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• W2892811509 abstract "SummaryBypassing agents are presently the standard of care for the treatment of bleeding episodes in patients with hemophilia and high‐titer inhibitors and are also used for bleed prevention. Only two bypassing agents are available to patients, and these products trace their lineage to the 1970s (activated prothrombin complex concentrates) and the 1980s (recombinant factor VIIa). Given the limited repertoire of available products, clinicians have relied on experience, empirical observation, registry data and individualized care to improve clinical outcomes on a case‐by‐case basis. Research over the past two decades has culminated in a greatly improved understanding of human coagulation; resulting from this, new products have been developed that offer treatment options and mechanisms of actions that differ from current bypassing agents. The most advanced in clinical development is emicizumab, a bispecific antibody that mimics the function of FVIIIa in the intrinsic Xase complex and is indicated for once‐weekly or every‐other‐week prophylactic dosing in inhibitor patients. Other non‐traditional products in clinical development include fitusiran and antibodies directed against tissue factor pathway inhibitor. As non‐factor‐based therapies become more widely utilized over time, the use of bypassing agents may be expected to decrease; however, bypassing agents will remain essential for the foreseeable future. As such, clinical development of bypassing agents continues, with some products (e.g. eptacog beta) under regulatory review. In this review we examine the optimal use of bypassing agents and their mechanism of action. We also discuss newer products and how these might theoretically be administered in conjunction with traditional bypassing agents. Bypassing agents are presently the standard of care for the treatment of bleeding episodes in patients with hemophilia and high‐titer inhibitors and are also used for bleed prevention. Only two bypassing agents are available to patients, and these products trace their lineage to the 1970s (activated prothrombin complex concentrates) and the 1980s (recombinant factor VIIa). Given the limited repertoire of available products, clinicians have relied on experience, empirical observation, registry data and individualized care to improve clinical outcomes on a case‐by‐case basis. Research over the past two decades has culminated in a greatly improved understanding of human coagulation; resulting from this, new products have been developed that offer treatment options and mechanisms of actions that differ from current bypassing agents. The most advanced in clinical development is emicizumab, a bispecific antibody that mimics the function of FVIIIa in the intrinsic Xase complex and is indicated for once‐weekly or every‐other‐week prophylactic dosing in inhibitor patients. Other non‐traditional products in clinical development include fitusiran and antibodies directed against tissue factor pathway inhibitor. As non‐factor‐based therapies become more widely utilized over time, the use of bypassing agents may be expected to decrease; however, bypassing agents will remain essential for the foreseeable future. As such, clinical development of bypassing agents continues, with some products (e.g. eptacog beta) under regulatory review. In this review we examine the optimal use of bypassing agents and their mechanism of action. We also discuss newer products and how these might theoretically be administered in conjunction with traditional bypassing agents. Bypassing agents have been the primary therapeutic option for hemophilia patients with high responding inhibitors (titers ≥ 5.0 Bethesda Units) for many years. Although greatly superior to earlier therapies such as plasmapheresis, bypassing agents have been associated with inconsistent predictability since the earliest uses of prothrombin complex concentrates (PCC), activated PCC (APCC) and recombinant factor VIIa (rFVIIa) 1.Buchanan G.R. Kevy S.V. Glader B.E. Use of prothrombin complex concentrates (PCC) in hemophiliacs with inhibitors: Lack of correlation between clinical response and laboratory parameters.Pediatr Res. 1977; 11: 468Google Scholar, 2.Aledort L. Inhibitors in hemophilia patients: current status and management.Am J Hematol. 