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2.
Asian Cardiovasc Thorac Ann ; 27(1): 42-44, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30789010

RESUMO

In cardiac surgery, supplementation with recombinant factor VIIa is the treatment of choice for patients with factor VII deficiency, but overzealous administration can be associated with thromboembolic side-effects. A 53-year-old man with factor VII activity 15.2%, international normalized ratio 2.9, and acute thrombotic critical coronary anatomy, underwent coronary artery bypass surgery and a thoracotomy with decortication 5 months later. He was managed successfully without recombinant factor VIIa supplementation. This case demonstrates that current bedside and laboratory tests such as thromboelastography, prothrombin time or international normalized ratio, and factor VII activity may not predict replacement therapy in these patients.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Ponte de Artéria Coronária , Doença das Coronárias/cirurgia , Deficiência do Fator VII/tratamento farmacológico , Fator VIIa/administração & dosagem , Hemostáticos/administração & dosagem , Espondilite Anquilosante/cirurgia , Toracotomia , Tomada de Decisão Clínica , Ponte de Artéria Coronária/efeitos adversos , Doença das Coronárias/complicações , Doença das Coronárias/diagnóstico , Esquema de Medicação , Monitoramento de Medicamentos/métodos , Deficiência do Fator VII/sangue , Deficiência do Fator VII/complicações , Deficiência do Fator VII/diagnóstico , Fator VIIa/efeitos adversos , Hemostáticos/efeitos adversos , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Valor Preditivo dos Testes , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Espondilite Anquilosante/complicações , Espondilite Anquilosante/diagnóstico , Toracotomia/efeitos adversos , Tromboelastografia , Resultado do Tratamento
3.
J Cardiothorac Vasc Anesth ; 33(5): 1269-1275, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30795967

RESUMO

OBJECTIVE: To evaluate the effect of recombinant activated factor VII (rFVIIa) administration on outcomes in pediatric cardiac surgery patients with postoperative bleeding. DESIGN: A propensity score-matched retrospective study. SETTING: Single tertiary medical center. PARTICIPANTS: The study comprised 151 patients who received treatment with rFVIIa and were matched with control patients at a 1:2 ratio. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary endpoints were thrombotic events, renal replacement therapy (RRT), and mortality. The secondary endpoints were length of intensive care unit stay and the reexploration rate. Patients in the rFVIIa group showed no significant differences in thrombotic events (odds ratio [OR] 1.03; 95% confidence interval [CI] 0.48-2.21; p = 0.948), mortality (OR 0.94; 95% CI 0.42-2.13; p = 0.891), and RRT (OR 1.38; 95% CI 0.73-2.58; p = 0.319). However, patients in the rFVIIa group experienced a prolonged length of intensive care unit stay (5.65 [3.00-12.28] d v 3.91 [1.83-6.77] d) and an increased reexploration rate (8.2% v 3.1%). High-dose rFVIIa was an independent risk factor of thrombotic events (OR 5.17; 95% CI 1.19-22.49; p = 0.029). CONCLUSION: This study found that rFVIIa is not associated with increased risks of postoperative thrombotic events, mortality, or RRT in pediatric patients undergoing cardiac surgery. Nevertheless, rFVIIa was associated with longer intensive care unit stay and increased reexploration rate. Furthermore, the risk for thrombotic events may increase with high-dose rFVIIa.


Assuntos
Ponte Cardiopulmonar/tendências , Fator VIIa/administração & dosagem , Cardiopatias Congênitas/tratamento farmacológico , Cardiopatias Congênitas/cirurgia , Hemorragia Pós-Operatória/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/tendências , Ponte Cardiopulmonar/efeitos adversos , Criança , Pré-Escolar , Fator VIIa/efeitos adversos , Feminino , Cardiopatias Congênitas/diagnóstico , Mortalidade Hospitalar/tendências , Humanos , Lactente , Masculino , Hemorragia Pós-Operatória/diagnóstico , Hemorragia Pós-Operatória/etiologia , Pontuação de Propensão , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
4.
J Pediatr Hematol Oncol ; 41(2): e72-e78, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30608491

RESUMO

BACKGROUND: Recombinant activated factor VII (rFVIIa) has been used off-label to treat or prevent severe bleeding in patients for whom conventional treatments are unsuccessful. However, studies in children remain limited. PROCEDURE: To examine the efficacy and safety of rFVIIa, we performed a retrospective analysis of rFVIIa off-label use in a pediatric hematology/oncology cohort at a single center from 2006 to 2014. RESULTS: Of 58 patients identified, 46 (79.3%) received rFVIIa to treat bleeding and 12 (20.7%) to prevent bleeding. Thirty-three (71.7%) patients had life-threatening bleeding. In the treatment group, 63.0% patients were responders (ie, bleeding decreased or stopped) and 37.0% were nonresponders (ie, bleeding did not change). Blood products usage was similar between responders and nonresponders. After rFVIIa administration, prothrombin time, partial thromboplastin time and lactate were significantly lower, but fibrinogen was significantly higher in responders than nonresponders. Venous thromboembolism developed in 5.2% (3/58) patients, but its relation to rFVIIa remains unclear. Responders had significantly lower mortality than nonresponders (17.2% vs. 82.4%, P<0.0001). CONCLUSIONS: rFVIIa controlled most bleeding events in this cohort, despite predominance of life-threatening bleeding, suggesting good efficacy. Venous thromboembolism rate was low. Further studies are warranted to identify predictors of favorable response to rFVIIa in similar patients.


