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1.
Tohoku J Exp Med ; 255(1): 1-8, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34511578

RESUMO

Endothelial nitric oxide synthase (eNOS) dysfunction is known to exacerbate the progression and prognosis of diabetic kidney disease (DKD). One of the mechanisms through which this is achieved is that low eNOS levels are associated with hypercoagulability, which promotes kidney injury. In the extrinsic coagulation cascade, the tissue factor (factor III) and downstream coagulation factors, such as active factor X (FXa), exacerbate inflammation through activation of the protease-activated receptors (PARs). Recently, it has been shown that the lack of or reduced eNOS expression in diabetic mice, as a model of advanced DKD, increases renal tissue factor levels and PAR1 and 2 expression in their kidneys. Furthermore, pharmaceutical inhibition or genetic deletion of coagulation factors or PARs ameliorated inflammation in DKD in mice lacking eNOS. In this review, we summarize the relationship between eNOS, coagulation, and PARs and propose a novel therapeutic option for the management of patients with DKD.


Assuntos
Nefropatias Diabéticas/etiologia , Óxido Nítrico Sintase Tipo III/deficiência , Receptores Ativados por Proteinase/metabolismo , Animais , Anticorpos Neutralizantes/administração & dosagem , Coagulação Sanguínea , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Inibidores do Fator Xa/farmacologia , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/genética , Receptores Ativados por Proteinase/deficiência , Receptores Ativados por Proteinase/genética , Transdução de Sinais , Tromboplastina/antagonistas & inibidores , Tromboplastina/metabolismo
2.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500640

RESUMO

Recently, the direct thrombin (thr) inhibitor dabigatran has proven to be beneficial in animal models of Alzheimer's disease (AD). Aiming at discovering novel multimodal agents addressing thr and AD-related targets, a selection of previously and newly synthesized potent thr and factor Xa (fXa) inhibitors were virtually screened by the Multi-fingerprint Similarity Searching aLgorithm (MuSSeL) web server. The N-phenyl-1-(pyridin-4-yl)piperidine-4-carboxamide derivative 1, which has already been experimentally shown to inhibit thr with a Ki value of 6 nM, has been flagged by a new, upcoming release of MuSSeL as a binder of cholinesterase (ChE) isoforms (acetyl- and butyrylcholinesterase, AChE and BChE), as well as thr, fXa, and other enzymes and receptors. Interestingly, the inhibition potency of 1 was predicted by the MuSSeL platform to fall within the low-to-submicromolar range and this was confirmed by experimental Ki values, which were found equal to 0.058 and 6.95 µM for eeAChE and eqBChE, respectively. Thirty analogs of 1 were then assayed as inhibitors of thr, fXa, AChE, and BChE to increase our knowledge of their structure-activity relationships, while the molecular determinants responsible for the multiple activities towards the target enzymes were rationally investigated by molecular cross-docking screening.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Trombina/metabolismo , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Animais , Butirilcolinesterase/metabolismo , Bovinos , Fator Xa/metabolismo , Inibidores do Fator Xa/farmacologia , Humanos , Simulação de Acoplamento Molecular , Piperidinas/farmacologia , Relação Estrutura-Atividade
3.
Medicine (Baltimore) ; 100(32): e26883, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397907

RESUMO

BACKGROUND AND PURPOSE: This study aimed to evaluate the comparative efficacy and safety of 4 non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in Asians with non-valvular atrial fibrillation in real-world practice through a network meta-analysis of observational studies. METHODS: We searched multiple comprehensive databases (PubMed, Embase, and Cochrane library) for studies published until August 2020. Hazard ratios and 95% confidence intervals were used for the pooled estimates. Efficacy outcomes included ischemic stroke (IS), stroke/systemic embolism (SSE), myocardial infarction (MI), and all-cause mortality, and safety outcomes included major bleeding, gastrointestinal (GI) bleeding, and intracerebral hemorrhage (ICH). The P score was calculated for ranking probabilities. Subgroup analyses were separately performed in accordance with the dosage range of NOACs ("standard-" and "low-dose"). RESULTS: A total of 11, 6, and 8 studies were allocated to the total population, standard-dose group, and low-dose group, respectively. In the total study population, edoxaban ranked the best in terms of IS and ICH prevention and apixaban ranked the best for SSE, major bleeding, and GI bleeding. In the standard-dose regimen, apixaban ranked the best in terms of IS and SSE prevention. For major bleeding, GI bleeding, and ICH, edoxaban ranked the best. In the low-dose regimen, edoxaban ranked the best for IS, SSE, GI bleeding, and ICH prevention. For major bleeding prevention, apixaban ranked best. CONCLUSIONS: All 4 NOACs had different efficacy and safety outcomes according to their type and dosage. Apixaban and edoxaban might be relatively better and more well-balanced treatment for Asian patients with non-valvular atrial fibrillation.


