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1.
BMJ Case Rep ; 13(11)2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33148560

RESUMO

A 60-year-old man recently admitted for bipedal oedema, endocarditis and a persistently positive COVID-19 swab with a history of anticoagulation on rivaroxaban for atrial fibrillation, transitional cell carcinoma, cerebral amyloid angiopathy, diabetes and hypertension presented with sudden onset diplopia and vertical gaze palsy. Vestibulo-ocular reflex was preserved. Simultaneously, he developed a scotoma and sudden visual loss, and was found to have a right branch retinal artery occlusion. MRI head demonstrated a unilateral midbrain infarct. This case demonstrates a rare unilateral cause of bilateral supranuclear palsy which spares the posterior commisure. The case also raises a question about the contribution of COVID-19 to the procoagulant status of the patient which already includes atrial fibrillation and endocarditis, and presents a complex treatment dilemma regarding anticoagulation.


Assuntos
Aspirina/administração & dosagem , Fibrilação Atrial , Cegueira , Infartos do Tronco Encefálico , Infecções por Coronavirus , Diplopia , Endocardite Bacteriana , Oftalmoplegia , Pandemias , Pneumonia Viral , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Oclusão da Artéria Retiniana , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Betacoronavirus/isolamento & purificação , Cegueira/diagnóstico , Cegueira/etiologia , Infartos do Tronco Encefálico/diagnóstico por imagem , Infartos do Tronco Encefálico/tratamento farmacológico , Infartos do Tronco Encefálico/fisiopatologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/fisiopatologia , Diplopia/diagnóstico , Diplopia/etiologia , Endocardite Bacteriana/complicações , Endocardite Bacteriana/diagnóstico , Endocardite Bacteriana/fisiopatologia , Inibidores do Fator Xa/administração & dosagem , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Oftalmoplegia/diagnóstico , Oftalmoplegia/etiologia , Inibidores da Agregação de Plaquetas/administração & dosagem , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/fisiopatologia , Oclusão da Artéria Retiniana/diagnóstico por imagem , Oclusão da Artéria Retiniana/tratamento farmacológico , Oclusão da Artéria Retiniana/etiologia , Oclusão da Artéria Retiniana/fisiopatologia , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento
2.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 148-157, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093778

RESUMO

Background: Patients with idiopathic pulmonary fibrosis (IPF) often do not tolerate pirfenidone in the recommended dose of 2400 mg/day. The proportion of patients requiring dose reduction and its impact on survival in the real-world remain unclear. Methods: Consecutive subjects with IPF were enrolled between March 2017 and June 2019. The maximum tolerated dose of pirfenidone (primary outcome) and adverse drug reactions (ADRs) were recorded. A post hoc logistic regression analysis was performed to evaluate the predictors of drug discontinuation due to ADRs. We also compared survival between the full-dose (2400 mg/day), reduced-dose (< 2400 mg/day), and the no-pirfenidone groups, with age and percentage of the predicted forced vital capacity (%pred FVC) as covariates. Results: Of the 128 subjects (mean age, 67.4 years; 77.3% men) included, 115 were initiated on pirfenidone. Forty-nine (42.6%) and 51 (44.3%) subjects tolerated the full dose and reduced doses, respectively. Ninety-six (83.5%) subjects developed at least one ADR; anorexia dyspepsia, and nausea being the most common. Twenty-two subjects discontinued the drug; 15 of them due to ADRs. Body mass index < 20 kg/m2 was the only predictor of drug discontinuation due to ADRs. Among subjects newly initiated on treatment during the study period (n = 80), survival was longer (hazard ratio [interquartile range], 0.19 [0.04-0.96]; p = 0.045) in the full-dose but not the reduced-dose group (p = 0.08) compared with the no-pirfenidone group, after adjusting for covariates. Conclusion: Pirfenidone was tolerated in the full dose in a minority of patients with IPF and appears to improve survival only with the full dose. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 148-157).


