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1.
N Engl J Med ; 382(2): 130-139, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31733182

RESUMO

BACKGROUND: Subclinical leaflet thickening and reduced leaflet motion of bioprosthetic aortic valves have been documented by four-dimensional computed tomography (CT). Whether anticoagulation can reduce these phenomena after transcatheter aortic-valve replacement (TAVR) is not known. METHODS: In a substudy of a large randomized trial, we randomly assigned patients who had undergone successful TAVR and who did not have an indication for long-term anticoagulation to a rivaroxaban-based antithrombotic strategy (rivaroxaban [10 mg] plus aspirin [75 to 100 mg] once daily) or an antiplatelet-based strategy (clopidogrel [75 mg] plus aspirin [75 to 100 mg] once daily). Patients underwent evaluation by four-dimensional CT at a mean (±SD) of 90±15 days after randomization. The primary end point was the percentage of patients with at least one prosthetic valve leaflet with grade 3 or higher motion reduction (i.e., involving >50% of the leaflet). Leaflet thickening was also assessed. RESULTS: A total of 231 patients were enrolled. At least one prosthetic valve leaflet with grade 3 or higher motion reduction was found in 2 of 97 patients (2.1%) who had scans that could be evaluated in the rivaroxaban group, as compared with 11 of 101 (10.9%) in the antiplatelet group (difference, -8.8 percentage points; 95% confidence interval [CI], -16.5 to -1.9; P = 0.01). Thickening of at least one leaflet was observed in 12 of 97 patients (12.4%) in the rivaroxaban group and in 33 of 102 (32.4%) in the antiplatelet group (difference, -20.0 percentage points; 95% CI, -30.9 to -8.5). In the main trial, the risk of death or thromboembolic events and the risk of life-threatening, disabling, or major bleeding were higher with rivaroxaban (hazard ratios of 1.35 and 1.50, respectively). CONCLUSIONS: In a substudy of a trial involving patients without an indication for long-term anticoagulation who had undergone successful TAVR, a rivaroxaban-based antithrombotic strategy was more effective than an antiplatelet-based strategy in preventing subclinical leaflet-motion abnormalities. However, in the main trial, the rivaroxaban-based strategy was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than the antiplatelet-based strategy. (Funded by Bayer; GALILEO-4D ClinicalTrials.gov number, NCT02833948.).


Assuntos
Valva Aórtica/fisiopatologia , Aspirina/farmacologia , Clopidogrel/farmacologia , Inibidores do Fator Xa/farmacologia , Próteses Valvulares Cardíacas , Inibidores da Agregação de Plaquetas/farmacologia , Rivaroxabana/farmacologia , Substituição da Valva Aórtica Transcateter , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/efeitos dos fármacos , Valva Aórtica/patologia , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Doenças Cardiovasculares/mortalidade , Clopidogrel/efeitos adversos , Clopidogrel/uso terapêutico , Quimioterapia Combinada , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/uso terapêutico , Feminino , Tomografia Computadorizada Quadridimensional , Hemorragia/induzido quimicamente , Humanos , Análise de Intenção de Tratamento , Masculino , Inibidores da Agregação de Plaquetas/efeitos adversos , Inibidores da Agregação de Plaquetas/uso terapêutico , Rivaroxabana/efeitos adversos , Rivaroxabana/uso terapêutico , Tromboembolia/etiologia , Tromboembolia/mortalidade
2.
Res Vet Sci ; 127: 113-121, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31693942

RESUMO

The aim of this study was to establish a thrombin generation assay (calibrated automated thrombogram, CAT) in cats by determining the precision (repeatability), reference values, and the sensitivity to anticoagulant treatment with the factor Xa inhibitor apixaban. The CAT method was performed on citrated plasma with different commercial tissue factor (TF) reagents (PPP Reagent 1 pM [LOW], PPP Reagent 5 pM, PPP Reagent 20 pM [HIGH]) according to the manufacturers` test instruction. Measurements in triplicate were performed in platelet poor plasma (PPP) of 58 healthy cats and in 6 cats at different times following the oral administration of 2.5 mg apixaban. The median CVs in healthy cats usually were < 10% with the exception of thrombin peak height measured using PPP Reagent 1 pM (14.6%). Reference values of all parameters showed marked inter-individual variability and depended largely on the TF concentration of the used activating reagent. Thrombin generation was significantly influenced by apixaban and reacted more sensitively than other tests of haemostasis including the prothrombin time, aPTT, and rotational elastometry. In conclusion, thrombin generation measured by the CAT method using commercially available reagents seems suitable for the examination of feline PPP and may be a valuable method to establish effective anticoagulant therapies for the feline patient and monitoring of such therapies in cats.