Assuntos
Fibrilação Atrial , Inibidores do Fator Xa , Acidente Vascular Cerebral , Varfarina/farmacologia , Anticoagulantes/farmacologia , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Fibrilação Atrial/etiologia , Fibrilação Atrial/prevenção & controle , Inibidores do Fator Xa/classificação , Inibidores do Fator Xa/farmacologia , Humanos , Avaliação de Resultados em Cuidados de Saúde , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico
4.
Int J Lab Hematol ; 43(4): 795-801, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34092030

RESUMO

INTRODUCTION: Andexanet alfa (AnXa) was developed for anticoagulant effect reversal of direct factor Xa inhibitors (DXaI) (apixaban, rivaroxaban, edoxaban) in emergency situations. Regular anti-Xa assays are not suitable to evaluate anti-Xa activity after AnXa administration because of the high sample dilution resulting in the AnXa-DXaI dissociation which gives inaccurately high DXaI measured concentrations. This study aimed at developing dedicated STA-Liquid anti-Xa test set-ups for accurately measuring DXaI after reversal with AnXa. METHODS: Modified anti-Xa test set-ups, with reduced sample dilution, were developed to overcome regular assays limitations and to improve measured accuracy with results comparable to Portola microplate reference method used in clinical studies. Both regular and optimized assays were used to measure DXaI concentration in AnXa-containing samples. Quality controls, normal pooled plasma spiked with five DXaI and three AnXa concentrations, samples from DXaI-treated patients spiked with AnXa and ex vivo healthy volunteers having received both DXaI and AnXa were used. RESULTS: The lower limit of quantitation of optimized anti-Xa assays was <10 ng/mL with CVs ≤10%. DXaI samples containing 300 ng/mL and 1 µmol/L AnXa resulted in DXaI residual concentrations of 29-72 ng/mL depending on the DXaI (76%-90% reversal), compared to 20-28 ng/mL with reference method (92%-94% reversal) and 135-165 ng/mL with regular assays (about 50% reversal). CONCLUSION: Modified test set-ups are automated alternative to reference method with improved precision and reproducibility. They can be run in all laboratories where regular anti-Xa assays are performed using commercially available reagents.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/farmacologia , Fator Xa/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Piridonas/farmacologia , Proteínas Recombinantes/farmacologia , Rivaroxabana/farmacologia , Tiazóis/farmacologia , Testes de Coagulação Sanguínea/métodos , Humanos
5.
Crit Care Med ; 49(10): e1025-e1036, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33967205

RESUMO

OBJECTIVES: To combine evidence on andexanet alfa and prothrombin complex concentrates for factor Xa inhibitor-associated bleeding to guide clinicians on reversal strategies. DATA SOURCES: Embase, Pubmed, Web of Science, and the Cochrane Library. STUDY SELECTION: Observational studies and randomized clinical trials studying hemostatic effectiveness of andexanet alfa or prothrombin complex concentrate for acute reversal of factor Xa inhibitor-associated hemorrhage. DATA EXTRACTION: Two independent reviewers extracted the data from the studies. Visualization and comparison of hemostatic effectiveness using Sarode et al or International Society of Thrombosis and Hemostasis Scientific and Standardization Committee criteria at 12 and 24 hours, (venous) thrombotic event rates, and inhospital mortality were performed by constructing Forest plots. Exploratory analysis using a logistic mixed model analysis was performed to identify factors associated with effectiveness and venous thromboembolic event. DATA SYNTHESIS: A total of 21 studies were included (andexanet: 438 patients; prothrombin complex concentrate: 1,278 patients). The (weighted) mean effectiveness for andexanet alfa was 82% at 12 hours and 71% at 24 hours. The (weighted) mean effectiveness for prothrombin complex concentrate was 88% at 12 hours and 76% at 24 hours. The mean 30-day symptomatic venous thromboembolic event rates were 5.0% for andexanet alfa and 1.9% for prothrombin complex concentrate. The mean 30-day total thrombotic event rates for andexanet alfa and prothrombin complex concentrate were 10.7% and 3.1%, respectively. Mean inhospital mortality was 23.3% for andexanet versus 15.8% for prothrombin complex concentrate. Exploratory analysis controlling for potential confounders did not demonstrate significant differences between both reversal agents. CONCLUSIONS: Currently, available evidence does not unequivocally support the clinical effectiveness of andexanet alfa or prothrombin complex concentrate to reverse factor Xa inhibitor-associated acute major bleeding, nor does it permit conventional meta-analysis of potential superiority. Neither reversal agent was significantly associated with increased effectiveness or a higher rate of venous thromboembolic event. These results underscore the importance of randomized controlled trials comparing the two reversal agents and may provide guidance in designing institutional guidelines.


