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2.
Thromb Res ; 184: 44-49, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31706067

RESUMO

This review provides the rationale for dual pathway inhibition with the combination of low-dose rivaroxaban (2.5 mg twice daily) to attenuate thrombin generation and aspirin (100 mg once daily) to reduce platelet activation. Such therapy has been licensed for secondary prevention in patients with coronary or peripheral artery disease.

4.
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.

5.
Clin Appl Thromb Hemost ; 25: 1076029619856433, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31234637

RESUMO

Direct oral anticoagulants (DOACs) are now widely used for the management of venous thromboembolism (VTE) that now includes cancer-associated thrombosis. This review summarizes recent data on VTE prophylaxis and treatment, new challenges, guidelines, and updates as well as the current place for DOACs on the emerging cancer-associated VTE management landscape.

6.
JAMA Cardiol ; 4(5): 408-417, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30942842

RESUMO

Importance: Studies have found that patients at high cardiovascular risk often fail to receive evidence-based therapies in community practice. Objective: To evaluate whether a multifaceted quality improvement intervention can improve the prescription of evidence-based therapies. Design, Setting, and Participants: In this 2-arm cluster randomized clinical trial, patients with established atherothrombotic disease from 40 public and private outpatient clinics (clusters) in Brazil were studied. Patients were recruited from August 2016 to August 2017, with follow-up to August 2018. Data were analyzed in September 2018. Interventions: Case management, audit and feedback reports, and distribution of educational materials (to health care professionals and patients) vs routine practice. Main Outcomes and Measures: The primary end point was prescription of evidence-based therapies (ie, statins, antiplatelet therapy, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) using the all-or-none approach at 12 months after the intervention period in patients without contraindications. Results: Of the 1619 included patients, 1029 (63.6%) were male, 1327 (82.0%) had coronary artery disease (843 [52.1%] with prior acute myocardial infarction), 355 (21.9%) had prior ischemic stroke or transient ischemic attack, and 197 (12.2%) had peripheral vascular disease, and the mean (SD) age was 65.6 (10.5) years. Among randomized clusters, 30 (75%) were cardiology sites, 6 (15%) were primary care units, and 26 (65%) were teaching institutions. Among eligible patients, those in intervention clusters were more likely to receive a prescription of evidence-based therapies than those in control clusters (73.5% [515 of 701] vs 58.7% [493 of 840]; odds ratio, 2.30; 95% CI, 1.14-4.65). There were no differences between the intervention and control groups with regards to risk factor control (ie, hyperlipidemia, hypertension, or diabetes). Rates of education for smoking cessation were higher among current smokers in the intervention group than in the control group (51.9% [364 of 701] vs 18.2% [153 of 840]; odds ratio, 11.24; 95% CI, 2.20-57.43). The rate of cardiovascular mortality, acute myocardial infarction, and stroke was 2.6% for patients from intervention clusters and 3.4% for those in the control group (hazard ratio, 0.76; 95% CI, 0.43-1.34). Conclusions and Relevance: Among Brazilian patients at high cardiovascular risk, a quality improvement intervention resulted in improved prescription of evidence-based therapies. Trial Registration: ClinicalTrials.gov identifier: NCT02851732.

7.
Clin Appl Thromb Hemost ; 25: 1076029618821184, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30808213

RESUMO

A variety of viral infections are associated with hypercoagulable states and may be linked to the development of deep venous thrombosis and pulmonary embolism. The Zika and Chikungunya viral infections spread through the South and Central American continents, moving to North America in 2016, with severe cases of polyarthralgia, fever, and Guillain-Barré syndrome leading eventually to death. A decreased trend for both infections was reported in the first quarter of 2017. In this article, we report the possible association of venous thromboembolic events associated with Zika infection. After 2 cases of deep venous thrombosis in patients with acute Zika infections, D-dimer levels were measured in 172 consecutive patients who presented to the emergency department of a university hospital in an endemic region of Brazil with either Zika or Chikungunya infections confirmed by polymerase chain reaction tests. D-dimer levels were increased in 19.4% of 31 patients with Zika and in 63.8% of 141 patients with Chikungunya infections. The mechanisms behind this association are yet to be elucidated as well as the potential for venous thromboembolism prevention strategies for in-hospital patients affected by Zika and Chikungunya infections.