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Piridonas/administração & dosagem , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/mortalidade , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/fisiopatologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Segurança do Paciente , Estudos Prospectivos , Piridonas/efeitos adversos , Recuperação de Função Fisiológica , Resultado do Tratamento , Capacidade Vital
3.
Int Heart J ; 61(5): 905-912, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32921660

RESUMO

There is little data on management and outcomes of atrial fibrillation (AF) patients on direct oral anticoagulants (DOAC) undergoing general surgery.We retrospectively assessed 98 surgeries in 85 nonvalvular AF patients aged 73 ± 8 (59 men) receiving DOACs. Cardiac, emergency, and minimally invasive surgeries were excluded.The CHA2DS2-VASc score ranged from 0 to 8. The DOACs being given were: dabigatran, 16; rivaroxaban, 25; apixaban, 28; and edoxaban, 16. While the DOACs were not suspended in 11 cases, they were interrupted for a median of 2.0 days before surgery and restarted at a median of 3.0 days after surgery. There were 9 complications (9.2%), 3 instances of thromboembolism and 6 bleeding. Thromboembolism occurred at a mean of 3.0 postoperative days, all of which occurred before resumption of DOACs, while bleeding events occurred at a mean of 4.0 postoperative days. Two of the 3 patients with thromboembolism went into cardiopulmonary arrest during the event, but were resuscitated. There were significantly more patients with congestive heart failure or combined antiplatelets in the patients with complications. The complication group had a significantly higher HAS-BLED score and lower preoperative hemoglobin level. There were no significant differences in the management of DOAC interruption between those with complications and without.The perioperative complication rate in nonvalvular AF patients undergoing elective surgery treating with DOACs was 9.2%. Patients with congestive heart failure, receiving combined therapy with antiplatelets, a higher HAS-BLED score, or lower preoperative hemoglobin level were at higher risk. Further studies evaluating the ideal perioperative DOAC protocol are warranted.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Doenças das Artérias Carótidas/epidemiologia , Infarto Cerebral/epidemiologia , Inibidores do Fator Xa/administração & dosagem , Infarto do Miocárdio/epidemiologia , Assistência Perioperatória/métodos , Hemorragia Pós-Operatória/epidemiologia , Tromboembolia/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/administração & dosagem , Fibrilação Atrial/complicações , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Dabigatrana/administração & dosagem , Procedimentos Cirúrgicos do Sistema Digestório , Procedimentos Cirúrgicos Eletivos , Embolia/epidemiologia , Endoscopia , Feminino , Humanos , Masculino , Procedimentos Ortopédicos , Complicações Pós-Operatórias/epidemiologia , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Piridonas/administração & dosagem , Estudos Retrospectivos , Rivaroxabana/administração & dosagem , Tiazóis/administração & dosagem , Tromboembolia/etiologia , Procedimentos Cirúrgicos Urológicos , Procedimentos Cirúrgicos Vasculares
4.
Pediatrics ; 146(3)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32859736

RESUMO

Arteriovenous malformations (AVMs) have recently been reported to have a high incidence of somatic KRAS mutations suggesting potential for treatment with mitogen-activated protein kinase inhibitors. In this case report, we describe genotype-targeted treatment of a KRAS mutant metameric AVM in a patient with Cobb syndrome using the mitogen-activated protein kinase inhibitor trametinib. Therapeutic response was monitored with phase-contrast magnetic resonance angiography to quantify AVM arterial inflow as an imaging biomarker. Treatment with trametinib resulted in a substantial decrease in blood flow to the AVM, with a >75% reduction in arterial inflow after 6 months of trametinib therapy.


Assuntos
Malformações Arteriovenosas/tratamento farmacológico , Genótipo , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Doenças da Medula Espinal/tratamento farmacológico , Adolescente , Sequência de Aminoácidos , Malformações Arteriovenosas/diagnóstico por imagem , Malformações Arteriovenosas/genética , Sistemas de Liberação de Medicamentos/métodos , Humanos , Masculino , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/genética , Síndrome , Resultado do Tratamento
5.
Lancet Oncol ; 21(9): 1234-1243, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32818466

RESUMO

BACKGROUND: Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer. METHODS: This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov, NCT02034110. These results are based on an interim analysis; the study is active but not recruiting. FINDINGS: Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6-15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36-67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31-62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported. INTERPRETATION: Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer. FUNDING: GlaxoSmithKline and Novartis.


Assuntos
Neoplasias do Sistema Biliar/tratamento farmacológico , Imidazóis/administração & dosagem , Oximas/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/patologia , Intervalo Livre de Doença , Feminino , Humanos , Imidazóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Oximas/efeitos adversos , Piridonas/efeitos adversos , Pirimidinonas/efeitos adversos , Resultado do Tratamento
6.
Khirurgiia (Mosk) ; (7): 68-75, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32736466

