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J Am Coll Cardiol ; 72(3): 255-267, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30012318


BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used medications that can potentially increase the risk of bleeding and thrombosis. OBJECTIVES: This study quantified the effect of NSAIDs in the RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy) trial. METHODS: This was a post hoc analysis of NSAIDs in the RE-LY study, which compared dabigatran etexilate (DE) 150 and 110 mg twice daily (b.i.d.) with warfarin in patients with atrial fibrillation. Treatment-independent, multivariate-adjusted Cox regression analysis assessed clinical outcomes by comparing NSAID use with no NSAID use. Interaction analysis was obtained from treatment-dependent Cox regression modeling. Time-varying covariate analysis for NSAID use was applied to the Cox model. RESULTS: Among 18,113 patients in the RE-LY study, 2,279 patients used NSAIDs at least once during the trial. Major bleeding was significantly elevated with NSAID use (hazard ratio [HR]: 1.68; 95% confidence interval [CI]: 1.40 to 2.02; p < 0.0001). NSAID use did not significantly alter the risk of major bleeding for DE 150 or 110 mg b.i.d. relative to warfarin (pinteraction = 0.63 and 0.93, respectively). Gastrointestinal major bleeding was significantly elevated with NSAID use (HR: 1.81; 95% CI: 1.35 to 2.43; p < 0.0001). The rate of stroke or systemic embolism (stroke/SE) with NSAID use was significantly elevated (HR: 1.50; 95% CI: 1.12 to 2.01; p = 0.007). The use of NSAIDs did not significantly alter the relative efficacy on stroke/SE for DE 150 or 110 mg b.i.d. relative to warfarin (pinteraction = 0.59 and 0.54, respectively). Myocardial infarction rates were similar with NSAID use compared with no NSAID use (HR: 1.22; 95% CI: 0.77 to 1.93; p = 0.40). Patients were more frequently hospitalized if they used an NSAID (HR: 1.64; 95% CI: 1.51 to 1.77; p < 0.0001). CONCLUSIONS: The use of NSAIDs was associated with increased risk of major bleeding, stroke/SE, and hospitalization. The safety and efficacy of DE 150 and 110 mg b.i.d. relative to warfarin were not altered. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY]; NCT00262600).

Anti-Inflamatórios não Esteroides , Fibrilação Atrial , Dabigatrana , Hemorragia Gastrointestinal , Acidente Vascular Cerebral/prevenção & controle , Tromboembolia , Varfarina , Idoso , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/administração & dosagem , Dabigatrana/efeitos adversos , Interações de Medicamentos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/diagnóstico , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/etiologia , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Varfarina/administração & dosagem , Varfarina/efeitos adversos
Lancet ; 390(10104): 1717-1718, 2017 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-28859948
Europace ; 18(7): 973-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26944733


AIMS: The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial allowed patients who completed the trial receiving their assigned dabigatran 150 mg (D150) or 110 mg (D110) twice a day to continue into the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial. This permitted assessment of outcomes over a median of 4.6 and a maximum of 6.7 years, respectively. METHODS AND RESULTS: The analysed population included only those patients who completed RE-LY on dabigatran and continued into RELY-ABLE without interruption of assigned dabigatran. Cumulative risk was expressed as Kaplan-Meier plots. Outcomes were compared using Cox proportional hazard modelling. Stroke or systemic embolization rates were 1.25 and 1.54% per year (D150 and D110, respectively); hazard ratio (HR) 0.81 [95% confidence interval (CI): 0.68-0.96] (P = 0.02). Ischaemic stroke was 1.03 (D150) and 1.29%/year (D110); HR 0.79 (95% CI: 0.66-0.95) (P = 0.01). Haemorrhagic stroke rates were 0.11 (D150) and 0.13%/year (D110); HR 0.91 (95% CI: 0.51-1.62) (P = 0.75). Rates of major haemorrhage were 3.34 (D150) and 2.76%/year (D110); HR 1.22 (95% CI: 1.08-1.37) (P = 0.0008). Intracranial haemorrhage rates were 0.32 (D150) and 0.23%/year (D110); HR 1.37 (95% CI: 0.93-2.01) (P = 0.11). Mortality was 3.43 (D150) and 3.55%/year (D110); HR 0.97 (95% CI: 0.87-1.08) (P = 0.54). CONCLUSION: Annualized rates of all outcomes were constant with better efficacy of D150, less major bleeding with D110, and low intracerebral haemorrhage rates for both doses. There were no additional safety concerns. This is the longest continuous randomized experience of a novel anticoagulant.