Assuntos
Vírus Chikungunya/patogenicidade , Tromboembolia Venosa/etiologia , Infecção por Zika virus/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tromboembolia Venosa/patologia
9.
Clin Appl Thromb Hemost ; : 1076029618812955, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30486661

RESUMO

Edoxaban, a direct factor Xa inhibitor (FXa), is the fourth direct oral anticoagulant (DOAC) approved for clinical use in the treatment of venous thromboembolism (VTE) in Latin America, following global approvals for this indication. Edoxaban features some particular characteristics when compared to the previously approved DOACs. This review summarizes the main properties of edoxaban, the outcomes results of its pivotal global clinical trials and the peculiar clinical features of this compound. This practical guide aims to help Latin America clinicians understand edoxaban, its proper indication and its use for the appropriate patients with VTE.

10.
Clin Appl Thromb Hemost ; 24(8): 1208-1215, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30021463

RESUMO

Several biosimilar versions of enoxaparin are already approved and in use globally. Analytical characterization can establish good quality control in manufacturing, but they may not assure similarity in clinical outcomes between biosimilar and branded enoxaparin. This study evaluated the efficacy and safety of biosimilar Cristália versus branded Sanofi enoxaparin in venous thromboembolism (VTE) prevention in patients undergoing major abdominal surgery at risk for VTE. In this randomized, prospective single-blind study, we compared Cristália enoxaparin (Ce), a biosimilar version, versus branded Sanofi enoxaparin (Se; at a dose of 40 mg subcutaneously per day postoperatively from 7 to 10 days) in 243 patients submitted to major abdominal surgery at risk for VTE for VTE prevention. The primary efficacy outcome was occurrence of VTE or death related to VTE. The principal safety outcomes were a combination of major bleeding and clinically relevant non-major bleeding. Bilateral duplex scanning of the legs was performed from days 10 to 14, and follow-ups were performed up to 60 days after surgery. The incidence of VTE was 4.9% in the Cristália group and 1.1% in the Sanofi group (absolute risk difference = 3.80%, 95% confidence interval [CI]: -1.4%-9.0%) yielding noninferiority since the 95% CI does not reach the prespecified value Δ = 20%. Clinically significant bleeding occurred in 9.9% in the Cristália group and in 5.5% in the Sanofi group (n.s. ). In conclusion, this study suggests that 40 mg once daily of Ce, a biosimilar enoxaparin, is as effective and safe as the branded Sanofi enoxaparin in the prophylaxis of VTE in patients submitted to major abdominal surgery at risk for VTE.

11.
Int Angiol ; 37(4): 255-260, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29745618

RESUMO

The late-breaking presentation of the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial at the European Society of Cardiology Congress in 2017 with a simultaneous publication in The New England Journal of Medicine described important information on the relative risk/benefit of combining anticoagulation with antiplatelet therapy in both coronary artery disease and/or peripheral artery disease (PAD) patients. In this special article, a review of the literature addressing the effects of antiplatelets and anticoagulants in symptomatic PAD patients focusing on the two most relevant clinical endpoints: major adverse cardiovascular events and major adverse limb events is addressed. In addition, a critical review of the COMPASS trial results, with emphasis on the PAD population is performed from a vascular surgery standpoint. It is concluded that this important study validated the combined anticoagulation/antiplatelet strategies in the management of vascular disorders including stable atherosclerotic patients. However, challenges in implementing this strategy in clinical practice are expected, with bleeding complications still remaining as major concern, particularly for vascular surgeons. Further studies with different combinations of different anticoagulants/antiplatelets, eventually on top of new strategies such as PCSK9 inhibition are warranted to address the significant unmet medical need in this population of symptomatic atherosclerotic patients.


Assuntos
Anticoagulantes/administração & dosagem , Doença Arterial Periférica/terapia , Inibidores da Agregação de Plaquetas/administração & dosagem , Anticoagulantes/efeitos adversos , Coagulação Sanguínea , Quimioterapia Combinada , Humanos , Inibidores da Agregação de Plaquetas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Procedimentos Cirúrgicos Vasculares
13.
Thromb Haemost ; 117(8): 1518-1527, 2017 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-28536722

RESUMO

The objective was to characterise apixaban pharmacodynamic (PD) activity in umbilical cord (UC), paediatric, and adult plasma. Plasma was obtained from blood samples from six UC donors, 70 paediatric (neonates [birth-≤1 month], infants [>1-≤6 months], toddlers [>6 months-≤2 years], young children [>2-≤6 years], children [>6-≤12 years], adolescents [>12-≤18 years]), and six adult (19-45 years) subjects. Plasma spiked with apixaban 0 (baseline), 30, or 110 ng/ml was analysed for anti-factor Xa activity, factor X levels, prothrombin time (PT), and modified PT (mPT). Apixaban had similar concentration-related effects on anti-factor Xa activity across groups (30 ng/ml: 0.223-0.295 IU/ml; 110 ng/ml: 1.212-1.474 IU/ml). Endogenous baseline factor X levels were 43 %-68 % lower in plasma from UC and subjects ≤6 months versus adults. Factor Xa inhibition (percentage change from baseline in apparent factor X levels) was similar for both apixaban concentrations across groups, except UC, neonate, and infant groups, which showed greater inhibition vs adults for apixaban 110 ng/ml. Baseline PT and mPT were similar across groups. Apixaban had no effect on PT at the concentrations tested. Apixaban 110 ng/ml prolonged mPT similarly across groups (44.4-53.2 s to 64.5-70.0 s); no prolongation was found with apixaban 30 ng/ml. Apixaban demonstrated consistent concentration-related effects on other PD endpoints in plasma samples from all age groups, except factor Xa inhibition.


