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BACKGROUND: The effects of rivaroxaban in patients with atrial fibrillation and a bioprosthetic mitral valve remain uncertain. METHODS: In this randomized trial, we compared rivaroxaban (20 mg once daily) with dose-adjusted warfarin (target international normalized ratio, 2.0 to 3.0) in patients with atrial fibrillation and a bioprosthetic mitral valve. The primary outcome was a composite of death, major cardiovascular events (stroke, transient ischemic attack, systemic embolism, valve thrombosis, or hospitalization for heart failure), or major bleeding at 12 months. RESULTS: A total of 1005 patients were enrolled at 49 sites in Brazil. A primary-outcome event occurred at a mean of 347.5 days in the rivaroxaban group and 340.1 days in the warfarin group (difference calculated as restricted mean survival time, 7.4 days; 95% confidence interval [CI], -1.4 to 16.3; P<0.001 for noninferiority). Death from cardiovascular causes or thromboembolic events occurred in 17 patients (3.4%) in the rivaroxaban group and in 26 (5.1%) in the warfarin group (hazard ratio, 0.65; 95% CI, 0.35 to 1.20). The incidence of stroke was 0.6% in the rivaroxaban group and 2.4% in the warfarin group (hazard ratio, 0.25; 95% CI, 0.07 to 0.88). Major bleeding occurred in 7 patients (1.4%) in the rivaroxaban group and in 13 (2.6%) in the warfarin group (hazard ratio, 0.54; 95% CI, 0.21 to 1.35). The frequency of other serious adverse events was similar in the two groups. CONCLUSIONS: In patients with atrial fibrillation and a bioprosthetic mitral valve, rivaroxaban was noninferior to warfarin with respect to the mean time until the primary outcome of death, major cardiovascular events, or major bleeding at 12 months. (Funded by PROADI-SUS and Bayer; RIVER ClinicalTrials.gov number, NCT02303795.).
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Anticoagulantes/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Bioprótese , Valva Mitral , Rivaroxabana/uso terapêutico , Varfarina/uso terapêutico , Idoso , Anticoagulantes/efeitos adversos , Fibrilação Atrial/complicações , Fibrilação Atrial/mortalidade , Doenças Cardiovasculares/epidemiologia , Inibidores do Fator Xa/uso terapêutico , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Rivaroxabana/efeitos adversos , Método Simples-Cego , Acidente Vascular Cerebral/prevenção & controle , Varfarina/efeitos adversosRESUMO
BACKGROUND: The safety and efficacy of ticagrelor in patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remain uncertain. OBJECTIVES: The primary objective of the TicagRElor in pAtients with ST elevation myocardial infarction treated with Thrombolysis (TREAT) trial is to evaluate the short-term safety of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. Key secondary objectives are to assess the safety and efficacy of ticagrelor compared with clopidogrel at 12-months. DESIGN: The TREAT trial is a multicenter, randomized, phase III, Prospective randomized open blinded end-point (PROBE) study that enrolled 3,799 patients in 152 sites from 10 countries. Following administration of fibrinolytic therapy patients were randomized to a loading dose of ticagrelor 180 mg or clopidogrel 300 mg followed by a maintenance dose of ticagrelor 90 mg twice daily or clopidogrel 75 mg/day for 12-months. The primary outcome is the rate of TIMI major bleeding at 30-days and will be assessed for non-inferiority using an intention-to-treat analysis. Co-treatments include aspirin and anticoagulants. Other evidence based therapies are also recommended. Secondary efficacy outcome include a composite of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack or other arterial thrombotic event. All-cause mortality as well as individual components of the combined efficacy endpoint will also be ascertained. SUMMARY: TREAT is an international randomized controlled trial comparing ticagrelor with clopidogrel in STEMI patients treated with fibrinolytic therapy. The results of this trial will inform clinical practice and international guidelines.
