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BACKGROUND: Nuts consumption is related to cardioprotective effects on primary cardiovascular prevention, but studies conducted in secondary prevention are small, scarce and controversial. The objective of this trial was to evaluate the effects of a regional and sustainable cardioprotective diet added or not with an affordable mixed nuts on cardiometabolic features in patients with previous myocardial infarction. METHODS: DICA-NUTS study is a national, multi-center, and superiority-parallel randomized clinical trial. Males and females over 40 years old diagnosed with previous myocardial infarction in the last 2 to 6 months were included. Patients were allocated into two groups: the Brazilian Cardioprotective diet (DICA Br) supplemented with 30 g/day of mixed nuts (10 g of peanuts; 10 g of cashew; 10 g of Brazil nuts) (intervention group, n = 193); or only DICA Br prescription (control group, n = 195). The primary outcome was low-density lipoprotein cholesterol means (in mg/dL) after 16 weeks. Secondary outcomes were other lipid biomarkers, glycemic and anthropometric data and diet quality. RESULTS: After adjustment for baseline values, participating study site, time since myocardial infarction and statin treatment regimen (high potency, moderate and low potency/no statins), no significant difference was found between the groups in low-density lipoprotein cholesterol concentrations (intervention-control difference: 3.48 mg/dL [-3.45 to 10.41], P = 0.32). Both groups improved their overall diet quality at the end of the study without differences between them after 16 weeks (intervention-control difference: 1.05 (-0.9 to 2.99); P = 0.29). Other lipids, glycemic profile and anthropometrics were also not different between study groups at the end of the study. CONCLUSION: Adding 30 g/day of mixed nuts to the DICA Br for 16 weeks did not change lipid, glycemic and anthropometric features in the post-myocardial infarction setting. TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov website under number NCT03728127 and its World Health Organization Universal Trial Number (WHO-UTN) is U1111-1259-8105.

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BACKGROUND: Critically ill patients are at increased risk of health care-associated infections due to various devices (central line-associated bloodstream infection, catheter-associated urinary tract infection, and ventilator-associated pneumonia), which pose a significant threat to this population. Among several strategies, daily bathing with chlorhexidine digluconate, a water-soluble antiseptic, has been studied as an intervention to decrease the incidence of health care-associated infections in the intensive care unit; however, its ability to reduce all health care-associated infections due to various devices is unclear. We designed the Daily Chlorhexidine Bath for Health Care Associated Infection Prevention (CLEAN-IT) trial to assess whether daily chlorhexidine digluconate bathing reduces the incidence of health care-associated infections in critically ill patients compared with soap and water bathing. METHODS: The CLEAN-IT trial is a multicenter, open-label, cluster randomized crossover clinical trial. All adult patients admitted to the participating intensive care units will be included in the trial. Each cluster (intensive care unit) will be randomized to perform either initial chlorhexidine digluconate bathing or soap and water bathing with crossover for a period of 3 to 6 months, depending on the time of each center's entrance to the study, with a 1-month washout period between chlorhexidine digluconate bathing and soap and water bathing transitions. The primary outcome is the incidence of health care-associated infections due to devices. The secondary outcomes are the incidence of each specific health care-associated infection, rates of microbiological cultures positive for multidrug-resistant pathogens, antibiotic use, intensive care unit and hospital length of stay, and intensive care unit and hospital mortality. CONCLUSION: The CLEAN-IT trial will be used to study feasible and affordable interventions that might reduce the health care-associated infection burden in critically ill patients.

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BACKGROUND: Cell therapy using adipose-derived mesenchymal stem cells (ADSCs) shows great potential as a treatment for cardiovascular diseases. OBJECTIVE: We conducted a systematic review to describe the safety and efficacy of ADSCs in ischemic heart disease. METHODS: We searched PubMed/MEDLINE, EMBASE, Web of Science, CENTRAL, and LILACS (from inception to March 2024) for clinical studies involving ADSCs in patients with ischemic heart disease. We excluded studies involving patients with other types of heart disease, studies using mesenchymal stem cells derived from other tissues, as well as ongoing studies. Two independent reviewers screened the retrieved citations, extracted relevant data, and assessed the risk of bias in the included trials, using the Cochrane Collaboration criteria modified by McMaster University and Methodological Index for Non-Randomized Studies (MINORS). We used a narrative synthesis to present the results. RESULTS: Ten studies (comprising 29 publications) met our inclusion criteria, including 8 randomized controlled trials and 2 uncontrolled trials. No severe adverse events associated with ADSC therapy were reported. While most efficacy endpoints did not reach statistical significance, there were reports of improved ischemic area, functional capacity, symptoms, and contractility in patients treated with ADSCs. CONCLUSIONS: The findings from our review suggest that ADSC therapy is generally safe for patients with ischemic heart disease. However, further investigation is warranted to confirm its efficacy, particularly with larger clinical trials and in specific conditions where improvements in microcirculation may have a notable impact on clinical outcomes.

