Publications by authors named "Alexandre B Cavalcanti"

47 Publications

Effect of Slower vs Faster Intravenous Fluid Bolus Rates on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial.

JAMA 2021 09;326(9):830-838

HCor Research Institute, São Paulo, Brazil.

Importance: Slower intravenous fluid infusion rates could reduce the formation of tissue edema and organ dysfunction in critically ill patients; however, there are no data to support different infusion rates during fluid challenges for important outcomes such as mortality.

Objective: To determine the effect of a slower infusion rate vs control infusion rate on 90-day survival in patients in the intensive care unit (ICU).

Design, Setting, And Participants: Unblinded randomized factorial clinical trial in 75 ICUs in Brazil, involving 11 052 patients requiring at least 1 fluid challenge and with 1 risk factor for worse outcomes were randomized from May 29, 2017, to March 2, 2020. Follow-up was concluded on October 29, 2020. Patients were randomized to 2 different infusion rates (reported in this article) and 2 different fluid types (balanced fluids or saline, reported separately).

Interventions: Patients were randomized to receive fluid challenges at 2 different infusion rates; 5538 to the slower rate (333 mL/h) and 5514 to the control group (999 mL/h). Patients were also randomized to receive balanced solution or 0.9% saline using a factorial design.

Main Outcomes And Measures: The primary end point was 90-day survival.

Results: Of all randomized patients, 10 520 (95.2%) were analyzed (mean age, 61.1 years [SD, 17.0 years]; 44.2% were women) after excluding duplicates and consent withdrawals. Patients assigned to the slower rate received a mean of 1162 mL on the first day vs 1252 mL for the control group. By day 90, 1406 of 5276 patients (26.6%) in the slower rate group had died vs 1414 of 5244 (27.0%) in the control group (adjusted hazard ratio, 1.03; 95% CI, 0.96-1.11; P = .46). There was no significant interaction between fluid type and infusion rate (P = .98).

Conclusions And Relevance: Among patients in the intensive care unit requiring fluid challenges, infusing at a slower rate compared with a faster rate did not reduce 90-day mortality. These findings do not support the use of a slower infusion rate.

Trial Registration: ClinicalTrials.gov Identifier: NCT02875873.
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http://dx.doi.org/10.1001/jama.2021.11444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356145PMC
September 2021

Design of a multifaceted strategy based on automated text messaging in patients with recent heart failure admission.

ESC Heart Fail 2021 Sep 18. Epub 2021 Sep 18.

HCor Research Institute, R. Des. Eliseu Guilherme, 147 - Paraíso, São Paulo, 04004-030, Brazil.

Aims: To evaluate a telemonitoring strategy based on automated text messaging and telephone support after heart failure (HF) hospitalization.

Methods And Results: The MESSAGE-HF study is a prospective multicentre, randomized, nationwide trial enrolling patients from 30 clinics in all regions of Brazil. HF patients with reduced left ventricular ejection fraction (<40%) and access to mobile phones are eligible after an acute decompensated HF hospitalization. Patients meeting eligibility criteria undergo an initial feasibility text messaging assessment and are randomized to usual care or telemonitoring intervention. All patients receive a HF booklet with basic information and recommendations about self-care. Patients in the intervention group receive four daily short text messages (educational and feedback) during the first 30 days of the protocol to optimize self-care; the feedback text messages from patients could trigger diuretic adjustments or a telephone call from the healthcare team. After 30 days, the frequency of text messages can be adjusted. Patients are followed up after 30, 90, and 180 days, with final status ascertained at 365 days by telephone. Our primary endpoint is the change in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels after 180 days. Secondary endpoints include changes in NT-proBNP after 30 days; health-related quality of life, HF self-care, and knowledge scales after 30 and 180 days; and a composite outcome of HF hospitalization and cardiovascular death, adjudicated by a blinded and independent committee.

Conclusions: The MESSAGE-HF trial is evaluating an educational and self-care promotion strategy involving a simple, intensive, and tailored telemonitoring system. If proven effective, it could be applied to a broader population worldwide.
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http://dx.doi.org/10.1002/ehf2.13516DOI Listing
September 2021

Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial.

JAMA 2021 Aug 10. Epub 2021 Aug 10.

HCor Research Institute, São Paulo, Brazil.

Importance: Intravenous fluids are used for almost all intensive care unit (ICU) patients. Clinical and laboratory studies have questioned whether specific fluid types result in improved outcomes, including mortality and acute kidney injury.

Objective: To determine the effect of a balanced solution vs saline solution (0.9% sodium chloride) on 90-day survival in critically ill patients.

Design, Setting, And Participants: Double-blind, factorial, randomized clinical trial conducted at 75 ICUs in Brazil. Patients who were admitted to the ICU with at least 1 risk factor for worse outcomes, who required at least 1 fluid expansion, and who were expected to remain in the ICU for more than 24 hours were randomized between May 29, 2017, and March 2, 2020; follow-up concluded on October 29, 2020. Patients were randomized to 2 different fluid types (a balanced solution vs saline solution reported in this article) and 2 different infusion rates (reported separately).

Interventions: Patients were randomly assigned 1:1 to receive either a balanced solution (n = 5522) or 0.9% saline solution (n = 5530) for all intravenous fluids.

Main Outcomes And Measures: The primary outcome was 90-day survival.

Results: Among 11 052 patients who were randomized, 10 520 (95.2%) were available for the analysis (mean age, 61.1 [SD, 17] years; 44.2% were women). There was no significant interaction between the 2 interventions (fluid type and infusion speed; P = .98). Planned surgical admissions represented 48.4% of all patients. Of all the patients, 60.6% had hypotension or vasopressor use and 44.3% required mechanical ventilation at enrollment. Patients in both groups received a median of 1.5 L of fluid during the first day after enrollment. By day 90, 1381 of 5230 patients (26.4%) assigned to a balanced solution died vs 1439 of 5290 patients (27.2%) assigned to saline solution (adjusted hazard ratio, 0.97 [95% CI, 0.90-1.05]; P = .47). There were no unexpected treatment-related severe adverse events in either group.

Conclusion And Relevance: Among critically ill patients requiring fluid challenges, use of a balanced solution compared with 0.9% saline solution did not significantly reduce 90-day mortality. The findings do not support the use of this balanced solution.

Trial Registration: ClinicalTrials.gov Identifier: NCT02875873.
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http://dx.doi.org/10.1001/jama.2021.11684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356144PMC
August 2021

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial.