RESUMO

The paper is a narrative review of the literature on the use of direct oral anticoagulants (DOACs) for the VTE treatment in challenging patients: senile age (≥75 years), impaired renal function (estimated glomerular filtration rate ≤50 ml/min), fragility (one of the previous characteristics and/or bodyweight ≤50 kg). The paper discusses the studies of EINSTEIN DVT and PE (rivaroxaban), AMPLIFY (apixaban), HOKUSAI-VTE (edoxaban), RE-COVER I and II (dabigatran) in the focus of the secondary analysis in the pre-specified patient's subgroups, as well as their pooled analyzes and meta-analyzes. Based on the results of this review, it was concluded that in a subgroup of senile age patients, dabigatran increases the risk of major bleeding by 4.8 times and has no advantages over vitamin K antagonists (VKA); rivaroxaban and apixaban retain superiority over VKA on the safety outcomes and reduce the risk of major bleeding by 73% and 77%. In the subgroup of patients with impaired renal function, the use of apixaban and dabigatran is associated with an increase in the risk of major bleeding by 6.5 and 7.3 times, and these DOACs do not have advantages over VKA; rivaroxaban retains its superiority over VKA and reduces the risk of major bleeding by 78%. For fragile patients, a secondary analysis is available only for rivaroxaban, which remains superior to VKA on safety endpoints and reduces the risk of major bleeding by 73%. In the absence of direct comparisons between the available DOACs, the presented data can be used as a rational approach for the choice of appropriate treatment for VTE in challenging patients.


Assuntos
Dabigatrana/efeitos adversos , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Insuficiência Renal/complicações , Rivaroxabana/efeitos adversos , Tromboembolia Venosa/tratamento farmacológico , Administração Oral , Fatores Etários , Idoso , Antitrombinas , Dabigatrana/administração & dosagem , Idoso Fragilizado , Humanos , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Rivaroxabana/administração & dosagem , Tromboembolia Venosa/complicações
7.
J Stroke Cerebrovasc Dis ; 29(9): 105034, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32807446

RESUMO

BACKGROUND: Data on independent risk factors for stroke recurrence in Japanese patients with nonvalvular atrial fibrillation are limited. METHODS: We performed a subgroup analysis of a postmarketing surveillance study of apixaban (STroke prevention ANticoagulant Drug Apixaban Real-world Data study) in Japanese patients with nonvalvular atrial fibrillation receiving oral apixaban (5 mg/2.5 mg twice daily) in routine clinical practice. Patients were categorized into primary and secondary prevention groups based on the absence or presence of a history of ischemic stroke/transient ischemic attack, respectively. RESULTS: Patients in the secondary prevention group (1101 of 6306 patients [17.5%] analyzed; mean observation period, 15.7 months) had a higher risk of ischemic stroke or hemorrhage than those in the primary prevention group. The incidence rates of major (3.92%/year vs 2.06%/year), intracranial (1.87%/year vs 0.55%/year), and cerebral (1.14%/year vs 0.37%/year) hemorrhage and effectiveness outcomes (ischemic stroke/systemic embolism/transient ischemic attack, 3.25%/year vs 0.57%/year) were significantly higher (all P < 0.001) in the secondary prevention group than in the primary prevention group. Multivariate analysis identified no independent risk factors in the secondary prevention group, while prior major bleeding, alcohol abuse, advanced age, male sex, lower body weight, higher serum creatinine, and antiplatelet drug use were identified as risk factors for major hemorrhage, and advanced age and antiplatelet drug use for effectiveness outcomes in the primary prevention group. CONCLUSIONS: Among Japanese patients with nonvalvular atrial fibrillation who received apixaban, presence of a history of ischemic stroke/transient ischemic attack was associated with higher incidence rates of hemorrhage and thromboembolic events.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Ataque Isquêmico Transitório/prevenção & controle , Prevenção Primária , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Prevenção Secundária , Acidente Vascular Cerebral/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Incidência , Ataque Isquêmico Transitório/diagnóstico , Ataque Isquêmico Transitório/epidemiologia , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Vigilância de Produtos Comercializados , Estudos Prospectivos , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Recidiva , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Fatores de Tempo , Resultado do Tratamento
10.
J Stroke Cerebrovasc Dis ; 29(8): 104982, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32689586