Assuntos
Testes de Coagulação Sanguínea/veterinária , Inibidores do Fator Xa/farmacologia , Pirazóis/farmacologia , Piridonas/farmacologia , Trombina/análise , Tromboplastina/análise , Animais , Testes de Coagulação Sanguínea/métodos , Gatos , Valores de Referência
4.
Eur J Med Chem ; 183: 111722, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31563807

RESUMO

Thrombosis is a pathological coagulation process and can lead to many serious thrombotic diseases. Here, we report a novel potent antithrombotic compound (6k) based on isosteviol with anticoagulant and antiplatelet activities. 6k selectively inhibited FXa (Ki = 0.015 µM) against a panel of serine proteases and showed excellent anticoagulant activity (significant prolongation of ex vivo PT and aPTT over the vehicle, p < 0.01). 6k also significantly inhibited ADP-induced platelet aggregation in rats relative to the vehicle (p < 0.01). Furthermore, 6k exhibited potent ex vivo and in vivo antithrombotic activity in rats relative to the vehicle (p < 0.01 and p < 0.0001, respectively). Novel structure 6k, with potent antithrombotic activity, is expected to lead a promising approach for the development of antithrombotic agents.


Assuntos
Diterpenos de Caurano/química , Diterpenos de Caurano/farmacologia , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacologia , Trombose/tratamento farmacológico , Animais , Descoberta de Drogas , Inibidores do Fator Xa/química , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Tempo de Tromboplastina Parcial , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Wistar , Trombina/metabolismo
5.
Toxicol Lett ; 316: 171-182, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442586

RESUMO

Australian elapid snakes are some of the most venomous snakes in the world and are unique among venomous snakes in having mutated forms of the blood clotting factor X in an activated form (FXa) as a key venom component. In human bite victims, an overdose of this activated clotting enzyme results in the systemic consumption of fibrinogen due to the large amounts of endogenous thrombin generated by the conversion of prothrombin to thrombin by venom FXa. Within Australian elapids, such procoagulant venom is currently known from the tiger snake clade (Hoplocephalus, Notechis, Paroplocephalus, and Tropidechis species), brown/taipan (Oxyuranus and Pseudonaja species) clade, and the red-bellied black snake Pseudechis porphyriacus. We used a STA-R Max coagulation analyser and TEG5000 thromboelastographers to test 47 Australian elapid venoms from 19 genera against human plasma in vitro. In addition to activity being confirmed in the two clades above, FXa-driven potent procoagulant activity was found in four additional genera (Cryptophis, Demansia, Hemiaspis, and Suta). Ontogenetic changes in procoagulant function was also identified as a feature of Suta punctata venom. Phylogenetic analysis of FX sequences confirmed that snake venom FXa toxins evolved only once, that the potency of these toxins against human plasma has increased in a stepwise fashion, and that multiple convergent amplifications of procoagulant activity within Australian elapid snakes have occurred. Cofactor dependence tests revealed all procoagulant venoms in our study, except those of the tiger snake clade, to be highly calcium-dependent, whereas phospholipid dependence was less of a feature but still displayed significant variation between venoms. Antivenom testing using CSL Tiger Snake Antivenom showed broad but differential cross-reactivity against procoagulant venoms, with P. porphyriacus and S. punctata extremely well neutralised but with Cryptophis, Demansia, and Hemiaspis less well-neutralised. The relative variation was not in accordance to genetic relatedness of the species used in antivenom production (Notechis scutatus), which underscores a fundamental principle that the rapid evolution characteristic of venoms results in organismal phylogeny being a poor predictor of antivenom efficacy. Our results have direct and immediate implications for the design of clinical management plans in the event of snakebite by such lesser known Australian elapid snake species that have been revealed in this study to be as potent as the better studied, and proven lethal, species.


Assuntos
Antivenenos/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Venenos Elapídicos/antagonistas & inibidores , Elapidae , Inibidores do Fator Xa/farmacologia , Fator Xa/metabolismo , Mordeduras de Serpentes/tratamento farmacológico , Animais , Reações Cruzadas , Venenos Elapídicos/genética , Venenos Elapídicos/imunologia , Venenos Elapídicos/metabolismo , Elapidae/classificação , Elapidae/genética , Elapidae/imunologia , Elapidae/metabolismo , Evolução Molecular , Fator Xa/genética , Fator Xa/imunologia , Fibrinólise/efeitos dos fármacos , Mutação , Filogenia , Mordeduras de Serpentes/imunologia , Mordeduras de Serpentes/metabolismo , Tromboelastografia
6.
Int J Mol Sci ; 20(17)2019 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-31450643