1994; 47: 208-17Crossref PubMed Scopus (83) Google Scholar. Although often attributed to the bypassing agent itself, this lack of predictability may arise from a combination of patient‐ and treatment‐specific influences, including the heterogeneity of bleeding events, time to treatment, individual patient response, lack of familiarity in their use, and under‐dosing for fear of thrombotic side‐effects. Although therapies for hemophilia have expanded in recent years, treatment options for inhibitor patients were virtually stable for almost two decades. During this period clinicians achieved greatly improved clinical outcomes through empirical observation, reviews of registry data, and investigations into the biological mechanism of action of bypassing agents. Gene therapy has shown rapid advances in non‐inhibitor hemophilia patients; as yet, patients with inhibitors are not eligible for these protocols. For inhibitor patients, mechanism of action‐based research has led to new prospective clinical studies with promising outcomes, with the recent approval of the first non‐factor‐based therapy, emicizumab‐kxwh (Hemlibra®, Roche, Basel, Switzerland) being a clear example. As we enter an era of improved therapeutics for inhibitor patients, the use of traditional bypassing agents may be expected to decrease; yet they will remain a necessity for the treatment of breakthrough bleeds in hemophilia A with inhibitors, and as the mainstay of treatment in patients with hemophilia B with inhibitors until novel agents applicable to this population also become available 3.Wang M. Lawrence J.B. Quon D.V. Ducore J. Simpson M.L. Boggio L.N. Mitchell I.S. Yuan G. Alexander W.A. Schved J.F. PERSEPT 1: a phase 3 trial of activated eptacog beta for on‐demand treatment of haemophilia inhibitor‐related bleeding.Haemophilia. 2017; 23: 832-43Crossref PubMed Scopus (18) Google Scholar. This review focuses on our understanding of the mechanism of action and the optimal use of traditional bypassing agents. The pipeline of potentially transformative products currently being developed will be reviewed along with a discussion of how these agents and traditional bypassing agents might theoretically be administered together. Twenty years ago, it was common for inhibitor‐related bleeding events to be prolonged. Today, clinicians are able to individualize and optimize bypassing agent therapies to achieve rapid bleed control in most circumstances, despite the lack of clinically validated assays to determine hemostatic status (recently, techniques such as thromboelastography, which measure changes in the viscoelasticity of blood during clot formation, have shown potential for clinical use 4.Chitlur M. Rivard G.E. Lillicrap D. Mann K. Shima M. Young G. Factor VIII, Factor IX, and Rare Coagulation Disorders Subcommittee of the Scientific and Standardisation Committee of the International Society on Thrombosis and HaemostasisRecommendations for performing thromboelastography/thromboelastometry in hemophilia: communication from the SSC of the ISTH.J Thromb Haemost. 2014; 12: 103-6Crossref PubMed Scopus (62) Google Scholar, 5.Qi X. Zhao Y. Li K. Fan L. Hua B. Evaluating and monitoring the efficacy of recombinant activated factor VIIa in patients with haemophilia and inhibitors.Blood Coagul Fibrinolysis. 2014; 25: 754-60Crossref PubMed Scopus (16) Google Scholar). Currently, bleeding is viewed as a time‐sensitive and volume‐dependent pathologic continuum. This time period can be viewed as comprised of three intervals: time from bleed onset to recognition, time from recognition to initiation of treatment, and time from initiation of treatment to clinical response. The first interval is dependent on patient education and a variety of other issues, including arthritis or associated injury. The second is dependent on patient education, sense of urgency and access to therapy. The third may be dependent on the severity of the bleed or associated injury, product and dose utilized, and individual response. The treatment goals of early