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Clopidogrel/uso terapêutico , Fibrinolíticos/uso terapêutico , Hemorragia/induzido quimicamente , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico , Ticagrelor/uso terapêutico , Adulto , Idoso , Anticoagulantes/uso terapêutico , Clopidogrel/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Antagonistas do Receptor Purinérgico P2Y/efeitos adversos , Projetos de Pesquisa , Infarto do Miocárdio com Supradesnível do Segmento ST , Método Simples-Cego , Ticagrelor/efeitos adversosRESUMO
PURPOSE: To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients. MATERIAL AND METHODS: Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life. RESULTS: From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference - 0.65, 95% confidence intervals from -2.95 to 1.36, p = 0.520). CONCLUSION: Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020. GOV IDENTIFIER: NCT04549922.
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OBJECTIVE: To evaluate the effectiveness of a nutritional strategy based on two components and adapted for the public health system on blood pressure, cardiometabolic features, self-care, qualify of life and diet quality in individuals with hypertension. METHODS: NUPRESS was an open-label, parallel-group, superiority randomized controlled clinical trial in which participants at least 21âyears with hypertension and poorly controlled blood pressure were randomly assigned (1â:â1 allocation ratio) to either an individualized dietary prescription according to nutritional guidelines (control group, n â=â205); or a two-component nutrition strategy, including a goal-directed nutritional counseling and mindfulness techniques (NUPRESS [intervention] group, n â=â205). Primary outcomes were SBP (mmHg) after 24 weeks of follow up and blood pressure control, defined as either having SBP more than 140âmmHg at baseline and achieving 140âmmHg or less after follow-up or having SBP 140âmmHg or less at baseline and reducing the frequency of antihypertensive drugs in use after follow-up. RESULTS: In total, 410 participants were randomized and submitted to an intention-to-treat analysis regarding primary outcomes. Both groups decreased blood pressure, but after adjusting for baseline values, there was no significant difference between them on SBP [intervention-control difference: -0.03 (-3.01; 2.94); P â=â0.98] nor blood pressure control [odds ratio 1.27 (0.82; 1.97); P â=â0.28]. No differences between groups were also detected regarding secondary and tertiary outcomes. CONCLUSION: There was no difference between a two-component nutritional strategy and an established dietary intervention on blood pressure in participants with hypertension.
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Pressão Sanguínea , Hipertensão , Humanos , Hipertensão/dietoterapia , Hipertensão/terapia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Adulto , Saúde Pública , Anti-Hipertensivos/uso terapêuticoRESUMO
BACKGROUND: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear. OBJECTIVE: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia. METHODS: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance. OUTCOMES: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide. CONCLUSION: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.
Assuntos
Infecções Comunitárias Adquiridas , Respiração com Pressão Positiva , Síndrome do Desconforto Respiratório , Humanos , Brasil/epidemiologia , Colômbia/epidemiologia , Infecções Comunitárias Adquiridas/terapia , Unidades de Terapia Intensiva , Pneumonia/terapia , Respiração com Pressão Positiva/métodos , Estudos Prospectivos , Síndrome do Desconforto Respiratório/terapia , Síndrome do Desconforto Respiratório/fisiopatologia , Volume de Ventilação Pulmonar , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
BACKGROUND: Halofuginone (PJS-539) is an oral prolyl-tRNA synthetase inhibitor that has a potent in vitro activity against SARS-CoV-2 virus. The safety and efficacy of halofuginone in Covid-19 patients has not been studied. METHODS: We conducted a phase II, randomized, double-blind, placebo-controlled, dose ranging, safety and tolerability trial of halofuginone in symptomatic (≤ 7 days), mostly vaccinated, non-hospitalized adults with mild to moderate Covid-19. Patients were randomized in a 1:1:1 ratio to receive halofuginone 0.5mg, 1mg or placebo orally once daily for 10 days. The primary outcome was the decay rate of the SARS-CoV-2 viral load logarithmic curve within 10 days after randomization. RESULTS: From September 25, 2021, to February 3, 2022, 153 patients were randomized. The mean decay rate in SARS-CoV-2 viral load log10 within 10 days was -3.75 (95% CI, -4.11; -3.19) in the placebo group, -3.83 (95% CI, -4.40; -2.27) in the halofuginone 0.5mg group and -4.13 (95% CI, -4.69; -3.57) in the halofuginone 1mg group, with no statistically significant difference in between placebo vs. halofuginone 0.5mg (mean difference -0.08; 95% CI -0.82 to 0.66, p = 0.96) and between placebo vs. halofuginone 1mg (mean difference -0.38; 95% CI, -1.11; 0.36, p = 0.41). There was no difference on bleeding episodes or serious adverse events at 28 days. CONCLUSIONS: Among non-hospitalized adults with mild to moderate Covid-19 halofuginone treatment was safe and well tolerated but did not decrease SARS-CoV-2 viral load decay rate within 10 days.
