Diagnosis and treatment challenges in lower resource countries: State-of-the-art.

The 2022 World Federation of Haemophilia Annual Global Survey (AGS) reports that 454,690 patients with inherited bleeding disorders (IBD) have been identified globally. While this represents noteworthy progress, haemophilia epidemiology data indicate that 75% of people with inherited bleeding disorders living in low-income and low-to-middle-income countries have yet to be diagnosed. The AGS also revealed that 11 billion clotting factor units are available to treat haemophilia A and B globally. Due to a lack of finance, these treatments are unavailable to haemophilia in low-income countries with a consequence lack of access equity for haemophilia treatment in these communities. This sobering reality is not limited to haemophilia but applies to von Willebrand Disease (VWD). While VWD is the most prevalent IBD, only 103,844 people living with this condition have been diagnosed globally. Of the diagnosed patients, only a fraction live in low- or middle-income countries. Moreover, the majority of VWD patients are still treated sub-optimally without replacement therapies or prophylaxis, both of which are now accepted as global standards of care. In this state-of-the-art review, the authors reflect on three issues. First, the minimum elements required to diagnose haemophilia in a resource-constrained setting are identified. Second, this review points to the critical stakeholders and outlines their roles in removing access to haemophilia treatment barriers. Finally, the authors examine von Willebrand disease's ongoing diagnostic and treatment challenges and compare these to haemophilia. With the rapidly evolving novel therapies, the therapeutic landscape of all IBD will likely change for the better.

Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study.

BACKGROUND: Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. OBJECTIVES: This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. METHODS: Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. RESULTS: In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). CONCLUSION: Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.

Advances and challenges in the purification of recombinant coagulation factors: A review.

Hemostasis is a complex process for the cessation of bleeding from an injured blood vessel, involving the interplay of 12 coagulation factors in the coagulation cascade with activated blood platelets and the vessel wall. Hence, the coagulation factors are important to control hemorrhage. However, the low abundance of many coagulation factors in human plasma proteins limited their production in therapeutic drugs and their clinical applications. With the development of modern biotechnology, commercially manufactured recombinant coagulation factors became available as hemostatic therapeutics, emerging a huge potential in pharmaceutical manufacturing market. Unlike antibodies, whose standard operation unit or platform purification processes in the industrial-scale downstream processing has been well-established, the complexity in post-translational modification and differences in structures of the coagulation factors posed specific challenges with respect to the downstream processing, which have long been limiting their industrial-scale production. This review presents a comprehensive overview of the technological development of commercially manufactured recombinant coagulation factors, with emphasis on their advances and challenges in the separation and purification processes. Firstly, the licensed products of the plasma derived and recombinant coagulation factors are summarized. Then, typical recombinant coagulation factors, i.e. factors VII, VIII and IX, are introduced with detailed discussion on their preparative separation procedures for both the licensed products of industrial-scale and the experimental cases of laboratory-scale. Finally, perspectives and challenges in the future development of the purification technology of recombinant coagulation factors are highlighted to provide new insight into the design of cost-effective purification processes of recombinant coagulation factors.

Valoctocogene roxaparvovec (ROCTAVIANTM) para adultos con hemofilia A severa / Valoctocogene roxaparvovec (ROCTAVIANTM) for adults with severe hemophilia A

