RESUMO
INTRODUCTION: Andexanet alfa is a recombinant modified factor Xa protein that has been developed to reverse factor Xa inhibitors. Since May 2018, the FDA has approved its utilization in patients treated with apixaban and rivaroxaban in case of life-threatening or uncontrolled bleeding. On 28 of February 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a conditional marketing authorization for andexanet alfa in Europe. Area covered: The authors provide an overview of andexanet alfa development and its pharmacokinetic and pharmacodynamic properties. The results of the clinical phase III trial ANNEXA as well as current limitations related to andexanet alfa are also discussed. Expert opinion: Although phase I and II studies have proven that andexanet alfa can be effective in reversing the effect of factor Xa inhibitors, its efficacy in major bleeding patients has only been shown for apixaban and rivaroxaban, without any comparator group. Well-designed studies comparing the efficacy and safety of andexanet alfa to other reversal strategies are required to confirm preliminary data. The benefit of andexanet alfa in specific settings needs to be investigated and its use in clinical practice needs to be facilitated by the implementation of international guidelines.
Assuntos
Inibidores do Fator Xa/imunologia , Fator Xa/uso terapêutico , Hemorragia/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Ensaios Clínicos como Assunto , Fator Xa/genética , Fator Xa/metabolismo , Fator Xa/farmacocinética , Meia-Vida , Humanos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacocinéticaAssuntos
Cardiologia/normas , Hemorragia/terapia , Hemostasia , Tromboembolia Venosa/sangue , Tromboembolia Venosa/terapia , Anticoagulantes , Coagulação Sanguínea , Elasticidade , Fibrinogênio/análise , Hospitalização , Humanos , Assistência Perioperatória , Período Perioperatório , Guias de Prática Clínica como Assunto , ViscosidadeAssuntos
Anemia , Consenso , Período Pós-Parto/sangue , Complicações Hematológicas na Gravidez , Adulto , Anemia/sangue , Anemia/terapia , Transfusão de Componentes Sanguíneos , Feminino , Ginecologia , Humanos , Obstetrícia , Guias de Prática Clínica como Assunto , Gravidez , Complicações Hematológicas na Gravidez/sangue , Complicações Hematológicas na Gravidez/terapiaRESUMO
Click to hear Dr Baglin's perspective on the role of the laboratory in treatment with new oral anticoagulants SUMMARY: One of the key benefits of the direct oral anticoagulants (DOACs) is that they do not require routine laboratory monitoring. Nevertheless, assessment of DOAC exposure and anticoagulant effects may become useful in various clinical scenarios. The five approved DOACs (apixaban, betrixaban, dabigatran etexilate, edoxaban and rivaroxaban) have different characteristics impacting assay selection and the interpretation of results. This article provides an updated overview on (i) which test to use (and their advantages and limitations), (ii) when to assay DOAC levels, (iii) how to interpret the results relating to bleeding risk, emergency situations and perioperative management, and (iv) what is the impact of DOACs on routine and specialized coagulation assays. Assays for anti-Xa or anti-IIa activity are the preferred methods when quantitative information is useful, although the situations in which to test for DOAC levels are still debated. Different reagent sensitivities and variabilities in laboratory calibrations impact assay results. International calibration standards for all specific tests for each DOAC are needed to reduce the inter-laboratory variability and allow inter-study comparisons. The impact of the DOACs on hemostasis testing may cause false-positive or false-negative results; however, these can be minimized by using specific assays and collecting blood samples at trough concentrations. Finally, prospective clinical trials are needed to validate the safety and efficacy of proposed laboratory thresholds in relation to clinical decisions. We offer recommendations on the tests to use for measuring DOACs and practical guidance on laboratory testing to help patient management and avoid diagnostic errors.
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Anticoagulantes/administração & dosagem , Testes de Coagulação Sanguínea , Coagulação Sanguínea/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Administração Oral , Anticoagulantes/efeitos adversos , Antitrombinas/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Hemorragia/induzido quimicamente , Humanos , Valor Preditivo dos Testes , Reprodutibilidade dos TestesAssuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Perda Sanguínea Cirúrgica/prevenção & controle , Medicina Baseada em Evidências/normas , Fator VIIa/uso terapêutico , Fator XIII/uso terapêutico , Fibrinogênio/uso terapêutico , Hemostáticos/uso terapêutico , Hemorragia Pós-Operatória/tratamento farmacológico , Fatores de Coagulação Sanguínea/efeitos adversos , Fatores de Coagulação Sanguínea/normas , Consenso , Fator VIIa/efeitos adversos , Fator VIIa/normas , Fator XIII/efeitos adversos , Fator XIII/normas , Fibrinogênio/efeitos adversos , Fibrinogênio/normas , Hemostáticos/efeitos adversos , Hemostáticos/normas , Humanos , Hemorragia Pós-Operatória/sangue , Hemorragia Pós-Operatória/diagnóstico , Proteínas Recombinantes/uso terapêutico , Fatores de Risco , Resultado do TratamentoRESUMO
The prevention of post-operative risk of venous thrombo-embolism (VTE) is of fundamental importance, but preventive methods have progressed with the introduction of direct oral anticoagulants (DOAC), the development of ambulatory surgery and enhanced recovery programs (ERP) after surgery. Surgery is, inherently a trigger for venous thrombo-embolic disease, as is prolonged immobilization. However, the risk of VTE is very low following ambulatory surgery, especially in this selected population. ERP, consists of a set of measures to optimize the patient's peri-operative management while reducing length of stay, costs and morbidity and mortality; one measure is the encouragement of early ambulation. This will undoubtedly have an impact on the incidence of VTE and lessen the need for prolonged thrombo-prophylaxis.