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COVID-19 , Piperidinas , Quinazolinonas , Adulto , Humanos , SARS-CoV-2 , Fatores de Tempo , Método Duplo-CegoRESUMO
Background: The best way to offer non-invasive respiratory support across several aetiologies of acute respiratory failure (ARF) is presently unclear. Both high flow nasal catheter (HFNC) therapy and non-invasive positive pressure ventilation (NIPPV) may improve outcomes in critically ill patients by avoiding the need for invasive mechanical ventilation (IMV). Objective: Describe the details of the protocol and statistical analysis plan designed to test whether HFNC therapy is non-inferior or even superior to NIPPV in patients with ARF due to different aetiologies. Methods: RENOVATE is a multicentre adaptive randomised controlled trial that is recruiting patients from adult emergency departments, wards and intensive care units (ICUs). It takes advantage of an adaptive Bayesian framework to assess the effectiveness of HFNC therapy versus NIPPV in four subgroups of ARF (hypoxaemic non-immunocompromised, hypoxaemic immunocompromised, chronic obstructive pulmonary disease exacerbations, and acute cardiogenic pulmonary oedema). The study will report the posterior probabilities of non-inferiority, superiority or futility for the comparison between HFNC therapy and NIPPV. The study assumes neutral priors and the final sample size is not fixed. The final sample size will be determined by a priori determined stopping rules for non-inferiority, superiority and futility for each subgroup or by reaching the maximum of 2000 patients. Outcomes: The primary endpoint is endotracheal intubation or death within 7 days. Secondary outcomes are 28-day and 90-day mortality, and ICU-free and IMV-free days in the first 28 days. Results and conclusions: RENOVATE is designed to provide evidence on whether HFNC therapy improves, compared with NIPPV, important patient-centred outcomes in different aetiologies of ARF. Here, we describe the rationale, design and status of the trial. Trial registration:ClinicalTrials.gov NCT03643939.
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Repurposed drugs are important in resource-limited settings because the interventions are more rapidly available, have already been tested safely in other populations and are inexpensive. Repurposed drugs are an effective solution, especially for emerging diseases such as COVID-19. The REVOLUTIOn trial has the objective of evaluating three repurposed antiviral drugs, atazanavir, daclatasvir and sofosbuvir, already used for HIV- and hepatitis C virus-infected patients in a randomized, placebo-controlled, adaptive, multiarm, multistage study. The drugs will be tested simultaneously in a Phase II trial to first identify whether any of these drugs alone or in combination reduce the viral load. If they do, a Phase III trial will be initiated to investigate if these medications are capable of increasing the number of days free respiratory support. Participants must be hospitalized adults aged ≥ 18 years with initiation of symptoms ≤ 9 days and SpO2 ≤ 94% in room air or a need for supplemental oxygen to maintain an SpO2 > 94%. The expected total sample size ranges from 252 to 1,005 participants, depending on the number of stages that will be completed in the study. Hence, the protocol is described here in detail together with the statistical analysis plan. In conclusion, the REVOLUTIOn trial is designed to provide evidence on whether atazanavir, daclatasvir or sofosbuvir decrease the SARS-CoV-2 load in patients with COVID-19 and increase the number of days patients are free of respiratory support. In this protocol paper, we describe the rationale, design, and status of the trial. ClinicalTrials.gov identifier: NCT04468087.