Assuntos
Inibidores do Fator Xa/efeitos adversos , Fator Xa/farmacologia , Hemorragia/tratamento farmacológico , Protrombina/farmacologia , Proteínas Recombinantes/farmacologia , Coagulantes/administração & dosagem , Coagulantes/farmacologia , Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacologia , Humanos , Protrombina/administração & dosagem , Proteínas Recombinantes/administração & dosagem
7.
Int J Lab Hematol ; 43(4): 771-778, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33974363

RESUMO

BACKGROUND: Lupus anticoagulants (LA) are detected by prolongation of clotting times for dilute Russell's viper venom time (dRVVT) and activated partial thromboplastin time (APTT) screening tests. Direct oral anticoagulants (DOACs) can interfere with both screening and confirmatory tests. The present study aimed to investigate the influence of direct factor Xa inhibitors (DiXaIs) on screen, confirm and mixing tests and establish a method for differentiation from other sample types. MATERIALS AND METHODS: A total of 257 samples including nonanticoagulated LA positive, LA positive with DiXaIs, factor deficiency, FVIII inhibitors, warfarin and non-APS DiXaIs were tested. APTT reagents Cephen LS/Cephen and dRVVT reagents LA1/LA2 were used, respectively, to screen/confirm the study group. Index of circulating anticoagulant (ICA) was calculated from clotting times based on the following formula as ICA screening and ICA confirmation. ICA= (1:1 Mix sample - Normal pooled plasma) / Screen patient x 100. An ICA matrix was established which suggested the presence of a DiXaI when both ICA screening and confirmation were above the cut-off. When only ICA screening is elevated, LA is suspected. RESULTS: Sensitivity and specificity of the ICA matrix were 52.2% and 92.8% for DiXaIs and 38.1% and 96.7% for LA in APTT, and 61.2% and 92.9% for DiXaIs and 22.2% and 88.4% for LA in dRVVT, respectively. CONCLUSION: The ICA matrix achieved high specificity with a lower apparent sensitivity for DiXaI samples comparatively to other devices but due only to less interferences: the matrix could contribute to differentiating DiXaIs from LA in samples where anticoagulation status is unknown.


Assuntos
Inibidores do Fator Xa/sangue , Inibidor de Coagulação do Lúpus/sangue , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea/métodos , Inibidores do Fator Xa/farmacologia , Humanos , Inibidor de Coagulação do Lúpus/farmacologia , Tempo de Tromboplastina Parcial/métodos , Tempo de Protrombina/métodos
8.
Eur J Med Chem ; 220: 113437, 2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-33894565

RESUMO

Factor XIa, as a blood coagulation enzyme, amplifies the generation of the last enzyme thrombin in the blood coagulation cascade. It was proved that direct inhibition of factor XIa could reduce pathologic thrombus formation without an enhanced risk of bleeding. WSJ-557, a nonpurine imidazole-based xanthine oxidase inhibitor in our previous reports, could delay blood coagulation during its animal experiments, which prompted us to investigate its action mechanism. Subsequently, during the exploration of the action mechanism, it was found that WSJ-557 exhibited weak in vitro factor XIa binding affinity. Under the guide of molecular modeling, we adopted molecular hybridization strategy to develop novel factor XIa inhibitors with WSJ-557 as an initial compound. This led to the identification of the most potent compound 44g with a Ki value of 0.009 µM, which was close to that of BMS-724296 (Ki = 0.0015 µM). Additionally, serine protease selectivity study indicated that compound 44g display a desired selectivity, more 400-fold than those of thrombin, factor VIIa and factor Xa in coagulation cascade. Moreover, enzyme kinetics studies suggested that the representative compound 44g acted as a competitive-type inhibitor for FXIa, and molecular modeling revealed that it could tightly bind to the S1, S1' and S2' pockets of factor XIa. Furthermore, in vivo efficacy in the rabbit arteriovenous shunt model suggested that compound 44g demonstrated dose-dependent antithrombotic efficacy. Therefore, these results supported that compound 44g could be a potential and efficacious agent for the treatment of thrombotic diseases.


