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Background: Morphine is commonly used to relieve pain, anxiety and dyspnea in STEMI but it lowers blood pressure and delays the activity of oral antiplatelet agents. The impact of morphine on clinical outcomes remains unknown. This analysis was performed to determine if morphine use was associated with increased risk of adverse clinical events among STEMI patients treated with fibrinolytic therapy and clopidogrel or ticagrelor. Methods: In the Ticagrelor in Patients with ST Elevation Myocardial Infarction Treated with Pharmacological Thrombolysis (TREAT) study, 3799 STEMI patients treated with fibrinolysis were randomized to receive clopidogrel or ticagrelor. Morphine use was left to the discretion of the treating physicians. In this pre-specified analysis, we evaluated clinical outcomes based on the use and timing of morphine administration. Outcomes were stratified by randomized treatment group. Multivariable analysis was performed using Inverse Probability Treatment Weighting (IPTW) weighting. Results: Morphine was used in 53% of patients. After adjustment using IPTW weighting, morphine use was associated with higher hazard of reinfarction at 7 days (HR 4.9, P = .0006) and 30 days (HR 1.7, P = .04), and lower hazard of major bleeding (HR 0.37, P = .006). There was no significant difference in mortality at any time point. Conclusions: Among patients with STEMI treated with fibrinolytic therapy, morphine use was associated with a higher risk of early reinfarction and a lower risk of major bleeding but no difference in mortality.

Aims To evaluate whether a strategy of double-dose influenza vaccination during hospitalization for an acute coronary syndrome (ACS) compared with standard-dose outpatient vaccination (as recommended by current guidelines) would further reduce the risk of major cardiopulmonary events. Methods and results Vaccination against Influenza to Prevent cardiovascular events after Acute Coronary Syndromes (VIP-ACS) was a pragmatic, randomized, multicentre, active-comparator, open-label trial with blinded outcome adjudication comparing two strategies of influenza vaccination following an ACS: double-dose quadrivalent inactivated vaccine before hospital discharge vs. standard-dose quadrivalent inactivated vaccine administered in the outpatient setting 30 days after randomization. The primary outcome was a hierarchical composite of all-cause death, myocardial infarction, stroke, unstable angina, hospitalization for heart failure, urgent coronary revascularization, and hospitalization for respiratory causes, analysed by the win ratio method. Patients were followed for 12 months. During two influenza seasons, 1801 participants were included at 25 centres in Brazil. The primary outcome was not different between groups, with 12.7% wins in-hospital double-dose vaccine group and 12.3% wins in the standard-dose vaccine group {win ratio: 1.02 [95% confidence interval (CI): 0.79–1.32], P = 0.84}. Results were consistent for the key secondary outcome, a hierarchical composite of cardiovascular death, myocardial infarction and stroke [win ratio: 0.94 (95% CI: 0.66–1.33), P = 0.72]. Time-to-first event analysis for the primary outcome showed results similar to those of the main analysis [hazard ratio 0.97 (95% CI: 0.75–1.24), P = 0.79]. Adverse events were infrequent and did not differ between groups. Conclusion Among patients hospitalized with an ACS, double-dose influenza vaccination before discharge did not reduce cardiopulmonary outcomes compared with standard-dose vaccination in the outpatient setting. Clinical Trial Registration ClinicalTrials.gov number: NCT04001504

PurposeThe Balanced versus Saline Trialists (BEST) -Living Study is an ongoing living systematic review with aggregated and individual patient data meta-analysis (IPDMA) from eligible trials that assessed the effects of using balanced solutions compared with saline in critically ill adults. We herein present the search strategies for the BEST-Living Study and provide details for future analysis and presentation.MethodsThe report will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Individual Participant Data (PRISMA-IPD) recommendations. Search was performed in Pubmed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). The primary endpoint will be hospital mortality, which will be analyzed using a Bayesian hierarchical model. Secondary endpoints include nurvival until longest follow-up available, use of kidney replacement therapy, and intensive care unit and hospital length-of-stay. Details on the analysis plan are provided in this statistical analysis plan.ConclusionThe study will provide the most up-to-date and comprehensive assessment using the best evidence available for the use of balanced solutions in critically ill patients.ApprovalsThe undersigned and all authors have reviewed this plan and approve it as final. They find it to be consistent with the requirements of the protocol as it applies to their respective areas. They also find it to be compliant with ICH-E9 principles and, in particular, confirm that this analysis plan was final prior to any analysis of the aggregated data.

