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This was an open-label, single-dose, phase I study to characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of edoxaban in pediatric subjects from birth to 18 years at risk for venous thromboembolism (VTE). Children requiring anticoagulant therapy were enrolled into 5 age cohorts (0 to < 6 months (N = 12), 0.5 to < 2 years (N = 13), 2 to < 6 years (N = 13), 6 to < 12 years (N = 13), and 12 to < 18 years (N = 15)) receiving tablet or oral suspension of edoxaban at doses expected to be equivalent to 30 or 60 mg once daily (q.d.) in adult subjects with VTE. Sixty-six pediatric subjects were enrolled and completed the study. Edoxaban plasma concentration peaked between 1 and 3 hours and declined rapidly until 4-8 hours. The range of mean total apparent clearance across 5 age cohorts at low and high doses was 0.47 to 1.11 L/h/kg. The ranges of mean volume of central compartment and apparent peripheral volume were 2.31 to 3.59 L/kg and 1.92 to 4.14 L/kg, respectively. Across all age groups, the estimated median exposures were within the 0.5- to 1.5-fold of the median area under the plasma drug concentration-time curve (AUC) in adult subjects receiving corresponding doses (30 mg q.d. for low dose and 60 mg q.d. for high dose). In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time, and anti-Factor Xa activity) showed a linear PK-PD relationship and were in line with previous adult data. The results support further evaluation of the pediatric doses in larger pivotal trials.
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Inibidores do Fator Xa , Piridinas , Tiazóis , Tromboembolia Venosa , Humanos , Piridinas/farmacocinética , Piridinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/sangue , Criança , Tiazóis/farmacocinética , Tiazóis/efeitos adversos , Tiazóis/administração & dosagem , Tiazóis/sangue , Pré-Escolar , Adolescente , Lactente , Masculino , Feminino , Recém-Nascido , Tromboembolia Venosa/tratamento farmacológico , Inibidores do Fator Xa/farmacocinética , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/administração & dosagem , Relação Dose-Resposta a Droga , Fatores Etários , Administração Oral , Área Sob a CurvaRESUMO
Thrombocytopenia occurs frequently in patients with cancer-associated thrombosis (CAT), however prospective evaluation of clinical outcomes following randomization to anticoagulants is limited. The HOKUSAI VTE Cancer study was a randomized, open-label, non-inferiority, phase III trial comparing dalteparin with edoxaban in CAT patients. This post hoc analysis of Hokusai VTE Cancer Study was performed to compare outcomes in patients with platelet count ≤100 K/µL at one or more specified time points (baseline, 1-month, or 3-month) versus those without thrombocytopenia. Cumulative incidences at 180 days were calculated with death as a competing risk. The primary outcome was major bleeding; secondary outcomes were clinically relevant non-major bleeding (CRNMB), recurrent thrombosis, and survival. The analysis included 1,045 patients with primarily solid tumor malignancies (89%), median age 65 years, and 52% male. The thrombocytopenia group comprised 9.6% (N=101) of the cohort and relative to the non-thrombocytopenia cohort (N=944), experienced significantly higher major bleeding (9.0% vs. 4.0%, sub-distribution hazard ratio (SHR) 2.4, P=0.02) and CRNMB (17.9% vs. 9.6%, SHR 2.0, P=0.01). Thrombocytopenia did not impact recurrent VTE (9.8% vs. 7.4%, SHR 1.3, P=0.37) nor overall mortality (21.8% vs. 26.0%, HR 0.9, P=0.48). Major bleeding was higher in patients with thrombocytopenia and gastrointestinal malignancies receiving edoxaban versus dalteparin (16.8% vs 0, p.
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Background: In the ENVISAGE-TAVI AF (Edoxaban vs Standard of Care and Their Effects on Clinical Outcomes in Patients Having Undergone Transcatheter Aortic Valve Implantation-Atrial Fibrillation) trial, edoxaban was noninferior to vitamin K antagonists (VKA) for a composite outcome of ischemic and bleeding complications but increased major bleeding in patients with atrial fibrillation after successful transcatheter aortic valve replacement. Women are at higher risk of bleeding and stroke than men after transcatheter aortic valve replacement. It is unclear whether the effect of edoxaban on these complications varies in relation to sex. Objectives: This study was to assess the effect of edoxaban vs VKA according to sex in the ENVISAGE-TAVI AF trial. Methods: The primary outcomes were net adverse cardiovascular events (NACE) and major bleeding, assessed considering the effective time on study medication (safety analysis). Results: Out of 1,377 patients, 658 (47.8%) were women. Risks for ischemic and major bleeding outcomes were similar between women and men. Edoxaban compared to VKA was associated with a similar risk of NACE in women (HR: 1.16; 95% CI: 0.81-1.65) and men (HR: 1.08; 95% CI: 0.76-1.53; P for interaction = 0.820) and a higher risk of major bleeding in both sexes (P for interaction = 0.170). The risk increase of major bleeding was attenuated in women (HR: 1.11; 95% CI: 0.69-1.79) as compared to men (HR: 1.75; 95% CI: 1.07-2.85). There were no treatment-related differences for ischemic complications in both sexes. Conclusions: Edoxaban compared to VKA was associated with a similar risk of NACE and higher risk of major bleeding in both sexes. The increase in bleeding complications with edoxaban was attenuated in women.