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Anticoagulantes/uso terapêutico , Deambulação Precoce/métodos , Segurança do Paciente , Complicações Pós-Operatórias/prevenção & controle , Tromboembolia Venosa/prevenção & controle , Adulto , Procedimentos Cirúrgicos Ambulatórios/normas , Procedimentos Cirúrgicos Ambulatórios/tendências , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Cuidados Pós-Operatórios/métodos , Embolia Pulmonar/prevenção & controle , Medição de Risco , Resultado do TratamentoRESUMO
BACKGROUND: Non-specific hemostatic agents, namely activated prothrombin complex concentrate (aPCC), PCC and recombinant activated factor (F) VII (rFVIIa), can be used, off-label, to reverse the effects of FXa inhibitors in the rare cases of severe hemorrhages, as no approved specific antidote is available. We have evaluated the ability of aPCC, PCC and rFVIIa to reverse apixaban. METHODS: Healthy volunteer whole blood was spiked with therapeutic or supra-therapeutic apixaban concentrations and two doses of aPCC, PCC or rFVIIa. Tests performed included a turbidimetry assay for fibrin polymerization kinetics analysis, scanning electron microscopy for fibrin network structure observation, thrombin generation assay (TGA), thromboelastometry, prothrombin time and activated partial thromboplastin time. RESULTS: aPCC generated a dense clot constituting thin and branched fibers similar to those of a control without apixaban, increased fibrin polymerization velocity and improved quantitative (endogenous thrombin potential and peak height) as well as latency (clotting and lag times) parameters. Adding PCC also improved the fibrin and increased quantitative parameters, but fibrin polymerization kinetics and latency parameters were not corrected. Finally, rFVIIa improved latency parameters but failed to restore the fibrin network structure, fibrin polymerization velocity and quantitative parameters. CONCLUSION: aPCC was more effective than PCC or rFVIIa in reversing in vitro the effects of apixaban. aPCC rapidly triggered the development of an apparently normal fibrin network and corrected latency and quantitative parameters, whereas PCC or rFVIIa had only a partial effect.
Assuntos
Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/toxicidade , Hemorragia/prevenção & controle , Hemostasia/efeitos dos fármacos , Hemostáticos/farmacologia , Pirazóis/toxicidade , Piridonas/toxicidade , Antídotos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Fatores de Coagulação Sanguínea/farmacologia , Fator VIIa/farmacologia , Fibrina/metabolismo , Fibrina/ultraestrutura , Voluntários Saudáveis , Hemorragia/sangue , Hemorragia/induzido quimicamente , Humanos , Cinética , Microscopia Eletrônica de Varredura , Tempo de Tromboplastina Parcial , Polimerização , Tempo de Protrombina , Proteínas Recombinantes/farmacologia , Tromboelastografia , Trombina/metabolismoRESUMO
OBJECTIVE(S): Assess the efficacy and safety of tranexamic acid administration for the prevention and/or the treatment of postpartum haemorrhage. STUDY DESIGN: Systematic review with meta-analysis. MATERIAL AND METHODS: Systematic review of the literature with the aim of identifying prospective, randomised, controlled trials that assessed the effect of tranexamic acid on peripartum blood loss and transfusion requirement in three clinical contexts: (i) prevention of post-partum haemorrhage in case of elective caesarean section, (ii) prevention of post-partum haemorrhage in case of vaginal delivery, (iii) treatment of post-partum haemorrhage. RESULTS: Prophylactic administration of tranexamic acid reduced blood loss (mean difference for intraoperative blood loss: -177.9mL, IC 95%: -189.51 to -166.35, total blood loss: -183.94, IC 95%: -198.29 to -169.60), and the incidence of severe post-partum haemorrhage (OR: 0.49, IC 95%: 0.33 to 0.74). None of the published trials assessed the effect of tranexamic acid on blood products administration or transfusion requirement. Only one study assessed and reported the efficacy of tranexamic acid when administered as a treatment for postpartum haemorrhage. A significant reduction in blood loss was reported within 30 minutes after randomisation (P=0.03) and confirmed after 6 hours (median: 170mL (58-323) vs 221mL (110-543), P=0.04). None of the included studies adequately studied the incidence of side effects after tranexamic acid administration. CONCLUSION: Although tranexamic acid administration seemed to significantly reduce blood loss and the incidence of severe post-partum haemorrhage, further prospective trials are needed to confirm the efficacy and safety of tranexamic administration in the treatment of postpartum haemorrhage. Those studies should assess the pharmacokinetic profile and the safety of this drug in pregnant women.