Os medicamentos reaproveitados são importantes em contextos de recursos limitados porque as intervenções estão mais rapidamente disponíveis, já foram testadas com segurança em outras populações e são, em geral, mais baratas. Os medicamentos reaproveitados são uma solução eficaz, especialmente para doenças emergentes, como a COVID-19. O estudo REVOLUTIOn visa avaliar três medicamentos antivirais reaproveitados: atazanavir, daclatasvir e sofosbuvir, já utilizados em pacientes infectados pelo HIV ou pelo vírus da hepatite C, em um estudo randomizado, controlado por placebo, adaptativo, multibraço e em múltiplos estágios. Os medicamentos serão testados simultaneamente em um ensaio de Fase II para primeiro identificar se algum deles, isoladamente ou em combinação, reduz a carga viral. Se reduzirem, será iniciado um estudo de Fase III para investigar se tais medicamentos são capazes de aumentar o número de dias sem suporte respiratório. Os participantes devem ser adultos hospitalizados com idade ≥ 18 anos com início dos sintomas ≤ 9 dias e saturação de oxigênio ≤ 94% em ar ambiente ou necessidade de oxigênio suplementar para manter saturação de oxigênio > 94%. O tamanho total esperado da amostra varia entre 252 e 1.005 participantes, dependendo do número de estágios que serão concluídos no estudo. Assim, o protocolo é aqui descrito em detalhes, juntamente do plano de análise estatística. Em conclusão, o estudo REVOLUTIOn foi concebido para fornecer evidências se o atazanavir, o daclatasvir ou o sofosbuvir reduzem a carga viral de SARS-CoV-2 em pacientes com COVID-19 e aumentam o número de dias em que os pacientes ficam sem suporte respiratório. Neste artigo de protocolo, descrevem-se a fundamentação, o desenho e a situação do ensaio. Identificador do ClinicalTrials.gov: NCT04468087.
Assuntos
Tratamento Farmacológico da COVID-19 , Adulto , Antivirais/uso terapêutico , Sulfato de Atazanavir , Brasil , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , SARS-CoV-2 , Sofosbuvir , Resultado do TratamentoRESUMO
OBJECTIVE: To describe the IMPACTO-MR, a Brazilian nationwide intensive care unit platform study focused on the impact of health care-associated infections due to multidrug-resistant bacteria. METHODS: We described the IMPACTO-MR platform, its development, criteria for intensive care unit selection, characterization of core data collection, objectives, and future research projects to be held within the platform. RESULTS: The core data were collected using the Epimed Monitor System® and consisted of demographic data, comorbidity data, functional status, clinical scores, admission diagnosis and secondary diagnoses, laboratory, clinical, and microbiological data, and organ support during intensive care unit stay, among others. From October 2019 to December 2020, 33,983 patients from 51 intensive care units were included in the core database. CONCLUSION: The IMPACTO-MR platform is a nationwide Brazilian intensive care unit clinical database focused on researching the impact of health care-associated infections due to multidrug-resistant bacteria. This platform provides data for individual intensive care unit development and research and multicenter observational and prospective trials.
OBJETIVO: Descrever o IMPACTO-MR, um estudo brasileiro de plataforma nacional em unidades de terapia intensiva focado no impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. MÉTODOS: Descrevemos a plataforma IMPACTO-MR, seu desenvolvimento, critérios para seleção das unidades de terapia intensiva, caracterização da coleta de dados, objetivos e projetos de pesquisa futuros a serem realizados na plataforma. RESULTADOS: Os dados principais foram coletados por meio do Epimed Monitor System® e consistiram em dados demográficos, dados de comorbidades, estado funcional, escores clínicos, diagnóstico de internação e diagnósticos secundários, dados laboratoriais, clínicos e microbiológicos e suporte de órgãos durante a internação na unidade de terapia intensiva, entre outros. De outubro de 2019 a dezembro de 2020, 33.983 pacientes de 51 unidades de terapia intensiva foram incluídos no banco de dados principal. CONCLUSÃO: A plataforma IMPACTO-MR é um banco de dados clínico brasileiro de unidades de terapia intensiva focado na pesquisa do impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Essa plataforma fornece dados para o desenvolvimento e pesquisa de unidades de terapia intensiva individuais e ensaios clínicos observacionais e prospectivos multicêntricos.