Assuntos
Desenho de Fármacos , Fator XIa/antagonistas & inibidores , Inibidores do Fator Xa/farmacologia , Relação Dose-Resposta a Droga , Fator XIa/metabolismo , Inibidores do Fator Xa/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
9.
Mil Med ; 186(7-8): 826-828, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33884426

RESUMO

This case report is about a 51-year-old active duty male with JAK2 mutation and medical history significant for prehepatic portal hypertension from portal vein thrombus on lifelong anticoagulation with rivaroxaban, an oral factor Xa inhibitor, presenting with closed-loop small bowel obstruction requiring emergent laparotomy. We present this surgical case as it required emergent reversal of the oral factor Xa inhibitor with andexanet alfa.


Assuntos
Inibidores do Fator Xa , Fator Xa , Coagulação Sanguínea , Inibidores do Fator Xa/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Rivaroxabana/farmacologia
10.
J Thromb Haemost ; 19(7): 1697-1708, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33829620

RESUMO

BACKGROUND: The prothrombinase complex consists of factors Xa (FXa) and Va (FVa) on an anionic phospholipid surface and converts prothrombin into thrombin. Both coagulation factors require activation before complex assembly. We recently identified TIX-5, a unique anticoagulant tick protein that specifically inhibits FXa-mediated activation of FV. Because TIX-5 inhibited thrombin generation in blood plasma, it was concluded that FV activation by FXa contributes importantly to coagulation. OBJECTIVE: We aimed to unravel the structure-function relationships of TIX-5. METHOD: We used a structure model generated based on homology with the allergen Der F7. RESULTS: Tick inhibitor of factor Xa toward FV was predicted to consist of a single rod formed by several beta sheets wrapped around a central C-terminal alpha helix. By mutagenesis we could show that two hydrophobic loops at one end of the rod mediate the phospholipid binding of TIX-5. On the other end of the rod an FV interaction region was identified on one side, whereas on the other side an EGK sequence was identified that could potentially form a pseudosubstrate of FXa. All three interaction sites were important for the anticoagulant properties of TIX-5 in a tissue factor-initiated thrombin generation assay as well as in the inhibition of FV activation by FXa in a purified system. CONCLUSION: The structure-function properties of TIX-5 are in perfect agreement with a protein that inhibits the FXa-mediated activation on a phospholipid surface. The present elucidation of the mechanism of action of TIX-5 will aid in deciphering the processes involved in the initiation phase of blood coagulation.


Assuntos
Anticoagulantes , Inibidores do Fator Xa , Coagulação Sanguínea , Fator V , Fator Va , Fator Xa , Inibidores do Fator Xa/farmacologia , Humanos , Protrombina , Trombina , Tromboplastina
11.
Nefrología (Madrid) ; 41(2): 137-153, mar.-abr. 2021. tab
Artigo em Espanhol | IBECS | ID: ibc-201567

RESUMO

La enfermedad renal crónica (ERC) y la fibrilación auricular (FA) frecuentemente coexisten, amplificando el riesgo de eventos cardiovasculares y de mortalidad. En pacientes con ERC estadio 3 y FA no valvular los anticoagulantes orales de acción directa (ACOD) han demostrado, comparados con antagonistas de la vitamina K (AVK), igual o superior eficacia en la prevención de ictus y embolismo sistémico, y mayor seguridad. No existen ensayos aleatorizados de la eficacia y la seguridad de ACOD y AVK en la ERC avanzada. Por otra parte, estudios observacionales sugieren que los ACOD, comparados con warfarina, se asocian a menor riesgo de daño renal agudo y de generación/progresión de la ERC. En este trabajo se revisan los aspectos epidemiológicos y fisiopatológicos de la asociación ERC y FA, las evidencias de la eficacia y seguridad de la warfarina y de los ACOD en las diversas fases de la ERC con FA, así como la comparación entre warfarina y ACOD en la eficacia y seguridad anticoagulante, y en sus efectos renales