FUNDAMENTO: A terapia celular utilizando células-tronco mesenquimais derivadas do tecido adiposo (ADSC, sigla em inglês) apresenta grande potencial como tratamento para doenças cardiovasculares. OBJETIVO: Realizamos uma revisão sistemática para descrever a segurança e a eficácia das ADSC na cardiopatia isquêmica. MÉTODOS: Pesquisamos na PubMed/MEDLINE, EMBASE, Web of Science, CENTRAL e LILACS (desde o início até março de 2024) por estudos clínicos envolvendo ADSC em pacientes com cardiopatia isquêmica. Excluímos estudos envolvendo pacientes com outros tipos de doenças cardíacas, estudos utilizando células-tronco mesenquimais derivadas de outros tecidos, bem como estudos em andamento. Dois revisores independentes realizaram a triagem das citações recuperadas, extraíram dados relevantes e avaliaram o risco de viés nos ensaios incluídos, utilizando os critérios da Colaboração Cochrane modificados pela Universidade McMaster e o Índice Metodológico para Estudos Não-Randomizados (MINORS). Utilizamos uma síntese narrativa para apresentar os resultados. RESULTADOS: Dez estudos (compreendendo 29 publicações) preencheram nossos critérios de inclusão, incluindo 8 ensaios controlados randomizados e 2 ensaios não controlados. Não foram relatados eventos adversos graves associados à terapia com ADSC. Embora a maioria dos desfechos de eficácia não tenha alcançado significância estatística, houve relatos de melhora da área isquêmica, capacidade funcional, sintomas e contratilidade em pacientes tratados com ADSC. CONCLUSÕES: Os resultados da nossa revisão sugerem que a terapia com ADSC é geralmente segura para pacientes com cardiopatia isquêmica. Contudo, são necessárias mais investigações para confirmar a sua eficácia, particularmente em ensaios clínicos de maior escala e em condições específicas onde as melhorias na microcirculação podem ter um impacto notável nos desfechos clínicos.

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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.

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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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Resumo Fundamento A terapia celular utilizando células-tronco mesenquimais derivadas do tecido adiposo (ADSC, sigla em inglês) apresenta grande potencial como tratamento para doenças cardiovasculares. Objetivo Realizamos uma revisão sistemática para descrever a segurança e a eficácia das ADSC na cardiopatia isquêmica. Métodos Pesquisamos na PubMed/MEDLINE, EMBASE, Web of Science, CENTRAL e LILACS (desde o início até março de 2024) por estudos clínicos envolvendo ADSC em pacientes com cardiopatia isquêmica. Excluímos estudos envolvendo pacientes com outros tipos de doenças cardíacas, estudos utilizando células-tronco mesenquimais derivadas de outros tecidos, bem como estudos em andamento. Dois revisores independentes realizaram a triagem das citações recuperadas, extraíram dados relevantes e avaliaram o risco de viés nos ensaios incluídos, utilizando os critérios da Colaboração Cochrane modificados pela Universidade McMaster e o Índice Metodológico para Estudos Não-Randomizados (MINORS). Utilizamos uma síntese narrativa para apresentar os resultados. Resultados Dez estudos (compreendendo 29 publicações) preencheram nossos critérios de inclusão, incluindo 8 ensaios controlados randomizados e 2 ensaios não controlados. Não foram relatados eventos adversos graves associados à terapia com ADSC. Embora a maioria dos desfechos de eficácia não tenha alcançado significância estatística, houve relatos de melhora da área isquêmica, capacidade funcional, sintomas e contratilidade em pacientes tratados com ADSC. Conclusões Os resultados da nossa revisão sugerem que a terapia com ADSC é geralmente segura para pacientes com cardiopatia isquêmica. Contudo, são necessárias mais investigações para confirmar a sua eficácia, particularmente em ensaios clínicos de maior escala e em condições específicas onde as melhorias na microcirculação podem ter um impacto notável nos desfechos clínicos.