RESUMO

We report a case of ophthalmic artery occlusion (OAO) in a young patient with COVID-19 infection that was on therapeutic anticoagulation with apixaban for deep venous thrombosis (DVT). A 48-year-old man with obesity was hospitalized with a severe form of COVID-19 infection, complicated with acute respiratory failure, septic shock, dilated cardiomyopathy and fungemia. Despite treatment with prophylactic enoxaparin (initial D-Dimer 1.14 µg/ml FEU (normal < 0.05 µg/ml FEU), D-Dimer increased to above 20 µg/ml FEU and patient continued to spike high fevers. This prompted further investigations and upper and lower extremities DVTs were confirmed and managed with enoxaparin 1 mg/kg twice daily. D-dimer level decreased to 4.98 µg/ml FEU while on therapeutic anticoagulation. Three weeks later pending hospital discharge, the anticoagulation was switched to oral apixaban 10 mg twice daily. Patient developed acute severe right eye visual loss of no light perception and was diagnosed with incomplete OAO. D-Dimer was elevated at 2.13 µg/ml FEU. Stroke etiological work-up found no embolic sources, resolution of the dilated cardiomyopathy and negative antiphospholipid antibodies. Treatment was changed to enoxaparin and no thrombotic events were encountered to date. Ocular vascular complications have not yet been reported in COVID-19. Controversy exists on the best management algorithm for the hypercoagulable state associated to COVID-19 Either direct oral anticoagulants or low-molecular-weight-heparin are considered appropriate at discharge for patients with venous thromboembolism. The optimum regimen for ischemic stroke prevention and the significance of D-Dimer for anticoagulation monitoring in COVID-19 remain unclear.


Assuntos
Arteriopatias Oclusivas/etiologia , Infecções por Coronavirus/tratamento farmacológico , Inibidores do Fator Xa/administração & dosagem , Artéria Oftálmica , Pneumonia Viral/tratamento farmacológico , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Trombose Venosa/tratamento farmacológico , Arteriopatias Oclusivas/diagnóstico por imagem , Betacoronavirus/patogenicidade , Infecções por Coronavirus/sangue , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Substituição de Medicamentos , Enoxaparina/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Oftálmica/diagnóstico por imagem , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Fatores de Risco , Resultado do Tratamento , Trombose Venosa/sangue , Trombose Venosa/diagnóstico , Trombose Venosa/virologia
11.
Clin Drug Investig ; 40(9): 839-845, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32607688

RESUMO

BACKGROUND AND OBJECTIVE: Current guidelines recommend anticoagulation with a vitamin K antagonist (warfarin) after a bioprosthetic valve replacement. There is minimal literature evaluating direct oral anticoagulants (DOACs) in patients who have just received a bioprosthetic aortic valve replacement (AVR) or mitral valve replacement (MVR). The purpose of this study was to investigate any differences in efficacy and safety for patients taking a DOAC, compared with warfarin, after a bioprosthetic AVR or MVR. METHODS: A retrospective cohort study was performed to evaluate anticoagulation in patients who received bioprosthetic valve replacements at a large teaching hospital from 2014 to 2018. Patients included in this study received either warfarin or a DOAC following bioprosthetic AVR or MVR, and were maintained on the same agent throughout the 6-month follow-up period. The primary efficacy outcome was the incidence of thromboembolic complications and the primary safety outcome was the incidence of major bleeding within 6 months following surgery. The rate of readmission was assessed as a secondary endpoint. RESULTS: A total of 197 patients were included; 70 patients received warfarin and 127 patients received a DOAC (apixaban, n = 86; rivaroxaban, n = 40; dabigatran, n = 1). Three patients experienced thromboembolic events, all of which occurred in the DOAC group (0% vs. 2.4%; p = 0.20). Major bleeding occurred in 11 patients-two in the warfarin group and nine in the DOAC group (2.9% vs. 7.1%; p = 0.22). Sixty-one patients were readmitted within the 6-month time frame, with 26 readmissions in the warfarin group and 35 readmissions in the DOAC group (37% vs. 27%; p = 0.16). CONCLUSIONS: This small, exploratory study found similar rates of thromboembolic complications and major bleeding events in patients who received a DOAC versus warfarin after a recent bioprosthetic AVR or MVR. This study was limited by its retrospective nature and its sample size. Larger, randomized controlled trials are needed to further determine the efficacy and safety of DOACs in this patient population.


Assuntos
Anticoagulantes/uso terapêutico , Bioprótese , Dabigatrana/uso terapêutico , Próteses Valvulares Cardíacas , Pirazóis/uso terapêutico , Piridonas/uso terapêutico , Rivaroxabana/uso terapêutico , Varfarina/uso terapêutico , Administração Oral , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Estudos Retrospectivos , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Tromboembolia/induzido quimicamente , Varfarina/administração & dosagem , Varfarina/efeitos adversos
12.
Stroke ; 51(8): 2364-2373, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32640949