RESUMO

The interplay between oxidative stress, inflammation, and tissue fibrosis leads to the progression of chronic kidney disease (CKD). Edoxaban, an activated blood coagulation factor Xa (FXa) inhibitor, ameliorates kidney disease by suppressing inflammation and tissue fibrosis in animal models. Interestingly, rivaroxaban, another FXa inhibitor, suppresses oxidative stress induced by FXa. Thus, FXa inhibitors could be multitargeted drugs for the three aforementioned risk factors for the progression of CKD. However, the exact mechanism responsible for eliciting the antioxidant effect of FXa inhibitors remains unclear. In this study, the antioxidant effect of edoxaban was evaluated. First, the intracellular antioxidant properties of edoxaban were evaluated using human proximal tubular cells (HK-2 cells). Next, direct radical scavenging activity was measured using the electron spin resonance and fluorescence analysis methods. Results show that edoxaban exhibited antioxidant effects on oxidative stress induced by FXa, indoxyl sulfate, and angiotensin II in HK-2 cells, as well as the FXa inhibitory activity, was involved in part of the antioxidant mechanism. Moreover, edoxaban exerted its antioxidative effect through its structure-specific direct radical scavenging activity. Edoxaban exerts antioxidant effects by inhibiting FXa and through direct radical-scavenging activity, and thus, may serve as multitargeted drugs for the three primary risk factors associated with progression of CKD.


Assuntos
Inibidores do Fator Xa/farmacologia , Depuradores de Radicais Livres/farmacologia , Piridinas/farmacologia , Tiazóis/farmacologia , Anticoagulantes/química , Anticoagulantes/farmacologia , Linhagem Celular , Espectroscopia de Ressonância de Spin Eletrônica , Inibidores do Fator Xa/química , Depuradores de Radicais Livres/química , Humanos , Radical Hidroxila/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Piridinas/química , Espécies Reativas de Oxigênio/metabolismo , Tiazóis/química
7.
Medicina (Kaunas) ; 55(8)2019 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-31382702

RESUMO

Valvular heart disease and atrial fibrillation often coexist. Oral vitamin K antagonists have represented the main anticoagulation management for antithrombotic prevention in this setting for decades. Novel direct oral anticoagulants (DOACs) are a new class of drugs and currently, due to their well-established efficacy and security, they represent the main therapeutic option in non-valvular atrial fibrillation. Some new evidences are exploring the role of DOACs in patients with valvular atrial fibrillation (mechanical and biological prosthetic valves). In this review we explore the data available in the medical literature to establish the actual role of DOACs in patients with valvular heart disease and atrial fibrillation.


Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Doenças das Valvas Cardíacas/tratamento farmacológico , Anticoagulantes/farmacologia , Fibrilação Atrial/fisiopatologia , Inibidores do Fator Xa/farmacologia , Inibidores do Fator Xa/uso terapêutico , Doenças das Valvas Cardíacas/fisiopatologia , Humanos , Fatores de Risco
8.
Clin Appl Thromb Hemost ; 25: 1076029619863493, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31298056

RESUMO

Recombinant coagulation factor Xa (FXa), inactivated Zh-zo, also known as andexanet alfa (AA), is a modified version of human FXa that has been developed to neutralize FXa inhibitors. We studied the reversal effect of AA for these inhibitors in various anticoagulant and thrombin generation (TG) assays. Individual aliquots of normal human plasma containing 1 µg/mL of apixaban, betrixaban, edoxaban, and rivaroxaban, were supplemented with saline or AA at a concentration of 100 µg/mL. Clotting profiles include prothrombinase-induced clotting time, activated partial thromboplastin time, and prothrombin time. Factor Xa activity was measured using an amidolytic method. Thrombin generation was measured using a calibrated automated thrombogram. Differential neutralization of all 4 anticoagulants was noted in the activated clotting time and other clotting tests. The FXa activity reversal profile varied with an observed decrease in apixaban (22%), betrixaban (56%), edoxaban (28%), and rivaroxaban (49%). Andexanet alfa also led to an increased TG in comparison to saline. The peak thrombin was higher (40%), area under the curve (AUC) increased (15%), whereas the lag time (LT) decreased (17%). Andexanet alfa added at 100 µg/mL to various FXa supplemented systems resulted in reversal of the inhibitory effects, restoring the TG profile; AUC, LT, and peak thrombin levels were comparable to those of unsupplemented samples. Andexanet alfa is capable of reversing anti-Xa activity of different oral FXa inhibitors but overshoots thrombogenesis in both the saline and FXa inhibitor supplemented systems. The degree of neutralization of Xa inhibitor is specific to each agent.