Abstract Background Cell therapy using adipose-derived mesenchymal stem cells (ADSCs) shows great potential as a treatment for cardiovascular diseases. Objective We conducted a systematic review to describe the safety and efficacy of ADSCs in ischemic heart disease. Methods We searched PubMed/MEDLINE, EMBASE, Web of Science, CENTRAL, and LILACS (from inception to March 2024) for clinical studies involving ADSCs in patients with ischemic heart disease. We excluded studies involving patients with other types of heart disease, studies using mesenchymal stem cells derived from other tissues, as well as ongoing studies. Two independent reviewers screened the retrieved citations, extracted relevant data, and assessed the risk of bias in the included trials, using the Cochrane Collaboration criteria modified by McMaster University and Methodological Index for Non-Randomized Studies (MINORS). We used a narrative synthesis to present the results. Results Ten studies (comprising 29 publications) met our inclusion criteria, including 8 randomized controlled trials and 2 uncontrolled trials. No severe adverse events associated with ADSC therapy were reported. While most efficacy endpoints did not reach statistical significance, there were reports of improved ischemic area, functional capacity, symptoms, and contractility in patients treated with ADSCs. Conclusions The findings from our review suggest that ADSC therapy is generally safe for patients with ischemic heart disease. However, further investigation is warranted to confirm its efficacy, particularly with larger clinical trials and in specific conditions where improvements in microcirculation may have a notable impact on clinical outcomes.

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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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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.

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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

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Rationale: Evidence from observational studies suggests that driving pressure is strongly associated with pulmonary injury and mortality, regardless of positive end-expiratory pressure (PEEP) levels, tidal volume, or plateau pressure. Therefore, it is possible that targeting driving pressure may improve the safety of ventilation strategies for patients with acute respiratory distress syndrome (ARDS). However, the clinical effects of a driving pressure-limited strategy for ARDS has not been assessed in randomized controlled trials.Objectives: To evaluate the feasibility of testing a driving pressure-limited strategy in comparison with a conventional lung-protective ventilation strategy in patients with ARDS and a baseline driving pressure of ≥13 cm H2O.Methods: This was a randomized, controlled, nonblinded trial that included 31 patients with ARDS who were on invasive mechanical ventilation and had a driving pressure of ≥13 cm H2O. Patients allocated to the driving pressure-limited strategy were ventilated with volume-controlled or pressure-support ventilation modes, with tidal volume titrated to 4-8 ml/kg of predicted body weight (PBW), aiming at a driving pressure of 10 cm H2O, or the lowest possible. Patients in the control group were ventilated according to the ARDSNet (Acute Respiratory Distress Syndrome Network) protocol, using a tidal volume of 6 ml/kg PBW, which was allowed to be set down to 4 ml/kg PBW if the plateau pressure was >30 cm H2O. The primary endpoint was the driving pressure on Days 1-3.Results: Sixteen patients were randomized to the driving pressure-limited group and 15 were randomized to the conventional strategy group. All patients were considered in analyses. Most of the patients had mild ARDS with a mean arterial oxygen tension/fraction of inspired oxygen ratio of 215 (standard deviation [SD] = 95). The baseline driving pressure was 15.0 cm H2O (SD = 2.6) in both groups. In comparison with the conventional strategy, driving pressure from the first hour to the third day was 4.6 cm H2O lower in the driving pressure-limited group (95% confidence interval [CI], 6.5 to 2.8; P < 0.001). From the first hour up to the third day, tidal volume in the driving pressure-limited strategy group was kept lower than in the control group (mean difference [ml/kg of PBW], 1.3; 95% CI, 1.7 to 0.9; P < 0.001). We did not find statistically significant differences in the incidence of severe acidosis (pH < 7.10) within 7 days (absolute difference -12.1; 95% CI, -41.5 to -17.3) or any clinical secondary endpoint.Conclusions: In patients with ARDS, a trial assessing the effects of a driving pressure-limited strategy using very low tidal volumes versus a conventional ventilation strategy on clinical outcomes is feasible.Clinical trial registered with ClinicalTrials.gov (NCT02365038).