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BACKGROUND: Standard of care (SOC) anticoagulation for thromboembolism (TE) prevention in children with cardiac disease includes low molecular weight heparins or vitamin K antagonists. Limited data exists for alternate use of direct oral anticoagulants in children. OBJECTIVES: The investigators aimed to obtain safety and efficacy data for edoxaban in children. METHODS: We performed a phase 3, multinational, prospective, randomized, open-label, blinded-endpoint trial in patients <18 years of age with cardiac disease (ENNOBLE-ATE [Edoxaban for Prevention of Blood Vessels Being Blocked by Clots (Thrombotic Events) in Children at Risk Because of Cardiac Disease] trial). Patients were randomized 2:1 to age- and weight-based oral edoxaban once daily vs SOC for 3 months (main study period), stratified by cardiac diagnosis. Both groups could continue in an open-label edoxaban extension arm through 1 year. The primary endpoint was adjudicated clinically relevant bleeding (CRB). The main secondary endpoint was symptomatic TE or asymptomatic intracardiac thrombosis. RESULTS: The modified intention-to-treat cohort included 167 children. One patient per group experienced a nonmajor CRB in the main period. Treatment-emergent adverse events occurred in 46.8% (51 of 109) with edoxaban and 41.4% (24 of 58) with SOC. One SOC patient experienced 2 TE events (DVT with PE). Among 147 children in the extension, 1 CRB event (0.7%) and 4 TEs occurred (2.8%; 2 strokes and 2 of 33 Kawasaki disease patients with coronary artery thromboses and/or myocardial infarctions). CONCLUSIONS: Edoxaban is a potential alternative mode of thromboprophylaxis in children with cardiac disease showing low rates of CRB and TEs with advantages of once daily dosing and infrequent monitoring requirement. (ENNOBLE-ATE [Edoxaban for Prevention of Blood Vessels Being Blocked by Clots] (Thrombotic Events) in Children at Risk Because of Cardiac Disease trial; NCT03395639).
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Cardiopatias , Tromboembolia Venosa , Criança , Humanos , Anticoagulantes , Estudos ProspectivosRESUMO
Edoxaban 60 mg is approved for stroke prevention in patients with atrial fibrillation (AF) not fulfilling any dose-reduction criteria. As edoxaban is partially renally cleared (≈50%), this study compared pharmacokinetics (PK) and pharmacodynamics of edoxaban 60 mg once daily with edoxaban 75 mg once daily in patients with AF with high renal clearance (creatinine clearance > 100 mL/min) over 12 months. Primary PK and pharmacodynamics end points were plasma edoxaban exposure and anti-factor Xa (FXa) concentration. A population PK model estimated edoxaban exposure at steady state. Efficacy and safety outcomes included composites of stroke, transient ischemic attack, systemic embolism, and major and clinically relevant nonmajor bleeding. Of 607 patients, 303 and 304 were randomized to edoxaban 60 and 75 mg, respectively. Edoxaban 75 mg provided ≈25% higher exposure than 60 mg. This increase was accurately depicted in the population PK model; anti-factor Xa concentration correlated with edoxaban exposure. Rates of composite and individual outcomes were similarly low between doses. In conclusion, the 25% increase in edoxaban dose (60-75 mg) resulted in ≈25% exposure increase in the 75-mg group. Higher exposure was not associated with reduced stroke risk in patients with AF with high renal clearance.