Assuntos
Fator VIIa/administração & dosagem , Hemorragia/prevenção & controle , Neoplasias/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Fator VIIa/efeitos adversos , Feminino , Hemorragia/sangue , Hemorragia/mortalidade , Humanos , Masculino , Neoplasias/sangue , Neoplasias/mortalidade , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos
5.
J Thromb Haemost ; 16(10): 1984-1993, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30151972

RESUMO

Essentials Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII. A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia. MarzAA was safe and tolerated at intravenous doses up to 30 µg kg-1 Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX. SUMMARY: Background Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia. Objectives To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non-bleeding patients with congenital hemophilia A or B with or without inhibitors. Methods This international, phase 1, open-label study (NCT01439971) enrolled males aged 18-64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single-dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 µg kg-1 ). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD. Results Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose-limiting toxicity. No treatment-emergent severe or serious adverse events occurred. MarzAA showed linear dose-response PK across the 4.5-30 µg kg-1 dose range, with a terminal half-life of ⁓ 3.5 h. Dose-dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses. Conclusions MarzAA was tolerated at doses up to 30 µg kg-1 . The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.


Assuntos
Coagulantes/administração & dosagem , Fator VIIa/administração & dosagem , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Administração Intravenosa , Adolescente , Adulto , Coagulantes/efeitos adversos , Coagulantes/farmacocinética , Europa (Continente) , Fator VIIa/efeitos adversos , Fator VIIa/farmacocinética , Hemofilia A/sangue , Hemofilia A/diagnóstico , Hemofilia B/sangue , Hemofilia B/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Índice de Gravidade de Doença , África do Sul , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto Jovem
6.
J Thorac Cardiovasc Surg ; 156(4): 1564-1573.e8, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29884487

RESUMO

OBJECTIVES: Although off-label use of recombinant activated factor VII against refractory bleeding is incorporated in current guideline recommendations, safety concerns persist predominantly with respect to thromboembolic complications. We analyzed the safety and efficacy of recombinant activated factor VII at a very low dose in cardiosurgical patients with refractory bleeding. METHODS: This prospective study includes 1180 cardiosurgical patients at risk of bleeding. Goal-directed substitution was based on real-time laboratory testing and clinical scoring of the bleeding intensity. All patients who fulfilled the criteria for enhanced risk of bleeding (n = 281) were consequently included in the present analysis. Patients in whom refractory bleeding developed despite substitution with specific hemostatic compounds (n = 167) received a single shot of very low-dose recombinant activated factor VII (≤20 µg/kg). Mortality and risk of thromboembolic complications, and freedom from stroke and acute myocardial infarction in particular, were analyzed (vs patients without recombinant activated factor VII) by multivariable logistic and Cox regression analyses, as well as Kaplan-Meier estimates. RESULTS: There was no increase in rates of mortality (30-day mortality 4.2% vs 7.0% with P = .418; follow-up survival 85.6% at 13.0 [interquartile range, 8.4-15.7] months vs 80.7% at 10.2 [interquartile range, 7.2-16.1] months with P = .151), thromboembolic complications (6.6% vs 9.6% with P = .637), renal insufficiency, need for percutaneous coronary intervention, duration of ventilation, duration of hospital stay, or rehospitalization in patients receiving very low-dose recombinant activated factor VII compared with patients not receiving recombinant activated factor VII. Complete hemostasis without any need for further hemostatic treatment was achieved after very low-dose recombinant activated factor VII administration in the majority of patients (up to 88.6% vs 0% with P < .001). The key results were confirmed after adjustment by propensity score-based analyses. CONCLUSIONS: When combined with early and specific restoration of hemostatic reserves after cardiac surgery, very low-dose recombinant activated factor VII treatment of refractory bleeding is effective and not associated with any apparent increase in adverse events.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Coagulantes/uso terapêutico , Fator VIIa/uso terapêutico , Hemorragia Pós-Operatória/prevenção & controle , Idoso , Procedimentos Cirúrgicos Cardíacos/métodos , Coagulantes/administração & dosagem , Coagulantes/efeitos adversos , Fator VIIa/administração & dosagem , Fator VIIa/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico
7.
Ann Hematol ; 97(10): 1889-1901, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29804265