recognition, prompt initiation of therapy and rapid bleed control are essential to limit immediate and long‐term sequelae. The healthcare cost of inhibitor patients is high and may limit access to therapy. An analysis by Earnshaw et al. in 2014 estimated the lifetime drug and hospitalization cost at over $43 million/patient for a prophylactic bypassing agent regimen in the USA ($613 000 per year), a figure that reflects high drug cost, the number of bleeding episodes and the anticipated hospitalizations and surgeries. On‐demand treatment was estimated to incur over $21 million in lifetime costs, albeit with a reduced quality of life compared with prophylaxis 6.Earnshaw S.R. Graham C.N. McDade C.L. Spears J.B. Kessler C.M. Factor VIII alloantibody inhibitors: cost analysis of immune tolerance induction vs. prophylaxis and on‐demand with bypass treatment.Haemophilia. 2015; 21: 310-9Crossref PubMed Scopus (37) Google Scholar. APCC (FEIBA®, anti‐inhibitor coagulant complex, Shire, Dublin, Ireland) is a plasma‐derived bypassing agent comprising multiple zymogens and activated coagulation factors. Its efficacy is primarily driven by prothrombin and activated factor X (FXa), with other components such as FVIIa playing a complementary role in its hemostatic effect 7.Negrier C. Gomperts E.D. Oldenburg J. The history of FEIBA: a lifetime of success in the treatment of haemophilia complicated by an inhibitor.Haemophilia. 2006; 12: 4-13Crossref Scopus (23) Google Scholar. Zymogen accumulation may occur with repeated use; for example, prothrombin has a half‐life of ~72 h. Because of the potential risk of thrombotic complications, a maximum daily dose of 200 U kg−1 is recommended, with individual doses ranging from 50 to 100 U kg−1 every 6 or 12 h, depending on the type of bleed. The volume and duration of APCC infusion have an impact on use: the US DOSE study indicated the mean preparation and administration times were 23.2 and 30.8 min, respectively, the latter matching the manufacturer's recommendations 8.Maahs J. Donkin J. Recht M. Cooper D.L. Mixing and administration times of bypassing agents: observations from the Dosing Observational Study in Hemophilia (DOSE).J Blood Med. 2014; 5: 153-6Crossref PubMed Google Scholar. Interestingly, the predominantly European‐based FEIBA® PASS observational study reported mean infusion rates to be twice that recommended by regulatory agencies, with the highest infusion rate being 12 times the maximum recommended rate of 2 U kg−1 min−1 9.Negrier C. Voisin S. Baghaei F. Numerof R. Novack A. Doralt J.E. Romanov V. Gringeri A. FEIBA PASS Study GroupGlobal Post‐Authorization Safety Surveillance Study: real‐world data on prophylaxis and on‐demand treatment using FEIBA (an activated prothrombin complex concentrate).Blood Coagul Fibrinolysis. 2016; 27: 551-6Crossref PubMed Scopus (8) Google Scholar. These accelerated infusion rates were not reported to be associated with systemic manifestations or other adverse events such as thrombotic complications; however, systemic reactions have previously been reported with increased infusion rates 10.Hilgartner M. Knatterud G. The use of factor eight inhibitor by‐passing activity (FEIBA immuno) product for treatment of bleeding episodes in hemophiliacs with inhibitors.Blood. 1983; 61: 36-40Crossref PubMed Google Scholar. A prospective clinical study to examine reduced infusion volumes and accelerated infusion times with FEIBA® is anticipated to begin in 2018 11.Shire. FEIBA Reconstitution Volume Reduction and Faster Infusion Study (FEIBA STAR). 2017. Available from: http://www.shiretrials.com/sitecore/content/studies/clinicaltrialsen/2017/11/21/10/36/091501?sc_lang=en. Accessed 12 February 2018.Google Scholar. Recombinant FVIIa (NovoSeven®, eptacog alfa, Novo Nordisk, Bagsværd, Denmark) activates the extrinsic coagulation pathway, bypassing the need for factor VIII (FVIII) or factor IX (FIX); a typical dose can boost FVIIa plasma levels > 100‐fold above normal. rFVIIa was initially licensed for use at 90 μg kg−1 administered every 2 h until hemostasis was achieved; however, doses of ~270 μg kg−1 have been utilized in clinical practice, with reports of increased response rates and convenience as a result of longer intervals between infusions. Administration of higher doses of rFVIIa may result in an increased thrombin burst and improved bleed control 12.Young G. Shafer F.E. Rojas P. Seremetis S. Single 270 microg kg(‐1)‐dose rFVIIa vs. standard 90 microg kg(‐1)‐dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison.Haemophilia. 