Assuntos
Antagonismo de Drogas , Inibidores do Fator Xa/farmacologia , Fator Xa/farmacologia , Proteínas Recombinantes/farmacologia , Trombina/biossíntese , Anticoagulantes/farmacologia , Benzamidas/farmacologia , Testes de Coagulação Sanguínea , Inibidores do Fator Xa/química , Humanos , Pirazóis/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Rivaroxabana/farmacologia , Tiazóis/farmacologia , Trombina/efeitos dos fármacos
9.
J Vasc Res ; 56(4): 181-190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31266015

RESUMO

BACKGROUND: Coagulant factor Xa inhibitors (XaIs) are prescribed for patients with atrial fibrillation for years. METHODS: Human umbilical venous endothelial cells (HUVECs) were cultured with or without (w/wo) a XaI (rivaroxaban) under high glucose (HG: 22 mM). Endothelial senescence was investigated by assessing senescence-associated-ß-galactosidase (SA-ß-gal), p53, and telomere length. Endothelial function and atherosclerosis were examined by nitric oxide-related-products (NOx: NO2- and NO3-), O2-, endothelial NO synthase (eNOS), NADPH oxidase (p22phox), and ICAM1. PAR1 (protease-activated receptor 1) and PAR2, which were reported to regulate eNOS phosphorylation, were inhibited by small interfering RNAs (siRNAs). Thirty-two male dyslipidemic type 2 diabetic rats (ZFDM LepRfa/fa) were fed a high-cholesterol diet w/wo XaI (50 µg/day/kg) for 1-4 weeks. RESULTS: SA-ß-gal, p53, p21, and p16INK4a were increased by HG and restored by XaI (50 nM) in HUVECs. XaI restored telomerase activity and preserved telomere length. XaI suppressed O2-, p22phox, and ICAM1 and restored NOx and eNOS. XaI decreased PAR1 following elevation by HG, which was confirmed by PAR1 siRNA and PAR2 siRNA. In in vivo experiments, plasma glucose, total cholesterol, and triglycerides were increased for 4 weeks but were not changed by XaI. XaI decreased SA-ß-gal and telomerase and preserved telomere length in the aortic endothelium. XaI activated eNOS, inhibited p22phox, increased plasma NOx, and decreased O2-. CONCLUSION: Rivaroxaban prevents replicative senescence in HUVECs and aortic endothelial cells in dyslipidemic diabetic mice. It restores endothelial function and prevents the progression of atherosclerosis.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Inibidores do Fator Xa/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Rivaroxabana/farmacologia , Animais , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/patologia , Glicemia/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Dieta Hiperlipídica , Modelos Animais de Doenças , Dislipidemias/sangue , Dislipidemias/complicações , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Lipídeos/sangue , Óxido Nítrico/metabolismo , Ratos Zucker , Espécies Reativas de Oxigênio/metabolismo , Receptores Ativados por Proteinase/metabolismo , Transdução de Sinais , Telomerase/metabolismo
10.
Thromb Haemost ; 119(9): 1419-1432, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31266079

RESUMO

The activation of protease-activated receptor (PAR)-2 by factor Xa (fXa) promotes the release of tissue factor-positive microvesicles (TF+MV), and contributes to proliferation in cancer cells. This study examined the ability of direct oral anticoagulants (DOACs), apixaban and rivaroxaban, to inhibit the release of TF+MV from two cell lines (MDA-MB-231 and AsPC-1) as well as cell proliferation.Activation of the cells with fXa (10 nM) enhanced the release of TF+MV but was suppressed in the presence of either DOAC. These MVs were found to contain fVIIa, but not fXa. Incubation of cell lines with apixaban (1.8 µM) but not rivaroxaban (1.8 µM), in the absence of fXa decreased the release of TF+MV below that of resting cells, in a PAR2-dependent manner. Furthermore, incubation with apixaban reduced the proliferation rate in both cells lines. Incubation of purified fVIIa with apixaban but not rivaroxaban resulted in complete inhibition of fVIIa proteolytic activity as measured using two fVIIa chromogenic substrates. Pre-incubation of the cells with an inhibitory anti-fVIIa antibody, with apixaban or the blocking of PAR2 suppressed the release of TF+MV to a comparable level, and reduced cell proliferation but the effect was not cumulative.This study has established that the activation of PAR2 by TF-fVIIa complex is the principal mediator in augmenting the release of TF+MV as well as cancer cell proliferation. Importantly, for the first time we have shown that apixaban selectively inhibits the proteolytic activity of fVIIa as well as the signalling arising from the TF-fVIIa complex.


Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Micropartículas Derivadas de Células/metabolismo , Inibidores do Fator Xa/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Pirazóis/farmacologia , Piridonas/farmacologia , Tromboplastina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Fator VIIa/metabolismo , Feminino , Humanos , Receptor PAR-2/metabolismo , Rivaroxabana/farmacologia , Transdução de Sinais
11.
Expert Rev Clin Pharmacol ; 12(8): 771-780, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31269825

RESUMO

Introduction: The current approach of using only antiplatelet therapy for secondary prevention leaves a substantial risk of recurrent cardiovascular complications and mortality. Areas covered: In this manuscript, the role of coagulation in atherothrombosis is reviewed, as well as the impact of vascular doses of rivaroxaban on major cardiovascular outcomes and major adverse limb events. Expert opinion: In COMPASS, among patients with coronary heart disease and/or peripheral artery disease, compared to aspirin, the addition of rivaroxaban 2.5 mg twice daily to aspirin, significantly reduced the risk of major atherosclerotic outcomes, cardiovascular death and death for any cause, with a significant increase in the risk of major bleeding, but not fatal or intracranial bleedings. Preclinical data strongly suggest that rivaroxaban exerts vascular protection through different mechanisms, including improvement of endothelial functionality and fibrinolytic activity at endothelium, anti-inflammatory properties, and platelet-dependent thrombin generation. All these data indicate that among patients with atherosclerotic vascular disease, the addition of rivaroxaban 2.5 mg may provide further vascular protection.


Assuntos
Aterosclerose/prevenção & controle , Inibidores do Fator Xa/administração & dosagem , Rivaroxabana/administração & dosagem , Animais , Aspirina/administração & dosagem , Aterosclerose/patologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/prevenção & controle , Quimioterapia Combinada , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/farmacologia , Hemorragia/induzido quimicamente , Humanos , Rivaroxabana/efeitos adversos , Rivaroxabana/farmacologia , Prevenção Secundária/métodos
12.
Pediatr Cardiol ; 40(7): 1431-1438, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31327027

RESUMO

Venous thromboembolism (VTE) is a rare, but life-threatening disease in those who have not reached their adulthood. This condition is usually treated with heparin or low molecular weight heparins which require parenteral administration and, in case of unfractionated heparin, also frequent laboratory monitoring and dose adjustment. Direct oral anticoagulants (DOACs)-direct thrombin inhibitor dabigatran, and direct oral factor Xa inhibitors rivaroxaban, apixaban, and edoxaban-are currently frequently used for the prevention and treatment of VTE in adult population. In fact, these agents offer several advantages compared to traditional agents, such as oral route of administration, short on-set and off-set of action, predictable pharmacologic profile with low risk of food and drug interactions, and no need for routine laboratory assessment of anticoagulant activity. However, clinical experience with these directly acting oral anticoagulants in pediatric population is very limited as these drugs had been tested and are used mostly in adult individuals. This article reviews the current data from pre- and post-marketing studies reporting the use of DOACs for the treatment of VTE in pediatric patients.


Assuntos
Inibidores do Fator Xa/administração & dosagem , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Criança , Ensaios Clínicos como Assunto , Inibidores do Fator Xa/farmacologia , Humanos
13.
Med Sci Monit ; 25: 5473-5481, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31335859

RESUMO

BACKGROUND The aim of this study was to systematically evaluate the effect of oral Xa inhibitors plus antiplatelet therapy in the treatment of coronary artery disease. MATERIAL AND METHODS All randomized controlled trials (RCTs) about antiplatelet therapy plus Xa factor inhibitors for coronary artery disease from database inception to January 2019 were searched for and collected from PubMed, Embase, and the Cochrane Library. Two reviewers extracted and analyzed the data independently. Additionally, RevMan 5.0 software was applied for meta-analysis. RESULTS Seven RCTs with 50 044 patients were included. The meta-analysis results showed that treatment with antiplatelet therapy plus Xa factor inhibitors in patients with coronary artery disease could significantly reduce the risk of ischemic events (P<0.00001). Besides, risk of all-cause mortality (P=0.003), myocardial infarction (P=0.02) and ischemic stroke (P<0.0001) were also significantly reduced. However, risk of massive hemorrhage after TIMI (P<0.00001), minor hemorrhage after TIMI (P<0.00001), and intracranial hemorrhage (P=0.006) were significantly increased, respectively. Xa inhibition drugs also intended to increase risk of fatal bleeding, but there was no significant difference (P=0.08). CONCLUSIONS Antiplatelet therapy plus Xa factor inhibitors in patients with coronary artery disease was effective, which could reduce the risk of ischemic composite endpoints, all-cause mortality, myocardial infarction, and ischemic stroke. However, it could significantly increase risk of bleeding in terms of safety.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Síndrome Coronariana Aguda/etiologia , Anticoagulantes/administração & dosagem , Doença da Artéria Coronariana/mortalidade , Inibidores do Fator Xa/farmacologia , Hemorragia/complicações , Humanos , Infarto do Miocárdio/etiologia , Inibidores da Agregação de Plaquetas/farmacologia , Acidente Vascular Cerebral/complicações , Resultado do Tratamento
14.
Br J Anaesth ; 123(2): 186-195, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31202564