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Importance: Loading doses of atorvastatin did not show reduction on clinical outcomes in the overall population of patients with acute coronary syndrome (ACS) enrolled in the Statins Evaluation in Coronary Procedures and Revascularization (SECURE-PCI) trial, but a potential benefit was identified in patients who subsequently underwent percutaneous coronary intervention (PCI). Objectives: To determine whether periprocedural loading doses of atorvastatin are associated with decreased 30-day major adverse cardiovascular events (MACE) in patients with ACS undergoing PCI according to type of ACS and timing of atorvastatin administration before PCI. Design, Setting, and Participants: Secondary analysis of a multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 53 sites that enrolled 4191 patients with ACS intended to be treated with PCI between April 18, 2012, and October 06, 2017. Interventions: Patients were randomized to 2 loading doses of 80 mg of atorvastatin or matching placebo before and 24 hours after a planned PCI. By protocol, all patients (regardless of treatment group) received 40 mg of atorvastatin for 30 days starting 24 hours after the second dose of study medication. Main Outcomes and Measures: The primary outcome was MACE through 30 days, composed by all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization. Cox regression models adjusting for key baseline characteristics were used to assess the association between atorvastatin and MACE in patients undergoing PCI. Results: From the overall trial population, 2710 (64.7%) underwent PCI (650 women [24.0%]; mean [SD] age, 62 [11.3] years). Loading atorvastatin was associated with reduced MACE at 30 days by 28% in the PCI group (adjusted hazard ratio [HR], 0.72; 95% CI 0.54-0.97; P = .03). Loading dose of atorvastatin was administered less than 12 hours before PCI in 2548 patients (95.3%) (45.1% < 2 hours and 54.3% between 2 and 12 hours). There was no significant interaction between treatment effect and timing of study drug administration. The treatment effect of loading atorvastatin was more pronounced in patients with ST-segment elevation myocardial infarction than in patients with non-ST-segment elevation ACS (adjusted HR, 0.59; 95% CI, 0.38-0.92; P = .02; HR, 0.85; 95% CI, 0.58-1.27; P = .43, respectively). Conclusions and Relevance: In patients with ACS undergoing PCI, periprocedural loading doses of atorvastatin appeared to reduce the rate of MACE at 30 days, most clearly in patients with ST-segment elevation myocardial infarction. This beneficial effect seemed to be preserved and consistent, irrespective of the timing of atorvastatin administration, including within 2 hours before PCI. Trial Registration: clinicaltrials.gov Identifier: NCT01448642.

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IMPORTANCE The effects of loading doses of statins on clinical outcomes in patients with acute coronary syndrome (ACS) and planned invasive management remain uncertain. OBJECTIVE To determine if periprocedural loading doses of atorvastatin decrease 30-day major adverse cardiovascular events (MACE) in patients with ACS and planned invasive management. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 53 sites in Brazil among 4191 patients with ACS evaluated with coronary angiography to proceed with a percutaneous coronary intervention (PCI) if anatomically feasible. Enrollment occurred between April 18, 2012, and October 6, 2017. Final follow-up for 30-day outcomes was on November 6, 2017. INTERVENTIONS Patients were randomized to receive 2 loading doses of 80 mg of atorvastatin (n = 2087) or matching placebo (n = 2104) before and 24 hours after a planned PCI. All patients received 40 mg of atorvastatin for 30 days starting 24 hours after the second dose of study medication. MAIN OUTCOMES AND MEASURES The primary outcome was MACE, defined as a composite of all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization through 30 days. RESULTS Among the 4191 patients (mean age, 61.8 [SD, 11.5] years; 1085 women [25.9%]) enrolled, 4163 (99.3%) completed 30-day follow-up. A total of 2710 (64.7%) underwent PCI, 333 (8%) underwent coronary artery bypass graft surgery, and 1144 (27.3%) had exclusively medical management. At 30 days, 130 patients in the atorvastatin group (6.2%) and 149 in the placebo group (7.1%) had a MACE (absolute difference, 0.85% [95% CI, −0.70% to 2.41%]; hazard ratio, 0.88; 95% CI, 0.69-1.11; P = .27). No cases of hepatic failure were reported; 3 cases of rhabdomyolysis were reported in the placebo group (0.1%) and 0 in the atorvastatin group. CONCLUSIONS AND RELEVANCE Among patients with ACS and planned invasive management with PCI, periprocedural loading doses of atorvastatin did not reduce the rate of MACE at 30 days. These findings do not support the routine use of loading doses of atorvastatin among unselected patients with ACS and intended invasive management.