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Fibrilação Atrial , Acidente Vascular Cerebral , Anticoagulantes , Fibrilação Atrial/tratamento farmacológico , Creatinina , Método Duplo-Cego , Humanos , Piridinas , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/prevenção & controle , Tiazóis , Resultado do Tratamento , VarfarinaRESUMO
Children with cardiac diseases suffer from significant morbidity and mortality secondary to thromboembolic complications. Anticoagulant agents currently used for thromboprophylaxis have many limitations, including subcutaneous administration (low molecular weight heparins) and requirement for frequent monitoring via venipuncture (vitamin K antagonists). Edoxaban is an oral direct factor Xa inhibitor without need of monitoring. In the treatment of venous thromboembolism in adults, edoxaban has shown to be effective and safe.This manuscript summarises the rationale and design of a phase 3, open-label, randomised controlled trial to evaluate and compare the safety and efficacy of edoxaban against standard of care (namely, vitamin K antagonist and low molecular weight heparin) in children with cardiac diseases.A goal of 150 children with cardiac diseases at risk of thromboembolic complications who need primary or secondary anticoagulant prophylaxis will be recruited. Eligible children between 6 months and <18 years of age will be randomised in a ratio of 2 to 1 for edoxaban versus standard of care. Randomisation will be stratified based on underlying cardiac disease and concomitant use of aspirin for patients other than Kawasaki disease. The primary outcome will be safety, comprised of major and clinically relevant non-major bleeding in first 3 months of treatment. Bleeding beyond 3 months, symptomatic and asymptomatic thromboembolic events, and pharmacokinetic and pharmacodynamic parameters will be evaluated as secondary outcomes.Randomised controlled anticoagulation trials are challenging in children. This study will evaluate a potentially valuable alternative of oral anticoagulant prophylactic use in children with cardiac diseases.
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Cardiopatias , Tromboembolia Venosa , Adulto , Anticoagulantes/efeitos adversos , Criança , Cardiopatias/complicações , Humanos , Piridinas , Tiazóis , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/prevenção & controleRESUMO
BACKGROUND: In the Hokusai VTE Cancer study, the risk of major bleeding was 2.9% higher in the edoxaban group compared with the dalteparin group, mainly due to more gastrointestinal bleedings in patients with gastrointestinal cancer. The identification of risk factors for gastrointestinal bleeding may help to guide the use of DOACs in these patients. OBJECTIVES: To evaluate risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. PATIENTS/METHODS: In this nested case-control study in patients with gastrointestinal cancer randomized to edoxaban in the Hokusai VTE Cancer study, cases (patients with clinically relevant gastrointestinal bleeding during treatment) were randomly matched to three controls (patients who had no gastrointestinal bleeding). Data for the 4-week period prior to bleeding were retrospectively collected. Odds ratios (ORs) were calculated in a crude conditional logistic regression model and a multivariable model adjusted for age, sex, and cancer type. RESULTS: Twenty-four cases and 64 matched controls were included. In the multivariable analysis, advanced cancer, defined as regionally advanced or metastatic cancer (OR 3.6, 95% CI 1.01-12.6) and low hemoglobin levels (OR 4.8, 95% CI 1.5-16.0) were significantly associated with bleeding. There was no significant difference in patients with resected tumors (OR 0.4, 95% CI 0.1-1.4), or in patients on chemotherapy (OR 1.3, 95% CI 0.5-3.5). CONCLUSION: Advanced cancer and low hemoglobin levels were associated with an increased risk of gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. We were unable to identify other risk factors, mainly due to limited statistical power.
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Neoplasias Gastrointestinais , Tromboembolia Venosa , Anticoagulantes/efeitos adversos , Estudos de Casos e Controles , Inibidores do Fator Xa/efeitos adversos , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/epidemiologia , Neoplasias Gastrointestinais/complicações , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Piridinas , Estudos Retrospectivos , Fatores de Risco , TiazóisRESUMO
BACKGROUND: The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied. METHODS: We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. RESULTS: A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P = 0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P = 0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11). CONCLUSIONS: In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785.).