Lancet 2021 06 4;397(10291):2253-2263. Epub 2021 Jun 4.

Brazilian Research in Intensive Care Network, São Paulo, Brazil; BP-A Beneficência Portuguesa de São Paulo, São Paulo, Brazil.

Background: COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population.

Methods: We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3-0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed.

Findings: From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59-1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61-8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group.

Interpretation: In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.

Funding: Coalition COVID-19 Brazil, Bayer SA.
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http://dx.doi.org/10.1016/S0140-6736(21)01203-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177770PMC
June 2021

Randomized clinical trial to evaluate a routine full anticoagulation Strategy in Patients with Coronavirus Infection (SARS-CoV2) admitted to hospital: Rationale and design of the ACTION (AntiCoagulaTlon cOroNavirus)-Coalition IV trial.

Am Heart J 2021 08 20;238:1-11. Epub 2021 Apr 20.

Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil.

Background: Observational studies have suggested a higher risk of thrombotic events in patients with coronavirus disease 2019 (COVID-19). Moreover, elevated D-dimer levels have been identified as an important prognostic marker in COVID-19 directly associated with disease severity and progression. Prophylactic anticoagulation for hospitalized COVID-19 patients might not be enough to prevent thrombotic events; therefore, therapeutic anticoagulation regimens deserve clinical investigation.

Design: ACTION is an academic-led, pragmatic, multicenter, open-label, randomized, phase IV clinical trial that aims to enroll around 600 patients at 40 sites participating in the Coalition COVID-19 Brazil initiative. Eligible patients with a confirmed diagnosis of COVID-19 with symptoms up to 14 days and elevated D-dimer levels will be randomized to a strategy of full-dose anticoagulation for 30 days with rivaroxaban 20 mg once daily (or full-dose heparin if oral administration is not feasible) vs standard of care with any approved venous thromboembolism prophylaxis regimen during hospitalization. A confirmation of COVID-19 was mandatory for study entry, based on specific tests used in clinical practice (RT-PCR, antigen test, IgM test) collected before randomization, regardless of in the outpatient setting or not. Randomization will be stratified by clinical stability at presentation. The primary outcome is a hierarchical analysis of mortality, length of hospital stay, or duration of oxygen therapy at the end of 30 days. Secondary outcomes include the World Health Organization's 8-point ordinal scale at 30 days and the following efficacy outcomes: incidence of venous thromboembolism , acute myocardial infarction, stroke, systemic embolism, major adverse limb events, duration of oxygen therapy, disease progression, and biomarkers. The primary safety outcomes are major or clinically relevant non-major bleeding according to the International Society on Thrombosis and Haemostasis criteria.

Summary: The ACTION trial will evaluate whether in-hospital therapeutic anticoagulation with rivaroxaban for stable patients, or enoxaparin for unstable patients, followed by rivaroxaban through 30 days compared with standard prophylactic anticoagulation improves clinical outcomes in hospitalized patients with COVID-19 and elevated D-dimer levels.
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http://dx.doi.org/10.1016/j.ahj.2021.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057688PMC
August 2021

Ventilatory Variables and Mechanical Power in Patients with Acute Respiratory Distress Syndrome.

Am J Respir Crit Care Med 2021 08;204(3):303-311

Laboratório de Pneumologia, Laboratório de Investigação Médica 09, Disciplina de Pneumologia, Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, São Paulo, Brazil.

Mortality in acute respiratory distress syndrome (ARDS) has decreased after the adoption of lung-protective strategies. Lower Vt, lower driving pressure (ΔP), lower respiratory rates (RR), and higher end-expiratory pressure have all been suggested as key components of lung protection strategies. A unifying theoretical explanation has been proposed that attributes lung injury to the energy transfer rate (mechanical power) from the ventilator to the patient, calculated from a combination of several ventilator variables. To assess the impact of mechanical power on mortality in patients with ARDS as compared with that of primary ventilator variables such as the ΔP, Vt, and RR. We obtained data on ventilatory variables and mechanical power from a pooled database of patients with ARDS who had participated in six randomized clinical trials of protective mechanical ventilation and one large observational cohort of patients with ARDS. The primary outcome was mortality at 28 days or 60 days. We included 4,549 patients (38% women; mean age, 55 ± 23 yr). The average mechanical power was 0.32 ± 0.14 J · min · kg of predicted body weight, the ΔP was 15.0 ± 5.8 cm HO, and the RR was 25.7 ± 7.4 breaths/min. The driving pressure, RR, and mechanical power were significant predictors of mortality in adjusted analyses. The impact of the ΔP on mortality was four times as large as that of the RR. Mechanical power was associated with mortality during controlled mechanical ventilation in ARDS, but a simpler model using only the ΔP and RR was equivalent.
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http://dx.doi.org/10.1164/rccm.202009-3467OCDOI Listing
August 2021

Three-year effects of bariatric surgery on obstructive sleep apnea in patients with obesity grade 1 and 2: a sub-analysis of the GATEWAY trial.

Int J Obes (Lond) 2021 04 15;45(4):914-917. Epub 2021 Feb 15.

Research Institute, Heart Hospital (HCor), São Paulo, Brazil.

Background: Most of the evidence on bariatric surgery on obstructive sleep apnea (OSA) is based on observational studies and/or short-term follow-up in patients with obesity grade 3.

Subjects/methods: This randomized study compared the effects of roux-en-Y gastric bypass (RYGB) or usual care (UC) on OSA severity in patients with obesity grade 1-2. Mild, moderate, and severe OSA was defined by the apnea-hypopnoea index (AHI): 5-14.9; 15-29.9, and ≥30 events/h, respectively. OSA remission was defined by converting any form of OSA into normal AHI (<5 events/h).

Results: After 3-year of follow-up, the body-mass index increased in the UC while decreased in the RYGB group: +1.7 (-1.9; 2.7) versus -10.6 (-12.7; -9.2) kg/m, respectively. The AHI increased by 5 (-4.2; 12.7) in the UC group while reduced in the RYGB group to -13.2 (-22.7; -7) events/h. UC significantly increase the frequency of moderate OSA (from 15.4 to 46.2%). In contrast, RYGB had a huge impact on reaching no OSA status (from 4.2 to 70.8%) in parallel to a decrease of moderate (from 41.7 to 8.3%) and severe OSA (from 20.8 to 0%).

Conclusions: RYGB is an attractive strategy for mid-term OSA remission or decrease moderate-to-severe forms of OSA in patients with obesity grade 1-2.
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http://dx.doi.org/10.1038/s41366-021-00752-2DOI Listing
April 2021

Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.