Assuntos
Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/sangue , Sangue Fetal/metabolismo , Pirazóis/sangue , Piridonas/sangue , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Fator Xa/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina , Adulto Jovem
15.
Arterioscler Thromb Vasc Biol ; 37(5): 942-948, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28232327

RESUMO

OBJECTIVE: Warfarin is the current standard for oral anticoagulation therapy in patients with mechanical heart valves, yet optimal therapy to maximize anticoagulation and minimize bleeding complications requires routine coagulation monitoring, possible dietary restrictions, and drug interaction monitoring. As alternatives to warfarin, oral direct acting factor Xa inhibitors are currently approved for the prophylaxis and treatment of venous thromboembolism and reduction of stroke and systemic embolization. However, no in vivo preclinical or clinical studies have been performed directly comparing oral factor Xa inhibitors such as apixaban to warfarin, the current standard of therapy. APPROACH AND RESULTS: A well-documented heterotopic aortic valve porcine model was used to test the hypothesis that apixaban has comparable efficacy to warfarin for thromboprophylaxis of mechanical heart valves. Sixteen swine were implanted with a bileaflet mechanical aortic valve that bypassed the ligated descending thoracic aorta. Animals were randomized to 4 groups: control (no anticoagulation; n=4), apixaban oral 1 mg/kg twice a day (n=5), warfarin oral 0.04 to 0.08 mg/kg daily (international normalized ratio 2-3; n=3), and apixaban infusion (n=4). Postmortem valve thrombus was measured 30 days post-surgery for control-oral groups and 14 days post-surgery for the apixaban infusion group. Control thrombus weight (mean) was significantly different (1422.9 mg) compared with apixaban oral (357.5 mg), warfarin (247.1 mg), and apixiban 14-day infusion (61.1 mg; P<0.05). CONCLUSIONS: Apixaban is a promising candidate and may be a useful alternative to warfarin for thromboprophylaxis of mechanical heart valves. Unlike warfarin, no adverse bleeding events were observed in any apixaban groups.


Assuntos
Anticoagulantes/farmacologia , Valva Aórtica/cirurgia , Coagulação Sanguínea/efeitos dos fármacos , Inibidores do Fator Xa/farmacologia , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/instrumentação , Próteses Valvulares Cardíacas , Pirazóis/farmacologia , Piridonas/farmacologia , Trombose/prevenção & controle , Varfarina/farmacologia , Administração Intravenosa , Administração Oral , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/toxicidade , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/toxicidade , Hemorragia/induzido quimicamente , Coeficiente Internacional Normatizado , Modelos Animais , Desenho de Prótese , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirazóis/toxicidade , Piridonas/administração & dosagem , Piridonas/farmacocinética , Piridonas/toxicidade , Sus scrofa , Trombose/sangue , Trombose/etiologia , Varfarina/administração & dosagem , Varfarina/toxicidade
16.
Clin Appl Thromb Hemost ; 23(7): 883-887, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28027659

RESUMO

PURPOSE: To study the safety and efficacy of rivaroxaban-a direct oral anticoagulant-use in patients with active cancer and venous thromboembolism (VTE). PATIENTS AND METHODS: Retrospective cohort study of 400 patients with active cancer and associated VTE, defined as deep venous thrombosis and/or pulmonary embolism. This single-center study was carried out from January 2012 to June 2015. The aim of this study was to determine the efficacy and safety, using the incidence of recurrent symptomatic VTE and major bleeding, respectively, throughout the treatment with rivaroxaban. RESULTS: Of the 400 patients enrolled, 223 (55.8%) were female. A total of 362 (90.5%) patients had solid tumors and 244 (61%) had metastatic disease. A total of 302 (75.5%) received initial parenteral therapy with enoxaparin (median: 3, mean: 5.6, standard deviation [SD]: 6.4 days) followed by rivaroxaban. Ninety-eight patients (24.5%) were treated with on label rivaroxaban treatment. Recurrence rates were 3.25% with major bleeding occurring in 5.5% during the anticoagulant therapy (median: 118, mean: 163.9, SD: 159.9 days). CONCLUSION: Rivaroxaban can be an attractive alternative for the treatment of cancer-associated thrombosis.