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4-Hidroxicumarinas/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Piridinas/uso terapêutico , Tiazóis/uso terapêutico , Substituição da Valva Aórtica Transcateter , Vitamina K/antagonistas & inibidores , 4-Hidroxicumarinas/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Inibidores do Fator Xa/efeitos adversos , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Masculino , Mortalidade , Fenindiona/análogos & derivados , Fenindiona/uso terapêutico , Complicações Pós-Operatórias/prevenção & controle , Piridinas/efeitos adversos , Tiazóis/efeitos adversos , Tromboembolia/prevenção & controle , Substituição da Valva Aórtica Transcateter/efeitos adversosRESUMO
BACKGROUND: Little evidence is available for treatment of pediatric venous thromboembolism (VTE). Large randomized controlled trials are challenging in children. Current antithrombotic agents have many limitations, including nonoral administration and frequent monitoring. Edoxaban is an oral direct inhibitor of factor Xa without need of monitoring. In adults with VTE, edoxaban has shown to be effective and safe. OBJECTIVES: The Edoxaban Hokusai VTE PEDIATRICS Study is an open-label, randomized clinical trial to evaluate pharmacokinetics (PK) and pharmacodynamics (PD) of edoxaban and whether edoxaban is noninferior to standard of care in treatment of pediatric VTE. METHODS: A goal of 274 patients will be recruited in 5 age categories. A multidose PK/PD assessment on day 5 in the first 12 patients of each age group is incorporated into this study. The primary composite efficacy outcome comprises symptomatic recurrent VTE, death due to VTE, and no change or extension of thrombotic burden. The principal safety end point is a combination of major and clinically relevant nonmajor bleeding. PK end points include apparent systemic clearance and volume of distribution of edoxaban. PD end points include prothrombin time, activated partial thromboplastin time, and anti-factor Xa level for the edoxaban treatment arm. RESULTS: To increase feasibility, the multidose PK/PD study is integrated in the phase 3 trial. In addition, thrombotic burden, which is a prognostic factor for post thrombotic syndrome in children, is one of the components of the primary composite efficacy outcome. CONCLUSION: This study will increase the level of evidence for treatment in pediatric VTE.
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Background Anticoagulation in patients with malignancy and atrial fibrillation is challenging because of enhanced risks for thrombosis and bleeding and the frequent need for invasive procedures. Data on direct oral antagonists in such patients are sparse. Methods and Results The ENGAGE AF - TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48) trial randomized 21 105 patients with atrial fibrillation to edoxaban or warfarin. Patients with malignancy, defined as a postrandomization new diagnosis or recurrence of remote cancer, were followed up over a median of 2.8 years. Adjusted Cox proportional hazard models were used to evaluate the safety and efficacy of edoxaban versus warfarin. Over a median of 495 days (interquartile range, 230-771 days), 1153 patients (5.5%) were diagnosed with new or recurrent malignancy, most commonly involving the gastrointestinal tract (20.6%), prostate (13.6%), and lung (11.1%). Malignancy was associated with increased risk of death (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.78-3.50) and major bleeding (adjusted HR, 2.45; 95% CI, 2.07-2.89), but not stroke/systemic embolism (adjusted HR, 1.08; 95% CI, 0.83-1.42). Relative outcomes with higher-dose edoxaban versus warfarin were consistent regardless of malignancy status for stroke/systemic embolism ( HR , 0.60 [95% CI, 0.31-1.15] for malignancy versus HR , 0.89 [95% CI, 0.76-1.05] for no malignancy; interaction P=0.25) and major bleeding ( HR , 0.98 [95% CI, 0.69-1.40] for malignancy versus HR , 0.79 [95% CI, 0.69-1.05] for no malignancy; interaction P=0.31). There was, however, a significant treatment interaction for the composite ischemic end point (ischemic stroke/systemic embolism/myocardial infarction), with greater efficacy of higher-dose edoxaban versus warfarin in patients with malignancy ( HR , 0.54; 95% CI, 0.31-0.93) compared with no malignancy ( HR , 1.02; 95% CI, 0.88-1.18; interaction P=0.026). Conclusions In patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.
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Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Hemorragia/induzido quimicamente , Neoplasias/epidemiologia , Piridinas/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Tiazóis/uso terapêutico , Idoso , Anticoagulantes/uso terapêutico , Fibrilação Atrial/complicações , Fibrilação Atrial/epidemiologia , Comorbidade , Embolia/etiologia , Embolia/prevenção & controle , Feminino , Neoplasias Gastrointestinais/epidemiologia , Hemorragia/epidemiologia , Humanos , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias da Próstata/epidemiologia , Acidente Vascular Cerebral/etiologia , Varfarina/uso terapêuticoRESUMO
BACKGROUND: Edoxaban is an orally active, direct factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation and for the treatment of venous thromboembolism. OBJECTIVES: This study assessed the pharmacokinetics, safety, and tolerability of the edoxaban 60-mg tablet crushed and administered via a nasogastric tube in a water suspension or orally mixed in apple puree. METHODS: This phase 1, open-label, crossover study randomized 30 healthy adults to receive three edoxaban treatment regimens (oral 60-mg edoxaban tablet, or 60-mg edoxaban tablet crushed and administered via a nasogastric tube or orally in apple puree) in one of six treatment sequences. RESULTS: Total edoxaban exposure was similar between the intact and crushed tablet regimens (mean area under the plasma concentration-time curve from time zero to infinity: whole tablet, 2132 ng·h/mL; nasogastric tube, 2021 ng·h/mL; apple puree, 2076 ng·h/mL). Mean maximum plasma concentration, area under the plasma concentration-time curve from time zero to the time of the last measurable concentration, terminal half-life, and apparent total body clearance values were also similar. Time to maximum plasma concentration was significantly shorter for the nasogastric tube suspension and apple puree vs. the whole tablet [Hodges-Lehmann estimate of median difference (90% confidence interval): -0.75 (-1.25, -0.28); p = 0.0003 and -0.62 (-0.99, -0.26); p = 0.0024, respectively]. The maximum plasma concentation, area under the plasma concentration-time curve from time zero to infinity, and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration were similar between treatment regimens; 90% confidence interval of the geometric least-squares means ratios were within the predefined 80-125% bioequivalence criterion. The safety and tolerability of edoxaban did not differ between treatment regimens. CONCLUSION: The results support the use of edoxaban tablets crushed and administered either via a nasogastric tube or orally mixed in apple puree in patients who are unable to swallow solid oral dose formulations.