BMJ 2021 01 20;372:n84. Epub 2021 Jan 20.

Hospital Alemão Oswaldo Cruz, São Paulo, Brazil.

Objective: To determine whether tocilizumab improves clinical outcomes for patients with severe or critical coronavirus disease 2019 (covid-19).

Design: Randomised, open label trial.

Setting: Nine hospitals in Brazil, 8 May to 17 July 2020.

Participants: Adults with confirmed covid-19 who were receiving supplemental oxygen or mechanical ventilation and had abnormal levels of at least two serum biomarkers (C reactive protein, D dimer, lactate dehydrogenase, or ferritin). The data monitoring committee recommended stopping the trial early, after 129 patients had been enrolled, because of an increased number of deaths at 15 days in the tocilizumab group.

Interventions: Tocilizumab (single intravenous infusion of 8 mg/kg) plus standard care (n=65) versus standard care alone (n=64).

Main Outcome Measure: The primary outcome, clinical status measured at 15 days using a seven level ordinal scale, was analysed as a composite of death or mechanical ventilation because the assumption of odds proportionality was not met.

Results: A total of 129 patients were enrolled (mean age 57 (SD 14) years; 68% men) and all completed follow-up. All patients in the tocilizumab group and two in the standard care group received tocilizumab. 18 of 65 (28%) patients in the tocilizumab group and 13 of 64 (20%) in the standard care group were receiving mechanical ventilation or died at day 15 (odds ratio 1.54, 95% confidence interval 0.66 to 3.66; P=0.32). Death at 15 days occurred in 11 (17%) patients in the tocilizumab group compared with 2 (3%) in the standard care group (odds ratio 6.42, 95% confidence interval 1.59 to 43.2). Adverse events were reported in 29 of 67 (43%) patients who received tocilizumab and 21 of 62 (34%) who did not receive tocilizumab.

Conclusions: In patients with severe or critical covid-19, tocilizumab plus standard care was not superior to standard care alone in improving clinical outcomes at 15 days, and it might increase mortality.

Trial Registration: ClinicalTrials.gov NCT04403685.
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http://dx.doi.org/10.1136/bmj.n84DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815251PMC
January 2021

Hydroxychloroquine with or without Azithromycin in Covid-19. Reply.

N Engl J Med 2021 01 2;384(2):191. Epub 2020 Dec 2.

HCor Research Institute, São Paulo, Brazil.

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http://dx.doi.org/10.1056/NEJMc2031780DOI Listing
January 2021

Rivaroxaban in Patients with Atrial Fibrillation and a Bioprosthetic Mitral Valve.

N Engl J Med 2020 11 14;383(22):2117-2126. Epub 2020 Nov 14.

From the HCor Research Institute (H.P.G., P.G.M.B.S., F.C.S.K., L.D., R.H.N.S., N.V., V.B.C., R.P., A.B.C., O.B.), Instituto Dante Pazzanese de Cardiologia (I.L.L.), Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (R.O.S., F.T.), Sociedade de Cardiologia do Estado de São Paulo (J.F.K.S., F.H.F., I.M.P., C.C.M., J.F.M.F., R.P., O.B.), and Hospital Israelita Albert Einstein (O.B.), São Paulo, Hospital Regional Hans Dieter Schmidt, Joinville (C.R.H.-F.), Hospital Metropolitano Sul Dom Helder Câmara, Cabo de Santo Agostinho (R.L.S.P.), Instituto de Cardiologia do Rio Grande do Sul, Porto Alegre (T.L.L.L.), Pronto Socorro Cardiológico Prof. Luiz Tavares, Procape (D.L.), Instituto de Medicina Integral Prof. Fernando Figueira (F.A.M.S.F.), Recife, Sociedade Hospitalar Angelina Caron, Campina Grande do Sul (D.B.P.), Instituto de Cardiologia do Distrito Federal, Brasília (F.A.A.), Centro de Pesquisa Clínica do Coração, Aracajú (F.S.S.), Quanta Diagnóstico e Terapia, Curitiba (F.R.F.), Hospital Evangélico de Vila Velha, Vila Velha (D.O.B.), Unidade Médico Cirúrgica-Unimec, Vitória da Conquista (A.P.A.), Hospital de Caridade São Vicente de Paulo, Jundiaí (A.C.Z.), Hospital de Messejana Dr. Carlos Alberto Studart Gomes, Fortaleza (J.D.S.N.), Hospital Regional de Presidente Prudente-Universidade do Oeste Paulista, Presidente Prudente (M.A.C.), and Instituto de Pesquisa Clínica de Campinas, Campinas (J.F.K.S.) - all in Brazil; and Duke Clinical Research Institute, Duke Health, Durham, NC (R.D.L., J.H.A.).

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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http://dx.doi.org/10.1056/NEJMoa2029603DOI Listing
November 2020

A randomized clinical trial to evaluate the efficacy and safety of rivaroxaban in patients with bioprosthetic mitral valve and atrial fibrillation or flutter: Rationale and design of the RIVER trial.

Am Heart J 2021 01 10;231:128-136. Epub 2020 Oct 10.

Research Institute - Heart Hospital (HCor), São Paulo, Brazil.

The efficacy and safety of rivaroxaban in patients with bioprosthetic mitral valves and atrial fibrillation or flutter remain uncertain. DESIGN: RIVER was an academic-led, multicenter, open-label, randomized, non-inferiority trial with blinded outcome adjudication that enrolled 1005 patients from 49 sites in Brazil. Patients with a bioprosthetic mitral valve and atrial fibrillation or flutter were randomly assigned (1:1) to rivaroxaban 20 mg once daily (15 mg in those with creatinine clearance <50 mL/min) or dose-adjusted warfarin (target international normalized ratio 2.0-30.); the follow-up period was 12 months. The primary outcome was a composite of all-cause mortality, stroke, transient ischemic attack, major bleeding, valve thrombosis, systemic embolism, or hospitalization for heart failure. Secondary outcomes included individual components of the primary composite outcome, bleeding events, and venous thromboembolism. SUMMARY: RIVER represents the largest trial specifically designed to assess the efficacy and safety of a direct oral anticoagulant in patients with bioprosthetic mitral valves and atrial fibrillation or flutter. The results of this trial can inform clinical practice and international guidelines.
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http://dx.doi.org/10.1016/j.ahj.2020.10.001DOI Listing
January 2021

Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial.