RESUMO

BACKGROUND AND PURPOSE: The comparative effectiveness of direct-acting oral anticoagulants, compared with warfarin, for risks of stroke/systemic embolism, major bleeding, or death have not been studied in Medicare beneficiaries with atrial fibrillation and nondialysis-dependent chronic kidney disease. METHODS: Medicare data from 2011 to 2017 were used to identify patients with stages 3, 4, or 5 chronic kidney disease and new atrial fibrillation who received a new prescription for warfarin, apixaban, rivaroxaban, or dabigatran. We estimated marginal hazard ratios with 95% CIs for the association of each direct-acting oral anticoagulant, compared with warfarin, for the outcomes of interest using inverse-probability-of-treatment weighted Cox proportional hazards models in as-treated and intention-to-treat analyses. RESULTS: A total of 22 739 individuals met criteria (46.3% warfarin, 29.6% apixaban, 17.2% rivaroxaban, 6.9% dabigatran). Across the groups of anticoagulant users, mean age was 78.4 to 79.0 years; 50.3% to 51.4% were women, and 80.3% to 82.8% had stage 3 chronic kidney disease. In the as-treated analysis, for stroke/systemic embolism, hazard ratios, all compared with warfarin, were 0.70 (0.51-0.96) for apixaban, 0.80 (0.54-1.17) for rivaroxaban, and 1.15 (0.69-1.94) for dabigatran. For major bleeding, analogous hazard ratios were 0.47 (0.37-0.59) for apixaban, 1.05 (0.85-1.30) for rivaroxaban, and 0.95 (0.70-1.31) for dabigatran. There was no difference in the risk of all-cause mortality between the direct-acting oral anticoagulants and warfarin. Results of the intention-to-treat analysis were similar. CONCLUSIONS: Apixaban, compared with warfarin, was associated with decreased risk of stroke/systemic embolism and major bleeding; risks for both outcomes with rivaroxaban and dabigatran did not differ from risks with warfarin.


Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Medicare , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Insuficiência Renal Crônica/tratamento farmacológico , Varfarina/administração & dosagem , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Fibrilação Atrial/epidemiologia , Estudos de Coortes , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Medicare/tendências , Pessoa de Meia-Idade , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Insuficiência Renal Crônica/epidemiologia , Estudos Retrospectivos , Acidente Vascular Cerebral/induzido quimicamente , Estados Unidos/epidemiologia , Varfarina/efeitos adversos , Adulto Jovem
13.
J Cardiovasc Pharmacol Ther ; 25(6): 523-530, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32476465

RESUMO

BACKGROUND: Direct-acting oral anticoagulants are indicated for the treatment of nonvalvular atrial fibrillation, but their use in patients after undergoing cardiac surgery is poorly defined despite a high prevalence of postoperative atrial fibrillation in this population. METHODS: Patients diagnosed with postoperative atrial fibrillation were prospectively randomized to warfarin or apixaban. Safety, efficacy, and economic outcomes were evaluated until their 4- to 6-week postoperative appointment. RESULTS: While this pilot study was not powered to determine a difference in safety or efficacy, adverse event rates were similar to the published literature. It was noted that a patient's course of therapy when utilizing apixaban was significantly less costly than warfarin when including medication, bridging, and laboratory expenses. CONCLUSION: Apixaban and warfarin both appeared to be safe and effective for anticoagulation throughout the duration of this pilot study in treating postoperative atrial fibrillation after coronary artery bypass grafting. Apixaban was associated with significantly less expense when bridging and monitoring costs were included in addition to medication expense.


Assuntos
Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Ponte de Artéria Coronária/efeitos adversos , Inibidores do Fator Xa/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Varfarina/administração & dosagem , Administração Oral , Idoso , Anticoagulantes/efeitos adversos , Anticoagulantes/economia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/economia , Fibrilação Atrial/etiologia , Ponte de Artéria Coronária/economia , Análise Custo-Benefício , Custos de Medicamentos , Monitoramento de Medicamentos , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/economia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , North Dakota , Projetos Piloto , Estudos Prospectivos , Pirazóis/efeitos adversos , Pirazóis/economia , Piridonas/efeitos adversos , Piridonas/economia , Fatores de Tempo , Resultado do Tratamento , Varfarina/efeitos adversos , Varfarina/economia
14.
Medicine (Baltimore) ; 99(25): e20570, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569181