Background Limited evidence is available addressing the potential role of sleep disorders on renal function. Here, we aimed to explore the associations of obstructive sleep apnea (OSA) and sleep duration (SD) with renal function in subjects with high cardiovascular risk. Methods Consecutive subjects with coronary artery disease (CAD) underwent clinical evaluation, sleep study to define OSA and one-week wrist actigraphy to objectively measure SD. OSA was defined by an apnea-hypopnea index (AHI) of ≥15 events/hour. The estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation. We analyzed the associations of OSA and SD with continuous eGFR values and according to the presence of CKD (eGFR Results We studied 242 subjects (62.8% men). The frequency of OSA was 55.4% and the median SD was 412.8 (363.4–457.25) min. There was no difference in the eGFRs between participants with and without OSA (69.3 ± 19.1 vs. 74.6 ± 19.3 mL/min/1.73 m2, p = 0.72) and the rate of eGFR Conclusion OSA severity and SD were not independently associated with CKD in subjects with CAD.

Non stent-based local drug delivery with drug-coated balloon (DCB) is an alternative to drug-eluting stent with favorable clinical applicability in the treatment of selected coronary lesions. Our purpose was to report the initial performance, safety and efficacy evaluations of a novel sirolimus-coated balloon in the treatment of coronary lesions.This was a phase I (first-in-man), prospective, multicenter, single-arm trial evaluating the novel SELUTION SLR™ DCB (M.A. Med Alliance SA, Nyon, Switzerland), which incorporates a polymeric microsphere-based technology for controlled and continuous release of sirolimus, in the treatment of de novo or restenotic lesions.A total of 56 patients/lesions were enrolled between November/2018 and March/2019. Diabetes was found in 46.6 %, and de novo lesions represented 79.6 % of cases. Device and procedural/clinical success were 100 % and 96.4 %, respectively. There was only one major adverse cardiac event (target lesion revascularization) reported at late follow-up. By quantitative coronary angiography analysis, mean % diameter stenosis was 30.5 ± 16.7 %, late lumen loss was 0.26 ± 0.45 mm and angiographic binary restenosis occurred in 4 of 45 cases at 6-month angiographic follow-up.The novel SELUTION sirolimus-coated balloon demonstrated safety and efficacy in the treatment of diseased coronary vessels, including absence of mortality and relatively low late lumen loss at late follow-up.

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. 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 (

Rationale: 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. Objectives: 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). Methods: 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. Results: One hundred and three patients (48 in the coated-device group and 55 in the uncoated-device group) were included in the perprotocol 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 catheterrelated 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). Conclusions: 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 (NCT 03868241).

Rationale: The effects of balanced crystalloid versus saline on clinical outcomes for ICU patients may be modified by the type of fluid that patients received for initial resuscitation and by the type of admission. Objectives: To assess whether the results of a randomized controlled trial could be affected by fluid use before enrollment and admission type. Methods: Secondary post hoc analysis of the BaSICS (Balanced Solution in Intensive Care Study) trial, which compared a balanced solution (Plasma-Lyte 148) with 0.9% saline in the ICU. Patients were categorized according to fluid use in the 24 hours before enrollment in four groups (balanced solutions only, 0.9% saline only, a mix of both, and no fluid before enrollment) and according to admission type (planned, unplanned with sepsis, and unplanned without sepsis). The association between 90-day mortality and the randomization group was assessed using a hierarchical logistic Bayesian model. Measurements and Main Results: A total of 10,520 patients were included. There was a low probability that the balanced solution was associated with improved 90-day mortality in the whole trial population (odds ratio [OR], 0.95; 89% credible interval [CrI], 0.66–10.51; probability of benefit, 0.58); however, probability of benefit was high for patients who received only balanced solutions before enrollment (regardless of admission type, OR, 0.78; 89% CrI, 0.56–1.03; probability of benefit, 0.92), mostly because of a benefit in unplanned admissions due to sepsis (OR, 0.70; 89% CrI, 0.50–0.97; probability of benefit, 0.96) and planned admissions (OR, 0.79; 89% CrI, 0.65–0.97; probability of benefit, 0.97). Conclusions: There is a high probability that balanced solution use in the ICU reduces 90-day mortality in patients who exclusively received balanced fluids before trial enrollment. Clinical trial registered with www.clinicaltrials.gov (NCT 02875873).