Assuntos
Neoplasias/complicações , Rivaroxabana/administração & dosagem , Tromboembolia Venosa/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Enoxaparina , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Tromboembolia Venosa/complicações , Adulto Jovem
18.
Am J Med Sci ; 352(1): 92-106, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27432042

RESUMO

Venous thromboembolism (VTE) is a prevalent, potentially fatal health problem. Although standard anticoagulant therapy is effective when compared with the newer direct oral anticoagulants (DOACs), it has disadvantages. Heparin and its derivatives must be administered parenterally, whereas use of oral vitamin K antagonists is complicated by unpredictable pharmacokinetics and pharmacodynamics, drug-food and drug-drug interactions and the requirement for frequent laboratory monitoring. Randomized phase 3 trials have demonstrated that patients receive similarly effective anticoagulation with the DOACs dabigatran, edoxaban, rivaroxaban and apixaban when compared with warfarin, with similar or reduced risk of bleeding. Extended therapy trials have consistently demonstrated superior effectiveness for DOAC treatment when compared with placebo in preventing VTE recurrence. This article presents a comprehensive review of the pharmacokinetics, pharmacodynamics and accumulated clinical trial evidence for each DOAC for short-term, long-term and extended VTE therapy, and it considers the potential implications these agents have for the clinical management of VTE.


Assuntos
Anticoagulantes/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Hemorragia/tratamento farmacológico , Humanos
19.
Clin Appl Thromb Hemost ; 22(8): 772-778, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26787712

RESUMO

BACKGROUND: Distal deep venous thrombosis (DVT) accounts for approximately half of all the cases of lower limb thrombosis. The impact and management of this condition is still controversial. This study aims to evaluate the incidence of pulmonary embolism (PE) in patients with distal DVT in comparison to proximal DVT and evaluate the correlation between DVT and PE extension. METHODS: 100 patients with acute lower limb DVT diagnosed with whole leg Doppler ultrasound from January 2006 to December 2014 were retrospectively analyzed. Active investigation for PE was carried out in all patients using multislice computed tomography angiography. Classification of DVT and PE was based on the proximal extension of the thrombus. RESULTS: The overall incidence of PE in our sample patients was 72%. In the subgroup analysis, incidence of PE was equal in both the proximal and distal DVT groups (77%, p > 0.99). PE was detected in 43% of the patients with isolated calf vein thrombosis (ICVT). No statistical difference was observed between the distribution of lobar, segmental and subsegmental PE in the 3 DVT subgroups (p = 0.665); however, truncular PE was only observed in the proximal DVT group. CONCLUSION: Distal DVT is associated with a high incidence of PE compared to proximal DVT. Distal DVT and ICVT can provoke PE with involvement of proximal vessels in the pulmonary arterial tree, even in asymptomatic patients. Our study arises discussion in the controversial debate regarding the need for routine anticoagulation in distal DVT.


Assuntos
Anticoagulantes/uso terapêutico , Embolia Pulmonar/tratamento farmacológico , Trombose Venosa/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Perna (Membro)/irrigação sanguínea , Perna (Membro)/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/diagnóstico por imagem , Estudos Retrospectivos , Fatores de Risco , Ultrassonografia/métodos , Trombose Venosa/diagnóstico por imagem
20.
Clin Appl Thromb Hemost ; 22(4): 377-80, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26739543

RESUMO

Rivaroxaban is a target-specific oral anticoagulant approved for the treatment of venous thromboembolism (VTE). On its major clinical trials, treatment was initiated directly with a 3-week dose of oral 15 mg twice daily followed by 20 mg every day for at least 3 months. We retrospectively evaluated an initial therapy for confirmed VTE with 1 to 18 days of enoxaparin (1 mg/kg twice daily parenteral) followed by oral rivaroxaban 20 mg every day. Of 49 patients, we found no symptomatic recurrence, no major bleeding, and only 1 clinically relevant nonmajor bleeding. We concluded in this pilot study that it is safe and effective to treat patients with enoxaparin course followed directly by a dose of 20 mg of rivaroxaban.


Assuntos
Enoxaparina/administração & dosagem , Extremidade Inferior/irrigação sanguínea , Rivaroxabana/administração & dosagem , Tromboembolia Venosa/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Enoxaparina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rivaroxabana/efeitos adversos
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