RESUMO

To conduct a systematic review of the literature reporting efficacy and safety of recombinant factor VIIa (rFVIIa) for the treatment of bleeding in acquired haemophilia and, if data permitted, undertake a meta-analysis of the current evidence. MEDLINE®, Embase®, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for all studies on rFVIIa treatment in acquired haemophilia. Heterogeneity of included studies was measured using the inconsistency index (I2). Of the 2353 publications screened, 290 potentially relevant references were identified: 12 studies published in 32 publications met inclusion criteria. In total, 1244 patients and 1714 bleeds were included (671 patients received rFVIIa treatment for 1063 bleeds). In seven of 12 studies, the initial dose of Recombinant FVIIa was 90 ± 10 µg/kg. Recombinant FVIIa was used as first-line therapy in the majority of cases. Median number of doses administered ranged from 10 to 28. Between 68 and 74% of bleeds were spontaneous, whereas 4-50% were traumatic. Thirty-nine to 90% of bleeds were severe. Haemostatic effectiveness was > 90% in 5/6 studies for both patient and bleed level. Recombinant FVIIa had a favourable safety profile with low risk of general adverse events and thromboembolic-associated events. The heterogeneity of the studies and data precluded a meta-analysis. Recombinant FVIIa demonstrated effectiveness for the treatment of bleeds and had a good safety profile. It is apparent from these data that there is a need for more standardised measures of clinical effectiveness in acquired haemophilia to enable comparison and pooling of results in the future.


Assuntos
Fator VIIa/uso terapêutico , Hemofilia A/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Fator VIIa/efeitos adversos , Feminino , Hemofilia A/complicações , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Tromboembolia/induzido quimicamente , Resultado do Tratamento , Adulto Jovem
8.
Cochrane Database Syst Rev ; 4: CD005951, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29664991

RESUMO

BACKGROUND: Outcome after spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume; up to one-third of ICHs enlarge within 24 hours of onset. Early haemostatic therapy might improve outcome by limiting haematoma growth. This is an update of a Cochrane Review first published in 2006, and last updated in 2009. OBJECTIVES: To examine 1) the effectiveness and safety of individual classes of haemostatic therapies, compared against placebo or open control, in adults with acute spontaneous intracerebral haemorrhage, and 2) the effects of each class of haemostatic therapy according to the type of antithrombotic drug taken immediately before ICH onset (i.e. anticoagulant, antiplatelet, or none). SEARCH METHODS: We searched the Cochrane Stroke Trials Register, CENTRAL; 2017, Issue 11, MEDLINE Ovid, and Embase Ovid on 27 November 2017. In an effort to identify further published, ongoing, and unpublished randomised controlled trials (RCT), we scanned bibliographies of relevant articles and searched international registers of RCTs in November 2017. SELECTION CRITERIA: We sought randomised controlled trials (RCTs) of any haemostatic intervention (i.e. pro-coagulant treatments such as coagulation factors, antifibrinolytic drugs, or platelet transfusion) for acute spontaneous ICH, compared with placebo, open control, or an active comparator, reporting relevant clinical outcome measures. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias, and contacted corresponding authors of eligible RCTs for specific data if they were not provided in the published report of an RCT. MAIN RESULTS: We included 12 RCTs involving 1732 participants. There were seven RCTs of blood clotting factors versus placebo or open control involving 1480 participants, three RCTs of antifibrinolytic drugs versus placebo or open control involving 57 participants, one RCT of platelet transfusion versus open control involving 190 participants, and one RCT of blood clotting factors versus fresh frozen plasma involving five participants. We were unable to include two eligible RCTs because they presented aggregate data for adults with ICH and other types of intracranial haemorrhage. We identified 10 ongoing RCTs. Across all seven criteria in the 12 included RCTs, the risk of bias was unclear in 37 (44%), high in 16 (19%), and low in 31 (37%). Only one RCT was at low risk of bias in all criteria.In one RCT of platelet transfusion versus open control for acute spontaneous ICH associated with antiplatelet drug use, there was a significant increase in death or dependence (modified Rankin Scale score 4 to 6) at day 90 (70/97 versus 52/93; risk ratio (RR) 1.29, 95% confidence interval (CI) 1.04 to 1.61, one trial, 190 participants, moderate-quality evidence). All findings were non-significant for blood clotting factors versus placebo or open control for acute spontaneous ICH with or without surgery (moderate-quality evidence), for antifibrinolytic drugs versus placebo (moderate-quality evidence) or open control for acute spontaneous ICH (moderate-quality evidence), and for clotting factors versus fresh frozen plasma for acute spontaneous ICH associated with anticoagulant drug use (no evidence). AUTHORS' CONCLUSIONS: Based on moderate-quality evidence from one trial, platelet transfusion seems hazardous in comparison to standard care for adults with antiplatelet-associated ICH.We were unable to draw firm conclusions about the efficacy and safety of blood clotting factors for acute spontaneous ICH with or without surgery, antifibrinolytic drugs for acute spontaneous ICH, and clotting factors versus fresh frozen plasma for acute spontaneous ICH associated with anticoagulant drug use.Further RCTs are warranted, and we await the results of the 10 ongoing RCTs with interest.