Lancet 2020 10 5;396(10256):959-967. Epub 2020 Sep 5.

Hospital Israelita Albert Einstein, São Paulo, Brazil.

Background: The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19.

Methods: We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278.

Findings: 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups.

Interpretation: In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19.

Funding: COALITION COVID-19 Brazil and EMS.
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http://dx.doi.org/10.1016/S0140-6736(20)31862-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836431PMC
October 2020

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial.

JAMA 2020 10;324(13):1307-1316

Aché Laboratórios Farmacêuticos, São Paulo, Brazil.

Importance: Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients.

Objective: To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19-associated ARDS.

Design, Setting, And Participants: Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients.

Interventions: Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148).

Main Outcomes And Measures: The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days.

Results: A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, -1.16; 95% CI, -1.94 to -0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events.

Conclusions And Relevance: Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.

Trial Registration: ClinicalTrials.gov Identifier: NCT04327401.
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http://dx.doi.org/10.1001/jama.2020.17021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489411PMC
October 2020

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis.

JAMA 2020 10;324(13):1330-1341

Australian and New Zealand Intensive Care Research Centre, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia.

Importance: Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support.

Objective: To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality.

Design, Setting, And Participants: Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance-weighted fixed-effect analysis using risk ratios.

Exposures: Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients).

Main Outcomes And Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events.

Results: A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as "low" for 6 of the 7 mortality results and as "some concerns" in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo.

Conclusions And Relevance: In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.
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http://dx.doi.org/10.1001/jama.2020.17023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489434PMC
October 2020

Three-Year Outcomes of Bariatric Surgery in Patients With Obesity and Hypertension : A Randomized Clinical Trial.

Ann Intern Med 2020 11 18;173(9):685-693. Epub 2020 Aug 18.

University of São Paulo Medical School, São Paulo, Brazil (L.A.B., L.F.D.).

Background: Midterm effects of bariatric surgery on patients with obesity and hypertension remain uncertain.

Objective: To determine the 3-year effects of Roux-en-Y gastric bypass (RYGB) on blood pressure (BP) compared with medical therapy (MT) alone.

Design: Randomized clinical trial. (ClinicalTrials.gov: NCT01784848).

Setting: Investigator-initiated study at Heart Hospital (HCor), São Paulo, Brazil.

Participants: Patients with hypertension receiving at least 2 medications at maximum doses or more than 2 medications at moderate doses and with a body mass index (BMI) between 30.0 and 39.9 kg/m were randomly assigned (1:1 ratio).

Intervention: RYGB plus MT or MT alone.

Measurements: The primary outcome was at least a 30% reduction in total number of antihypertensive medications while maintaining BP less than 140/90 mm Hg. Key secondary outcomes were number of antihypertensive medications, hypertension remission, and BP control according to current guidelines (<130/80 mm Hg).

Results: Among 100 patients (76% female; mean BMI, 36.9 kg/m [SD, 2.7]), 88% from the RYGB group and 80% from the MT group completed follow-up. At 3 years, the primary outcome occurred in 73% of patients from the RYGB group compared with 11% of patients from the MT group (relative risk, 6.52 [95% CI, 2.50 to 17.03]; 0.001). Of the randomly assigned participants, 35% and 31% from the RYGB group and 2% and 0% from the MT group achieved BP less than 140/90 mm Hg and less than 130/80 mm Hg without medications, respectively. Median (interquartile range) number of medications in the RYGB and MT groups at 3 years was 1 (0 to 2) and 3 (2.8 to 4), respectively ( 0.001). Total weight loss was 27.8% and -0.1% in the RYGB and MT groups, respectively. In the RYGB group, 13 patients developed hypovitaminosis B and 2 patients required reoperation.

Limitation: Single-center, nonblinded trial.

Conclusion: RYGB is an effective strategy for midterm BP control and hypertension remission, with fewer medications required in patients with hypertension and obesity.

Primary Funding Source: Ethicon, represented in Brazil by Johnson & Johnson do Brasil.
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http://dx.doi.org/10.7326/M19-3781DOI Listing
November 2020

Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19.

N Engl J Med 2020 11 23;383(21):2041-2052. Epub 2020 Jul 23.

From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., L.K.-D., T.L., D.L.M.J., P.G.M.B.S., L.T., E.O.A.-S., L.N.L., I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., F.R.M.), Hospital Sírio Libanês Research and Education Institute (L.C.P.A.), BP-A Beneficência Portuguesa de São Paulo (V.C.V.), International Research Center, Hospital Alemão Oswaldo Cruz (A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., R.D.L.), Hospital São Camilo (A.T.S.), Hospital Moriah (L.S.E.), Academic Research Organization of Hospital Israelita Albert Einstein (R.H.M.F., O.B.), Hospital Israelita Albert Einstein (L.S.E., A.J.P., A.S.-N.), Hospital Sepaco (F.G.R.F.), and Hospital Santa Paula (O.C.E.G.), São Paulo, Hospital Moinhos de Vento, Porto Alegre (R.G.R., M.F.), Hospital Naval Marcílio Dias, Rio de Janeiro (V.C.S.D.), Hospital Giselda Trigueiro, Natal (E.P.M.), Instituto Tacchini de Pesquisa em Saúde, Hospital Tacchini, Bento Gonçalves (N.A.G.), Hospital Bruno Born, Lajeado (F.F.C.), Hospital Baia Sul, Florianópolis (I.S.M.), Hospital Regional Hans Dieter Schmidt, Joinville (C.R.H.F.); Angiocor Blumenau, Blumenau (A.P.M.K.), and EMS Pharma, Hortolândia (R.B.A., M.F.B.O.) - all in Brazil; and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (R.D.L.).

Background: Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited.

Methods: We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed.

Results: A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent.

Conclusions: Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.).
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http://dx.doi.org/10.1056/NEJMoa2019014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397242PMC
November 2020

Structure and process associated with the efficiency of intensive care units in low-resource settings: An analysis of the CHECKLIST-ICU trial database.

J Crit Care 2020 10 18;59:118-123. Epub 2020 Jun 18.

D'Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil; Brazilian Research in Intensive Care Network (BRICNet), Brazil; Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, RJ, Brazil. Electronic address:

Purpose: Characteristics of structure and process impact ICU performance and the outcomes of critically ill patients. We sought to identify organizational characteristics associated with efficient ICUs in low-resource settings.