RESUMO

The CHA2DS2-VASc scale does not include potential risk factors for left atrial appendage thrombus (LAAT) formation such as a form of atrial fibrillation (AF) and impaired kidney function. The real risk of thromboembolic complications in AF patients is still unclear as well as an optimal anticoagulant treatment in males with a CHA2DS2-VASc score of 1 and females with a CHA2DS2-VASc score of 2.The aim of this study was to compare the predictive value of the CHA2DS2-VASc scale and other scales to estimate the risk of LAAT formation in AF patients treated with non-vitamin K oral anticoagulants (NOACs) and to assess the prevalence of thrombi in patients at intermediate risk of stroke.The observational study included consecutive patients with a diagnosis of non-valvular AF treated with NOACs, admitted to 3 high-reference institutions between 2013 and 2018. All individuals underwent transoesophageal echocardiography before cardioversion or ablation.Out of 1163 enrolled AF patients (62.1% male, mean age 62 years) the LAAT had been detected in 50 individuals (4.3%). Among patients with LAAT, 1 patient (2.0%) was classified as a low-risk category, 9 (18.0%) were at intermediate-risk, and 40 (80.0%) were at high risk of thromboembolic complications according to CHA2DS2-VASc scale. All patients were treated with NOACs: 51.0% rivaroxaban, 47.1% dabigatran, and 1.9% apixaban.Patients at intermediate stroke-risk with detected LAAT had higher R2CHADS2 score (2.1 ±â€Š1.2 vs 1.2 ±â€Š0.8, P = .007), higher CHA2DS2-VASc-RAF score (6.4 ±â€Š4.4 vs 3.7 ±â€Š2.6, P = .027) and more often had an estimated glomerular filtration rate below 56 mL/min/1.73 m (44.4% vs 13.2%, P = .026) compared to patients without LAAT. The receiver operating characteristics revealed that the CHA2DS2-VASc-RAF scale had better predictive ability to distinguish between patients with and without LAAT in the study group than CHA2DS2-VASc (P = .0006), CHADS2 (P = .0006) and R2CHADS2 scale (P = .0140).The CHA2DS2-VASc scale should be supplemented with an assessment of renal function and form of AF to improve stroke risk estimation. The application of additional scales to estimate the risk of LAAT might be especially useful among males with a CHA2DS2-VASc score of 1 and females with a CHA2DS2-VASc score of 2.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Dabigatrana/administração & dosagem , Inibidores do Fator Xa/administração & dosagem , Pirazóis/administração & dosagem , Piridonas/administração & dosagem , Rivaroxabana/administração & dosagem , Idoso , Apêndice Atrial/efeitos dos fármacos , Ecocardiografia Transesofagiana , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Tromboembolia/prevenção & controle
15.
Lancet HIV ; 7(7): e472-e481, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32497491

RESUMO

BACKGROUND: Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial. METHODS: HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18-65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52-76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov, NCT02178800. FINDINGS: Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p<0·0001). At 52-60 weeks after final injection, nine (23%) of 40 male participants had detectable cabotegravir concentrations and at week 76, four (13%) of 30 male participants had detectable cabotegravir concentrations compared with 52 (63%) of 82 female participants and 27 (42%) of 64 female participants at the same timepoints. The median time from the last injection to the time when cabotegravir concentration decreased below the LLOQ was 43·7 weeks (IQR 31·1-66·6; range 20·4-152·5) for male participants and 67·3 weeks (29·1-89·6; 17·7-225·5) for female participants (p=0·0003). t1/2app was longer for female participants than male participants (geometric mean fold-change 1·33, 95% CI 1·06-1·68; p=0·014), and longer for participants with a high body-mass index (BMI) than those with a low BMI (1·31, 1·06-1·63; p=0·015). INTERPRETATION: The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials. FUNDING: National Institute of Allergy and Infectious Diseases.


Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/prevenção & controle , Inibidores de Integrase de HIV/farmacologia , Piridonas/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Brasil , Estudos de Coortes , Método Duplo-Cego , Feminino , Inibidores de Integrase de HIV/administração & dosagem , Humanos , Injeções , Malaui , Masculino , Pessoa de Meia-Idade , Placebos , Piridonas/administração & dosagem , África do Sul , Estados Unidos , Adulto Jovem
16.
PLoS One ; 15(6): e0234048, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497116