Assuntos
Ácido Aminocaproico/uso terapêutico , Antifibrinolíticos/uso terapêutico , Hemorragia Cerebral/tratamento farmacológico , Fator VIIa/uso terapêutico , Hemostáticos/uso terapêutico , Doença Aguda , Adulto , Antifibrinolíticos/efeitos adversos , Hemorragia Cerebral/mortalidade , Progressão da Doença , Fator VIIa/efeitos adversos , Hemostasia , Humanos , Plasma , Transfusão de Plaquetas/efeitos adversos , Transfusão de Plaquetas/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico
9.
Am J Surg ; 215(5): 775-779, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29338845

RESUMO

INTRODUCTION: Life-threatening bleeding can complicate warfarin therapy. Rapid anticoagulant reversal via replacement of vitamin-K dependent clotting factors is essential for hemostasis. We compare two methods of rapid factor replacement for warfarin reversal. METHODS: A retrospective cohort study of warfarin-treated patients experiencing life-threatening bleeding who received a reversal protocol comprised of 4F PCC or 3F PCC and rFVIIa was performed. Demographic, clinical and anticoagulant reversal information, and all adverse events attributed to warfarin reversal were recorded. RESULTS: 195 patients were included in final analysis. While baseline demographics were similar between groups, the 3F-PCC group had a longer ICU LOS and higher in-hospital mortality (p < .01, .01). Pre-reversal INR was similar between both groups, but post-reversal INR was significantly lower in the 3F-PCC group, 0.8 versus 1.3 (p < .01). Significantly more patients experienced thromboembolic complications in the 3F-PCC group than the 4F-PCC group (p < .01). Receipt of rFVIIa was significantly associated with thromboembolic complications. DISCUSSION: A 4F PCC reversal strategy is efficacious in INR reversal and provides lower thromboembolic risk as compared to 3F PCC with rFVIIa.


Assuntos
Anticoagulantes/efeitos adversos , Fatores de Coagulação Sanguínea/efeitos adversos , Fator VIIa/efeitos adversos , Hemostasia , Tromboembolia/induzido quimicamente , Varfarina/efeitos adversos , Idoso , Fatores de Coagulação Sanguínea/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Feminino , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Humanos , Coeficiente Internacional Normatizado , Masculino , Proteínas Recombinantes/efeitos adversos , Estudos Retrospectivos , Varfarina/administração & dosagem
11.
J Thromb Haemost ; 16(1): 131-141, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29080382

RESUMO

Essentials Factor XIII (FXIII)-mediated fibrin crosslinking is delayed in hemophilia. We determined effects of FXIII cotreatment with hemostatic agents on clot parameters. FXIII cotreatment accelerated FXIII activation and crosslinking of fibrin and α2 -antiplasmin. These data provide biochemical rationale for FXIII cotreatment in hemophilia. SUMMARY: Background Hemophilia A results from the absence, deficiency or inhibition of factor VIII. Bleeding is treated with hemostatic agents (FVIII, recombinant activated FVII [rFVIIa], anti-inhibitor coagulation complex [FEIBA], or recombinant porcine FVIII [rpFVIII]). Despite treatment, some patients have prolonged bleeding. FXIII-A2 B2 (FXIII) is a protransglutaminase. During clot contraction, thrombin-activated FXIII (FXIIIa) crosslinks fibrin and α2 -antiplasmin, which promotes red blood cell retention and increases clot stability and weight. We hypothesized that FXIII cotreatment in hemophilia would accelerate FXIII activation, leading to increased fibrin crosslinking. Methods FVIII-deficient plasma and whole blood were clotted with or without hemostatic agents (FVIII, rFVIIa, FEIBA, or recombinant B-domain-deleted porcine FVIII [rpFVIII]) and/or FXIII. The effects on FXIII activation, thrombin generation, fibrin and α2 -antiplasmin crosslinking, clot formation and clot weight were measured by western blotting, calibrated automated thrombography, thromboelastography, and clot contraction assays. Results As compared with FVIII-treated hemophilic plasma, FVIII + FXIII cotreatment accelerated FXIIIa formation without increasing thrombin generation. As compared with buffer-treated or FXIII-treated hemophilic plasma, FVIII treatment and FVIII + FXIII cotreatment increased the generation and amount of crosslinked fibrin, including α-chain-rich high molecular weight species and crosslinked α2 -antiplasmin. In the presence of FVIII inhibitors, as compared with hemostatic treatments (rFVIIa, FEIBA, or rpFVIII) alone, FXIII cotreatment increased whole blood clot weight. Conclusion In hemophilia A plasma and whole blood, FXIII cotreatment with hemostatic agents accelerated FXIIIa formation, increased the generation and amount of fibrin α-chain crosslinked species, accelerated α2 -antiplasmin crosslinking, and increased clot weight. FXIII cotreatment with hemostatic therapy may augment hemostasis through increased crosslinking of fibrin and α2 -antiplasmin.


Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Coagulantes/uso terapêutico , Fator VIII/uso terapêutico , Fator VIIa/uso terapêutico , Fator XIII/uso terapêutico , Fibrina/metabolismo , Hemofilia A/tratamento farmacológico , Idoso , Fatores de Coagulação Sanguínea/efeitos adversos , Coagulantes/efeitos adversos , Fator VIII/efeitos adversos , Fator VIIa/efeitos adversos , Fator XIII/efeitos adversos , Feminino , Fibrina/química , Hemofilia A/sangue , Hemofilia A/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , alfa 2-Antiplasmina/metabolismo
12.
Thromb Haemost ; 117(12): 2267-2273, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29212114

RESUMO

Patients with haemophilia and inhibitors to factors VIII or IX require bypassing therapy. The primary safety concern of bypassing agents is thromboembolism; however, the incidence of thromboembolic adverse events (TAEs) in haemophilia patients with inhibitors remains poorly characterized. The aim of this study was to assess the incidence of TAEs following exposure to bypassing agents in patients with haemophilia. Using U.S. Medicaid database (2000­2010), we identified a cohort of 719 males (mean age: 10 years at cohort entry) with haemophilia A or B and use of either recombinant factor VIIa (rFVIIa) or activated prothrombin complex concentrate (aPCC). Patients were followed up until loss of insurance eligibility, end of study period, or the first occurrence of TAE. Exposure was assessed on as-treated basis, and outcomes were adjudicated through review of healthcare claims. During the observation of a total of 2,823 person-years (py; mean follow-up: 3.9 years), 22 TAEs were identified, leading to incidence rates of 4.2 events (95% confidence interval [CI]: 1.8­8.3) per 1,000 unexposed py; 15.4 events (95% CI: 6.7­30.3) per 1,000 aPCC-exposed py; 18.2 events (95% CI: 8.3­34.6) per 1,000 rFVIIa-exposed py; and 29.7 events (95% CI: 6.1­86.7) per 1,000 py of concomitant exposure to both agents. The results were consistent across sensitivity analyses. In conclusion, we found no difference in the rate of TAEs across agents, but the data are compatible with a possibly increased rate associated with a combination therapy, highlighting the need for continuing safety monitoring through prospective registries or observational data.


Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Fator VIIa/uso terapêutico , Hemofilia A/epidemiologia , Hemofilia B/epidemiologia , Tromboembolia/epidemiologia , Adolescente , Adulto , Fatores de Coagulação Sanguínea/efeitos adversos , Criança , Pré-Escolar , Estudos de Coortes , Fator VIIa/efeitos adversos , Seguimentos , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Risco , Tromboembolia/etiologia , Estados Unidos/epidemiologia , Adulto Jovem
13.
J Thorac Cardiovasc Surg ; 154(6): 1852-1859.e2, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28967418

RESUMO

BACKGROUND: Surgery for acute type A aortic dissection (ATAAD) is often complicated by excessive bleeding. Recombinant factor VIIa (rFVIIa) effectively treats refractory bleeding associated with ATAAD surgery; however, adverse effects of rFVIIa in these patients have not been fully assessed. Here we evaluated rFVIIa treatment in ATAAD surgery using the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) database. METHODS: This was a multicenter, propensity score-matched, retrospective study. Information about rFVIIa use was available for 761 patients, of whom 171 were treated with rFVIIa. We successfully matched 120 patients treated with rFVIIa with 120 controls. Primary endpoints were in-hospital mortality, postoperative stroke, and renal replacement therapy (RRT). Survival data were presented using Kaplan-Meier estimates. RESULTS: Compared with controls, patients treated with rFVIIa received more transfusions of packed red blood cells (median, 9.0 U [4.0-17.0 U] vs 5.0 U [2.0-11.0 U]; P = .008), platelets (4.0 U [2.0-8.0 U] vs 2.0 U [1.0-4.4 U]; P <.001), and fresh frozen plasma (8.0 U [4.0-18.0 U] vs 5.5 U [2.0-10.3 U]; P = .01) underwent reexploration for bleeding more often (31.0% vs 16.8%; P = .014); and had greater 24-hour chest tube output (1500 L [835-2500 mL] vs 990 mL [520-1720 mL]). Treatment with rFVIIa was not associated with significantly increased rates of in-hospital mortality (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.34-1.55; P = .487), postoperative stroke (OR, 1.75; 95% CI, 0.82-3.91; P = .163), or RRT (OR, 1.18; 95% CI, 0.48-2.92; P = .839). CONCLUSIONS: In this propensity-matched cohort study of patients undergoing ATAAD surgery, treatment with rFVIIa for major bleeding was not associated with a significantly increased risk of stroke, RRT, or mortality.