Chronic kidney disease (CKD) and atrial fibrillation (AF) frequently coexist, amplifying the risk of cardiovascular events and mortality. In patients with CKD stage 3 and non-valvular AF, direct oral anticoagulants (DOACs) have shown, compared to vitamin K antagonists (VKA), equal or greater efficacy in the prevention of stroke and systemic embolism, and greater safety. There are no randomized trials of the efficacy and safety of DOACs and VKA in advanced CKD. On the other hand, observational studies suggest that DOACs, compared to warfarin, are associated with a lower risk of acute kidney damage and generation/progression of CKD. This paper reviews the epidemiological and pathophysiological aspects of the CKD and AF association, the evidence of the efficacy and safety of warfarin and ACODs in various stages of CKD with AF as well as the comparison between warfarin and ACODs in efficacy and anticoagulant safety, and in its renal effects


Assuntos
Humanos , Insuficiência Renal Crônica/complicações , Fibrilação Atrial/etiologia , Fibrilação Atrial/prevenção & controle , Inibidores do Fator Xa/farmacologia , Varfarina/farmacologia , Fatores de Risco , Acidente Vascular Cerebral/prevenção & controle , Insuficiência Renal Crônica/terapia , Diálise Renal
12.
Blood Coagul Fibrinolysis ; 32(3): 209-215, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33560005

RESUMO

Previously, we reported that a direct thrombin inhibitor melagatran paradoxically increased thrombin generation in human plasma in the presence of thrombomodulin. The aim of this study is to test the hypothesis that melagatran may exert a deleterious effect on tissue-type plasminogen activator (t-PA)-induced fibrinolysis via enhancement of thrombin generation and subsequent activation of thrombin-activatable fibrinolysis inhibitor (TAFI) and factor XIII (FXIII). Clot formation in human plasma containing t-PA and thrombomodulin was induced by tissue factor. The absorbance at 405 nm was measured to obtain clot lysis time. Effects of melagatran and a factor Xa inhibitor edoxaban on clot lysis time were determined. In the presence of thrombomodulin, melagatran significantly prolonged clot lysis time, but edoxaban shortened it. In the absence of thrombomodulin, melagatran did not inhibit fibrinolysis. Prolongation of clot lysis time by melagatran was reversed by activated protein C (which suppressed thrombin generation increased by melagatran) and a TAFIa inhibitor. Melagatran significantly suppressed plasmin generation, while edoxaban significantly increased it. However, both melagatran and edoxaban suppressed FXIII activation. In the clot formed in the presence of melagatran and edoxaban, the fibrin fibre was thin compared with control, showing no clear difference in the clot structures between melagatran and edoxaban. These results indicated that melagatran, not edoxaban, prolonged clot lysis time through the paradoxical enhancement of thrombin generation, and subsequent TAFI activation and inhibition of plasmin generation. Neither FXIII activation nor change in fibrin clot structure contributed to the inhibition of fibrinolysis by melagatran.


Assuntos
Antitrombinas/farmacologia , Azetidinas/farmacologia , Benzilaminas/farmacologia , Inibidores do Fator Xa/farmacologia , Fibrinólise/efeitos dos fármacos , Piridinas/farmacologia , Tiazóis/farmacologia , Trombina/metabolismo , Tempo de Lise do Coágulo de Fibrina , Humanos
13.
PLoS One ; 16(2): e0246253, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33539391

RESUMO

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting about 1.6% of the population in England. Novel oral anticoagulants (NOACs) are approved AF treatments that reduce stroke risk. In this study, we estimate the equality in individual NOAC prescriptions with high spatial resolution in Clinical Commissioning Groups (CCGs) across England from 2014 to 2019. METHODS: A Bayesian spatio-temporal model will be used to estimate and predict the individual NOAC prescription trend on 'prescription data' as an indicator of health services utilisation, using a small area analysis methodology. The main dataset in this study is the "Practice Level Prescribing in England," which contains four individual NOACs prescribed by all registered GP practices in England. We will use the defined daily dose (DDD) equivalent methodology, as recommended by the World Health Organization (WHO), to compare across space and time. Four licensed NOACs datasets will be summed per 1,000 patients at the CCG-level over time. We will also adjust for CCG-level covariates, such as demographic data, Multiple Deprivation Index, and rural-urban classification. We aim to employ the extended BYM2 model (space-time model) using the RStan package. DISCUSSION: This study suggests a new statistical modelling approach to link prescription and socioeconomic data to model pharmacoepidemiologic data. Quantifying space and time differences will allow for the evaluation of inequalities in the prescription of NOACs. The methodology will help develop geographically targeted public health interventions, campaigns, audits, or guidelines to improve areas of low prescription. This approach can be used for other medications, especially those used for chronic diseases that must be monitored over time.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/farmacologia , Anticoagulantes/uso terapêutico , Teorema de Bayes , Bases de Dados Factuais , Atenção à Saúde/estatística & dados numéricos , Inglaterra/epidemiologia , Inibidores do Fator Xa/administração & dosagem , Humanos , Modelos Estatísticos , Padrões de Prática Médica/estatística & dados numéricos , Prescrições/estatística & dados numéricos , Análise de Pequenas Áreas , Acidente Vascular Cerebral/tratamento farmacológico , Varfarina/uso terapêutico
14.
South Med J ; 114(1): 46-50, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33398361