INTRODUCCIÓN: La hemofilia A (deficiencia de factor VIII [factor 8]) y la hemofilia B (deficiencia de factor IX [factor 9]) son trastornos del factor de coagulación ligados al cromosoma X asociados con sangrado de gravedad variable, desde potencialmente mortal hasta clínicamente asintomático. Tanto el factor VIII como el IX contribuyen a la hemostasia secundaria (formación de un coágulo de fibrina) a través de su papel en el complejo X-asa de la vía intrínseca, que activa el factor X. 1 Se estima que la hemofilia afecta a más de 1,2 millones de personas en todo el Mundo, donde la mayoría de estos casos son hombres y la hemofilia A es más común que la hemofilia B. La hemofilia A tiene una incidencia de aproximadamente 1 cada 4.000 a 10.000 nacimientos de varones vivos, y aproximadamente de la mitad a dos tercios tienen una enfermedad severa. En Argentina, se desconoce la prevalencia real de la hemofilia A y se encuentra dentro del listado de enfermedades poco frecuentes reconocidas por el Ministerio de Salud Nacional (ORPHACODE 98878). El manejo de las personas con hemofilia tiene el objetivo de mejorar la salud y la calidad de vida de los pacientes con la prevención de hemorragias y daño articular, la aplicación inmediata de un tratamiento para las hemorragias y el manejo de las complicaciones. Los agentes hemostáticos y tratamiento pueden administrarse a demanda o de forma profiláctica. Los mismos comprenden los concentrados de factor de coagulación como los concentrados de factor VIII y IX fraccionados del plasma, los concentrados recombinantes de FVIII y FIX de vida media estándar y de vida media prolongada; los productos de plasma como los crioprecipitados y plasma fresco congelado; y otras opciones como la desmopresina, fibrinolíticos y emicizumab. En este documento se plantea evaluar la eficacia y seguridad del uso de valoctocogene roxaparvovec en adultos con hemofilia A severa. TECNOLOGÍA: Valoctocogene roxaparvovec (ROCTAVIAN™) es un medicamento de terapia génica que expresa la variante SQ del factor de coagulación humano VIII (hFVIII-SQ) con el dominio B eliminado. El hFVIII-SQ expresado reemplaza el factor de coagulación VIII ausente, necesario para la hemostasia eficaz. Esta terapia es un vector vírico adenoasociado de serotipo AAV5 recombinante, que contiene el ADN de la variante SQ de gen del factor de coagulación humano VIII con el dominio B eliminado bajo el control de un promotor específico del hígado. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de valoctocogene roxaparvovec en el tratamiento de adultos con hemofilia A severa. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. La fecha de búsqueda. EVIDENCIA CLÍNICA: Se hallaron un estudio de Fase III (270-301) y su seguimiento a dos años y un estudio de Fase I/II (270-201) y su estudio de seguimiento a tres años para valoctocogene roxaparvovec en el tratamiento de adultos con hemofilia A severa. También se identificaron otros dos estudios en curso sin resultados publicados. CONCLUSIONES: La evidencia que sustenta la aprobación de comercialización de valoctocogene roxaparvovec para el tratamiento de hombres adultos con hemofilia A severa se basa en un estudio de Fase III en abierto, no comparativo, multicéntrico y sin representantes por Argentina. Este estudio demostraría que en hombres adultos muy seleccionado con hemofilia A severa, la infusión única de la terapia génica aumentaría la actividad del factor VIII, disminuiría las hemorragías y la necesidad de infundir de factor VIII exógeno al mediano plazo. Sin embargo, no hay evidencia de su efecto sobre otros desenlaces importante como la calidad de vida, y al largo plazo se observaría una disminución importante de actividad del factor VIII junto con un leve aumento de la necesidad de infundir de factor VIII exógeno. Todos los participantes tuvieron al menos un evento adverso y el 16,4% presentó algún evento adverso grave, principalmente reacciones de hipersensibilidad, mientras que no se informaron muertes ni desarrollo de trombosis. Al momento, solo una agencia regulatoria han autorizado recientemente su comercialización en la indicación evaluada, junto con la designación de medicamento huérfano, de forma condicional sujeta a estudios de confirmación. No se hallaron recomendaciones actualizadas en Argentina y en el Mundo que mencionen la tecnología en la indicación evaluada. No se hallaron evaluaciones económicas publicadas, aunque su precio de adquisición es extremadamente elevado.

Activated prothrombin complex concentrate to treat bleeding events in acquired hemophilia A: BAHAS study.

OBJECTIVE: Activated prothrombin complex concentrate (aPCC) is a bypassing agent indicated to treat bleeds in patients with acquired hemophilia A (AHA). Nevertheless, its efficacy and safety in the real-world setting have not often been addressed. METHODS: We report the experience of Spanish reference centers for coagulation disorders and from acquired hemophilia Spanish Registry (AHASR) from August 2012 to February 2021. Follow-up period of 30 days after aPCC withdrawal. RESULTS: Thirty patients with a median age of 70 years old, suffering from 51 bleeds treated with aPCC were finally evaluated. As first-line treatment, aPCC stopped bleeding in 13 of 14 (92.9%) cases. aPCC as the second line after recombinant factor VIIa failure, stopped bleeding in all cases. In 17 patients, aPCC was used far from initial bleed control as prophylaxis of rebleeding with 94% effectiveness. No thromboembolic episodes were communicated. One patient developed hypofibrinogenemia, which did not prevent aPCC from halting bleeding. No other serious adverse events possibly or probably associated with aPCC were reported. CONCLUSIONS: This data support aPCC as hemostatic treatment in AHA with high effectiveness and excellent safety profile in acute bleeds and as extended use to prevent rebleedings, even in aging people with high cardiovascular risk.

The important impact of dental care on haemostatic treatment burden in patients with mild haemophilia.

BACKGROUND: Mild haemophilia (MH) is mainly characterized by haemorrhages secondary to surgery/invasive procedures or trauma. Haemostatic treatment in MH ranges from on demand to short prophylaxis according to the type of bleeding events and the basal clotting factor level. Oral surgery and dental extractions can represent a frequent haemostatic challenge in MH requiring appropriate treatment. However, only few studies on limited numbers of patients are available in the literature regarding the implications of dental management in patients with MH. OBJECTIVES: The purpose of the study was to evaluate the impact of dental care on the burden of haemostatic treatment in patients affected by MH. METHODS: We conducted a retrospective multicentre study evaluating adult patients with MH regularly examined at the Haemophilia Treatment Centres (HTCs) of the Saint-Luc University Hospital, Brussels (Belgium) and of Paolo Giaccone Hospital, Palermo (Italy). The population consisted of 107 male patients with MH, with a mean age of 39 years (range 18-81 years). RESULTS: The majority of patients (86/107, 79%) needed at least one treatment within the study period, and 44% (38/86) of them received haemostatic therapy for dental care. Haemostatic therapy in our study varied from antifibrinolytic therapy alone and perioperative factor replacement to the absence of treatment at all. The great majority of oral interventions (27/42, 64%) were managed with clotting factor concentrate. CONCLUSION: This study demonstrates that dental care currently represents a major reason for haemostatic treatments in patients with MH. Maintaining good oral health appears as a priority to minimize avoidable replacement therapy and optimize resources.

The long-term clinical benefits and economic costs associated with increased use of prophylaxis among patients with haemophilia A in China: Population-based predictions from 2018 to 2033.