Assuntos
Aneurisma Dissecante/cirurgia , Aneurisma Aórtico/cirurgia , Implante de Prótese Vascular , Coagulantes/uso terapêutico , Fator VIIa/uso terapêutico , Hemorragia Pós-Operatória/tratamento farmacológico , Doença Aguda , Idoso , Aneurisma Dissecante/diagnóstico por imagem , Aneurisma Dissecante/mortalidade , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/mortalidade , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/mortalidade , Coagulantes/efeitos adversos , Fator VIIa/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/etiologia , Hemorragia Pós-Operatória/mortalidade , Pontuação de Propensão , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Países Escandinavos e Nórdicos , Fatores de Tempo , Resultado do Tratamento
14.
Haemophilia ; 23(6): 844-851, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28984010

RESUMO

INTRODUCTION: Varying initial doses of activated eptacog beta (recombinant human FVIIa, rhFVIIa) may provide therapeutic options when treating bleeding in patients with congenital haemophilia who have developed inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX). This study evaluated escalated doses of a new rhFVIIa product as a prelude to selecting the doses for clinical efficacy evaluation in haemophilia patients. AIM: To assess the safety, pharmacokinetics, and laboratory pharmacodynamics of 3 doses of rhFVIIa in non-bleeding patients with congenital haemophilia A or B with or without inhibitors. METHODS: Adult male patients (18-75 years old) with congenital haemophilia A or B (with or without inhibitors) received infusions of rhFVIIa at doses of 25, 75 or 225 µg/kg body weight. Ten patients were treated at each dose level, and each patient received 2 different dose levels. Descriptive methods were used to analyse the data. RESULTS: Administration of rhFVIIa at all doses was well tolerated. Pharmacokinetic analyses showed that peak FVIIa plasma levels (Cmax ) were approximately proportional to dose and correlated well with peak thrombin generation. Total AUC0-inf also was approximately dose proportional. Clot formation and duration correlated with FVIIa activity. Repeat doses did not produce an immunological response. CONCLUSION: In the first dose-escalation study of rhFVIIa to support product registration, eptacog beta at doses of 25, 75, and 225 µg/kg was pharmacodynamically active and well tolerated in non-bleeding patients with congenital haemophilia A or B.


Assuntos
Fator VIIa/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Adulto , Área Sob a Curva , Tontura/induzido quimicamente , Relação Dose-Resposta a Droga , Fator VIIa/efeitos adversos , Fator VIIa/farmacocinética , Cefaleia/induzido quimicamente , Hemofilia A/metabolismo , Hemofilia B/metabolismo , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Adulto Jovem
15.
Haemophilia ; 23(6): 832-843, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28776894

RESUMO

INTRODUCTION: Haemophilia A or B patients with inhibitors have been treated with FVIIa-containing bypassing agents for over 20 years. However, due to uncertainty regarding dose response and thrombotic risk, the use of a gradual, titrated, minimal dosing strategy remains prevalent, potentially hampering early haemostasis. AIM: Evaluate the dose-dependent efficacy, safety and immunogenicity of activated eptacog beta (rhFVIIa), a new recombinant inhibitor bypassing agent for the treatment of bleeding episodes (BEs). METHODS: A Phase 3, randomized, cross-over study of initial dose regimens (IDRs) in 27 bleeding congenital haemophilia A or B subjects with inhibitors was conducted to evaluate on-demand treatment of mild/moderate BEs. Intravenous 75 µg/kg or 225 µg/kg initial doses with 75 µg/kg subsequent doses by schedule were administered until clinical response. RESULTS: The primary endpoint was sustained clinical response within 12 hours, determined by a composite of objective and pain measures. In the 75 µg/kg IDR, 84.9% (95% CI; 74.0%, 95.7%) of mild/moderate BEs at 12 hours were successfully treated compared to 93.2% (95% CI; 88.1%, 98.3%) treated in the 225 µg/kg IDR. Efficacy between the IDRs was statistically different (P<.020) in mild/moderate bleeding episodes. Both IDRs were well tolerated with no detectable immunogenic or thrombotic responses to rhFVIIa or host cell proteins. CONCLUSION: The dose-dependent efficacy seen in this study supports individualizing the initial dose of eptacog beta to optimize clinical response. By reducing uncertainty, the PERSEPT 1 results should increase the adoption of early haemostasis as a treatment goal for clinicians who treat haemorrhage in the inhibitor population.