RESUMO

BACKGROUND: Warfarin is an anticoagulant medication proven effective in the initial treatment and secondary prevention of venous thromboembolism. Anti-Xa direct oral anticoagulants are alternatives to warfarin; however there is limited data assessing satisfaction after switching from warfarin to an anti-Xa direct oral anticoagulant in patients for treatment of venous thromboembolism. OBJECTIVES: To assess medication satisfaction in patients requiring anticoagulation for venous thromboembolism after conversion from warfarin to an anti-Xa direct oral anticoagulant. METHODS: A retrospective cohort study with prospective assessment of satisfaction and review of adverse events following anti-Xa direct oral anticoagulant replacement of warfarin for treatment of venous thromboembolism. Out of 165 patients who had switched from warfarin to rivaroxaban or apixaban from an outpatient haematology practice, 126 patients consented for a survey of patient's relative satisfaction of anti-Xa direct oral anticoagulant therapy compared with previous warfarin therapy using the Anti-Clot Burden and Benefits Treatment Scale and SWAN Score. RESULTS: The mean Anti-Clot Burden and Benefits and SWAN Score was 93% (56/60) and 83% (24.8/30) respectively reflecting high satisfaction with anti-Xa direct oral anticoagulants. 120 patients stated preference for anti-Xa direct oral anticoagulants over warfarin. Leading perceptions driving this was the reduction in frequency of medical contact and fewer bleeding side effects. Thirteen patients (10.3%) experienced an adverse event after the anti-Xa direct oral anticoagulant switch (majority were non-major bleeding) but most remained on anti-Xa direct oral anticoagulant treatment after management options were implemented with continued high satisfaction scores. CONCLUSIONS: Patient satisfaction with anti-Xa direct oral anticoagulant therapy for the treatment and prevention of venous thromboembolism after switching from warfarin in routine clinical practice appeared high. Improved patient convenience including reduced frequency of medical contact and fewer unpredictable side effects were perceived as significant advantages of anti-Xa direct oral anticoagulants compared to warfarin.


Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/uso terapêutico , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/uso terapêutico , Satisfação do Paciente , Tromboembolia Venosa/tratamento farmacológico , Varfarina/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Estudos Retrospectivos , Rivaroxabana/administração & dosagem , Rivaroxabana/uso terapêutico , Inquéritos e Questionários , Fatores de Tempo , Adulto Jovem
18.
Acta Neurol Scand ; 142(2): 131-138, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32430908

RESUMO

OBJECTIVE: To evaluate the time course of changes in perampanel levels when co-administered with carbamazepine, and following carbamazepine discontinuation, using a physiologically based pharmacokinetic (PBPK) model. METHODS: The PBPK model was developed, verified using clinical PK data, and used to simulate the effect of abrupt discontinuation and down-titration (75 mg twice daily [bid]/wk) of co-administered carbamazepine 300 mg bid on the PK of perampanel once daily (qd). Perampanel dose tapering (8-4 mg) and up-titration (2-6 mg) were simulated during abrupt carbamazepine 300 mg bid discontinuation to identify a titration schedule that minimizes changes in perampanel plasma concentrations. RESULTS: The PBPK model accurately reproduced perampanel plasma concentration-time profiles from clinical studies in single- and multiple-dose regimen simulations, including multiple-dose carbamazepine co-administration. The time course of return to pre-induced perampanel levels occurred more slowly following carbamazepine down-titration (~48 days after first down-titration) vs abrupt discontinuation (~25 days). Perampanel dose tapering (8-4 mg) at abrupt carbamazepine discontinuation produced minimal changes in steady-state concentrations, which returned to the levels observed during carbamazepine co-administration in ~15 days from the time of carbamazepine discontinuation. When perampanel was up-titrated in the presence of carbamazepine, return to steady state occurred more slowly when carbamazepine was down-titrated weekly (~45 days) vs abrupt discontinuation (~24 days). CONCLUSION: This PBPK model simulated and predicted optimal perampanel dose tapering and up-titration schedules for maintaining perampanel levels during conversion to monotherapy. These results may guide physicians when managing conversion from perampanel polytherapy with concomitant enzyme-inducing anti-seizure medications to monotherapy.


Assuntos
Anticonvulsivantes/sangue , Carbamazepina/sangue , Simulação por Computador , Modelos Biológicos , Piridonas/sangue , Suspensão de Tratamento , Adulto , Anticonvulsivantes/administração & dosagem , Carbamazepina/administração & dosagem , Simulação por Computador/tendências , Relação Dose-Resposta a Droga , Interações Medicamentosas/fisiologia , Feminino , Humanos , Masculino , Piridonas/administração & dosagem , Suspensão de Tratamento/tendências
19.
J Thromb Haemost ; 18(6): 1320-1323, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-116313