AIM: To predict the long-term benefits and economic costs of the improvements in haemophilia care in China demonstrated by increasing use of prophylaxis, compared with the current status. METHODS: City-level predictions from 2018 to 2033 were conducted for five representative cities in China. The long-term clinical and economic outcomes in the scenario where haemophilia care has significantly improved and the existing scenario of haemophilia care were calculated and compared. The model input data were obtained from local records, expert interviews, published literature, and other sources. Outcome measures including number of bleeds and joint bleeds, number of target joints, disability rate, direct and indirect costs were calculated at the patient and population levels. RESULTS: The long-term predictions for 2033 demonstrated significantly improved bleed control and joint outcomes due to increased use of prophylaxis. The total number of averted bleed events per patient ranged from 3.9 in Shenyang to 16.1 in Zhengzhou in 2033, and the population-level averted bleed events ranged from 1963 in Xiamen to 14,868 in Zhengzhou. The treatment improvement also leads to significant economic costs driven by increase in clotting factor costs (more than 90%). At the population level, the additional total costs were highest in Zhengzhou (CNY 177.4 million) and lowest in Shenyang (CNY 45.4 million), due to their different population sizes and various existing treatment regimens. The outpatient and hospitalization costs decreased, while the factor costs increased. CONCLUSION: The long-term prophylaxis is associated with avoided bleed events and disabilities. The improved treatment regimens are also associated with a significant economic burden, driven by factor costs.

Cost-effectiveness of andexanet alfa versus four-factor prothrombin complex concentrate for the treatment of oral factor Xa inhibitor-related intracranial hemorrhage in the US.

AIM: To conduct a cost-effectiveness analysis (CEA) on the use of andexanet alfa for the treatment of factor Xa inhibitor-related intracranial hemorrhage (ICH) from the US third-party payer and societal perspectives. METHODS: CEA compared andexanet alfa to prothrombin complex concentrate for the treatment of patients receiving factor Xa inhibitors admitted to hospital inpatient care with an ICH. The model comprised two linked phases. Phase 1 utilized a decision tree to model the acute treatment phase (admission of a patient with ICH into intensive care for the first 30 days). Phase 2 modeled long-term costs and outcomes using three linked Markov models comprising the six health states defined by the modified Rankin score. RESULTS: The analysis showed that the strategy of using andexanet alfa for the treatment of factor Xa inhibitor-related ICH is cost-effective, with incremental cost-effectiveness per quality-adjusted life-year gained of $35,872 from a third-party payer perspective and $40,997 from a societal perspective over 20 years. LIMITATIONS: (1) Absence of head-to-head trials comparing therapies included in the economic model, (2) lack of comparative long-term data on treatment efficacy, and (3) bias resulting from the study designs of published literature. CONCLUSION: Given these results, the use of andexanet alfa for the reversal of anticoagulation in patients with factor Xa inhibitor-related ICH may improve quality of life and is likely to be cost-effective in a US context.

In silico evaluation of limited sampling strategies for individualized dosing of extended half-life factor IX concentrates in hemophilia B patients.

PURPOSE: Hemophilia B is a bleeding disorder, caused by a factor IX (FIX) deficiency. Recently, FIX concentrates with extended half-life (EHL) have become available. Prophylactic dosing of EHL-FIX concentrates can be optimized by assessment of individual pharmacokinetic (PK) parameters. To determine these parameters, limited sampling strategies (LSSs) may be applied. The study aims to establish adequate LSSs for estimating individual PK parameters of EHL-FIX concentrates using in silico evaluation. METHODS: Monte Carlo simulations were performed to obtain FIX activity versus time profiles using published population PK models for N9-GP (Refixia), rFIXFc (Alprolix), and rIX-FP (Idelvion). Fourteen LSSs, containing three or four samples taken within 8 days after administration, were formulated. Bayesian analysis was applied to obtain estimates for clearance (CL), half-life (t1/2), time to 1% (Time1%), and calculated weekly dose (Dose1%). Bias and precision of these estimates were assessed to determine which LSS was adequate. RESULTS: For all PK parameters of N9-GP, rFIXFc and rIX-FP bias was generally acceptable (range: -5% to 5%). For N9-GP, precision of all parameters for all LSSs was acceptable (< 25%). For rFIXFc, precision was acceptable for CL and Time1%, except for t1/2 (range: 27.1% to 44.7%) and Dose1% (range: 12% to 29.4%). For rIX-FP, all LSSs showed acceptable bias and precision, except for Dose1% using LSS with the last sample taken on day 3 (LSS 6 and 10). CONCLUSION: Best performing LSSs were LSS with samples taken at days 1, 5, 7, and 8 (N9-GP and rFIXFc) and at days 1, 4, 6, and 8 (rIX-FP), respectively.

Impact of a pharmacist driven anticoagulation reversal program at a large academic medical center.