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Importance: The effects of loading doses of statins on clinical outcomes in patients with acute coronary syndrome (ACS) and planned invasive management remain uncertain. Objective: To determine if periprocedural loading doses of atorvastatin decrease 30-day major adverse cardiovascular events (MACE) in patients with ACS and planned invasive management. Design, Setting, and Participants: Multicenter, double-blind, placebo-controlled, randomized clinical trial conducted at 53 sites in Brazil among 4191 patients with ACS evaluated with coronary angiography to proceed with a percutaneous coronary intervention (PCI) if anatomically feasible. Enrollment occurred between April 18, 2012, and October 6, 2017. Final follow-up for 30-day outcomes was on November 6, 2017. Interventions: Patients were randomized to receive 2 loading doses of 80 mg of atorvastatin (n = 2087) or matching placebo (n = 2104) before and 24 hours after a planned PCI. All patients received 40 mg of atorvastatin for 30 days starting 24 hours after the second dose of study medication. Main Outcomes and Measures: The primary outcome was MACE, defined as a composite of all-cause mortality, myocardial infarction, stroke, and unplanned coronary revascularization through 30 days. Results: Among the 4191 patients (mean age, 61.8 [SD, 11.5] years; 1085 women [25.9%]) enrolled, 4163 (99.3%) completed 30-day follow-up. A total of 2710 (64.7%) underwent PCI, 333 (8%) underwent coronary artery bypass graft surgery, and 1144 (27.3%) had exclusively medical management. At 30 days, 130 patients in the atorvastatin group (6.2%) and 149 in the placebo group (7.1%) had a MACE (absolute difference, 0.85% [95% CI, -0.70% to 2.41%]; hazard ratio, 0.88; 95% CI, 0.69-1.11; P = .27). No cases of hepatic failure were reported; 3 cases of rhabdomyolysis were reported in the placebo group (0.1%) and 0 in the atorvastatin group. Conclusions and Relevance: Among patients with ACS and planned invasive management with PCI, periprocedural loading doses of atorvastatin did not reduce the rate of MACE at 30 days. These findings do not support the routine use of loading doses of atorvastatin among unselected patients with ACS and intended invasive management. Trial Registration: clinicaltrials.gov Identifier: NCT01448642.

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BACKGROUND: The Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) is an international multicenter randomized pragmatic controlled trial with allocation concealment involving 120 intensive care units in Brazil, Argentina, Colombia, Italy, Poland, Portugal, Malaysia, Spain, and Uruguay. The primary objective of ART is to determine whether maximum stepwise alveolar recruitment associated with PEEP titration, adjusted according to the static compliance of the respiratory system (ART strategy), is able to increase 28-day survival in patients with acute respiratory distress syndrome compared to conventional treatment (ARDSNet strategy). OBJECTIVE: To describe the data management process and statistical analysis plan. METHODS: The statistical analysis plan was designed by the trial executive committee and reviewed and approved by the trial steering committee. We provide an overview of the trial design with a special focus on describing the primary (28-day survival) and secondary outcomes. We describe our data management process, data monitoring committee, interim analyses, and sample size calculation. We describe our planned statistical analyses for primary and secondary outcomes as well as pre-specified subgroup analyses. We also provide details for presenting results, including mock tables for baseline characteristics, adherence to the protocol and effect on clinical outcomes. CONCLUSION: According to best trial practice, we report our statistical analysis plan and data management plan prior to locking the database and beginning analyses. We anticipate that this document will prevent analysis bias and enhance the utility of the reported results. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01374022.