2008; 14: 287-94Crossref PubMed Scopus (139) Google Scholar. Observational studies lacking statistical significance have supported this concept 13.Pan‐Petesch B. Laguna P. Mital A. Stanley J. Torchet M.F. Salek S.Z. Salaj P. Single‐dose (270 microg kg(‐1)) recombinant activated factor VII for the treatment and prevention of bleeds in haemophilia A patients with inhibitors: experience from seven European haemophilia centres.Haemophilia. 2009; 15: 760-5Crossref PubMed Scopus (17) Google Scholar, 14.Salaj P. Brabec P. Penka M. Pohlreichova V. Smejkal P. Cetkovsky P. Dusek L. Hedner U. Effect of rFVIIa dose and time to treatment on patients with haemophilia and inhibitors: analysis of HemoRec registry data from the Czech Republic.Haemophilia. 2009; 15: 752-9Crossref PubMed Scopus (65) Google Scholar; however, prospective clinical studies with eptacog alfa (NovoSeven®) have not demonstrated increased efficacy with a high dose compared to a regimen of multiple smaller doses 12.Young G. Shafer F.E. Rojas P. Seremetis S. Single 270 microg kg(‐1)‐dose rFVIIa vs. standard 90 microg kg(‐1)‐dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison.Haemophilia. 2008; 14: 287-94Crossref PubMed Scopus (139) Google Scholar, 15.Kavakli K. Makris M. Zulfikar B. Erhardtsen E. Abrams Z.S. Kenet G. Novoseven Trial (F7HAEM‐1510) InvestigatorsHome treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi‐centre, randomised, double‐blind, cross‐over trial.Thromb Haemost. 2006; 95: 600-5Crossref PubMed Scopus (141) Google Scholar, 16.Santagostino E. Mancuso M.E. Rocino A. Mancuso G. Scaraggi F. Mannucci P.M. A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors.J Thromb Haemost. 2006; 4: 367-71Crossref PubMed Scopus (148) Google Scholar. Instead, one 270 μg kg−1 dose has been shown to be roughly comparable to three sequential 90 μg kg−1 doses administered at 3‐h intervals. These higher doses have repeatedly been shown to be safe, and the risk of thrombosis in inhibitor patients lacking thrombotic risk factors is low 17.Neufeld E.J. Negrier C. Arkhammar P. Benchikh el Fegoun S. Simonsen M.D. Rosholm A. Seremetis S. Safety update on the use of recombinant activated factor VII in approved indications.Blood Rev. 2015; 29: S34-41Crossref PubMed Scopus (45) Google Scholar; experience in elderly patients is limited. Despite the lack of statistically significant data showing improved efficacy with higher doses, rFVIIa is indicated for use at both 90 and 270 μg kg−1 in the EU (European Union), with the higher dose being recommended in certain circumstances 18.Sorensen B. Dargaud Y. Kenet G. Lusher J. Mumford A. Pipe S. Tiede A. On‐demand treatment of bleeds in haemophilia patients with inhibitors: strategies for securing and maintaining predictable efficacy with recombinant activated factor VII.Haemophilia. 2012; 18: 255-62Crossref PubMed Scopus (14) Google Scholar; in the USA and Canada, licensure is limited to 90 μg kg−1 dosed every 2 h. Compared with APCC, rFVIIa has shorter mean preparation and administration times (6.5 and 5.7 min, respectively) 8.Maahs J. Donkin J. Recht M. Cooper D.L. Mixing and administration times of bypassing agents: observations from the Dosing Observational Study in Hemophilia (DOSE).J Blood Med. 2014; 5: 153-6Crossref PubMed Google Scholar. A Bayesian meta‐regression model using data from over 2000 published bleeding events predicted greater efficacy for rFVIIa (66% at 12 h, 88% at 24 h and 95% at 36 h) compared with APCC (39% at 12 h, 62% at 24 h and 76% at 36 h) 19.Treur M.J. McCracken F. Heeg B. Joshi A.V. Botteman M.F. De C.h.a.r.r.o. .F. Van H.o.u.t. .B. Efficacy of recombinant activated factor VII vs. activated prothrombin complex concentrate for patients suffering from haemophilia complicated with inhibitors: a Bayesian meta‐regression.Haemophilia. 