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Antifibrinolíticos/uso terapêutico , Hemorragia Pós-Parto/prevenção & controle , Ácido Tranexâmico/uso terapêutico , Adulto , Feminino , Humanos , GravidezRESUMO
The current issues debate brings together experts around the themes of self-sufficiency (in its national and European aspects) and of needs in cellular blood products. The point of view of the manufacturer and prescribers of blood products are confronted.
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Segurança do Sangue , Bancos de Sangue , Doadores de Sangue/provisão & distribuição , Segurança do Sangue/normas , Transfusão de Sangue/estatística & dados numéricos , França , Necessidades e Demandas de Serviços de Saúde , Humanos , Prescrições/estatística & dados numéricosRESUMO
New direct oral anticoagulants (NOAC), inhibitors of factor IIa or Xa, are expected to be widely used for the treatment of venous thromboembolic disease, or in case of atrial fibrillation. Such anticoagulant treatments are known to be associated with haemorrhagic complications. Moreover, it is likely that such patients on long-term treatment with NOAC will be exposed to emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose management for optimal safety as regards the risk of bleeding in such emergency conditions. In this article, only dabigatran and rivaroxaban were discussed. For emergency surgery at risk of bleeding, we propose to dose the plasmatic concentration of drug. Levels inferior or equal to 30ng/mL for both dabigatran and rivaroxaban, should enable the realization of a high bleeding risk surgery. For higher concentration, it was proposed to postpone surgery by monitoring the evolution of the drug concentration. Action is then defined by the kind of NOAC and its concentration. If the dosage of the drug is not immediately available, proposals only based on the usual tests, PT and aPTT, also are presented. However, these tests do not really assess drug concentration or bleeding risk. In case of severe haemorrhage in a critical organ, it is proposed to reduce the effect of anticoagulant therapy using a nonspecific procoagulant drug (activated prothrombin concentrate, FEIBA, 30-50U/kg, or non-activated 4-factors prothrombin concentrates 50U/kg). For any other type of severe haemorrhage, the administration of such a procoagulant drug, potentially thrombogenic in these patients, will be discussed regarding concentration of NACO and possibilities for mechanical haemostasis.
Assuntos
Anticoagulantes/uso terapêutico , Serviços Médicos de Emergência/métodos , Inibidores do Fator Xa , Hemorragia/terapia , Hemostasia/fisiologia , Assistência Perioperatória/métodos , Trombina/antagonistas & inibidores , Anticoagulantes/sangue , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/uso terapêutico , Dabigatrana , Emergências , Hemorragia/tratamento farmacológico , Humanos , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Morfolinas/uso terapêutico , Rivaroxabana , Procedimentos Cirúrgicos Operatórios , Tiofenos/administração & dosagem , Tiofenos/efeitos adversos , Tiofenos/uso terapêutico , beta-Alanina/administração & dosagem , beta-Alanina/efeitos adversos , beta-Alanina/análogos & derivados , beta-Alanina/uso terapêuticoRESUMO
BACKGROUND: In several small studies, anticoagulant therapy reduced the incidence of venous thromboembolism (VTE) in patients with isolated lower-limb injuries. OBJECTIVES: To compare the efficacy and safety of fondaparinux 2.5 mg (1.5 mg in patients with a creatinine clearance between 30 and 50 mL min(-1) ) over nadroparin 2850 anti-factor Xa IU. PATIENTS AND METHODS: In this international, multicenter, randomized, open-label study, patients with an isolated non-surgical unilateral below-knee injury having at least one additional major risk factor for VTE and requiring, in the Investigator's opinion, rigid or semi-rigid immobilization for 21-45 days with thromboprophylaxis up to complete mobilization received subcutaneously once-daily either fondaparinux or nadroparin. The primary efficacy outcome was the composite of VTE (symptomatic or ultrasonographically detected asymptomatic deep vein thrombosis of the lower limb or symptomatic pulmonary embolism) and death up to complete mobilization. The main safety outcome was major bleeding. RESULTS: We randomized 1349 patients (mean age 46 years): 88.7% had a bone fracture, and 83.8% had a plaster cast fitted (mean duration of immobilization, 34 days). The primary efficacy outcome occurred in 15 of 584 patients (2.6%) in the fondaparinux group and 48 of 586 patients (8.2%) in the nadroparin group (odds ratio, 0.30; 95% confidence interval [CI], 0.15-0.54; P < 0.001). A single major bleed was experienced by fondaparinux-treated patients and none by nadroparin-treated patients. These results were maintained up to the end of follow-up. CONCLUSIONS: Fondaparinux 2.5 mg day(-1) may be a valuable therapeutic option over nadroparin 2850 anti-FXa IU day(-1) for preventing VTE after below-knee injury requiring prolonged immobilization in patients with additional risk factors.