Assuntos
Fator VIIa/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Hemorragia/tratamento farmacológico , Proteínas Recombinantes/uso terapêutico , Adolescente , Adulto , Estudos Cross-Over , Relação Dose-Resposta a Droga , Fator VIIa/administração & dosagem , Fator VIIa/efeitos adversos , Cefaleia/induzido quimicamente , Hemartrose/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Adulto Jovem
17.
Haemophilia ; 23(4): 575-582, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28440004

RESUMO

INTRODUCTION: A room temperature stable formulation of recombinant activated factor VII (NovoSeven® ), allowing convenient storage and therefore improved treatment access, has been developed. Bioequivalence to the previous NovoSeven® was demonstrated in healthy humans, leading to European approval (2008). Although no confirmed cases of neutralising antibodies to rFVIIa in patients with haemophilia A or B have been observed with the original formulation, changes in formulation or storage condition may alter immunogenicity. AIM: SMART-7™ was designed to investigate the safety of NovoSeven® in a real-world setting in patients with haemophilia A or B with inhibitors. METHODS: Study medication was not provided by the sponsor, and treatment was at the discretion of the treating physician, in accordance with the local label. Patient baseline information was collected at enrolment. Information on safety, drug exposure and bleeding episodes was collected and FVII antibody screening was encouraged at baseline and performed at the investigator's discretion. RESULTS: Fifty-one patients were enrolled and 31 completed the study. Forty-one adverse events (AEs) were reported in 23 patients; 25 AEs in 14 patients were serious. No thromboembolic events were observed. Although four cases of reduced therapeutic response were reported, FVII antibody screening was negative. Forty-eight patients experienced 618 bleeding episodes and 93.4% of 609 evaluated bleeds were stopped by treatment. Of the 538 bleeding episodes treated with NovoSeven® monotherapy, 94.2% stopped by end of treatment. CONCLUSION: Data collected during the SMART-7™ study revealed no treatment-related safety issues and no FVII-binding antibodies for patients treated with NovoSeven® under real-world conditions.


Assuntos
Fator VIIa/efeitos adversos , Fator VIIa/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia B/tratamento farmacológico , Segurança , Temperatura , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estabilidade de Medicamentos , Fator VIIa/farmacologia , Feminino , Hemofilia A/complicações , Hemofilia B/complicações , Hemorragia/complicações , Humanos , Lactente , Internacionalidade , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Adulto Jovem
18.
Anesth Analg ; 124(5): 1431-1436, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28319507

RESUMO

BACKGROUND: Recombinant factor VIIa (rFVIIa) is routinely used as an off-label hemostatic agent in children undergoing cardiac surgery. Despite evidence that rFVIIa use is associated with an increased incidence of thrombotic complications in adult cardiac surgery, the safety of rFVIIa as a rescue hemostatic agent in the pediatric cardiac surgical population is less definitively delineated. In this retrospective study, we used propensity score matching to compare the incidence of thrombotic complications between children treated with rFVIIa and their matched controls. METHODS: We retrospectively reviewed medical records and pharmacy data from all neonates and children who underwent congenital cardiac surgery between May 1, 2011, and October 31, 2013, at Boston Children's Hospital, and identified those who received rFVIIa during the perioperative period. Using existing knowledge, we chose 10 factors associated with bleeding after cardiac surgery to be used in our propensity score: age, sex, body weight, neonates, prematurity, previous sternotomy, cardiopulmonary bypass time, deep hypothermic circulatory arrest time, aortic cross-clamp time, and the operative surgeon. We then used propensity-matched analysis to match children treated with rFVIIa with 2 controls. The primary outcome was thrombotic complications. Secondary outcomes included reexploration for bleeding, length of cardiac intensive care unit stay, length of hospital stay, and 30-day mortality. RESULTS: One hundred forty-nine patients received perioperative rFVIIa during the study period. Propensity matching yielded 143 rFVIIa patients matched to 2 control patients each (n = 286). Three control patients were found to have received rFVIIa during the perioperative course and were removed from the analysis, for a total of 283 control patients. The administration of rFVIIa was associated with an increased incidence of thrombotic complications (20% vs 8%; odds ratio [OR]: 3.9 [95% confidence interval {CI}: 2.6-5.9], P < .001). Administration of rFVIIa was associated with a prolonged median length of cardiac intensive care unit stay (8 days [interquartile range {IQR}: 4-24] vs 5 days [IQR: 2-10], P < .001) and prolonged length of hospital stay (20 [IQR: 9-44] vs 11 days [IQR: 7-23], P < .001). No difference in reexploration for bleeding (rFVII = 14% vs controls = 9%; OR: 1.7 [95% CI, 0.92-3.1], P = .12) or 30-day mortality was observed (8% vs 6%; OR 1.3 [95% CI, 0.60-2.89], P = .51). CONCLUSIONS: This retrospective analysis confirmed that perioperative administration of rFVIIa is associated with an increased incidence of postoperative thrombotic complications in neonates and children undergoing cardiac surgery, without increase in 30-day mortality. In conclusion, rFVIIa should be used with extreme caution in pediatric patients undergoing cardiac surgery.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Fator VIIa/efeitos adversos , Complicações Pós-Operatórias/induzido quimicamente , Trombose/induzido quimicamente , Adolescente , Procedimentos Cirúrgicos Cardíacos/mortalidade , Ponte Cardiopulmonar/efeitos adversos , Criança , Pré-Escolar , Parada Circulatória Induzida por Hipotermia Profunda , Cuidados Críticos/estatística & dados numéricos , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Tempo de Internação , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/mortalidade , Pontuação de Propensão , Proteínas Recombinantes/efeitos adversos , Estudos Retrospectivos , Risco , Cirurgiões , Trombose/epidemiologia , Trombose/mortalidade
19.
Asian Cardiovasc Thorac Ann ; 25(2): 99-104, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28114794