2009; 15: 420-36Crossref PubMed Scopus (38) Google Scholar; however, a controlled head‐to‐head comparison in the FENOC study showed similar overall efficacy between the two products, although the regimens studied are not necessarily reflective of the current standard of care 20.Astermark J. Donfield S.M. DiMichele D.M. Gringeri A. Gilbert S.A. Waters J. Berntorp E. FENOC Study GroupA randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study.Blood. 2007; 109: 546-51Crossref PubMed Scopus (357) Google Scholar. During the development of the rFVIIa variant eptacog beta (LFB, Les Ulis, France/HEMA Biologics, Louisville, KY, USA), the long‐theorized clinical dose‐dependence was observed: a statistically significant improvement in efficacy was noted when the product was administered at a higher initial dose compared with the same cumulative dose administered as multiple smaller infusions 3.Wang M. Lawrence J.B. Quon D.V. Ducore J. Simpson M.L. Boggio L.N. Mitchell I.S. Yuan G. Alexander W.A. Schved J.F. PERSEPT 1: a phase 3 trial of activated eptacog beta for on‐demand treatment of haemophilia inhibitor‐related bleeding.Haemophilia. 2017; 23: 832-43Crossref PubMed Scopus (18) Google Scholar, 21.Ducore J. Lawrence J.B. Simpson M. Boggio L. Bellon A. Burggraaf J. Stevens J. Moerland M. Frieling J. Reijers J. Wang M. Safety and dose‐dependency of eptacog beta (activated) in a dose escalation study of non‐bleeding congenital haemophilia A or B patients, with or without inhibitors.Haemophilia. 2017; 23: 844-51Crossref PubMed Scopus (12) Google Scholar. It was also shown that the majority of bleeding events (85%) could be successfully treated with a single 225‐μg kg−1 dose, whereas lower doses (75 μg kg−1) required multiple treatments and a longer treatment time to achieve the same rate of hemostatic success 3.Wang M. Lawrence J.B. Quon D.V. Ducore J. Simpson M.L. Boggio L.N. Mitchell I.S. Yuan G. Alexander W.A. Schved J.F. PERSEPT 1: a phase 3 trial of activated eptacog beta for on‐demand treatment of haemophilia inhibitor‐related bleeding.Haemophilia. 2017; 23: 832-43Crossref PubMed Scopus (18) Google Scholar. These observations align with the current treatment goal of rapid hemostasis. Patients may have an improved response to one bypassing agent compared with the other, and this response may change over time, including during the course of a single hemorrhage 20.Astermark J. Donfield S.M. DiMichele D.M. Gringeri A. Gilbert S.A. Waters J. Berntorp E. FENOC Study GroupA randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study.Blood. 2007; 109: 546-51Crossref PubMed Scopus (357) Google Scholar, 22.Hayashi T. Tanaka I. Shima M. Yoshida K. Fukuda K. Sakurai Y. Matsumoto T. Giddings J.C. Yoshioka A. Unresponsiveness to factor VIII inhibitor bypassing agents during haemostatic treatment for life‐threatening massive bleeding in a patient with haemophilia A and a high responding inhibitor.Haemophilia. 2004; 10: 397-400Crossref PubMed Scopus (56) Google Scholar. In addition, 10–20% of bleeding events may not be effectively controlled with either APCC or rFVIIa 23.Gringeri A. Fischer K. Karafoulidou A. Klamroth R. Lopez‐Fernandez M.F. Mancuso E. Sequential combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with haemophilia and inhibitors.Haemophilia. 2011; 17: 630-5Crossref PubMed Scopus (50) Google Scholar. In hospitalized patients, some unresponsive severe bleeds have been successfully treated with sequential dosing of both APCC and rFVIIa. Gringeri et al. reported 11 cases of unresponsive hemorrhage, which when treated with a sequential APCC/rFVIIa regimen, resulted in bleed control within 12–24 h in all cases 23.Gringeri A. Fischer K. Karafoulidou A. Klamroth R. Lopez‐Fernandez M.F. Mancuso E. Sequential combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with haemophilia and inhibitors.Haemophilia. 2011; 17: 630-5Crossref PubMed Scopus (50) Google Scholar. No clinical signs of thrombosis were noted, although D‐dimer levels were elevated in several subjects. Other clinicians have noted similar results 24.Schneiderman J. Rubin E. Nugent D.J. Young G. Sequential therapy with activated prothrombin complex concentrates and recombinant FVIIa in patients with severe haemophilia and inhibitors: update of our previous experience.Haemophilia. 