FUNDAMENTAÇÃO: O estudo Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) é um ensaio clínico internacional, multicêntrico, randomizado, pragmático e controlado com ocultação da alocação que envolve 120 unidades de terapia intensiva no Brasil, Argentina, Colômbia, Espanha, Itália, Polônia, Portugal, Malásia e Uruguai, com o objetivo primário de determinar se o recrutamento alveolar gradual máximo associado com titulação da pressão positiva expiratória final, ajustada segundo a complacência estática do sistema respiratório (estratégia ART), é capaz de aumentar, quando comparada aos resultados do tratamento convencional (estratégia ARDSNet), a sobrevivência em 28 dias de pacientes com síndrome do desconforto respiratório agudo. OBJETIVO: Descrever o processo de gerenciamento dos dados e o plano de análise estatística em um ensaio clínico internacional. MÉTODOS: O plano de análise estatística foi delineado pelo comitê executivo e revisado pelo comitê diretivo do ART. Foi oferecida uma visão geral do delineamento do estudo, com foco especial na descrição de desfechos primário (sobrevivência aos 28 dias) e secundários. Foram descritos o processo de gerenciamento dos dados, o comitê de monitoramento de dados, a análise interina e o cálculo do tamanho da amostra. Também foram registrados o plano de análise estatística para os desfechos primário e secundários, e os subgrupos de análise pré-especificados. Detalhes para apresentação dos resultados, inclusive modelos de tabelas para as características basais, adesão ao protocolo e efeito nos desfechos clínicos, foram fornecidos. CONCLUSÃO: Em acordo com as melhores práticas em ensaios clínicos, submetemos nossos planos de análise estatística e de gerenciamento de dados para publicação antes do fechamento da base de dados e início das análises. Antecipamos que este documento deve prevenir viés em análises e incrementar a utilidade dos resultados a serem relatados. REGISTRO DO ESTUDO: Número no registro ClinicalTrials.gov NCT01374022.

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Importance: The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain. Objective: To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy. Design, Setting, and Participants: Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS. Interventions: An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory-system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning. Main Outcomes and Measures: The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality. Results: A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, -1.1; 95% CI, -2.1 to -0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality. Conclusions and Relevance: In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT01374022.

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RESUMO Fundamentação: O estudo Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) é um ensaio clínico internacional, multicêntrico, randomizado, pragmático e controlado com ocultação da alocação que envolve 120 unidades de terapia intensiva no Brasil, Argentina, Colômbia, Espanha, Itália, Polônia, Portugal, Malásia e Uruguai, com o objetivo primário de determinar se o recrutamento alveolar gradual máximo associado com titulação da pressão positiva expiratória final, ajustada segundo a complacência estática do sistema respiratório (estratégia ART), é capaz de aumentar, quando comparada aos resultados do tratamento convencional (estratégia ARDSNet), a sobrevivência em 28 dias de pacientes com síndrome do desconforto respiratório agudo. Objetivo: Descrever o processo de gerenciamento dos dados e o plano de análise estatística em um ensaio clínico internacional. Métodos: O plano de análise estatística foi delineado pelo comitê executivo e revisado pelo comitê diretivo do ART. Foi oferecida uma visão geral do delineamento do estudo, com foco especial na descrição de desfechos primário (sobrevivência aos 28 dias) e secundários. Foram descritos o processo de gerenciamento dos dados, o comitê de monitoramento de dados, a análise interina e o cálculo do tamanho da amostra. Também foram registrados o plano de análise estatística para os desfechos primário e secundários, e os subgrupos de análise pré-especificados. Detalhes para apresentação dos resultados, inclusive modelos de tabelas para as características basais, adesão ao protocolo e efeito nos desfechos clínicos, foram fornecidos. Conclusão: Em acordo com as melhores práticas em ensaios clínicos, submetemos nossos planos de análise estatística e de gerenciamento de dados para publicação antes do fechamento da base de dados e início das análises. Antecipamos que este documento deve prevenir viés em análises e incrementar a utilidade dos resultados a serem relatados. Registro do estudo: Número no registro ClinicalTrials.gov NCT01374022.