In major/life-threatening bleeding, administration of timely and appropriate reversal agents is imperative to reduce morbidity and mortality. Due to complexities associated with the use of reversal agents, a clinical pharmacist-driven anticoagulation reversal program (ARP) was developed. The goal of this program was to ensure appropriateness of reversal agents based on the clinical scenario, optimize selection and avoid unintended consequences. This study describes the impact of a pharmacist-driven anticoagulation program on patient outcomes and cost. A single center retrospective chart review of adult patients whom the ARP was consulted from October 2018 to January 2020 was performed. Patients were included in the efficacy analysis if they were > 18 years of age and presented with acute bleeding. Patients were excluded from the efficacy analysis if the recommended reversal agent was not administered, if a repeat head CT was not available for patients who presented with intracranial hemorrhage (ICH), or if the patient was not bleeding. All patients were included in the economic evaluation. The primary outcome was the percentage of patients who achieved effective hemostasis within 24 h of anticoagulation reversal. Secondary outcomes include incidence of thromboembolic events, in-hospital mortality, and cost avoidance. One hundred twenty-one patients were evaluated by the ARP with 92 patients included in the efficacy analysis. The primary sites of bleeding were ICH in 46% and gastrointestinal (GI) in 29%. Hemostasis was achieved in 84% of patients. Thrombotic events occurred in 7.4% of patients and in-hospital mortality was 26.4%. Total cost avoidance was $1,005,871.78. To our knowledge, this is the first study to evaluate the impact of a pharmacist-driven ARP on clinical and economic outcomes. Implementation of a pharmacist-driven ARP was associated with favorable outcomes and cost savings.

Réévaluation de RebinynMC (nonacog bêta pégol): hémophilie de type B / RebinynTM (nonacog beta pegol): type B Hemophilia (re-evaluation)

MANDAT: À la demande du fabricant Novo Nordisk Canada Inc., l'Institut national d'excellence en santé et en services sociaux (INESSS) a procédé à la réévaluation du produit du système du sang RebinynMC (nonacog bêta pégol), un facteur IX (FIX) de coagulation humain recombinant à demi-vie prolongée qui s'administre par voie intraveineuse. Au Canada, le nonacog bêta pégol est indiqué pour la maîtrise et la prévention des épisodes hémorragiques ainsi que pour la maîtrise et la prévention des saignements dans un contexte périopératoire chez les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas). Il est aussi indiqué pour la prophylaxie de routine afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence chez les patients de 18 ans et plus atteints d'hémophilie B. Les indications visées pour cette réévaluation sont identiques à celles reconnues par Santé Canada. Le nonacog bêta pégol a déjà été évalué par l'INESSS (avis de juin 2020). Lors de son évaluation précédente, l'INESSS a formulé une recommandation défavorable à son ajout sur la Liste des produits du système du sang du Québec, car la valeur thérapeutique n'avait pas été reconnue par le Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscription (CSEMI). Il s'agit de la deuxième évaluation de ce produit. Les cinq FIX suivants sont présentement inscrits sur la Liste des produits du système du sang du Québec et ont servi de comparateurs : BeneFIXMC (nonacog alfa; FIX recombinant à action standard), RixubisMC (nonacog gamma; FIX recombinant à action standard), AlprolixMC (eftrénonacog alfa; FIX recombinant à demi-vie prolongée), IdelvionMC (albutrepenonacog alfa; FIX recombinant à demi-vie prolongée), ImmunineMC (FIX d'origine plasmatique). DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin de documenter l'efficacité, l'innocuité et l'efficience du nonacog bêta pégol. Des données contextuelles et expérientielles issues de la consultation d'experts sont également présentées. DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin de documenter l'efficacité, l'innocuité et l'efficience du nonacog bêta pégol. Des données contextuelles et expérientielles issues de la consultation d'experts sont également présentées. BESOIN DE SANTÉ: L'hémophilie B, causée par une défaillance du FIX, se manifeste par des temps de coagulation plus longs que la normale. Dans les cas sévères, le déficit en FIX mène à des épisodes de saignement fréquents aux articulations, appelés hémarthroses, et aux tissus mous même sans traumatisme. La prophylaxie à l'aide de FIX plasmatique ou recombinant constitue le traitement privilégié. Celle-ci consiste en plusieurs injections intraveineuses hebdomadaires pour remplacer le FIX manquant. Malgré une bonne prise en charge de l'hémophilie B au Québec, certaines lacunes liées aux traitements actuels demeurent. Outre le souhait d'un traitement curatif permanent, les besoins suivants ont été reconnus par les experts rencontrés : une meilleure prévention contre le développement d'inhibiteurs (anticorps neutralisants contre le FIX), la prévention d'arthropathies hémophiliques et des douleurs chroniques, des traitements offrant une protection hémostatique supérieure qui perdure plus longtemps et l'atténuation des contraintes liées aux injections intraveineuses répétées. RÉSULTATS: La combinaison des données d'une étude canadienne en contexte réel de soins, des données du rapport de surveillance postcommercialisation du nonacog bêta pégol et des données des études cliniques évaluées aux fins de l'avis précédent a été considérées. PERSPECTIVE DES EXPERTS: À la lumière des données présentées dans le cadre de cette réévaluation, les experts consultés sont d'avis que l'efficacité de la prophylaxie avec le nonacog bêta pégol est comparable à celle des comparateurs, soit tous les FIX inscrits à la Liste. Selon les experts, le profil de l'innocuité du nonacog bêta pégol est comparable à celui des autres options disponibles pour la population ciblée. De plus, les préoccupations relatives à l'accumulation potentielle de PEG dans le plexus choroïde demeurent théoriques chez l'humain et ne les empêcheraient pas d'utiliser le produit chez la population québécoise indiquée. RECOMMANDATIONS DE L'INESSS SUR LE NONACOG BÊTA PÉGOL: À la lumière des informations disponibles, l'INESSS recommande d'ajouter RebinynMC (nonacog bêta pégol) à la Liste des produits du système du sang du Québec pour la maîtrise et la prévention des épisodes hémorragiques et la maîtrise et la prévention des saignements dans un contexte périopératoire chez les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas) ainsi que pour la prophylaxie de routine afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence chez les patients de 18 ans ou plus atteints d'hémophilie B. Précision sur la recommandation: Dans une perspective de justice distributive, le remboursement du nonacog bêta pégol pour l'indication demandée constituerait une décision responsable, juste et équitable si le coût d'utilisation du nonacog bêta pégol ne surpasse pas celui des FIX à demi-vie prolongée lors du prochain appel d'offres.