2007; 13: 244-8Crossref PubMed Scopus (93) Google Scholar, 25.Key N.S. Christie B. Henderson N. Nelsestuen G.L. Possible synergy between recombinant factor VIIa and prothrombin complex concentrate in hemophilia therapy.Thromb Haemost. 2002; 88: 60-5Crossref PubMed Scopus (60) Google Scholar; however, severe complications such as pulmonary embolism have been reported, highlighting the need for caution if both products are administered 26.Rosenfeld S.B. Watkinson K.K. Thompson B.H. Macfarlane D.E. Lentz S.R. Pulmonary embolism after sequential use of recombinant factor VIIa and activated prothrombin complex concentrate in a factor VIII inhibitor patient.Thromb Haemost. 2002; 87: 925-6Crossref PubMed Scopus (56) Google Scholar. Sequential APCC/rFVIIa therapy requires close clinical monitoring by knowledgeable care providers because of the increased risk of thrombotic events; it is not considered an outpatient therapy. Both APCC and rFVIIa are utilized in prophylactic regimens to suppress development of bleeding events. A variety of dosing regimens have been reported: rFVIIa is most commonly administered daily; dosing with APCC varies but is typically administered three to five times a week, depending on the patient. Studies examining rFVIIa (PRO‐PACT) and APCC (PRO‐FEIBA) support the prophylactic use of these agents, with subjects experiencing fewer bleeding events and an increase in health‐related quality of life 27.Young G. Auerswald G. Jimenez‐Yuste V. Lambert T. Morfini M. Santagostino E. Blanchette V. PRO‐PACT: retrospective observational study on the prophylactic use of recombinant factor VIIa in hemophilia patients with inhibitors.Thromb Res. 2012; 130: 864-70Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 28.Stasyshyn O. Antunes S. Mamonov V. Ye X. Epstein J. Xiong Y. Tangada S. 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: 644-50Crossref PubMed Scopus (25) Google Scholar, 29.Leissinger C. Gringeri A. Antmen B. Berntorp E. Biasoli C. Carpenter S. Cortesi P. Jo H. Kavakli K. Lassila R. Morfini M. Négrier C. Rocino A. Schramm W. Serban M. Uscatescu M.V. Windyga J. Zülfikar B. Mantovani L. Anti‐inhibitor coagulant complex prophylaxis in hemophilia with inhibitors.N Engl J Med. 2011; 365: 1684-92Crossref PubMed Scopus (181) Google Scholar, 30.Hoots W.K. Ebbesen L.S. Konkle B.A. Auerswald G.K. Roberts H.R. Weatherall J. Ferran J.M. Ljung R.C. Novoseven I. Secondary prophylaxis with recombinant activated factor VII improves health‐related quality of life of haemophilia patients with inhibitors.Haemophilia. 2008; 14: 466-75Crossref PubMed Scopus (73) Google Scholar, 31.Konkle B.A. Ebbesen L.S. Erhardtsen E. Bianco R.P. Lissitchkov T. Rusen L. Serban M.A. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors.J Thromb Haemost. 2007; 5: 1904-13Crossref PubMed Scopus (284) Google Scholar. The role of APCC prophylaxis in slowing or preventing joint damage is patient and joint dependent: one study suggested that APCC prophylaxis might prevent joint damage or slow its progression, whereas others have shown that APCC prophylaxis cannot prevent arthropathic progression where pre‐existing joint damage exists 32.Hilgartner M.W. Makipernaa A. Dimichele D.M. Long‐term FEIBA prophylaxis does not prevent progression of existing joint disease.Haemophilia. 2003; 9: 261-8Crossref PubMed Scopus (71) Google Scholar, 33.Ewing N. Escuriola‐Ettingshausen C. Kreuz W. Prophylaxis with FEIBA in paediatric patients with haemophilia A and inhibitors.Haemophilia. 2015; 21: 358-64Crossref PubMed Scopus (18) Google Scholar, 34.Dimichele D. Negrier C. A retrospective postlicensure survey of FEIBA efficacy and safety.Haemophilia. 2006; 12: 352-62Crossref PubMed Scopus (103) Google Scholar, 35.Leissinger C.A. Becton D.L. Ewing N.P. Valentino L.A. 