RESUMO

OBJECTIVE: To compare the efficacy and safety of nonvitamin K oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) following bioprosthetic cardiac valve replacement. METHODS: This was a retrospective analysis conducted at a community teaching hospital in the southeastern United States between August 2015 and August 2018. Patients 18 years of age and older who underwent cardiac valve replacement and were prescribed oral anticoagulation were screened for inclusion. Patients were excluded if they had a mechanical valve replacement, experienced a venous thromboembolism, cerebrovascular accident, or acute coronary syndrome within 1 month before valve replacement, changed oral anticoagulation during the study period, were lost to follow-up, or declined to participate in the follow-up survey. The primary outcome was a composite of thromboembolic events within 90 days following bioprosthetic cardiac valve replacement. The safety outcome was major bleeding within 180 days of bioprosthetic cardiac valve replacement. RESULTS: The primary outcome of a composite of thromboembolic events within 90 days following bioprosthetic cardiac valve replacement occurred in 1 patient (4.3%) in the VKA group and 4 patients (7.4%) in the NOAC group. Major bleeding occurred in 2 patients (8.7%) in the VKA group and 0 patients in the NOAC group. CONCLUSION: Our study is the first to report the efficacy and safety of NOACs compared with VKA therapy following bioprosthetic cardiac valve replacement irrespective of an atrial fibrillation diagnosis. Notably, two of the thromboembolic events in the NOAC group occurred while therapy was held or inappropriately dosed; when these events are removed, the rate of thromboembolism is 3.8%. This rate is consistent with the VKA group. Our study adds to a small pool of literature regarding the use of NOACs following bioprosthetic cardiac valve replacement and suggests that NOACs may have similar efficacy and improved safety as compared with VKA therapy. Large randomized controlled trials are warranted to confirm our observations.


Assuntos
Inibidores do Fator Xa/normas , Próteses Valvulares Cardíacas/efeitos adversos , Tromboembolia Venosa/prevenção & controle , Adolescente , Adulto , Anticoagulantes/farmacologia , Anticoagulantes/uso terapêutico , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sudeste dos Estados Unidos , Tromboembolia Venosa/tratamento farmacológico
15.
Am J Med ; 134(6): 788-796, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33444586

RESUMO

BACKGROUND: Although direct oral anticoagulants (DOACs) have been shown to be effective at reducing the risk of stroke in patients with atrial fibrillation/flutter (AF), they are sometimes underdosed off-label to mitigate their associated higher bleeding risk. We sought to evaluate frequency and clinical outcomes of inappropriate underdosing of DOACS in patients with AF. METHODS: We conducted a study of subjects with AF who had a clinical indication for stroke prophylaxis (with a congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack, vascular disease, age 65 to 47 years, sex category [CHA2DS2-VASc] of 2 or greater) and were prescribed 1 of the 4 clinically approved DOACs (apixaban, rivaroxaban, dabigatran, or edoxaban). We compared all-cause mortality, composite of stroke and systemic embolism, composite of myocardial infarction (MI), acute coronary syndromes (ACS), and coronary revascularization, and major bleeding between patients appropriately dosed and inappropriately underdosed. RESULTS: A total of 8125 patients met inclusion criteria, with a mean follow up of 2.2 ± 2 years. Of those, 1724 patients (21.2%) were inappropriately dosed. After adjusting for baseline variables, there was no difference in all-cause mortality, risk of stroke or systemic embolism, International Society on Thrombosis and Haemostasis (ISTH) major bleeding, or composite of myocardial infarction, acute coronary syndromes, or coronary revascularization between patients appropriately dosed and inappropriately underdosed. In subgroup analysis, only apixaban demonstrated an increased incidence all-cause mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.03-1.49) with inappropriate underdosing. There was no difference in the remaining clinical outcomes noted on subgroup analysis. CONCLUSION: Underdosing of DOACs did not minimize risk of bleeding, systemic embolization or all-cause mortality in patients with AF. Inappropriate underdosing with apixaban in particular was associated with increased all-cause mortality.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Flutter Atrial/tratamento farmacológico , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/farmacologia , Tempo , Adulto , Idoso , Análise de Variância , Fibrilação Atrial/complicações , Flutter Atrial/complicações , Índice de Massa Corporal , Inibidores do Fator Xa/uso terapêutico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estatísticas não Paramétricas , Fatores de Tempo
16.
Ann Pharmacother ; 55(3): 286-293, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32844675