Materials And Methods: This is a secondary analysis of a multicenter cluster-randomized clinical trial in Brazil (CHECKLIST-ICU). Efficient units were defined by standardized mortality ratio (SMR) and standardized resource use (SRU) lower than the overall medians and non-efficient otherwise. We used a regularized logistic regression model to evaluate associations between organizational factors and efficiency.

Results: From 118 ICUs (13,635 patients), 47 units were considered efficient and 71 non-efficient. Efficient units presented lower incidence rates (median[IQR]) of central line-associated bloodstream infections (4.95[0.00-22.0] vs 6.29[0.00-25.6], p = .04), utilization rates of mechanical ventilation (0.41[0.07-0.73] vs 0.58[0.19-0.82], p < .001), central venous catheter (0.67[0.15-0.98] vs 0.78[0.33-0.98], p = .04), and indwelling urinary catheter (0.62[0.22-0.95] vs 0.76[0.32-0.98], p < .01) than non-efficient units. The reported active surveillance of ventilator-associated pneumonia (OR = 1.72; 95%CI, 1.16-2.57) and utilization of central venous catheters (OR = 1.94; 95%CI, 1.32-2.94) were associated with efficient ICUs.

Conclusions: In low-resource settings, active surveillance of nosocomial infections and the utilization of invasive devices were associated with efficiency, supporting the management and evaluation of performance indicators as a starting point for improvement in ICU.
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http://dx.doi.org/10.1016/j.jcrc.2020.06.008DOI Listing
October 2020

Bundle of Coated Devices to Reduce Nosocomial Infections in the Intensive Care Unit. CRITIC Pilot Randomized Controlled Trial.

Ann Am Thorac Soc 2020 10;17(10):1257-1263

Instituto de Pesquisa, Hospital do Coração, São Paulo, Brazil.

Coated devices may reduce biofilm formation and reduce the occurrence of device-related infections in critically ill patients. A bundle of coated devices (an endotracheal tube [ETT], central venous catheter [CVC], and urinary catheter [UC]) simultaneously inserted may optimize benefits of coated devices in patients with the most severe illness. To assess the feasibility of a randomized controlled trial on simultaneous insertion of gold/silver/palladium-coated devices versus uncoated devices in severely ill patients, which required sequential insertion of all three devices (an ETT, CVC, and UC) for support in the intensive care unit (ICU). This was a multicenter randomized controlled pilot trial. Patients who required simultaneous insertion of an ETT, CVC, and UC were randomized to treatment with coated versus uncoated devices, which were used as necessary for up to 28 days. The primary endpoint was feasibility, defined as the trial being able to enroll enough participants to have the sample size necessary for its secondary primary endpoint (estimating sepsis incidence in this population) in less than 1 year and for estimating the number of admitted patients who require simultaneous insertion of all three devices. Secondary endpoints included the incidence of sepsis and device-associated infections (ventilator-associated pneumonia, catheter-related bloodstream infection, and catheter-related urinary-tract infection) within each group as well as the number of days alive and free of antibiotics during the ICU stay. All events were adjudicated. One hundred and three patients (48 in the coated-device group and 55 in the uncoated-device group) were included in the per-protocol analysis. The inclusion period was 8 months. There were 13 septic events in each group (26 in total), with an approximate incidence of sepsis of 32.3 (95% credible interval [CrI], 22.4-44.9) per 100 patient-days. The overall incidences of ventilator-associated pneumonia, catheter-related urinary-tract infection, and catheter-related bloodstream infection were 15.2 (95% CrI, 7.8-26.4), 6.3 (95% CrI, 2.4-13.7), and 7.9 (95% CrI, 3.6-15.1) per 1,000 patient-days, and incidence rates were not statistically different between groups. Patients in the coated-device group had more days alive and free of antibiotics in the ICU (28.97 d vs. 19.62 d per 100 patient-days; mean ratio, 1.48; 95% CrI, 1.16-1.89). Use of a bundle of coated devices as the initial treatment for of severely ill patients is feasible. Coated devices may be associated with more days alive and free of antibiotics.Clinical trial registered with www.clinicaltrials.gov (NCT03868241).
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http://dx.doi.org/10.1513/AnnalsATS.202003-206OCDOI Listing
October 2020

Reply to Topeli and to Akinosoglou

Am J Respir Crit Care Med 2020 07;202(1):154

Instituto Latino-Americano de SepsisSão Paulo, Brazil.

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http://dx.doi.org/10.1164/rccm.202003-0628LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328319PMC
July 2020

Hydroxyethyl Starch for Fluid Replacement Therapy in High-Risk Surgical Patients: Context and Caution.

JAMA 2020 01;323(3):217-218

Research Institute, HCor (Hospital do Coração), São Paulo, Brazil.

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http://dx.doi.org/10.1001/jama.2019.20141DOI Listing
January 2020

Predictive Accuracy of the Quick Sepsis-related Organ Failure Assessment Score in Brazil. A Prospective Multicenter Study.

Am J Respir Crit Care Med 2020 04;201(7):789-798

Instituto Latino-Americano de Sepsis, São Paulo, Brazil.

Although proposed as a clinical prompt to sepsis based on predictive validity for mortality, the Quick Sepsis-related Organ Failure Assessment (qSOFA) score is often used as a screening tool, which requires high sensitivity. To assess the predictive accuracy of qSOFA for mortality in Brazil, focusing on sensitivity. We prospectively collected data from two cohorts of emergency department and ward patients. Cohort 1 included patients with suspected infection but without organ dysfunction or sepsis (22 hospitals: 3 public and 19 private). Cohort 2 included patients with sepsis (54 hospitals: 24 public and 28 private). The primary outcome was in-hospital mortality. The predictive accuracy of qSOFA was examined considering only the worst values before the suspicion of infection or sepsis. Cohort 1 contained 5,460 patients (mortality rate, 14.0%; 95% confidence interval [CI], 13.1-15.0), among whom 78.3% had a qSOFA score less than or equal to 1 (mortality rate, 8.3%; 95% CI, 7.5-9.1). The sensitivity of a qSOFA score greater than or equal to 2 for predicting mortality was 53.9% and the 95% CI was 50.3 to 57.5. The sensitivity was higher for a qSOFA greater than or equal to 1 (84.9%; 95% CI, 82.1-87.3), a qSOFA score greater than or equal to 1 or lactate greater than 2 mmol/L (91.3%; 95% CI, 89.0-93.2), and systemic inflammatory response syndrome plus organ dysfunction (68.7%; 95% CI, 65.2-71.9). Cohort 2 contained 4,711 patients, among whom 62.3% had a qSOFA score less than or equal to 1 (mortality rate, 17.3%; 95% CI, 15.9-18.7), whereas in public hospitals the mortality rate was 39.3% (95% CI, 35.5-43.3). A qSOFA score greater than or equal to 2 has low sensitivity for predicting death in patients with suspected infection in a developing country. Using a qSOFA score greater than or equal to 2 as a screening tool for sepsis may miss patients who ultimately die. Using a qSOFA score greater than or equal to 1 or adding lactate to a qSOFA score greater than or equal to 1 may improve sensitivity.Clinical trial registered with www.clinicaltrials.gov (NCT03158493).
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http://dx.doi.org/10.1164/rccm.201905-0917OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124712PMC
April 2020

Effects of a Resuscitation Strategy Targeting Peripheral Perfusion Status versus Serum Lactate Levels among Patients with Septic Shock. A Bayesian Reanalysis of the ANDROMEDA-SHOCK Trial.