RESUMO

BACKGROUND: Andexanet alfa (andexanet) reverses the anticoagulant effects of factor Xa inhibitors, but it has not been assessed in clinical studies for apixaban reversal in trauma. This study evaluated andexanet for reversing apixaban anticoagulation in a porcine polytrauma model. METHODS: Oral apixaban (20 mg q.d., n=21) or placebo (n=7; sham group) was administered to male pigs for 4 days before blunt liver injury and bi-lateral femur fracture. After trauma, animals were randomised 1:1:1 to a single andexanet bolus (1000 mg), a bolus (1000 mg) plus infusion (1200 mg over 2 h), or vehicle (control). Haemodynamic and coagulation variables were monitored for 5 h or until death. The primary endpoint was blood loss. RESULTS: Mean blood loss in sham animals was 472 (standard deviation, 58) ml 12 min after injury and 658 (98) ml at 300 min, with 100% survival. Anticoagulation with apixaban significantly increased blood loss 12 min after injury [888 (133) ml, P<0.01]. Controls exhibited total blood loss of 3403 (766) ml, with 100% mortality. Andexanet bolus or bolus plus infusion significantly reduced blood loss to 1264 (205) and 1202 (95) ml, respectively), and increased survival to 100%. Haemodynamic parameters and markers of shock recovered to pre-trauma levels in andexanet-treated animals. CONCLUSION: Andexanet effectively reversed apixaban anticoagulation and reduced blood loss induced by severe trauma. Andexanet bolus alone had a similar impact on survival and blood loss as bolus plus infusion. Therefore, a 2 h andexanet infusion after the bolus may not be necessary to restore normal haemostatic mechanisms.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/farmacologia , Fator Xa/farmacologia , Traumatismo Múltiplo , Pirazóis/farmacologia , Piridonas/farmacologia , Proteínas Recombinantes/farmacologia , Animais , Anticoagulantes/farmacologia , Modelos Animais de Doenças , Masculino , Suínos
15.
J Thromb Thrombolysis ; 48(3): 528-531, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31041653

RESUMO

Current guidelines recommend caution in prescribing concomitant use of direct-acting oral anticoagulants (DOACs) and antiepileptic drugs due to drug-drug interactions leading to potential risk of DOACs subtherapeutic concentration and treatment failure. Herein we report a significant interaction between carbamazepine (CZP) and apixaban, causing subtherapeutic concentration of the drug in a patient with atrial fibrillation who had a transient ischemic attack (TIA) episode. Another anti-Xa DOAC, edoxaban, administered to the patient after TIA occurrence did not show significant interaction with CZP. In addition to confirm that cautions should be used when antiepileptic and DOACs are concomitantly prescribed, the present case also demonstrates that, in the management of certain subsets of patients who need anticoagulant treatment, measurement of DOAC plasma concentration can help guide a personalized management and avoid adverse clinical outcomes.


Assuntos
Carbamazepina/farmacologia , Inibidores do Fator Xa/farmacologia , Medicina de Precisão/métodos , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Carbamazepina/uso terapêutico , Interações de Medicamentos , Monitoramento de Medicamentos , Inibidores do Fator Xa/uso terapêutico , Humanos , Ataque Isquêmico Transitório/tratamento farmacológico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Tiazóis/farmacologia , Tiazóis/uso terapêutico
16.
Eur J Clin Pharmacol ; 75(8): 1069-1075, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31139866