RESUMO

Objectives Recombinant activated factor VII has been used for the treatment of hemophilia, factor VII deficiency, and Glanzmann's thrombasthenia. Off-label uses have recently been increasing, and there are reports that recombinant activated factor VII is effective for the treatment of excessive bleeding during or after cardiovascular surgery. We retrospectively reviewed the effectiveness of recombinant activated factor VII and its influence on the coagulation system as a treatment for uncontrollable bleeding during cardiovascular surgery. Methods Between April 2009 and May 2015, recombinant activated factor VII was used to treat uncontrollable bleeding during cardiovascular surgery in 17 patients at our hospital. The indications for recombinant activated factor VII administration were critical uncontrollable bleeding during surgery and normal platelet and fibrinogen levels. Results Blood loss significantly decreased in every case after recombinant activated factor VII administration ( p < 0.05). No adverse thromboembolic events were encountered. The prothrombin time-international normalized ratio, activated partial thromboplastin time, fibrin degradation product and D-dimer levels decreased significantly after recombinant activated factor VII administration. One day later, all blood coagulation test values were almost within the normal ranges. Conclusions Recombinant activated factor VII has a strong hemostatic action, but it is necessary to exclude surgical bleeding to exhibit the hemostatic effect. Administration that does not comply with the indications for recombinant activated factor VII may lead to serious complications such as thromboembolism. In properly selected patients, recombinant activated factor VII is an effective agent for the treatment of uncontrollable bleeding during cardiovascular surgery.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Perda Sanguínea Cirúrgica/prevenção & controle , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Fator VIIa/uso terapêutico , Hemostáticos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Testes de Coagulação Sanguínea , Fator VIIa/efeitos adversos , Feminino , Hemostáticos/efeitos adversos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Uso Off-Label , Seleção de Pacientes , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
20.
Haemophilia ; 23(1): 50-58, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27457022

RESUMO

INTRODUCTION: Patients with acquired haemophilia A (AHA) have autoantibodies against factor VIII (FVIII), and may develop spontaneous bleeding that requires treatment with FVIII inhibitor bypassing agents such as recombinant activated FVII (rFVIIa, NovoSeven® ). However, data regarding the use of rFVIIa are limited. AIM: To investigate the use, efficacy and safety of rFVIIa for the treatment of AHA by analysis of 10-year multicentre Japanese postmarketing surveillance data. METHODS: Treatment regimens, haemostatic efficacy and adverse events were recorded for rFVIIa therapy of AHA patients with bleeding episodes. Treatment was evaluated as markedly effective, effective, moderate or ineffective. RESULTS: Data were collected for 371 bleeding episodes in 132 patients. Bleeding improved after rFVIIa therapy in 92% of episodes (markedly effective in 41%, effective in 10%, moderate in 41%). The response rate was significantly better in patients who received an initial dose of ≥90 µg kg-1 than in those who received an initial dose of <90 µg kg-1 . The response rate was also significantly better when rFVIIa was administered earlier after the onset of bleeding. Twelve serious adverse events were recorded in six patients, including five serious thromboembolic events in three patients who were all elderly with significant comorbidities. CONCLUSION: This is the largest, single-country study of rFVIIa therapy in AHA patients reported to date. The Japanese surveillance data show comparable efficacy and safety to prior multinational studies. Doses of 90-120 µg kg-1 and prompt initiation of treatment may be important to achieve good bleeding control.


Assuntos
Fator VIIa/uso terapêutico , Hemofilia A/complicações , Hemorragia/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Monitoramento Epidemiológico , Fator VIIa/efeitos adversos , Feminino , Hemofilia A/tratamento farmacológico , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Adulto Jovem
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