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Composição de Medicamentos/métodos , Inibidores do Fator Xa/administração & dosagem , Intubação Gastrointestinal , Piridinas/administração & dosagem , Tiazóis/administração & dosagem , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Estudos Cross-Over , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/farmacocinética , Feminino , Meia-Vida , Humanos , Masculino , Malus , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Piridinas/farmacocinética , Suspensões , Comprimidos , Equivalência Terapêutica , Tiazóis/efeitos adversos , Tiazóis/farmacocinética , Adulto JovemRESUMO
BACKGROUND: Evidence on the optimal time to initiation of complementary feeding in preterm infants is scarce. We examined the effect of initiation of complementary feeding at 4 months versus 6 months of corrected age on weight for age at 12 months corrected age in preterm infants less than 34 weeks of gestation. METHODS: In this open-label, randomised trial, we enrolled infants born at less than 34 weeks of gestation with no major malformation from three public health facilities in India. Eligible infants were tracked from birth and randomly assigned (1:1) at 4 months corrected age to receive complementary feeding at 4 months corrected age (4 month group), or continuation of milk feeding and initiation of complementary feeding at 6 months corrected age (6 month group), using computer generated randomisation schedule of variable block size, stratified by gestation (30 weeks or less, and 31-33 weeks). Iron supplementation was provided as standard. Participants and the implementation team could not be masked to group assignment, but outcome assessors were masked. Primary outcome was weight for age Z-score at 12 months corrected age (WAZ12) based on WHO Multicentre Growth Reference Study growth standards. Analyses were by intention to treat. The trial is registered with Clinical Trials Registry of India, number CTRI/2012/11/003149. FINDINGS: Between March 20, 2013, and April 24, 2015, 403 infants were randomly assigned: 206 to receive complementary feeding from 4 months and 197 to receive complementary feeding from 6 months. 22 infants in the 4 month group (four deaths, two withdrawals, 16 lost to follow-up) and eight infants in the 6 month group (two deaths, six lost to follow-up) were excluded from analysis of primary outcome. There was no difference in WAZ12 between two groups: -1·6 (SD 1·2) in the 4 month group versus -1·6 (SD 1·3) in the 6 month group (mean difference 0·005, 95% CI -0·24 to 0·25; p=0·965). There were more hospital admissions in the 4 month group compared with the 6 month group: 2·5 episodes per 100 infant-months in the 4 month group versus 1·4 episodes per 100 infant-months in the 6 month group (incidence rate ratio 1·8, 95% CI 1·0-3·1, p=0·03). 34 (18%) of 188 infants in the 4 month group required hospital admission, compared with 18 (9%) of 192 infants in the 6 month group. INTERPRETATION: Although there was no evidence of effect for the primary endpoint of WAZ12, the higher rate of hospital admission in the 4 month group suggests a recommendation to initiate complementary feeding at 6 months over 4 months of corrected age in infants less than 34 weeks of gestation. FUNDING: Indian Council of Medical Research supported the study until Nov 14, 2015. Subsequently, Shuchita Gupta's salary was supported for 2 months by an institute fellowship from All India Institute Of Medical Sciences, and a grant by Wellcome Trust thereafter.