RESUMO

BACKGROUND: Routine laboratory monitoring of rivaroxaban and dose adjustment relating to exposure is currently not recommended. However, in certain clinical situations, assessment of rivaroxaban levels is desirable. OBJECTIVES: To examine inter- and intra-subject plasma rivaroxaban variability in patients with atrial fibrillation (AF) and to correlate these results to clinical outcomes. PATIENTS/METHODS: We included 60 patients with AF treated with rivaroxaban: half on 20 mg daily (R20) and half on 15 mg daily (R15). Three trough and peak blood samples were collected with an interval of 6-8 weeks apart. Plasma rivaroxaban concentration was measured directly by liquid chromatography-tandem mass-spectrometry (LC-MS/MS) and indirectly by anti-Xa for rivaroxaban, prothrombin time (PT), and activated partial thromboplastin time (APTT). RESULTS: Patients on R15 were older (76 ± 6 vs 71 ± 6 years), had lower creatinine clearance (60 ± 26 vs 99 ± 32 mL/min), higher CHADS2 (2.5 ± 1.2 vs 1.8 ± 1.3), all p < 0.01, but had similar rivaroxaban concentrations in trough samples to patients on R20. There was no significant intra-individual variability for trough or peak rivaroxaban concentration assessed by LC-MS/MS, anti-Xa, or PT. Trough rivaroxaban levels determined by LC-MS/MS (48 ± 30 vs 34 ± 26, p = 0.02) and anti-Xa, but not with PT and APTT, were higher in patients with bleeding than in patients without it. CONCLUSIONS: There is a pronounced inter-, but not intra-individual variability in the rivaroxaban trough levels in patients with AF. Assessment of trough rivaroxaban concentration with LC-MS/MS or anti-Xa, but not with APTT or PT, may help to identify patients at increased risk of bleeding.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Variação Biológica Individual , Variação Biológica da População , Inibidores do Fator Xa/farmacologia , Hemorragia/epidemiologia , Rivaroxabana/farmacologia , Idoso , Idoso de 80 Anos ou mais , Testes de Coagulação Sanguínea/estatística & dados numéricos , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/estatística & dados numéricos , Inibidores do Fator Xa/uso terapêutico , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Medição de Risco , Rivaroxabana/uso terapêutico
17.
Blood ; 134(8): 699-708, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31133602

RESUMO

Ixolaris is a potent tick salivary anticoagulant that binds coagulation factor Xa (FXa) and zymogen FX, with formation of a quaternary tissue factor (TF)/FVIIa/ FX(a)/Ixolaris inhibitory complex. Ixolaris blocks TF-induced coagulation and PAR2 signaling and prevents thrombosis, tumor growth, and immune activation. We present a high-resolution structure and dynamics of Ixolaris and describe the structural basis for recognition of FX. Ixolaris consists of 2 Kunitz domains (K1 and K2) in which K2 is strikingly dynamic and encompasses several residues involved in FX binding. This indicates that the backbone plasticity of K2 is critical for Ixolaris biological activity. Notably, a nuclear magnetic resonance-derived model reveals a mechanism for an electrostatically guided, high-affinity interaction between Ixolaris and FX heparin-binding (pro)exosite, resulting in an allosteric switch in the catalytic site. This is the first report revealing the structure-function relationship of an anticoagulant targeting a zymogen serving as a scaffold for TF inhibition.


Assuntos
Inibidores do Fator Xa/química , Inibidores do Fator Xa/farmacologia , Fator Xa/metabolismo , Proteínas e Peptídeos Salivares/química , Proteínas e Peptídeos Salivares/farmacologia , Animais , Fator Xa/química , Humanos , Simulação de Acoplamento Molecular , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Domínios Proteicos , Carrapatos/química
18.
Clin Appl Thromb Hemost ; 25: 1076029619847524, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31088146

RESUMO

The currently available oral anti-Xa agents are claimed to produce their anticoagulant and antithrombotic effects solely by the inhibition of factor Xa. This study profiled various anti-Xa drugs in routinely used laboratory assays to demonstrate that their effects are not solely related to the anti-Xa activities. Apixaban, betrixaban, edoxaban, and rivaroxaban were obtained commercially. Native and citrated whole blood was used for the activated clotting time (ACT) and thromboelastography (TEG). Citrated plasma was used for monitoring the prothrombin time (PT), activated partial thromboplastin time (aPTT), Heptest, and prothrombinase-induced clotting time (PiCT) tests. An amidolytic method was used for the determination of anti-Xa effects. Thrombin-induced fibrinokinetics was monitored optically. Thrombin generation studies were carried out using the calibrated automated thrombogram. All of the anti-Xa agents produced concentration- and assay-dependent effects. In the ACT at 2.5 µg/mL and TEG at 1.0 µg/mL, edoxaban exhibited the strongest anticoagulation effect. In the PiCT, PT, and aPTT assay at 1 µg/mL, edoxaban showed stronger effects than other agents. The half maximal inhibitory concentration of these agents for the inhibition of factor Xa ranged from 340 to >1000 ng/mL. In the thrombin generation inhibition assay, apixaban showed the strongest activity. In the fibrinokinetics, different anti-Xa agents produced varying degrees of inhibition. These results demonstrate that the measured anti-Xa activity alone does not fully reflect the overall biologic spectrum of these agents.