ABSTRACT Background: The Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) is an international multicenter randomized pragmatic controlled trial with allocation concealment involving 120 intensive care units in Brazil, Argentina, Colombia, Italy, Poland, Portugal, Malaysia, Spain, and Uruguay. The primary objective of ART is to determine whether maximum stepwise alveolar recruitment associated with PEEP titration, adjusted according to the static compliance of the respiratory system (ART strategy), is able to increase 28-day survival in patients with acute respiratory distress syndrome compared to conventional treatment (ARDSNet strategy). Objective: To describe the data management process and statistical analysis plan. Methods: The statistical analysis plan was designed by the trial executive committee and reviewed and approved by the trial steering committee. We provide an overview of the trial design with a special focus on describing the primary (28-day survival) and secondary outcomes. We describe our data management process, data monitoring committee, interim analyses, and sample size calculation. We describe our planned statistical analyses for primary and secondary outcomes as well as pre-specified subgroup analyses. We also provide details for presenting results, including mock tables for baseline characteristics, adherence to the protocol and effect on clinical outcomes. Conclusion: According to best trial practice, we report our statistical analysis plan and data management plan prior to locking the database and beginning analyses. We anticipate that this document will prevent analysis bias and enhance the utility of the reported results. Trial registration: ClinicalTrials.gov number, NCT01374022.

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BACKGROUND: Early termination of clinical trials due to low recruitment represents an understudied challenge for clinical research. We aimed to describe characteristics of cardiovascular trials terminated because of low recruitment and identify the major predictors of such early termination. METHODS: We reviewed all cardiovascular clinical trials (7,042 studies) registered in ClinicalTrials.gov from February 29, 2000, to January 17, 2013, and assessed information about trials that were completed and those that were terminated early. Logistic regression models were developed to identify independent predictors of early termination due to low recruitment. RESULTS: Our search strategy identified 6,279 cardiovascular clinical trials, of which 684 (10.9%) were terminated prematurely. Of these halted trials, the main reason for termination was lower than expected recruitment (278 trials; 53.6%). When comparing trials that terminated early because of low recruitment with those that were completed, we found that studies funded by the National Institutes of Health or other US federal agencies (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.14-0.89), studies of behavior/diet intervention (OR 0.35, 95% CI 0.19-0.65), and single-arm design studies (OR 0.57, 95% CI 0.42-0.78) were associated with a lower risk of early termination. University/hospital-funded (OR 1.52, 95% CI 1.10-2.10) and mixed-source-funded studies (OR 2.14, 95% CI 1.52-3.01) were associated with a higher likelihood of early termination due to lower than expected recruitment rates. CONCLUSIONS: Low recruitment represents the main cause of early termination of cardiovascular clinical trials. Funding source, type of intervention, and study design are factors associated with early termination due to low recruitment and might be good targets for improving enrollment into cardiovascular clinical trials.

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Tight control of blood glucose reduces cardiovascular events and total mortality is conflicting. To summarize clinical effects of tight versus conventional glucose control in patients with type 2 diabetes. We systematically searched MEDLINE, EMBASE, Cochrane Library, and ISI Web of Knowledge with no limits of language and time. Further trials were searched from the reference lists of identified studies. We included randomized controlled comparing different levels of blood glucose control intensity in type 2 diabetic patients. Two independent reviewers extracted data of eligible studies using standard case report forms. We investigated total mortality, cardiovascular and microvascular events, and hypoglycemia in patients with type 2 diabetes. We used random-effects models to obtain relative risks (RR) with 95% confidence intervals (CI). We included 6 trials involving 27,654 patients. There was no significant effect of tight blood glucose control on all-cause mortality (RR 1.03; 95% CI 0.90-1.17) or cardiovascular mortality (RR 1.04; 95% CI 0.83-1.29). Tight glucose control reduced the risk for nonfatal MI (RR 0.85; 95% CI 0.76-0.95), although had no effect on the incidence of nonfatal stroke (RR 1.02; 95% CI 0.88-1.17). For microvascular events, tight glucose control reduced the risk progression of retinopathy (RR 0.80; 95% CI 0.71-0.91), incidence of peripheral neuropathy (RR 0.94; 95% CI 0.89-0.99), and progression of nephropathy (RR 0.55; 95% CI 0.37-0.80), but had not significant effect on the incidence of nephropathy (RR 0.69; 95% CI 0.42-1.14). The risk of severe hypoglycemia increased with tight glucose control (RR 2.39; 95% CI 1.79-3.18). Tight blood glucose control reduces the risk for some macrovascular and microvascular events, without effect on all-cause mortality and cardiovascular mortality. Tight glucose control increases the risk of severe hypoglycemia.

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