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Infecção Hospitalar , Unidades de Terapia Intensiva , Humanos , Estudos Prospectivos , Brasil , Infecção Hospitalar/epidemiologia , Farmacorresistência Bacteriana MúltiplaRESUMO
BACKGROUND: The efficacy of ticagrelor in the long-term post-ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remains uncertain. OBJECTIVES: The purpose of this study was to evaluate the efficacy of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. METHODS: This international, multicenter, randomized, open-label with blinded endpoint adjudication trial enrolled 3,799 patients (age <75 years) with STEMI receiving fibrinolytic therapy. Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). The key outcomes were cardiovascular mortality, myocardial infarction, or stroke, and the same composite outcome with the addition of severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events at 12 months. RESULTS: The combined outcome of cardiovascular mortality, myocardial infarction, or stroke occurred in 129 of 1,913 patients (6.7%) receiving ticagrelor and in 137 of 1,886 patients (7.3%) receiving clopidogrel (hazard ratio: 0.93; 95% confidence interval: 0.73 to 1.18; p = 0.53). The composite of cardiovascular mortality, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events occurred in 153 of 1,913 patients (8.0%) treated with ticagrelor and in 171 of 1,886 patients (9.1%) receiving clopidogrel (hazard ratio: 0.88; 95% confidence interval: 0.71 to 1.09; p = 0.25). The rates of major, fatal, and intracranial bleeding were similar between the ticagrelor and clopidogrel groups. CONCLUSION: Among patients age <75 years with STEMI, administration of ticagrelor after fibrinolytic therapy did not significantly reduce the frequency of cardiovascular events when compared with clopidogrel. (Ticagrelor in Patients With ST Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis [TREAT]; NCT02298088).
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Clopidogrel/uso terapêutico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Terapia Trombolítica/métodos , Ticagrelor/uso terapêutico , Idoso , Causas de Morte , Clopidogrel/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Análise de Sobrevida , Ticagrelor/efeitos adversos , Resultado do TratamentoRESUMO
ABSTRACT Background: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear. Objective: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia. Methods: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance. Outcomes: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide. Conclusion: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.
RESUMO Contexto: Em estudos observacionais sobre a síndrome do desconforto respiratório agudo, sugeriu-se que a driving pressure é o principal fator de lesão pulmonar induzida por ventilador e de mortalidade. Não está claro se uma estratégia de limitação da driving pressure pode melhorar os desfechos clínicos. Objetivo: Descrever o protocolo e o plano de análise estatística que serão usados para testar se uma estratégia de limitação da driving pressure envolvendo a titulação da pressão positiva expiratória final de acordo com a melhor complacência respiratória e a redução do volume corrente é superior a uma estratégia padrão envolvendo o uso da tabela de pressão positiva expiratória final baixa do protocolo ARDSNet, em termos de aumento do número de dias sem ventilador em pacientes com síndrome do desconforto respiratório agudo devido à pneumonia adquirida na comunidade. Métodos: O estudo STAMINA (ventilator STrAtegy for coMmunIty acquired pNeumoniA) é randomizado, multicêntrico e aberto e compara uma estratégia de limitação da driving pressure com a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet em pacientes com síndrome do desconforto respiratório agudo moderada a grave devido à pneumonia adquirida na comunidade internados em unidades de terapia intensiva. Esperamos recrutar 500 pacientes de 20 unidades de terapia intensiva brasileiras e duas colombianas. Eles serão randomizados para um grupo da estratégia de limitação da driving pressure ou para um grupo de estratégia padrão usando a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet. No grupo da estratégia de limitação da driving pressure, a pressão positiva expiratória final será titulada de acordo com a melhor complacência do sistema respiratório. Desfechos: O desfecho primário é o número de dias sem ventilador em 28 dias. Os desfechos secundários são a mortalidade hospitalar e na unidade de terapia intensiva e a necessidade de terapias de resgate, como suporte de vida extracorpóreo, manobras de recrutamento e óxido nítrico inalado. Conclusão: O STAMINA foi projetado para fornecer evidências sobre se uma estratégia de limitação da driving pressure é superior à estratégia da tabela de pressão positiva expiratória final baixa do protocolo ARDSnet para aumentar o número de dias sem ventilador em 28 dias em pacientes com síndrome do desconforto respiratório agudo moderada a grave. Aqui, descrevemos a justificativa, o desenho e o status do estudo.