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Peso Corporal , Aleitamento Materno , Hospitalização , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido Prematuro/crescimento & desenvolvimento , Adulto , Animais , Feminino , Idade Gestacional , Humanos , Índia , Lactente , Recém-Nascido , Masculino , Leite , Fatores de Tempo , Adulto JovemRESUMO
A clear challenge for the coming decades is decreasing the carbon intensity of the global energy supply while simultaneously accommodating a rapid worldwide increase in power demand. Meeting this challenge of providing abundant, clean energy undoubtedly requires synergistic efforts between basic and applied researchers in the chemical sciences to develop and deploy new technologies. Among the available options, solar energy is one of the promising targets because of the high abundance of solar photons over much of the globe. Similarly, decarbonization of the global energy supply will require clean sources of hydrogen to use as reducing equivalents for fuel and chemical feedstocks. In this report, we discuss the importance of translational research-defined as work that explicitly targets basic discovery as well as technology development-in the context of photovoltaics and solar fuels. We focus on three representative research programs encompassing translational research in government, industry, and academia. We then discuss more broadly the benefits and challenges of translational research models and offer recommendations for research programs that address societal challenges in the energy sector and beyond.
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Compared with the coronary setting, knowledge about antithrombotic therapies after endovascular treatment (EVT) is inadequate in patients with peripheral artery disease (PAD). Based on a review of trials and guidelines, which is summarized in this article, there is scant evidence that antithrombotic drugs improve outcome after peripheral EVT. To address this knowledge gap, the randomized, open-label, multinational edoxaban in patients with Peripheral Artery Disease (ePAD) study (ClinicalTrials.gov identifier NCT01802775) was designed to explore the safety and efficacy of a combined regimen of antiplatelet therapy with clopidogrel and anticoagulation with edoxaban, a selective and direct factor Xa inhibitor, both combined with aspirin. As of July 2014, 203 patients (144 men; mean age 67 years) from 7 countries have been enrolled. These patients have been allocated to once-daily edoxaban [60 mg for 3 months (or 30 mg in the presence of factors associated with increased exposure)] or clopidogrel (75 mg/d for 3 months). All patients received aspirin (100 mg/d) for the 6-month duration of the study. The primary safety endpoint is major or clinically relevant nonmajor bleeding; the primary efficacy endpoint is restenosis or reocclusion at the treated segment(s) measured at 1, 3, and 6 months using duplex ultrasound scanning. All outcomes will be assessed and adjudicated centrally in a masked fashion. The ePAD study is the first of its kind to investigate a combined regimen of antiplatelet therapy and anticoagulation through factor Xa inhibition with edoxaban.
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Angioplastia , Aspirina/uso terapêutico , Inibidores do Fator Xa/uso terapêutico , Artéria Femoral , Fibrinolíticos/uso terapêutico , Doença Arterial Periférica/terapia , Inibidores da Agregação Plaquetária/uso terapêutico , Artéria Poplítea , Piridinas/uso terapêutico , Projetos de Pesquisa , Tiazóis/uso terapêutico , Ticlopidina/análogos & derivados , Idoso , Angioplastia/efeitos adversos , Angioplastia/instrumentação , Aspirina/efeitos adversos , Clopidogrel , Quimioterapia Combinada , Europa (Continente) , Inibidores do Fator Xa/efeitos adversos , Feminino , Artéria Femoral/fisiopatologia , Fibrinolíticos/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Israel , Masculino , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Inibidores da Agregação Plaquetária/efeitos adversos , Artéria Poplítea/fisiopatologia , Piridinas/efeitos adversos , Fatores de Risco , Stents , Tiazóis/efeitos adversos , Ticlopidina/efeitos adversos , Ticlopidina/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND AND PURPOSE: The once-daily oral factor Xa inhibitor, edoxaban, is as effective as warfarin in preventing stroke and systemic embolism while decreasing bleeding in a phase III trial of patients with atrial fibrillation at moderate-high stroke risk. Limited data regarding cerebrovascular events with edoxaban were reported previously. METHODS: We analyzed the subtypes of cerebrovascular events in 21 105 patients participating in Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) comparing outcomes among patients randomized to warfarin versus 2 edoxaban regimens (high dose, low dose). The primary end point for this prespecified analysis of cerebrovascular events was all stroke (ischemic plus hemorrhagic), defined as an abrupt onset of focal neurological deficit because of infarction or bleeding with symptoms lasting ≥24 hours or fatal in <24 hours. Independent stroke neurologists unaware of treatment adjudicated all cerebrovascular events. RESULTS: Patients randomized to high-dose edoxaban had fewer strokes on-treatment (hazard ratio, 0.80; 95% confidence interval, 0.65-0.98) than warfarin (median time-in-therapeutic range, 68.4%); patients in the low-dose edoxaban group had similar rates (hazard ratio, 1.10 versus warfarin; 95% confidence interval, 0.91-1.32). Rates of ischemic stroke or transient ischemic attack were similar with high-dose edoxaban (1.76% per year) and warfarin (1.73% per year; P=0.81), but more frequent with low-dose edoxaban (2.48% per year; P<0.001). Both edoxaban regimens significantly reduced hemorrhagic stroke and other subtypes of intracranial bleeds. CONCLUSIONS: In patients with atrial fibrillation, once-daily edoxaban was as effective as warfarin in preventing all strokes, with significant reductions in various subtypes of intracranial bleeding. Ischemic cerebrovascular event rates were similar with high-dose edoxaban and warfarin, whereas low-dose edoxaban was less effective than warfarin. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.