Am J Respir Crit Care Med 2020 02;201(4):423-429

Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

A recent randomized controlled trial showed that a peripheral perfusion-guided resuscitation strategy was associated with lower mortality and less organ dysfunction when compared with lactate-guided resuscitation strategy in patients with septic shock, but the difference in the primary outcome, 28-day mortality, did not reach the proposed statistical significance threshold ( = 0.06). We tested different analytic methods to aid in the interpretation of these results. To reassess the results of the ANDROMEDA-SHOCK trial using both Bayesian and frequentist frameworks. All patients recruited in ANDROMEDA-SHOCK were included. Both a Bayesian analysis and a mixed logistic regression analysis were performed. The Bayesian analysis included four different priors (optimistic, neutral, null, and pessimistic) for mortality endpoints. The probability of having a Sequential Organ Failure Assessment in the lowest quartile at 72 hours was assessed using Bayesian networks. In the Bayesian analysis, the posterior probability that a peripheral perfusion-targeted resuscitation strategy is superior to lactate-targeted resuscitation at 28 days was above 90% for all priors; the probability of benefit at 90 days was above 90% for all but the pessimistic prior. Using an optimistic prior, posterior median odds ratios were 0.61 (95% credible interval, 0.41-0.90) and 0.68 (95% credible interval, 0.47-1.01) for 28-day and 90-day mortality, respectively. The comparable frequentist odds ratios for 28-day and 90-day mortality were 0.61 (95% confidence interval [CI], 0.38-0.92) and 0.70 (95% CI, 0.45-1.08), respectively. The odds that that patients in the peripheral perfusion-targeted resuscitation arm had Sequential Organ Failure Assessment scores in the lower quartile at 72 hours was 1.55 (95% CI, 1.02-2.37). Peripheral perfusion-targeted resuscitation may result in lower mortality and faster resolution of organ dysfunction when compared with a lactate-targeted resuscitation strategy.
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http://dx.doi.org/10.1164/rccm.201905-0968OCDOI Listing
February 2020

Implementation of a Brazilian Cardioprotective Nutritional (BALANCE) Program for improvement on quality of diet and secondary prevention of cardiovascular events: A randomized, multicenter trial.

Am Heart J 2019 09 21;215:187-197. Epub 2019 Jun 21.

Hospital Universitário Pedro Ernesto, Rio de Janeiro-RJ, Brazil.

Background: Appropriate dietary recommendations represent a key part of secondary prevention in cardiovascular disease (CVD). We evaluated the effectiveness of the implementation of a nutritional program on quality of diet, cardiovascular events, and death in patients with established CVD.

Methods: In this open-label, multicenter trial conducted in 35 sites in Brazil, we randomly assigned (1:1) patients aged 45 years or older to receive either the BALANCE Program (experimental group) or conventional nutrition advice (control group). The BALANCE Program included a unique nutritional education strategy to implement recommendations from guidelines, adapted to the use of affordable and regional foods. Adherence to diet was evaluated by the modified Alternative Healthy Eating Index. The primary end point was a composite of all-cause mortality, cardiovascular death, cardiac arrest, myocardial infarction, stroke, myocardial revascularization, amputation, or hospitalization for unstable angina. Secondary end points included biochemical and anthropometric data, and blood pressure levels.

Results: From March 5, 2013, to Abril 7, 2015, a total of 2534 eligible patients were randomly assigned to either the BALANCE Program group (n = 1,266) or the control group (n = 1,268) and were followed up for a median of 3.5 years. In total, 235 (9.3%) participants had been lost to follow-up. After 3 years of follow-up, mean modified Alternative Healthy Eating Index (scale 0-70) was only slightly higher in the BALANCE group versus the control group (26.2 ± 8.4 vs 24.7 ± 8.6, P < .01), mainly due to a 0.5-serving/d greater intake of fruits and of vegetables in the BALANCE group. Primary end point events occurred in 236 participants (18.8%) in the BALANCE group and in 207 participants (16.4%) in the control group (hazard ratio, 1.15; 95% CI 0.95-1.38; P = .15). Secondary end points did not differ between groups after follow-up.

Conclusions: The BALANCE Program only slightly improved adherence to a healthy diet in patients with established CVD and had no significant effect on the incidence of cardiovascular events or death.
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http://dx.doi.org/10.1016/j.ahj.2019.06.010DOI Listing
September 2019

Heterogeneous effects of alveolar recruitment in acute respiratory distress syndrome: a machine learning reanalysis of the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial.

Br J Anaesth 2019 07 5;123(1):88-95. Epub 2019 Apr 5.

Research Institute, HCor-Hospital do Coração, São Paulo, Brazil.

Background: Despite a robust physiological rationale, recruitment manoeuvres with PEEP titration were associated with harm in the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART). We sought to investigate the potential heterogeneity in treatment effects in patients enrolled in the ART, using a machine learning approach.

Methods: The primary outcome was hospital mortality. Patients were clustered using baseline clinical and physiological data using the k-means for mixed large data method. The heterogeneity in treatment effect between clusters was investigated using Bayesian methods. We further investigated whether baseline driving pressure could modulate the association between treatment arm, cluster, and mortality.

Results: Data from all 1010 patients enrolled in the ART were analysed. Partitioning suggested that three clusters were present in the ART population. The largest cluster (Cluster 1) was characterised by patients with pneumonia and requiring vasopressor support. Recruitment manoeuvres with PEEP titration were associated with higher mortality in Cluster 1 (probability of harm of >98%), but this association was absent in Clusters 2 and 3 (probability of harm of 45% and 68%, respectively). Higher baseline driving pressure was associated with a progressive reduction in the association between alveolar recruitment with PEEP titration and mortality.