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Importance: The bleeding safety of ticagrelor in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy remains uncertain. Objective: To evaluate the short-term safety of ticagrelor when compared with clopidogrel in patients with ST-elevation myocardial infarction treated with fibrinolytic therapy. Design, Setting and Participants: We conducted a multicenter, randomized, open-label with blinded end point adjudication trial that enrolled 3799 patients (younger than 75 years) with ST-segment elevation myocardial infarction receiving fibrinolytic therapy in 152 sites from 10 countries from November 2015 through November 2017. The prespecified upper boundary for noninferiority for bleeding was an absolute margin of 1.0%. Interventions: Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter). Patients were randomized with a median of 11.4 hours after fibrinolysis, and 90% were pretreated with clopidogrel. Main Outcomes and Measures: The primary outcome was thrombolysis in myocardial infarction (TIMI) major bleeding through 30 days. Results: The mean (SD) age was 58.0 (9.5) years, 2928 of 3799 patients (77.1%) were men, and 2177 of 3799 patients (57.3%) were white. At 30 days, TIMI major bleeding had occurred in 14 of 1913 patients (0.73%) receiving ticagrelor and in 13 of 1886 patients (0.69%) receiving clopidogrel (absolute difference, 0.04%; 95% CI, -0.49% to 0.58%; P < .001 for noninferiority). Major bleeding defined by the Platelet Inhibition and Patient Outcomes criteria and by the Bleeding Academic Research Consortium types 3 to 5 bleeding occurred in 23 patients (1.20%) in the ticagrelor group and in 26 patients (1.38%) in the clopidogrel group (absolute difference, -0.18%; 95% CI, -0.89% to 0.54; P = .001 for noninferiority). The rates of fatal (0.16% vs 0.11%; P = .67) and intracranial bleeding (0.42% vs 0.37%; P = .82) were similar between the ticagrelor and clopidogrel groups, respectively. Minor and minimal bleeding were more common with ticagrelor than with clopidogrel. The composite of death from vascular causes, myocardial infarction, or stroke occurred in 76 patients (4.0%) treated with ticagrelor and in 82 patients (4.3%) receiving clopidogrel (hazard ratio, 0.91; 95% CI, 0.67-1.25; P = .57). Conclusions and Relevance: In patients younger than 75 years with ST-segment elevation myocardial infarction, delayed administration of ticagrelor after fibrinolytic therapy was noninferior to clopidogrel for TIMI major bleeding at 30 days. Trial Registration: clinicaltrials.gov Identifier: NCT02298088.
Assuntos
Clopidogrel/uso terapêutico , Fibrinolíticos/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Ticagrelor/uso terapêutico , Idoso , Clopidogrel/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Ticagrelor/efeitos adversosRESUMO
RESUMO Os medicamentos reaproveitados são importantes em contextos de recursos limitados porque as intervenções estão mais rapidamente disponíveis, já foram testadas com segurança em outras populações e são, em geral, mais baratas. Os medicamentos reaproveitados são uma solução eficaz, especialmente para doenças emergentes, como a COVID-19. O estudo REVOLUTIOn visa avaliar três medicamentos antivirais reaproveitados: atazanavir, daclatasvir e sofosbuvir, já utilizados em pacientes infectados pelo HIV ou pelo vírus da hepatite C, em um estudo randomizado, controlado por placebo, adaptativo, multibraço e em múltiplos estágios. Os medicamentos serão testados simultaneamente em um ensaio de Fase II para primeiro identificar se algum deles, isoladamente ou em combinação, reduz a carga viral. Se reduzirem, será iniciado um estudo de Fase III para investigar se tais medicamentos são capazes de aumentar o número de dias sem suporte respiratório. Os participantes devem ser adultos hospitalizados com idade ≥ 18 anos com início dos sintomas ≤ 9 dias e saturação de oxigênio ≤ 94% em ar ambiente ou necessidade de oxigênio suplementar para manter saturação de oxigênio > 94%. O tamanho total esperado da amostra varia entre 252 e 1.005 participantes, dependendo do número de estágios que serão concluídos no estudo. Assim, o protocolo é aqui descrito em detalhes, juntamente do plano de análise estatística. Em conclusão, o estudo REVOLUTIOn foi concebido para fornecer evidências se o atazanavir, o daclatasvir ou o sofosbuvir reduzem a carga viral de SARS-CoV-2 em pacientes com COVID-19 e aumentam o número de dias em que os pacientes ficam sem suporte respiratório. Neste artigo de protocolo, descrevem-se a fundamentação, o desenho e a situação do ensaio. Identificador do ClinicalTrials.gov:NCT04468087