Assuntos
Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Piridinas/uso terapêutico , Acidente Vascular Cerebral/induzido quimicamente , Tiazóis/uso terapêutico , Varfarina/uso terapêutico , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Resultado do Tratamento , Varfarina/administração & dosagem , Varfarina/efeitos adversosRESUMO
The purpose of this article is to share our institution's experience in optimizing the suitability of composite donor tissue for use in hand transplantation. The centerpiece of this process includes procurement techniques, preservation and timing issues, and anatomical matching. Recovery of the donor hand must proceed in an efficient, organized, and expedient manner. Proper timing of the donor operation not only ensures the quality of donor tissue and outcome for the hand recipient, but also allows surgeons recovering other organs to obtain high quality tissue for those recipients. Timing remains a critical factor in preserving tissue after removal from the donor. We will also consider the factors of temperature and preservation solution during transport.
Assuntos
Transplante de Mão , Procedimentos de Cirurgia Plástica/métodos , Manejo de Espécimes , Doadores de Tecidos , Preservação de Tecido , Obtenção de Tecidos e Órgãos , Feminino , Mãos/inervação , Humanos , Masculino , Manejo de Espécimes/métodos , Fatores de Tempo , Preservação de Tecido/métodos , Obtenção de Tecidos e Órgãos/métodos , Transplante HomólogoRESUMO
BACKGROUND: Controversy exists as to whether the benefits of facial transplantation outweigh the risk of continuous immunosuppression. Utility scores [range, 0 (death) to 1 (perfect health)] are a standardized tool with which to objectify health states or diseases and can help answer such controversy. METHODS: An Internet-based utility assessment study using visual analogue scale, time trade-off, and standard gamble was used to obtain utilities for facial disfigurement requiring facial transplantation from a sample of the general population and medical students at McGill University. Average utility scores were compared using t test, and linear regression was performed using age, race, and education as independent predictors of each of the utility scores. RESULT: A total of 307 people participated in the study. All measures (visual analogue scale, time trade off, and standard gamble) for facial disfigurement (0.46 + or - 0.02, 0.68 + or - 0.03, and 0.66 + or - 0.03, respectively) were significantly different (p < 0.001) from the corresponding ones for monocular blindness (0.62 + or - 0.02, 0.83 + or - 0.02, and 0.82 + or - 0.02, respectively) and binocular blindness (0.33 + or - 0.02, 0.62 + or - 0.03, and 0.61 + or - 0.03, respectively). Age was inversely proportional to the utility scores in all groups (p < 0.01), decreasing a utility score of 0.006 for every increase in year of age. CONCLUSION: A sample of the general population and medical students, if faced with facial disfigurement, would undergo a face transplant procedure with a 34 percent chance of death and be willing to trade 12 years of their life to attain perfect health.
Assuntos
Anormalidades Craniofaciais/cirurgia , Traumatismos Faciais/cirurgia , Transplante de Face/métodos , Internet , Qualidade de Vida , Fatores Etários , Imagem Corporal , Estudos de Coortes , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/psicologia , Traumatismos Faciais/diagnóstico , Traumatismos Faciais/psicologia , Feminino , Indicadores Básicos de Saúde , Humanos , Escala de Gravidade do Ferimento , Modelos Lineares , Masculino , Medição da Dor , Preferência do Paciente , Probabilidade , Quebeque , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Percepção Social , Inquéritos e Questionários , Adulto JovemRESUMO
Facial rhytidectomy is a complex and multi-faceted operation performed by different methodologies between practitioners. This study elucidates current international trends in facelift surgery, including patient selection, operative technique, and postoperative care. A 43-item questionnaire was sent electronically to 7247 members of the following societies: ASPS, ISAPS, CSPS, IFFPS, and the AAFPRS. The survey focused on 3 main areas: (a) background information, (b) intraoperative technique, and (c) postoperative care. The response rate was 11.4%. The majority of our population was from the United States (US) (73%). Most (85%) of the respondents have practices where over 50% of their procedures are considered aesthetic surgery. Statistical differences between the uses of minimally invasive adjuvant treatments (thread lifts, endotine mid-face devices, superficial and deep skin resurfacing procedures) were found between plastic surgeons (PS) and facial plastic surgeons (FPS), as well as between US, Canadian, and international surgeons. Suture imbrication (42%) was the most common way of handling the submuscular aponeurotic system. International surgeons were more likely (49.6% vs. 37.7%, P < 0.05) to use this technique than US or Canadian surgeons. Difference in handling patients who smoke and postoperative management differences were also found between the groups queried. No differences were found between FPS and PS in the handling of the submuscular aponeurotic system, treatment of platysmal bands, treatment of ptotic submandibular glands, or treatment of submental fat deposits (P > 0.05). Differences exist between FPS and PS, and between US, Canadian, and international surgeons with regard to facelift techniques and perioperative management. These differences need to be addressed in order to measure outcomes across specialties and between techniques. This data will additionally be helpful for less experienced and younger surgeons who wish to define best practice patterns.