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Anticoagulantes/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Imobilização/efeitos adversos , Traumatismos da Perna/terapia , Polissacarídeos/uso terapêutico , Tromboembolia Venosa/prevenção & controle , Adulto , Feminino , Fondaparinux , Humanos , MasculinoAssuntos
Anestésicos Dissociativos/uso terapêutico , Ketamina/uso terapêutico , Neoplasias/complicações , Dor Intratável/tratamento farmacológico , Anestésicos Dissociativos/administração & dosagem , Anestésicos Dissociativos/efeitos adversos , Humanos , Injeções Espinhais , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Neuralgia/tratamento farmacológico , Dor Intratável/etiologia , Cuidados PaliativosAssuntos
Plaquetas/efeitos dos fármacos , Hematologia/normas , Hemostasia/efeitos dos fármacos , Inibidores da Agregação Plaquetária/química , Coleta de Dados , Hematologia/métodos , Hemorragia/prevenção & controle , Humanos , Cooperação Internacional , Guias de Prática Clínica como Assunto , Risco , Sociedades Médicas , Tromboembolia/prevenção & controle , Trombose/prevenção & controle , Resultado do TratamentoRESUMO
The management of massive bleeding has improved, thanks to high-quality blood components and new transfusion strategies. However, it remains controversial and, despite a huge body of literature, randomised control trials are still lacking. However, the therapeutic approach has also evolved, requiring earlier and more active management. If a 'no delay' management is well recognized, its modes are still discussed. Immediate delivery of blood products with ratios close to 1:1:1 for RBC units/fresh frozen plasma/platelet concentrates, through massive transfusion protocol using blood packs, has been advocated, but yet this approach is not evidence-based. Secondly, a targeted strategy to provide fibrinogen concentrates is under evaluation. Tranexamic acid is effective in trauma patients. Recombinant factor VIIa should only be used on a compassionate basis.
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Transfusão de Componentes Sanguíneos/métodos , Gerenciamento Clínico , Hemorragia/terapia , Doença Aguda , Transfusão de Componentes Sanguíneos/tendências , Terapia Combinada , Transfusão de Eritrócitos , Fator VIIa/uso terapêutico , Feminino , Fibrinogênio/uso terapêutico , Hemorragia/tratamento farmacológico , Hemostáticos/uso terapêutico , Humanos , Plasma , Hemorragia Pós-Operatória/terapia , Hemorragia Pós-Parto/terapia , Gravidez , Proteínas Recombinantes/uso terapêutico , Ácido Tranexâmico/uso terapêuticoRESUMO
The current issues debate will bring together experts around the themes of self-sufficiency (in its national and European aspects) and of needs in cellular blood products. The point of view of the manufacturer and prescribers of blood products will be confronted.
Assuntos
Produtos Biológicos/provisão & distribuição , Bancos de Sangue/estatística & dados numéricos , Segurança do Sangue , Transfusão de Sangue , Sangue , Necessidades e Demandas de Serviços de Saúde , Prescrições , Produtos Biológicos/normas , Bancos de Sangue/ética , Doadores de Sangue/provisão & distribuição , Transfusão de Sangue/normas , Transfusão de Eritrócitos/normas , Europa (Continente) , França , Política de Saúde , Humanos , VoluntáriosRESUMO
Rare inherited bleeding disorders include fibrinogen disorders, and deficiencies of factors II (prothrombin), V, VII, X, XI, XIII, and combined V+VIII, and combined vitamin K-dependent factors, with general population prevalence rates between 1/500,000 and 1/2,000,000. These inherited disorders, transmitted as autosomal recessive traits, are characterized by a heterogeneous clinical presentation (asymptomatic, mild, moderate or severe bleeding tendency); this variability is more important for deficiencies with factor levels ranging from 5 to 50%. Individual bleeding risk assessment before an invasive procedure or during peri-partum period remains difficult, although an essential step to decide whether a substitution with clotting factor is necessary or not. Because there is a poor correlation between factor activity levels and the severity of bleeding symptoms, factor correction before an invasive procedure should not be based on factor level only, but physicians must also take into account the patient phenotype as well as the haemorrhagic risk of the procedure.