Assuntos
Benzamidas , Inibidores do Fator Xa , Fator Xa/metabolismo , Tempo de Protrombina , Pirazóis , Piridinas , Piridonas , Rivaroxabana , Benzamidas/farmacocinética , Benzamidas/farmacologia , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/farmacologia , Humanos , Tempo de Tromboplastina Parcial , Pirazóis/farmacocinética , Pirazóis/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Piridonas/farmacocinética , Piridonas/farmacologia , Rivaroxabana/farmacocinética , Rivaroxabana/farmacologia , Tiazóis/farmacocinética , Tiazóis/farmacologia , Tromboelastografia
19.
Br J Biomed Sci ; 76(3): 122-128, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30967043

RESUMO

Background: The prothrombin time may be used to monitor the plasma concentration of rivaroxaban. However, there is variability in the responsiveness of rivaroxaban to different thromboplastins. We aimed to develop a rivaroxaban-monitoring method using the prothrombin time to reduce the differences in the sensitivity among reagents. Methods: Rivaroxaban-spiked pooled normal plasma at a 0-1000 ng/ml concentration was used to generate a rivaroxaban-adjusted sensitivity index (SI) values, and was tested with three thromboplastins. The warfarin-adjusted international sensitivity index (ISI-warfarin), rivaroxaban-adjusted sensitivity index (SI-rivaroxaban), international normalized ratio (INR) calculated with ISI-warfarin, normalized ratio (NR) calculated with SI-rivaroxaban, and their coefficient of variances (CVs) were compared. The NR-rivaroxaban value was compared with the results of an anti-Xa assay. Results: The ISI-warfarin and SI-rivaroxaban using different thromboplastins were 1.02 and 1.88, respectively, with Thromborel S, 0.90 and 1.00 using Recombiplastin 2G, and 1.30 and 1.15 using Neoplastin CI-plus. Between-thromboplastin variability expressed as CV were 6.3%-25.1% when expressed as INR-warfarin and 1.7%-4.7% when expressed as NR-rivaroxaban. CVs for the NR-rivaroxaban with another laboratory were significantly lower than those for INR-warfarin. Anti-Xa assay v NR-rivaroxaban correlation coefficients were 0.97-0.99. Conclusion: Using a rivaroxaban-specific NR effectively minimises inter-thromboplastin variability. By utilizing a NR-rivaroxaban, standardized prothrombin time results could be rapidly obtained, especially useful in standardizing the therapeutic effect of rivaroxaban.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/sangue , Coeficiente Internacional Normatizado , Tempo de Protrombina , Rivaroxabana/sangue , Tiofenos/sangue , Adulto , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Reprodutibilidade dos Testes , Rivaroxabana/farmacologia , Tiofenos/farmacologia , Adulto Jovem
20.
J Atheroscler Thromb ; 26(10): 915-930, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30867376

RESUMO

AIM: A direct oral anti-coagulant, FXa inhibitor, has been applied to the clinical treatment of myocardial infarction (MI). Experimental studies in mice indicated that FXa inhibitors reduced atherosclerosis and prevented cardiac dysfunction after coronary ligation. These studies suggested that protease-activated receptor (PAR) 2, a major receptor of activated FX, may play an important role in atherosclerosis and cardiac remodeling. METHODS: The effects of a FXa inhibitor, rivaroxaban, were investigated in a new murine model of ischemic cardiomyopathy (ICM) using SR-BI KO/ApoeR61h/h mice (Hypo E mice) that developed MI by high-fat diet loading. RESULTS: Hypo E mice were fed rivaroxaban-containing (n=49) or control chow diets (n=126) after the induction of MI. The survival curve of the rivaroxaban-treated group 2 weeks after the induction of MI was improved significantly as compared with the non-treatment group (survival rate: 75.5% vs. 47.4%, respectively, p=0.0012). Echocardiography and the expression of BNP showed that rivaroxaban attenuated heart failure. Histological analyses revealed that rivaroxaban reduced aortic atherosclerosis and coronary occlusion, and markedly attenuated cardiac fibrosis. Rivaroxaban treatment decreased cardiac PAR2 levels and pro-inflammatory genes. In vitro, rivaroxaban application demonstrated the increase of cell viability against hypoxia in cardiac myocytes and the reduction of hypoxia-induced inflammation and fibrosis-related molecules in cardiac fibroblasts. The effects of the PAR2 antagonist against hypoxia-induced inflammation were comparable to rivaroxaban in cardiac fibroblasts. CONCLUSIONS: Rivaroxaban treatment just after MI in Hypo E mice prevented the progression of ICM by attenuating cardiac remodeling, partially through the suppression of the PAR2-mediated inflammatory pathway.


Assuntos
Cardiomiopatias/prevenção & controle , Dieta/efeitos adversos , Modelos Animais de Doenças , Inibidores do Fator Xa/farmacologia , Infarto do Miocárdio/complicações , Isquemia Miocárdica/prevenção & controle , Rivaroxabana/farmacologia , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Progressão da Doença , Masculino , Camundongos , Camundongos Knockout , Camundongos Knockout para ApoE , Infarto do Miocárdio/patologia , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/patologia , Receptores Depuradores Classe B/fisiologia
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