factor IX products for prophylactic treatment of hemophilia B in comparison with rIX-FP
Journal of medical economics. 2019;:1
AIMS: Prophylaxis with standard-acting recombinant factor IX (rFIX) in hemophilia B patients requires frequent injections. Extended half-life (EHL) products allow for prolonged dosing intervals and so reduce this treatment burden. Three technologies are employed to extend the half-life of FIX; glycopegylation, Fc-fusion, and albumin fusion. rIX-FP is a novel albumin fusion protein, which allows for a prolonged dosing interval of up to 14 days. A systematic review and indirect statistical comparison was performed to evaluate the efficacy of both EHL and standard-acting rFIX products compared with rIX-FP in Phase III trials for prophylaxis in adult hemophilia B patients. MATERIALS AND METHODS A systematic search was conducted in both EMBASE and PubMed to identify Phase III trials of prophylactic rFIX treatment in previously treated, hemophilia B patients aged ≥12 years (FIX: ≤2%). Annualized bleeding rate (ABR), spontaneous ABR (AsBR), and joint ABR (AjBR) data were extracted from each study. A z-test was performed using the mean of each parameter, and the mean difference in outcome between studies was calculated. RESULTS Seven articles investigating six rFIX products were identified. Median ABR, AsBR and AjBR ranged from 0-3.0, 0-1.0, and 0-1.1 (means 0.8-4.26, 0.13-2.6, and 0.34-2.85), respectively. rIX-FP achieved lowest median and mean values in all three parameters. Z-tests showed that mean ABR was significantly lower for rIX-FP 7-day prophylaxis compared with the majority of standard-acting and other EHL rFIX products. LIMITATIONS The low number of appropriate trials available for comparison limits the quantity of data available for comparison and restricts the use of methods of adjustment for variance in study design or patient characteristics. However, these limitations are shared with similar analyses published in this field. CONCLUSION This indirect comparison of Phase III trials indicates that rIX-FP efficacy compares favorably versus other rFIX products for prophylaxis in hemophilia B.
Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity
Journal of Thrombosis & Haemostasis. 2015;13((11)):1989-98.
BACKGROUND Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double-blind, crossover, confirmatory phase III trial (adept(TM) 2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti-drug antibodies (ADAs) to vatreptacog alfa. OBJECTIVES To characterize the formation of anti-vatreptacog alfa ADAs in hemophilia patients with inhibitors. METHODS/PATIENTS This was a post hoc analysis of adept(TM) 2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross-reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs. RESULTS Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow-up evaluation, the rFVIIa cross-reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care. CONCLUSIONS Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.Copyright © 2015 International Society on Thrombosis and Haemostasis.
Recombinant factor VIIa analog in the management of hemophilia with inhibitors: results from a multicenter, randomized, controlled trial of vatreptacog alfa
Journal of Thrombosis & Haemostasis. 2014;12((8):):1244-53.
BACKGROUND Vatreptacog alfa, a recombinant factor VIIa (rFVIIa) analog with three amino acid substitutions and 99% identity to native FVIIa, was developed to improve the treatment of hemophilic patients with inhibitors. OBJECTIVES To confirm the safety and assess the efficacy of vatreptacog alfa in treating bleeding episodes in hemophilic patients with inhibitors. PATIENTS AND METHODS In this international, multicenter, randomized, double-blind, active-controlled, crossover, confirmatory phase III trial (adept() 2) in patients with hemophilia A or B and inhibitors, bleeds were randomized 3 : 2 to treatment with vatreptacog alfa (one to three doses at 80 mug kg(-1) ) or rFVIIa (one to three doses at 90 mug kg(-1) ). Treatment failures after three doses of trial product (TP) were managed according to the local standard of care. RESULTS In the 72 patients enrolled, 567 bleeds were treated with TP. Both vatreptacog alfa and rFVIIa gave 93% effective bleeding control at 12 h. Vatreptacog alfa was superior to rFVIIa in secondary efficacy outcomes, including the number of doses used to treat a bleed and sustained bleeding control 24-48 h after the first dose. Eight patients (11%) developed antibodies against vatreptacog alfa, including four with cross-reactivity against rFVIIa and one with an in vitro neutralizing effect to vatreptacog alfa. CONCLUSIONS This large randomized controlled trial confirmed the well-established efficacy and safety profile of rFVIIa, and showed that vatreptacog alfa had similar or better efficacy than rFVIIa. However, because of the development of anti-drug antibodies, a positive benefit-risk profile is unlikely to be achieved with vatreptacog alfa. 2014 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.
Anti-drug antibody formation induced by recombinant activated FVII analogue (vatreptacog alfa) results from the phase 3 adept 2 trial in haemophilia patients with inhibitors
Journal of Thrombosis and Haemostasis. 2013;11((S2):):268. Abstract No. OC 83.5.
Intra-articular injection of tranexamic acid reduces not only blood loss but also knee joint swelling after total knee arthroplasty
International Orthopaedics. 2011;35((11):):1639-45.
PURPOSE This is a randomised controlled trial to examine whether intra-articular injection of tranexamic acid (TXA) decreases blood loss, as well as reducing leg swelling after total knee arthroplasty (TKA). METHODS We performed 100 TKA in osteoarthritis patients. At closure, a total of 2,000 mg/20 ml TXA was injected into the knee joint through a closed suction drain (TXA group). For the control group, the same volume of physiological saline was injected. The pre-operative condition of the patients, post-operative haemoglobin (Hb) levels, discharge volumes from drain, D-dimer and needs for transfusion were compared between these two groups. Furthermore, leg diameters (thigh, suprapatellar portion and calf girth) were measured pre- and post-operatively to investigate whether TXA has an influence on leg swelling after surgery. RESULTS The results revealed that post-operative decrease in Hb level was significantly reduced in the TXA group. Furthermore, knee joint swelling after operation was significantly suppressed in the TXA group compared to the control group. CONCLUSIONS The results revealed intra-articular administration of TXA decreased not only blood loss, but also knee joint swelling after TKA.
Drainage does not increase anemia after cementless total hip arthroplasty
Clinical Orthopaedics and Related Research. 2007;458:101-5.
We performed a prospective randomized controlled study to determine whether drainage increased the degree of anemia after primary cementless total hip arthroplasty. After implanting the components, we randomly divided 40 patients (40 hips) into a group who had drains (20 patients, 20 hips) and a group without drains (20 patients, 20 hips). There were no differences in the mean preoperative hemoglobin or hematocrit values, length of skin incision, operative time, intraoperative blood loss, or the donated and transfused volumes of autologous blood between the two groups. There were also no differences in decreased hemoglobin or hematocrit values 3 days postoperatively compared with preoperative values (hemoglobin, 0. 7 g/dL versus 0. 7 g/dL; hematocrit, 2. 2% versus 2. 4%). Drainage did not increase the degree of postoperative anemia after cementless total hip arthroplasty.