Assuntos
Técnicas Cosméticas , Prática Profissional/estatística & dados numéricos , Ritidoplastia/métodos , Materiais Biocompatíveis , Canadá , Pesquisas sobre Atenção à Saúde , Humanos , Internacionalidade , Seleção de Pacientes , Cuidados Pós-Operatórios , Padrões de Prática Médica , Estados UnidosRESUMO
Patients with impaired glucose tolerance (IGT) have increased risk for developing type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Lifestyle modification and medication can prevent or delay progression to diabetes (PD), but whether such interventions also reduce the risk of CVD has not been rigorously tested. The Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial is a multinational, randomized, double-blind, 2 x 2 factorial trial in subjects with IGT (on a screening oral glucose tolerance test [OGTT]) aged > or = 50 years with known CVD or aged > or = 55 years with > or = 1 CVD risk factor. Enrollment began in January 2002 and was completed January 2004, with 9,518 patients randomized to receive 1 of 4 possible treatment combinations as follows: nateglinide with valsartan, nateglinide with valsartan-placebo, nateglinide-placebo with valsartan, or nateglinide-placebo with valsartan-placebo. All subjects are participating in a clinic-based and telephone-based lifestyle intervention aimed at reducing weight and dietary fat and increasing physical activity. The 3 coprimary end points are new onset of T2DM, a "core" composite of major cardiovascular events (death, myocardial infarction, stroke, or hospitalization for heart failure), and an "extended" composite including the components of the core composite plus coronary revascularization and hospitalization for unstable angina. The study was designed to evaluate whether reducing postprandial hyperglycemia, blockade of the renin-angiotensin-aldosterone system, or both interventions reduce the risk of T2DM or cardiovascular events in patients with IGT.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Cicloexanos/uso terapêutico , Angiopatias Diabéticas/prevenção & controle , Intolerância à Glucose/prevenção & controle , Hipoglicemiantes/uso terapêutico , Fenilalanina/análogos & derivados , Tetrazóis/uso terapêutico , Valina/análogos & derivados , Angiopatias Diabéticas/tratamento farmacológico , Angiopatias Diabéticas/fisiopatologia , Progressão da Doença , Método Duplo-Cego , Intolerância à Glucose/tratamento farmacológico , Humanos , Estilo de Vida , Nateglinida , Avaliação de Resultados em Cuidados de Saúde , Fenilalanina/uso terapêutico , Projetos de Pesquisa , Valina/uso terapêutico , ValsartanaRESUMO
OBJECTIVE: To survey and improve the pathological reporting of colorectal cancer (CRC) specimens in a tertiary care pathology department. METHODS: We identified CRC specimens reported in a 6-month period before and after educational sessions and the introduction of a standardized CRC synoptic reporting protocol. Gross and microscopic descriptions were analyzed according to published guidelines for important staging and prognostic features. We then reexamined these parameters for a further 6-month period 15 months later to ensure that the quality of reporting had been maintained. RESULTS: In total, 108 and 166 cases were analyzed before and after standardization, respectively. Many features were reported appropriately, including tumour size, type and grade, depth of invasion, nodal status and proximal and distal margin status. Several underreported features showed significant improvement after standardization, including serosal involvement (reporting increased from 22% to 84%), distance to radial margin (from 14% to 64%), extramural venous invasion (from 18% to 88%), host response (from 19% to 94%) and mean number of nodes retrieved (mean numbers retrieved increased from 11 to 16). The subsequent review 15 months later showed continued long-term improvement in these areas. CONCLUSION: Education and synoptic reporting significantly improved CRC reporting at our centre.