MANDATE: At the request of the manufacturer Novo Nordisk Canada Inc., the Institut national d'excellence en santé et en services sociaux (INESSS) re-evaluated the blood system product RebinynTM (nonacog beta pegol), an intravenously injected recombinant factor IX (FIX) indicated in adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. The indications assessed for this re-evaluation are identical to those accorded by Health Canada. INESSS previously evaluated nonacog beta pegol (evaluation of June 2020). During the first evaluation, INESSS issued an unfavourable recommendation for the addition of the product to the Liste des produits du système du sang du Québec because the therapeutic value had not been recognized by the Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscriptions (CSEMI). This is the second evaluation of this product. The following five FIX currently listed on the Liste des produits du système du sang du Québec were used as the comparators of nonacog beta pegol: BeneFIXTM (nonacog alfa; standard half-life recombinant FIX), RixubisTM (nonacog gamma; standard half-life recombinant FIX), AlprolixTM (eftrénonacog alfa; extended half-life recombinant FIX), IdelvionTM (albutrepenonacog alfa; extended half-life recombinant FIX), ImmunineTM (plasma-derived FIX). EVALUATION PROCESS: Published trials and manufacturer data were reviewed to document the efficacy, safety and efficiency of nonacog beta pegol. Experiential and contextual data from expert consultations and patients are presented as well. HEALTH NEED: Type B hemophilia is caused by a deficiency in FIX and is characterized by longer clotting times. In severe cases, FIX deficiency leads to frequent bleeding episodes in joints (hemarthrosis) and soft tissue in the absence of trauma. Prophylaxis with plasma or recombinant FIX is the preferred treatment. This consists of several weekly intravenous injections to replace the missing FIX. Despite a good management of Quebecers living with type B hemophilia, the need for new treatment remains. In addition to permanent curative treatment, the following needs were identified by the experts consulted: better prevention of inhibitor development (neutralizing antibodies against FIX), prevention of hemophilic arthropathies and chronic pain, treatments that provide superior hemostatic protection that lasts longer and alleviates the stresses associated with repeated intravenous injections. RESULTS: Combined data from a real-world Canadian study, a post-market surveillance report on nonacog beta pegol, as well as previously evaluated clinical studies were considered for this evaluation. RECOMMANDATIONS DE L'INESSS SUR LE NONACOG BÊTA PÉGOL: In light of the available data, INESSS recommends that RebinynTM (nonacog beta pegol) be added to the Liste des produits du système du sang du Québec for the treatment of hemophilia B (congenital factor IX deficiency or Christmas disease) in adults and children for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. Precision regarding the recommendation: From a distributive justice perspective, the reimbursement of nonacog beta pegol for the requested indication would constitute a responsible, fair and equitable decision if the cost of using nonacog beta pegol does not exceed that of extended half-life FIX during the next call for tenders.

Economic Evaluation of Andexanet Versus Prothrombin Complex Concentrate for Reversal of Factor Xa-Associated Intracranial Hemorrhage.

[Figure: see text].

Trends in coagulation factor replacement therapy and medical costs in patients with haemophilia in Taiwan: A population-based, 15-year analysis.

INTRODUCTION: Taiwan's National Health Insurance Program approved reimbursement of prophylactic coagulation factor replacement therapy (CFRT) for patients with haemophilia (PWH) in 2014. AIM: To examine 15-year trends and the impact of reimbursement for prophylactic CFRT on its utilization and related medical costs for PWH. METHODS: We analysed Taiwan's National Health Insurance Database from 2003 to 2017. We included patients with haemophilia A (PWHA) or B (PWHB) receiving coagulating factor. Female patients were excluded because of small sample size. We analysed annual consumption of CFRT units and medical costs. High proportion of days covered (PDC) with CFRT served as an indicator for prophylactic treatment since it reflects routine use of CFRT. We applied interrupted time series analysis (ITSA) to evaluate the impact of reimbursement for prophylactic CFRT on usage patterns and medical costs. RESULTS: We included 896 male PWHA and 181 male PWHB, with 38.1% and 37.0% aged under 18 years, respectively. By ITSA, we found the trends in coagulation factor consumption and PDC significantly increased after reimbursement for prophylactic CFRT in both PWHA and PWHB (p values for trend change <0.05). The overall medical costs per patient increased with increasing consumption of coagulation factor; however, ITSA revealed non-CFRT cost decreased after reimbursement of prophylactic CFRT for both PWHA and PWHB (p values <.05). CONCLUSION: Reimbursement for prophylactic CFRT facilitated growth in rates of prophylactic CFRT and increased related costs, but curbed rising non-CFRT costs. These findings provide strong grounds for future cost-effectiveness studies to leverage prophylactic CFRT for its therapeutic benefits.