RESUMO

BACKGROUND: Clinical practice guidelines recommend that cerebral venous thrombosis (CVT) be managed with long-term anticoagulant therapy using warfarin or low-molecular-weight heparin (LMWH) for 3 to 12 months. However, oral factor Xa inhibitors may offer preferable alternative treatment options for these patients. OBJECTIVE: The primary objective was to determine the effectiveness and safety of rivaroxaban or apixaban compared with warfarin or enoxaparin as long-term anticoagulation therapy for patients with a new diagnosis of CVT. METHODS: This was a single-center retrospective review of patients with newly diagnosed CVT who received acute and maintenance anticoagulation treatment. Study groups compared patients who received warfarin, enoxaparin, or an oral factor Xa inhibitor as their maintenance anticoagulant. The primary outcome was recurrent thrombotic events while on anticoagulation. Secondary outcomes included modified Rankin Scale, improved cerebral venous sinus opacification, duration of anticoagulant therapy, bleeding events during anticoagulant therapy, and adverse effects. RESULTS: A total of 119 patients were included in the analysis: warfarin (89), enoxaparin (11), and oral factor Xa inhibitor (19). The risk of recurrent thrombotic events were 11.2%, 0%, and 10.5% in the warfarin, enoxaparin, and oral factor Xa inhibitor treatment groups, respectively (P = 0.7635). There were no significant between-group differences observed regarding any of the secondary outcomes. CONCLUSIONS: Although the sample size is limited, these findings indicate that oral factor Xa inhibitors are a reasonable treatment option for patients with CVT. There was a trend toward more persistent symptoms in patients on warfarin, suggesting a potential improvement in recovery among patients that received an oral factor Xa inhibitor.


Assuntos
Inibidores do Fator Xa/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Adulto , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
17.
J Clin Pathol ; 74(4): 251-256, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32796051

RESUMO

AIMS: While antithrombin (AT)-independent inhibitors targeting thrombin or activated factor X have been assessed through clot waveform (CWA), there are no reports on assessment with respect to AT-dependent anticoagulants. The present study aims to characterise AT-dependent anticoagulants through CWA to distinguish them from AT-independent inhibitors. METHODS: CWA was applied to the activated partial thromboplastin time (APTT) assay of plasma samples spiked with each of AT-dependent drugs (unfractionated heparin, enoxaparin and fondaparinux) and AT-independent drugs (rivaroxaban, apixaban, edoxaban, dabigatran, argatroban, hirudin and bivalirudin), which was performed using the CS-5100 or CN-6000 (Sysmex). The APTT-CWA data were automatically gained by the analyser program. The positive mode of clotting reaction curves was defined as the direction towards fibrin generation. RESULTS: Regarding dose-response curves in AT-dependent anticoagulants, the maximum positive values of the first and secondary derivatives (Max1 and Maxp2, respectively) and the maximum negative values of the secondary derivative (Maxn2) seemed to drop to zero without making an asymptotic line, consistent with the irreversibility. Such a feature was observed also in hirudin, as reported previously. Notably, the symmetric property of Max1 peaks in the waveforms was distorted dose dependently in AT independent but not AT-dependent drugs. A plot of Maxp2 logarithm versus Maxn2 logarithm was linear. The slope was about 1 in AT-dependent drugs while that was more than 1 in AT-independent drugs. These features made it possible to distinguish AT-dependent and AT-independent drugs. CONCLUSIONS: The results aid in further understanding of the pharmacological aspects of anticoagulation and in screening of candidates for novel anticoagulants.