Conclusions: Recruitment manoeuvre with PEEP titration may be harmful in acute respiratory distress syndrome (ARDS) patients with pneumonia or requiring vasopressor support. Driving pressure appears to modulate the association between the ART study intervention, aetiology of ARDS, and mortality. This machine learning approach may help tailor future RCTs.

Clinical Trial Registration: NCT01374022.
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http://dx.doi.org/10.1016/j.bja.2019.02.026DOI Listing
July 2019

Effects of oral supplementation with probiotics or synbiotics in overweight and obese adults: a systematic review and meta-analyses of randomized trials.

Nutr Rev 2019 06;77(6):430-450

Research Institute at Hospital do Coração, São Paulo, Brazil.

Context: Recent evidence suggests that modulation of the gut microbiota may contribute to body weight control.

Objective: This systematic review aimed to assess the effects of oral supplementation with probiotics or synbiotics on body weight, body mass index (BMI), and waist circumference in overweight and obese adults (BMI ≥ 25 kg/m2).

Data Sources: Five electronic databases-PubMed, Embase, Cochrane Library/CENTRAL, LILACS, and Web of Science-were searched from inception to August 2017. No language restrictions were applied.

Study Selection: Randomized and quasi-randomized parallel trials that assessed the effects of oral supplementation with probiotics or synbiotics vs any other intervention but bariatric surgery or fecal transplantation in overweight or obese adults were selected.

Data Extraction: Three teams of 2 authors independently assessed risk of bias and extracted data from the included trials. Data were pooled using inverse-variance random-effects meta-analyses. The quality of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.

Results: Nineteen randomized trials (28 publications, 1412 participants) were included. There were no differences in mean body weight change [mean difference (MD), -0.54 kg; 95%CI, -1.09 to 0.01; I2 = 0%; moderate quality of evidence) or mean BMI change (MD, -0.19 kg/m2; 95%CI, -0.43 to 0.04; I2 = 51%; low quality of evidence) between groups who received probiotics or synbiotics and control groups. Oral supplementation with probiotics or synbiotics reduced mean waist circumference compared with control (MD, -0.82 cm; 95%CI, -1.43 to -0.21; I2 = 46%; low quality of evidence).

Conclusions: The findings suggest that oral supplementation with probiotics or synbiotics has a small effect to reduce waist circumference but no effect on body weight or BMI, although the quality of evidence is low to moderate. Therefore, the current evidence is not definitive. Large-scale trials are needed and may help to better inform clinical practice.

Systematic Review Registration: PROSPERO registration number CRD42018075126.
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http://dx.doi.org/10.1093/nutrit/nuz001DOI Listing
June 2019

Effects of Bariatric Surgery Versus Medical Therapy on the 24-Hour Ambulatory Blood Pressure and the Prevalence of Resistant Hypertension.

Hypertension 2019 03;73(3):571-577

Hypertension Unit, Renal Division (S.d.B., L.F.D.), University of São Paulo Medical School, Brazil.

Bariatric surgery is an effective strategy for blood pressure (BP) reduction, but most of the evidence relies on office BP measurements. In this study, we evaluated the impact of bariatric surgery on 24-hour BP profile, BP variability, and resistant hypertension prevalence. This is a randomized trial including obese patients with grade 1 and 2 using at least 2 antihypertensive drugs at maximal doses or >2 at moderate doses. Patients were allocated to either Roux-en-Y Gastric Bypass (RYGB) combined with medical therapy or medical therapy alone for 12 months. The primary outcome was the 24-hour BP profile and variability (average real variability of daytime and night time BP). We evaluated the nondipping status and prevalence of resistant hypertension as secondary end points. We included 100 patients (76% female, body mass index, 36.9±2.7 kg/m). The 24-hour BP profile (including nondipping status) was similar after 12 months, but the RYGB group required less antihypertensive classes as compared to the medical therapy alone (0 [0-1] versus 3 [2.5-4] classes; P<0.01). The average real variability of systolic nighttime BP was lower after RYGB as compared to medical therapy (between-group difference, -1.63; 95% CI, -2.91 to -0.36; P=0.01). Prevalence of resistant hypertension was similar at baseline (RYGB, 10% versus MT, 16%; P=0.38), but it was significantly lower in the RYGB at 12 months (0% versus 14.9%; P<0.001). In conclusion, RYGB significantly reduced antihypertensive medications while promoting similar 24-hour BP profile and nondipping status. Interestingly, bariatric surgery improved BP variability and may decrease the burden of resistant hypertension associated with obesity. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT01784848.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.12290DOI Listing
March 2019

Double Blinded Randomized Trial of Subcutaneous Trigeminal Nerve Stimulation as Adjuvant Treatment for Major Unipolar Depressive Disorder.

Neurosurgery 2019 11;85(5):717-728

HCor Neuroscience Institute, Heart Hos-pital (HCor), São Paulo, São Paulo, Brazil.

Background: More than 30% of major depressive disorder patients fail to respond to adequate trials of medications and psychotherapy. While modern neuromodulation approaches (ie, vagal nerve stimulation, deep brain stimulation) are yet to prove their efficacy for such cases in large randomized controlled trials, trigeminal nerve stimulation (TNS) has emerged as an alternative with promising effects on mood disorders.

Objective: To assess efficacy, safety, tolerability, and placebo effect duration of continuous subcutaneous TNS (sTNS) in treatment-resistant depression (TRD).

Methods: The TREND study is a single-center, double-blind, randomized, controlled, phase II clinical trial. Twenty unipolar TRD patients will receive V1 sTNS as adjuvant to medical therapy and randomized to active vs sham stimulation throughout a 24-wk period. An additional 24-wk open-label phase will follow. Data concerning efficacy, placebo response, relapse, and side effects related to surgery or electrical stimulation will be recorded. We will use the HDRS-17, BDI-SR, IDS_SR30, and UKU scales.

Expected Outcomes: The main outcome measure is improvement in depression scores using HAM-17 under continuous sTNS as adjuvant to antidepressants. Active stimulation is expected to significantly impact response and remission rates. Minor side effects are expected due to the surgical procedure and electrical stimulation. The open-label phase should further confirm efficacy and tolerability.