Choosing the Best Approach to Warfarin Reversal After Traumatic Intracranial Hemorrhage.

BACKGROUND: Patients on warfarin with traumatic intracranial hemorrhage often have the warfarin effects pharmacologically reversed. We compared outcomes among patients who received 4-factor prothrombin complex concentrate (PCC), fresh frozen plasma (FFP), or no reversal to assess the real-world impact of PCC on elderly patients with traumatic intracranial hemorrhage (ICH). MATERIALS AND METHODS: This was a retrospective analysis of 150 patients on preinjury warfarin. Data were manually abstracted from the electronic medical record of an academic level 1 trauma center for patients admitted between January 2013 and December 2018. Outcomes were ICH progression on follow-up computed tomography scan, mortality, need for surgical intervention, and trends in the use of reversal agents. RESULTS: Of 150 patients eligible for analysis, 41 received FFP, 60 PCC, and 49 were not reversed. On multivariable analysis, patients not reversed [OR 0.25 95% CI (0.31-0.85)] and women [OR 0.38 95% CI (0.17-0.88)] were less likely to experience progression of their initial bleed on follow-up computed tomography while subdural hemorrhage increased the risk [OR 3.69 95% CI (1.27-10.73)]. There was no difference between groups in terms of mortality or need for surgery. Over time use of reversal with PCC increased while use of FFP and not reversing warfarin declined (P < 0.001). CONCLUSIONS: Male gender and using a reversal agent were associated with progression of ICH. Choice of reversal did not impact the need for surgery, hospital length of stay, or mortality. Some ICH patients may not require warfarin reversal and may bias studies, especially retrospective studies of warfarin reversal.

Thromboelastometry assessment of the effects of fibrinogen, activated prothrombin complex concentrate, and tranexamic acid on clot formation and fibrinolysis in a model of trauma-induced coagulopathy.

PURPOSE: Coagulation abnormalities are common following major trauma. The aim of this study was to assess the improvement of trauma-induced coagulopathy (TIC) in an in vitro model. METHODS: TIC was created on blood taken from healthy individuals by inducing hemodilution, acidosis, hypothermia and fibrinolysis. Next, blood samples were subjected to rotational thromboelastometry to assess the effect of hemostasis modulators on blood coagulation and fibrinolysis. RESULTS: Introducing to blood fibrinogen at 0.75 mg/mL, prothrombin complex concentrate at 0.66 IU/mL or tranexamic acid at 95 µg/mL increased clot strength. Higher effect was observed by combination of fibrinogen with tranexamic acid and prothrombin complex with tranexamic acid, whereas the maximal effect was achieved using all agents together. Fibrinolysis was inhibited by tranexamic acid and stronger by triple combination of the agents. Selective treating the TIC blood with fibrinogen, prothrombin complex or tranexamic acid at two time lower concentrations did not affect clot strength. Combining fibrinogen with prothrombin complex or with tranexamic acid stimulated clot strength but at lower extent compared to higher concentrations. Lysis onset time was prolonged by tranexamic acid. Maximal effect on both clot formation and fibrinolysis was achieved using all three agents together. CONCLUSIONS: Blood clotting stimulation and fibrinolysis inhibition in the TIC model was enough combining subthreshold concentrations of fibrinogen, prothrombin complex and tranexamic acid. Further experiments are warranted in both in vitro and in vivo conditions with minimally effective concentrations of both pro-coagulant and anti-fibrinolytic drugs assuming that this combinatorial approach may not only improve coagulopathy but also minimize the risk of thrombotic complications.

Assessment of Endothelial Injury and Pro-Coagulant Activity Using Circulating Microvesicles in Survivors of Allogeneic Hematopoietic Cell Transplantation.

(1) Background: survivors of allogeneic hematopoietic cell transplantation (alloHCT) suffer from morbidity and mortality due to cardiovascular events. We hypothesized that vascular injury and pro-coagulant activity are evident in alloHCT survivors without existing alloHCT complications or relapse. (2) Methods: we enrolled consecutive adult alloHCT survivors without established cardiovascular disease and control individuals matched for traditional cardiovascular risk factors (January-December 2019). Circulating microvesicles (MVs) of different cellular origins (platelet, erythrocyte, and endothelial) were measured by a standardized flow cytometry protocol as novel markers of vascular injury and pro-coagulant activity. (3) Results: we recruited 45 survivors after a median of 2.3 (range 1.1-13.2) years from alloHCT, and 45 controls. The majority of patients suffered from acute (44%) and/or chronic (66%) graft-versus-host disease (GVHD). Although the two groups were matched for traditional cardiovascular risk factors, alloHCT survivors showed significantly increased platelet and erythrocyte MVs compared to controls. Within alloHCT survivors, erythrocyte MVs were significantly increased in patients with a previous history of thrombotic microangiopathy. Interestingly, endothelial MVs were significantly increased only in alloHCT recipients of a myeloablative conditioning. Furthermore, MVs of different origins showed a positive association with each other. (4) Conclusions: endothelial dysfunction and increased thrombotic risk are evident in alloHCT recipients long after alloHCT, independently of traditional cardiovascular risk factors. An apparent synergism of these pathophysiological processes may be strongly involved in the subsequent establishment of cardiovascular disease.

Emergent reversal of oral factor Xa inhibitors with four-factor prothrombin complex concentrate.