Assuntos
Anticoagulantes/farmacologia , Antitrombinas/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Retração do Coágulo , Tempo de Tromboplastina Parcial , Relação Dose-Resposta a Droga , Inibidores do Fator Xa/farmacologia , Humanos , Valor Preditivo dos Testes
18.
J Vet Emerg Crit Care (San Antonio) ; 31(1): 18-24, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33118685

RESUMO

OBJECTIVE: To evaluate a panel of coagulation assays for their potential utility in rivaroxaban monitoring as alternatives to the rivaroxaban-specific anti-Xa activity (RIVA). DESIGN: Prospective experimental study. SETTING: University research laboratory. ANIMALS: Five healthy neutered male Beagles. INTERVENTIONS: Dogs were administered a median dose of 1.8 mg/kg rivaroxaban (range, 1.6-1.8 mg/kg) orally once daily for 2 consecutive days as part of a pharmacodynamic study. Blood was collected from a preplaced jugular catheter at time points relative to their rivaroxaban administration (0, 2, 4, 8, 24, 36, and 48 h) for measurement of RIVA, prothrombin time (PT), activated partial thromboplastin time, RapidTEG, and thrombin generation variables. MEASUREMENTS AND MAIN RESULTS: One hundred forty data points were available for analysis. There was poor correlation between RIVA and RapidTEG variables: R time (R) (min) (r = 0.554, P < 0.0001), K time (K) (min) (r = -0.204, P = 0.016), alpha angle (degrees) (r = 0.152, P = 0.073), Maximum amplitude (MA) (mm) (r = 0.106, P = 0.215), and G value (G) (dynes/s) (r = 0.108, P = 0.205). A good correlation was noted between thrombin generation variables and RIVA: lag time (min) (r = 0.827, P < 0.0001), peak (nM) (r = -0.752, P < 0.0001), and endogenous thrombin potential (nM·min) (r = -0.762, P < 0.0001). There was an excellent correlation between PT and RIVA (r = 0.915, P < 0.0001) and a good correlation between activated partial thromboplastin time and RIVA (r = 0.772, P < 0 .0001). CONCLUSIONS: Of all the coagulation tests investigated, the PT correlated best with RIVA. There is potential for PT being a convenient second-line monitoring option in dogs receiving rivaroxaban, but further work is necessary to validate other PT assays. Thromboelastography performed with strong activators correlated poorly with anti-Xa activity.


Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/farmacologia , Rivaroxabana/farmacologia , Administração Oral , Animais , Anticoagulantes/administração & dosagem , Testes de Coagulação Sanguínea/veterinária , Cães , Inibidores do Fator Xa/administração & dosagem , Masculino , Tempo de Tromboplastina Parcial/veterinária , Testes Imediatos , Estudos Prospectivos , Tempo de Protrombina/veterinária , Valores de Referência , Rivaroxabana/administração & dosagem , Tromboelastografia/veterinária
19.
Ir J Med Sci ; 190(1): 169-175, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32642982

RESUMO

INTRODUCTION: Several studies have shown a reduction in the rate of thromboembolic events with LMWH thromboprophylaxis in patients immobilised in lower limb cast. However, the literature is limited on the use of rivaroxaban in this setting. Therefore the aim of this study was to assess the associated impact of rivaroxaban on the incidence of venous thromboembolism in trauma patients with lower limb cast immobilisation. METHOD: Adult patients treated with lower limb cast immobilisation for different types of lower limb injuries were included in this study. One cohort of patients (n = 518) received rivaroxaban thromboprophylaxis. This was compared with a historical cohort (n = 486), who received no rivaroxaban for thromboprophylaxis. RESULTS: The number of patients developing VTEs in the rivaroxaban group was zero, compared with 6 cases (1.2%) in the nonrivaroxaban group p = 0.013. There were no major or minor bleeding incidences; no wound complications reported in the rivaroxaban group. All the side effects reported in association with rivaroxaban use did not require further intervention. CONCLUSION: This study has shown that rivaroxaban is associated with a significant reduction in the risk of VTEs in patients with lower limb cast immobilisation without increasing the risk of bleeding or associated untoward effect. Lower limb immobilisation is high risk factor for VTE per se. However, there is still limited data in the literature to make further recommendations.


Assuntos
Inibidores do Fator Xa/efeitos adversos , Extremidade Inferior/lesões , Rivaroxabana/efeitos adversos , Tromboembolia Venosa/etiologia , Estudos de Coortes , Inibidores do Fator Xa/farmacologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Comportamento de Redução do Risco , Rivaroxabana/farmacologia
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