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: 249-55Crossref PubMed Scopus (58) Google Scholar. No comparable long‐term studies have been reported for rFVIIa. Regardless, prophylaxis results in a decreased incidence of bleeding events, an improvement in quality of life and probably can contribute to a decreased rate of progression of joint disease if bleeding patterns are positively impacted. Early treatment has implications beyond management of acute symptoms, including pain, swelling and decreased mobility; early treatment and bleed control impact development of long‐term sequelae, including target joint development and ultimately arthropathy. Clinical data to support the importance of early treatment with FVIIa were first reported in 1993 by Verroust et al. based on results from 220 bleeding events treated with Acset® (LFB), a plasma‐derived FVIIa concentrate 36.Verroust F. Laurian Y. Chabbat J. Larrieu M. Three year experience with plasma derived factor VIIa concentrate.in: Rivat C Stoltz J‐F Biotechnology of Blood Proteins. John Libbey Eurotext, Montrouge1993: 131-3Google Scholar. Lusher confirmed this observation for rFVIIa: the compassionate use program showed an overall efficacy of 63% (mean 5 days to treatment; 13.6 infusions/bleeding event); the dose‐finding study reported an efficacy of 72% (mean 9 h to treatment; 3.6 infusions/bleeding event); and the US home‐treatment study reported an efficacy of 92% (mean 1.2 h to treatment; 2.3 infusions/bleeding event) 37.Lusher J.M. Early treatment with recombinant factor VIIa results in greater efficacy with less product.Eur J Haematol Suppl. 1998; 63: 7-10PubMed Google Scholar. As our scientific understanding of the long‐term consequences of poorly controlled bleeding into joints has improved, the concept of early initial treatment, optimally within 1 h, has been emphasized 18.Sorensen B. Dargaud Y. Kenet G. Lusher J. Mumford A. Pipe S. Tiede A. On‐demand treatment of bleeds in haemophilia patients with inhibitors: strategies for securing and maintaining predictable efficacy with recombinant activated factor VII.Haemophilia. 2012; 18: 255-62Crossref PubMed Scopus (14) Google Scholar. The advantages of early treatment include: improved efficacy, as confirmed in the prospective WIRK study by Birschmann et al. 38.Birschmann I. Klamroth R. Eichler H. Schenk J. Kirchmaier C.M. Halimeh S. Results of the WIRK prospective, non‐interventional observational study of recombinant activated factor VII (rFVIIa) in patients with congenital haemophilia with inhibitors and other bleeding disorders.Haemophilia. 2013; 19: 679-85Crossref PubMed Scopus (16) Google Scholar; reduced rebleeding events, as reported by Salaj et al. 14.Salaj P. Brabec P. Penka M. Pohlreichova V. Smejkal P. Cetkovsky P. Dusek L. Hedner U. Effect of rFVIIa dose and time to treatment on patients with haemophilia and inhibitors: analysis of HemoRec registry data from the Czech Republic.Haemophilia. 2009; 15: 752-9Crossref PubMed Scopus (65) Google Scholar; and decreased overall cost, as noted by Kavakli et al. 39.Kavakli K. Yesilipek A. Antmen B. Aksu S. Balkan C. Yilmaz D. Kupesiz A. Sasmaz I. Lindgren P. Mesterton J. The value of early treatment in patients with haemophilia and inhibitors.Haemophilia. 2010; 16: 487-94PubMed Google Scholar. The improved efficacy and reduced rebleeding offered by early treatment directly impact the development and long‐term progression of arthropathy. The goal of a more potent and/or longer‐acting rFVIIa variant to reduce dosing and improve patient outcomes dates back almost 20 years 40.Persson E. Kjalke M. Olsen O.H. Rational design of coagulation factor VIIa variants with substantially increased intrinsic activity.Proc Natl Acad Sci U S A. 2001; 98: 13583-8Crossref PubMed Scopus (114) Google Scholar. Advances in biotechnology, along with an improved understanding of the mechanism of action of rFVIIa, have guided the development of new variants, each with unique pharmacokinetic properties and different binding affinities for tissue factor (TF), platelets and endothelial protein C receptor (EPCR). The cell‐based model of coagulation 41.Hoffman M. A cel" @default.
• W2892811509 created "2018-10-05" @default.
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• W2892811509 date "2018-12-01" @default.
• W2892811509 modified "2023-09-30" @default.
• W2892811509 title "The future of bypassing agents for hemophilia with inhibitors in the era of novel agents" @default.
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