BACKGROUND: Controversy exists regarding first-line use of the recently approved reversal agent andexanet alfa due to limitations of the ANEXXA-4 study, thrombotic risks, and high medication acquisition cost. The purpose of this study was to evaluate the safety and effectiveness of 4F-PCC for the reversal of emergent oral fXa inhibitor-related bleeding. Furthermore, we aimed to evaluate a subgroup using strict ANNEXA-4 patient selection criteria. METHODS: This was a retrospective study conducted utilizing chart review of adult patients that received 4F-PCC for oral fXa inhibitor-related bleeding. The primary endpoint was the rate of clinical success defined as achieving excellent or good hemostatic effectiveness following the administration of 4F-PCC. Secondary endpoints included in-hospital mortality and arterial/venous thromboembolism, and cost compared with andexanet alfa. RESULTS: A total of 119 patients were included, with 83 patients in the ANNEXA-4 criteria subgroup. Eighty-five of the 119 patients (71%) required reversal due to intracranial bleeding. Prior to reversal, 70 patients (59%) were taking apixaban and 49 patients (41%) were taking rivaroxaban. Clinical success was achieved in 106 of 119 patients (89%) and 74 of 83 patients (90%) in the strict criteria subgroup. Three of 119 patients (2.5%) had a thrombotic event during hospital stay and the overall mortality rate was 13%. The average cost increase of andexanet alfa compared to 4F-PCC would have been $29,500 per patient. CONCLUSIONS: Administration of 4F-PCC for the reversal of oral fXa inhibitors was effective with relatively low thrombotic risk. Further direct prospective comparison of 4F-PCC to andexanet alfa is warranted.

RebinynMC, Facteur IX de coagulation (recombinant): nonacog bêta pégol / RebinynTM (nonacog beta pegol): coagulation factor IX (recombinant)

MANDAT: L'Institut national d'excellence en santé et en services sociaux (INESSS) a procédé à l'évaluation du produit du système du sang RebinynMC (nonacog bêta pégol, N9-GP), un facteur IX recombinant (FIXr) administré par injection intraveineuse. Le nonacog bêta pégol est indiqué chez les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas) pour la maîtrise et la prévention des épisodes hémorragiques et la maîtrise et la prévention des saignements dans un contexte périopératoire ainsi que chez les patients de 18 ans ou plus atteints d'hémophilie B pour la prophylaxie de routine, afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence. Quatre FIX recombinants sont présentement inscrits à la Liste des produits du système du sang du Québec et ont été utilisés comme comparateurs : BeneFIXMC (nonacog alfa), RixubisMC (nonacog gamma), AlprolixMC (eftrénonacog alfa) et IdelvionMC (albutrepenonacog alfa). DÉMARCHE D'ÉVALUATION: Une revue des données issues de la littérature et de celles fournies par le fabricant a été réalisée afin de documenter l'efficacité, l'innocuité et l'efficience du nonacog bêta pégol. Des données expérientielles et contextuelles issues de la consultation d'experts et de patients sont également présentées. BESOIN DE SANTÉ: L'hémophilie B est une pathologie génétique récessive liée au chromosome X et caractérisée par un déficit congénital en facteur IX (FIX). Ce déficit se traduit par un temps de coagulation prolongé menant à des épisodes de saignements fréquents aux articulations (hémarthroses), aux muscles, ainsi qu'aux muqueuses. Certains épisodes de saignements peuvent mettre en danger la vie de l'individu ou mener à des handicaps moteurs importants. Les traitements de remplacement par FIX actuels permettent aux hémophiles de type B du Québec de prévenir et de traiter leurs épisodes de saignements. Parmi les besoins recensés auprès des experts et patients consultés, on retrouve une meilleure prévention contre le développement d'inhibiteurs, la prévention d'arthropathies hémophiliques et des douleurs chroniques, des traitements offrant une protection hémostatique supérieure qui perdure plus longtemps et l'atténuation des contraintes liées aux injections intraveineuses répétées. RÉSULTATS: Les résultats d'efficacité du nonacog bêta pégol sont basés sur quatre études de phase III ouvertes et non contrôlées. En raison de la restriction de l'indication du nonacog bêta pégol, les résultats de l'efficacité de la prophylaxie à long terme pour les moins de 18 ans n'ont pas été considérés. La force de la preuve de l'efficacité du nonacog bêta pégol a été jugée très faible. DÉLIBÉRATION SUR LE NONACOG BÊTA PÉGOL: Délibération RebinynMC: Les membres du Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscription sont unanimement d'avis que la valeur thérapeutique de RebinynMC n'est pas démontrée pour les adultes et les enfants atteints d'hémophilie B (déficit congénital en facteur IX ou maladie de Christmas) pour la maîtrise et la prévention des épisodes hémorragiques et la maîtrise et la prévention des saignements dans un contexte périopératoire ainsi que chez les patients de 18 ans ou plus atteints d'hémophilie B pour la prophylaxie de routine, afin de prévenir les épisodes hémorragiques ou d'en réduire la fréquence. MOTIFS DE LA POSITION UNANIME: Les membres du Comité ont reconnu l'importance du fardeau associé à la prise en charge de la maladie. Ils ont également reconnu que la fréquence réduite des injections représente un avantage pour les patients. Néanmoins, après un examen minutieux de l'ensemble de la preuve, les constats suivants ont été établis: En raison de la faiblesse de la preuve, les études disponibles ne permettent pas de reconnaitre une valeur thérapeutique non inférieure à RebinynMC par rapport aux autres produits actuellement disponibles; Des préoccupations ont été soulevées par les membres en lien avec l'accumulation de PEG dans le cerveau des animaux observée lors d'études précliniques ainsi qu'aux risques potentiels à long terme leur étant associés; Considérant la disponibilité d'autres options de traitement bien établies, les membres préconisent la prudence. CONSIDÉRANT LA DISPONIBILITÉ D'AUTRES OPTIONS DE TRAITEMENT BIEN ÉTABLIES, LES MEMBRES PRÉCONISENT LA PRUDENCE: À la lumière des informations disponibles, l'INESSS ne recommande pas l'ajout de RebinynMC (nonacog bêta pégol) à la Liste des produits du système du sang du Québec puisque la valeur thérapeutique du produit n'a pas été démontrée. Davantage de données d'efficacité et d'innocuité provenant d'études avec un meilleur niveau de preuve sont requises pour soutenir une reconnaissance de la valeur thérapeutique.