RESUMO

BACKGROUND: Antiviral drugs are administered in patients with severe COVID-19 respiratory syndrome, including those treated with direct oral anticoagulants (DOACs). Concomitant administration of antiviral agents has the potential to increase their plasma concentration. A series of patients managed in the Cremona Thrombosis Center were admitted at Cremona Hospital for SARS-CoV-2 and started antiviral drugs without stopping DOAC therapy. DOAC plasma levels were measured in hospital and results compared with those recorded before hospitalization. METHODS: All consecutive patients on DOACs were candidates for administration of antiviral agents (lopinavir, ritonavir, or darunavir). Plasma samples for DOAC measurement were collected 2to 4 days after starting antiviral treatment, at 12 hours from the last dose intake in patients on dabigatran and apixaban, and at 24 hours in those on rivaroxaban and edoxaban. For each patient, C-trough DOAC level, expressed as ng/mL, was compared with the one measured before hospitalization. RESULTS: Of the 1039 patients hospitalized between February 22 and March 15, 2020 with COVID-19 pneumonia and candidates for antiviral therapy, 32 were on treatment with a DOAC. DOAC was stopped in 20 and continued in the remaining 12. On average, C-trough levels were 6.14 times higher during hospitalization than in the pre-hospitalization period. CONCLUSION: DOAC patients treated with antiviral drugs show an alarming increase in DOAC plasma levels. In order to prevent bleeding complications, we believe that physicians should consider withholding DOACs from patients with SARS-CoV-2 and replacing them with alternative parenteral antithrombotic strategies for as long as antiviral agents are deemed necessary and until discharge.


Assuntos
Antitrombinas/sangue , Antivirais/efeitos adversos , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Dabigatrana/sangue , Inibidores do Fator Xa/sangue , Pneumonia Viral/tratamento farmacológico , Pirazóis/sangue , Piridinas/sangue , Piridonas/sangue , Tiazóis/sangue , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/administração & dosagem , Antitrombinas/efeitos adversos , Antivirais/administração & dosagem , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Darunavir/efeitos adversos , Interações Medicamentosas , Monitoramento de Medicamentos , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Itália , Lopinavir/efeitos adversos , Masculino , Pandemias , Segurança do Paciente , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Medição de Risco , Fatores de Risco , Ritonavir/efeitos adversos , Índice de Gravidade de Doença , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos
20.
Open Heart ; 7(1): e001232, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32341789

RESUMO

Objective: To assess the safety (ie, risk of bleeding) and effectiveness (ie, risk of stroke/systemic embolism (SE)) separately for four non-vitamin K oral anticoagulants (NOACs; apixaban, dabigatran, edoxaban and rivaroxaban) versus warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF), including those at high risk of bleeding and treated with reduced doses of NOACs. Methods: We conducted a retrospective analysis of electronic health records and claims data from 372 acute care hospitals in Japan for patients with NVAF newly initiated on NOACs or warfarin. Baseline characteristics were balanced using inverse probability of treatment weighting with stabilised weights (s-IPTW). Bleeding risk and stroke/SE risk were expressed as HRs with 95% CIs. Two sensitivity analyses were conducted. Results: A total of 73 989 patients were eligible for analysis. Notably, 52.8%-81.9% of patients received reduced doses of NOACs. After applying s-IPTW, patient characteristics were well balanced across warfarin/NOAC cohorts. The mean within-cohort age, CHADS2 score and CHA2DS2-VASc score were 76 years, 2.2-2.3 and 3.8, respectively. In all age categories, the majority of the HRs for major bleeding, any bleeding and stroke/SE were equal to or below 1 for all NOACs versus warfarin. Apixaban was the only NOAC associated with a significantly lower risk of any bleeding. There was a trend towards increased risk reduction with NOACs versus warfarin in patients with body weight ≥60 kg. In patients with renal disease, the HRs for apixaban versus warfarin were below 1 for major bleeding, any bleeding and stroke/SE, with statistical significance observed for the risk reduction in stroke/SE versus warfarin. In the sensitivity analysis, there were no large differences in HRs between the two observational periods. Conclusions: In patients with NVAF primarily treated with reduced-dose NOACs, the risks of stroke/SE and major bleeding were significantly lower with NOACs versus warfarin.


Assuntos
Anticoagulantes/administração & dosagem , Antitrombinas/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Acidente Vascular Cerebral/prevenção & controle , Varfarina/administração & dosagem , Administração Oral , Demandas Administrativas em Assistência à Saúde , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Antitrombinas/efeitos adversos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Dabigatrana/administração & dosagem , Registros Eletrônicos de Saúde , Feminino , Hemorragia/induzido quimicamente , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Piridonas/administração & dosagem , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Rivaroxabana/administração & dosagem , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Tiazóis/administração & dosagem , Fatores de Tempo , Resultado do Tratamento , Vitamina K/antagonistas & inibidores , Varfarina/efeitos adversos
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