Discussion: This study protocol is designed to define efficacy of a novel adjuvant therapy for TRD. We must strive to develop safe, reproducible, predictable, and well-tolerated neuromodulation approaches for TRD patients impaired to manage their lives and contribute with society.
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http://dx.doi.org/10.1093/neuros/nyy420DOI Listing
November 2019

Period-dependent Associations between Hypotension during and for Four Days after Noncardiac Surgery and a Composite of Myocardial Infarction and Death: A Substudy of the POISE-2 Trial.

Anesthesiology 2018 02;128(2):317-327

From the Departments of Outcomes Research (D.I.S., N.M.Z., G.M.) and Quantitative Health Sciences (N.M.Z., G.M.), Cleveland Clinic, Cleveland, Ohio; the Department of Anaesthesia and Intensive Care, Bispebjerg Hospital (C.S.M.) and the Department of Anaesthesiology, Herlev Hospital (C.S.M., R.M.D.), University of Copenhagen, Copenhagen, Denmark; the Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Melbourne, Australia (K.L.); the Department of Research, Grupo de Cardiología Preventiva Universidad Autónoma de Bucaramanga, Fundación CardioInfantil Instituto de Cardiología, Bucaramanga, Colombia (S.M.V.); the Anaesthetic Department, Hull and East Yorkshire Hospitals, National Health Service Trust, Hull, East Yorkshire, United Kingdom (P.B.); Department of Cardiology, Hospital de la Santa Creu i Sant Pau, IIB-SantPau, Universidad Autónoma de Barcelona, Barcelona (J.A.-G.); the Research Institute, Hospital do Coração, São Paulo, Brazil (A.B.C.); the Department of Anesthesia, Queen's University and Kingston General Hospital, Kingston, Canada (J.L.P.); Rahate Surgical Hospital, Nagpur, Maharashtra, India (P.V.R.); the Department of Anesthesia and Intensive Care Medicine, University Hospital Basel, University of Basel, Basel, Switzerland (M.D.S.); the Department of Vascular Surgery, Sapienza University of Rome, Rome, Italy (B.G.); Counties Manukau District Health, Aukland, New Zealand (S.A.W.); the Krishna Institute of Medical Sciences, Hyderbad, India (R.K.P.); the Department of Pediatrics, Hvidovre Hospital, Copenhagen, Denmark (R.M.D.); the Department of Anaesthetics, University of KwaZulu-Natal, Pietermaritzburg, South Africa (R.R.), the Hypertension and Vascular Aging Center, Hospital Universitario Austral, Pilar, Argentina (F.B.); the Departments of Health Research Methods, Evidence, and Impact and Medicine, McMaster University, Hamilton, Canada (P.J.D.); and the Population Health Research Institute, Hamilton, Canada (E.D., P.J.D., D.I.S.).

Background: The relative contributions of intraoperative and postoperative hypotension to perioperative morbidity remain unclear. We determined the association between hypotension and a composite of 30-day myocardial infarction and death over three periods: (1) intraoperative, (2) remaining day of surgery, and (3) during the initial four postoperative days.

Methods: This was a substudy of POISE-2, a 10,010-patient factorial-randomized trial of aspirin and clonidine for prevention of myocardial infarction. Clinically important hypotension was defined as systolic blood pressure less than 90 mmHg requiring treatment. Minutes of hypotension was the exposure variable intraoperatively and for the remaining day of surgery, whereas hypotension status was treated as binary variable for postoperative days 1 to 4. We estimated the average relative effect of hypotension across components of the composite using a distinct effect generalized estimating model, adjusting for hypotension during earlier periods.

Results: Among 9,765 patients, 42% experienced hypotension, 590 (6.0%) had an infarction, and 116 (1.2%) died within 30 days of surgery. Intraoperatively, the estimated average relative effect across myocardial infarction and mortality was 1.08 (98.3% CI, 1.03, 1.12; P < 0.001) per 10-min increase in hypotension duration. For the remaining day of surgery, the odds ratio was 1.03 (98.3% CI, 1.01, 1.05; P < 0.001) per 10-min increase in hypotension duration. The average relative effect odds ratio was 2.83 (98.3% CI, 1.26, 6.35; P = 0.002) in patients with hypotension during the subsequent four days of hospitalization.

Conclusions: Clinically important hypotension-a potentially modifiable exposure-was significantly associated with a composite of myocardial infarction and death during each of three perioperative periods, even after adjustment for previous hypotension.
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http://dx.doi.org/10.1097/ALN.0000000000001985DOI Listing
February 2018

Low- Versus High-Chloride Content Intravenous Solutions for Critically Ill and Perioperative Adult Patients: A Systematic Review and Meta-analysis.

Anesth Analg 2018 02;126(2):513-521

From the Research Institute, Hospital do Coração (HCor), São Paulo, Brazil.

Background: To assess whether use of low-chloride solutions in unselected critically ill or perioperative adult patients for maintenance or resuscitation reduces mortality and renal replacement therapy (RRT) use when compared to high-chloride fluids.

Methods: Systematic review and meta-analysis with random-effects inverse variance model. PubMed, Cochrane library, EMBASE, LILACS, and Web of Science were searched from inception to October 2016. Published and unpublished randomized controlled trials in any language that enrolled critically ill and/or perioperative adult patients and compared a low- to a highchloride solution for volume maintenance or resuscitation. The primary outcomes were mortality and RRT use. We conducted trial sequential analyses and assessed risk of bias of individual trials and the overall quality of evidence. Fifteen trials with 4067 patients, most at low risk of bias, were identified. Of those, only 11 and 10 trials had data on mortality and RRT use, respectively. A total of 3710 patients were included in the mortality analysis and 3724 in the RRT analysis.

Results: No statistically significant impact on mortality (odds ratio, 0.90; 95% confidence interval, 0.69-1.17; P = .44; I = 0%) or RRT use (odds ratio, 1.12; 95% confidence interval, 0.80-1.58; P = .52; I = 0%) was found. Overall quality of evidence was low for both primary outcomes. Trial sequential analyses highlighted that the sample size needed was much larger than that available for properly powered outcome assessment.

Conclusions: The current evidence on low- versus high-chloride solutions for unselected critically ill or perioperative adult patients demonstrates no benefit, but suffers from considerable imprecision. We noted a limited exposure volume for study fluids and a relatively low risk of the populations in each study. Together with the relatively small pooled sample size, these data leave us underpowered to detect potentially important differences. Results from well-conducted, adequately powered randomized controlled trials examining sufficiently large fluid exposure are necessary.
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http://dx.doi.org/10.1213/ANE.0000000000002641DOI Listing
February 2018
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