Antitrombinas/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Antitrombinas/efeitos adversos , Fibrilação Atrial/mortalidade , Dabigatrana/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Hemorragias Intracranianas/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Acidente Vascular Cerebral/epidemiologia , Resultado do Tratamento , Varfarina/uso terapêutico , Adulto Jovem
J Neurosurg ; 124(6): 1773-9, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26613165


OBJECT Patients presenting with large-territory ischemic strokes may develop intractable cerebral edema that puts them at risk of death unless intervention is performed. The purpose of this study was to identify predictors of outcome for decompressive hemicraniectomy (DH) in ischemic stroke. METHODS The authors conducted a retrospective electronic medical record review of 1624 patients from 2006 to 2014. Subjects were screened for DH secondary to ischemic stroke involving the middle cerebral artery, internal carotid artery, or both. Ninety-five individuals were identified. Univariate and multivariate analyses were performed for an array of clinical variables in relationship to functional outcome according to the modified Rankin Scale (mRS). Clinical outcome was assessed at 90 days and at the latest follow-up (mean duration 16.5 months). RESULTS The mean mRS score at 90 days and at the latest follow-up post-DH was 4. Good functional outcome was observed in 40% of patients at 90 days and in 48% of patient at the latest follow-up. The mortality rate at 90 days was 18% and at the last follow-up 20%. Univariate analysis identified a greater likelihood of poor functional outcome (mRS scores of 4-6) in patients with a history of stroke (OR 6.54 [95% CI1.39-30.66]; p = 0.017), peak midline shift (MLS) > 10 mm (OR 3.35 [95% CI 1.33-8.47]; p = 0.011), or a history of myocardial infarction (OR 8.95 [95% CI1.10-72.76]; p = 0.04). Multivariate analysis demonstrated elevated odds of poor functional outcome associated with a history of stroke (OR 9.14 [95% CI 1.78-47.05]; p = 0.008), MLS > 10 mm (OR 5.15 [95% CI 1.58-16.79; p = 0.007), a history of diabetes (OR 5.63 [95% CI 1.52-20.88]; p = 0.01), delayed time from onset of stroke to DH (OR 1.32 [95% CI 1.02-1.72]; p = 0.037), and evidence of pupillary dilation prior to DH (OR 4.19 [95% CI 1.06-16.51]; p = 0.04). Patients with infarction involving the dominant hemisphere had higher odds of unfavorable functional outcome at 90 days (OR 4.73 [95% CI 1.36-16.44]; p = 0.014), but at the latest follow-up, cerebral dominance was not significantly related to outcome (OR 1.63 [95% CI 0.61-4.34]; p = 0.328). CONCLUSIONS History of stroke, diabetes, myocardial infarction, peak MLS > 10 mm, increasing duration from onset of stroke to DH, and presence of pupillary dilation prior to intervention are associated with a worse functional outcome.

Isquemia Encefálica/cirurgia , Craniectomia Descompressiva/métodos , Acidente Vascular Cerebral/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/cirurgia , Artéria Carótida Interna , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Artéria Cerebral Média , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/diagnóstico por imagem , Resultado do Tratamento , Adulto Jovem
Mamm Genome ; 24(7-8): 257-65, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23722970


Human coding variants in scavenger receptor class B member 1 (SR-BI; gene name SCARB1) have recently been identified as being associated with plasma levels of HDL cholesterol. However, a link between coding variants and atherosclerosis has not yet been established. In this study we set out to examine the impact of a SR-BI coding variant in vivo. A mouse model with a coding variant in SR-BI (I179N), identified through a mutagenesis screen, was crossed with Ldlr (-/-) mice, and these mice were maintained on a Western-type diet to promote atherosclerosis. Mice showed 56 and 125 % increased atherosclerosis in female and male Ldlr (-/-) Scarb1 (I179N) mice, respectively, when compared to gender-matched Ldlr (-/-) control mice. As expected, HDL cholesteryl ester uptake was impaired in Ldlr (-/-) Scarb1 (I179N) mice compared to Ldlr (-/-) control mice, with a net effect of increased small and very small LDL cholesterol in Ldlr (-/-) Scarb1 (I179N) mice being the most probable cause of the observed increased atherosclerosis. Our data show that non-null coding variants in SR-BI can have a large significant impact on atherosclerosis, even if plasma lipid levels are not dramatically affected, and that human mutations in other candidate lipid genes could significantly impact atherosclerosis.

Aterosclerose/genética , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Receptores de LDL/genética , Receptores Depuradores Classe B/genética , Animais , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Fígado/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esplenomegalia/genética
Hepat Med ; 3: 29-44, 2011 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-24367219


Scavenger receptor class B member 1 (SR-BI, also known as SCARB1) is the primary receptor for the selective uptake of cholesterol from high-density lipoprotein (HDL). SR-BI is present in several key tissues; however, its presence and function in the liver is deemed the most relevant for protection against atherosclerosis. Cholesterol is transferred from HDL via SR-BI to the liver, which ultimately results in the excretion of cholesterol via bile and feces in what is known as the reverse cholesterol transport pathway. Much of our knowledge of SR-BI hepatic function and regulation is derived from mouse models and in vitro characterization. Multiple independent regulatory mechanisms of SR-BI have been discovered that operate at the transcriptional and post-transcriptional levels. In this review we summarize the critical discoveries relating to hepatic SR-BI cholesterol metabolism, atherosclerosis, and regulation of SR-BI, as well as alternative functions that may indirectly affect atherosclerosis.