ABSTRACT Repurposed drugs are important in resource-limited settings because the interventions are more rapidly available, have already been tested safely in other populations and are inexpensive. Repurposed drugs are an effective solution, especially for emerging diseases such as COVID-19. The REVOLUTIOn trial has the objective of evaluating three repurposed antiviral drugs, atazanavir, daclatasvir and sofosbuvir, already used for HIV- and hepatitis C virus-infected patients in a randomized, placebo-controlled, adaptive, multiarm, multistage study. The drugs will be tested simultaneously in a Phase II trial to first identify whether any of these drugs alone or in combination reduce the viral load. If they do, a Phase III trial will be initiated to investigate if these medications are capable of increasing the number of days free respiratory support. Participants must be hospitalized adults aged ≥ 18 years with initiation of symptoms ≤ 9 days and SpO2 ≤ 94% in room air or a need for supplemental oxygen to maintain an SpO2 > 94%. The expected total sample size ranges from 252 to 1,005 participants, depending on the number of stages that will be completed in the study. Hence, the protocol is described here in detail together with the statistical analysis plan. In conclusion, the REVOLUTIOn trial is designed to provide evidence on whether atazanavir, daclatasvir or sofosbuvir decrease the SARS-CoV-2 load in patients with COVID-19 and increase the number of days patients are free of respiratory support. In this protocol paper, we describe the rationale, design, and status of the trial. ClinicalTrials.gov identifier:NCT04468087
RESUMO
RESUMO Objetivo: Descrever o IMPACTO-MR, um estudo brasileiro de plataforma nacional em unidades de terapia intensiva focado no impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Métodos: Descrevemos a plataforma IMPACTO-MR, seu desenvolvimento, critérios para seleção das unidades de terapia intensiva, caracterização da coleta de dados, objetivos e projetos de pesquisa futuros a serem realizados na plataforma. Resultados: Os dados principais foram coletados por meio do Epimed Monitor System® e consistiram em dados demográficos, dados de comorbidades, estado funcional, escores clínicos, diagnóstico de internação e diagnósticos secundários, dados laboratoriais, clínicos e microbiológicos e suporte de órgãos durante a internação na unidade de terapia intensiva, entre outros. De outubro de 2019 a dezembro de 2020, 33.983 pacientes de 51 unidades de terapia intensiva foram incluídos no banco de dados principal. Conclusão: A plataforma IMPACTO-MR é um banco de dados clínico brasileiro de unidades de terapia intensiva focado na pesquisa do impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Essa plataforma fornece dados para o desenvolvimento e pesquisa de unidades de terapia intensiva individuais e ensaios clínicos observacionais e prospectivos multicêntricos.
ABSTRACT Objective: To describe the IMPACTO-MR, a Brazilian nationwide intensive care unit platform study focused on the impact of health care-associated infections due to multidrug-resistant bacteria. Methods: We described the IMPACTO-MR platform, its development, criteria for intensive care unit selection, characterization of core data collection, objectives, and future research projects to be held within the platform. Results: The core data were collected using the Epimed Monitor System® and consisted of demographic data, comorbidity data, functional status, clinical scores, admission diagnosis and secondary diagnoses, laboratory, clinical, and microbiological data, and organ support during intensive care unit stay, among others. From October 2019 to December 2020, 33,983 patients from 51 intensive care units were included in the core database. Conclusion: The IMPACTO-MR platform is a nationwide Brazilian intensive care unit clinical database focused on researching the impact of health care-associated infections due to multidrug-resistant bacteria. This platform provides data for individual intensive care unit development and research and multicenter observational and prospective trials.