MANDATE: The Institut national d'excellence en santé et en services sociaux (INESSS) evaluated the blood system product RebinynTM (nonacog beta pegol), an intravenously injected recombinant factor IX (FIX) indicated in adults and children with hemophilia B (congenital factor IX deficiency or Christmas disease) for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. The following four recombinant FIX, currently indicated for the treatment of hemophilia B and listed in the Liste des produits du système du sang du Québec, served as comparators: BeneFIXTM (nonacog alfa), RixubisTM (nonacog gamma), AlprolixTM (eftrenonacog alfa) et IdelvionTM (albutrepenonacog alfa). EVALUATION PROCESS Published trials and manufacturer data were reviewed to document the efficacy, safety and efficiency of nonacog beta pegol. Experiential and contextual data from expert consultations and patients are presented as well. HEALTH NEED: Hemophilia B is an X chromosome-linked recessive genetic disease characterized by coagulation factor IX (FIX) deficiency. This deficiency prolongs coagulation times, which can lead to frequent bleeding episodes in the joints (hemarthrosis), muscles and mucus membranes. Some bleeding events can also lead to severe motor handicaps or even be life-threatening. The current FIX replacement therapies enable Quebecers who are type B hemophiliacs to prevent or stop their bleeding episodes. Experts and patients were queried about health needs in the hemophilia B community. Treatments that better prevent the development of inhibitors, hemophiliac arthropathies and chronic pain, and therapies that provide superior, longer-lasting hemostatic protection with fewer intravenous injections were among the needs mentioned most frequently. RESULTS: Efficacy: The efficacy evaluation for nonacog beta pegol was based on four phase III, open-label and non-controlled trials. As a result of the restriction of the indication, efficacy results for the prophylactic use of nonacog beta pegol in children and adolescents under 18 years f age were not considered. The overall efficacy evidence was considered very low. DELIBERATION ON NONACOG BETA PEGOL: Deliberation on RebinynTM: Members of the Comité scientifique permanent de l'évaluation des médicaments aux fins d'inscription (CSEMI) unanimously share the opinion that the therapeutic value of RebinynTM (nonacog beta pegol) has not been demonstrated for the treatment of hemophilia B (congenital factor IX deficiency or Christmas disease) in adults and children for the control and prevention of bleeding episodes and in the perioperative setting as well as in patients 18 years and above with hemophilia B for routine prophylaxis to prevent or reduce the frequency of bleeding episodes. Reasons for the unanimous position: Members of the Committee recognized the considerable burden associated with the disease. They also recognized that the reduced injection frequency is considered an advantage for patients. Nevertheless, after careful examination of all the evidence, the following observations were made: Given the weakness of the evidence, the available studies do not permit us to conclude that the therapeutic value of nonacog beta pegol is noninferior to that of the other recombinant FIXs currently available; Concerns were raised by the members of the CSEMI regarding the accumulation of PEG in the brain of animals during preclinical studies as well as the potential risks associated with long term deposits of PEG; Considering the availability of safer therapeutic options, the members advise caution. INESSS' recommendation regarding RebinynTM: In light of the available data, INESSS recommends that RebinynTM (nonacog beta pegol) not be added to the Liste des produits du système du sang du Québec since the product's therapeutic value has not demonstrated. Additional efficacy and safety data with a higher level of evidence are required to support the therapeutic value for the proposed indications.

Seasonal and meteorological associations of vitamin K-dependent coagulation factors in 1-month-old infants: assessment of Normotest values.

: We aimed to determine the presence of seasonal and meteorological associations of the activity of vitamin K-dependent coagulation factors to explain the seasonal variation in vitamin K deficiency-related bleeding. Seasonal and monthly changes in Normotest values in 1759 healthy 1-month-old infants were retrospectively accessed, and the impact of meteorological parameters on Normotest values was analyzed. Normotest values peaked in winter and were the lowest in summer, with statistically significant differences among the seasonal values (P < 0.001). Comparing monthly variations, the values peaked in January and were the lowest in August (P < 0.001). Only the average daily air temperature significantly correlated with the Normotest values on multiple linear regression (P < 0.001) and with low Normotest values on multiple logistic regression analysis (odds ratio, 1.023; P = 0.002). Seasonal and monthly variations in Normotest values were observed in 1-month-old infants, possibly due to fluctuations in daily air temperature.