Background Patients with Coronavirus Disease 2019 (COVID-19) may present high risk features during hospitalization, including cardiovascular manifestations. However, less is known about the factors that may further increase the risk of death in these patients. Methods We included patients with COVID-19 and high risk features according to clinical and/or laboratory criteria at 21 sites in Brazil from June 10th to October 23rd of 2020. All variables were collected until hospital discharge or in-hospital death. Results A total of 2546 participants were included (mean age 65 years; 60.3% male). Overall, 70.8% were admitted to intensive care units and 54.2% had elevated troponin levels. In-hospital mortality was 41.7%. An interaction among sex, age and mortality was found (p = 0.007). Younger women presented higher rates of death than men (30.0% vs 22.9%), while older men presented higher rates of death than women (57.6% vs 49.2%). The strongest factors associated with in-hospital mortality were need for mechanical ventilation (odds ratio [OR] 8.2, 95% confidence interval [CI] 5.4–12.7), elevated C-reactive protein (OR 2.3, 95% CI 1.7–2.9), cancer (OR 1.8, 95 %CI 1.2–2.9), and elevated troponin levels (OR 1.8, 95% CI 1.4–2.3). A risk score was developed for risk assessment of in-hospital mortality. Conclusions This cohort showed that patients with COVID-19 and high risk features have an elevated rate of in-hospital mortality with differences according to age and sex. These results highlight unique aspects of this population and might help identifying patients who may benefit from more careful initial surveillance and potential subsequent interventional therapies.

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

Background: The efficacy of ticagrelor in the long-term post–ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remains uncertain.Objectives: The purpose o...

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 2 ). 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 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 Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01784848.

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

Made available in DSpace on 2022-04-29T08:29:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-06-12 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. Duke Clinical Research Institute Duke University Medical Center Brazilian Clinical Research Institute HCor Research Institute Hospital Samaritano Paulista Academic Research Organization Hospital Israelita Albert Einstein Instituto do Coração Universidade de São Paulo Instituto do Câncer do Estado de São Paulo Hospital das Clínicas da Faculdade de Medicina Universidade de São Paulo Science Valley Research Institute Hemostasis & Thrombosis Research Laboratories at Loyola University Medical Center Hospital Estadual Dr Jayme Santos Neves Hospital Cárdio Pulmonar Escola Bahiana de Medicina Universidade Federal da Bahia Hospital Vera Cruz Hospital Da Bahia Hospital Naval Marcílio Dias Hospital Santa Paula Santa Casa de Misericórdia de Votuporanga Hospital das Clínicas da Faculdade de Medicina de Botucatu Brazilian Research in Intensive Care Network BP—A Beneficência Portuguesa de São Paulo Hospital Universitário da Universidade Estadual de Londrina Hospital Felício Rocho Santa Casa de Misericórdia da Bahia–Hospital Santa Izabel Centro Universitário Faculdade de Tecnologia e Ciências Hospital Moinhos de Vento Instituto Dante Pazzanese de Cardiologia Hospital de Amor de Barretos (Pio XII) Hospital de Base de São José do Rio Preto Anesthesiology Pain and Intensive Care Department Federal University of São Paulo Instituto Socrates Guanaes Hospital Sírio Libanês Research and Education Institute International Research Center Hospital Alemão Oswaldo Cruz Hospital das Clínicas da Faculdade de Medicina de Botucatu

Background: Specific algorithms for use of optical coherence tomography (OCT) to guide percutaneous coronary intervention (PCI) are scarce. Also, the relative benefits of intravascular imaging guidance have not been tested against an optimized angiography-guided PCI strategy. In iSIGHT (Optical Coherence Tomography Versus Intravascular Ultrasound and Angiography to Guide Percutaneous Coronary Interventions), we aimed to investigate whether OCT-guided PCI achieves noninferior stent expansion compared with intravascular ultrasound (IVUS) guidance and if both imaging modalities lead to superior stent expansion compared with an optimized angiography-based strategy. Methods: Patients ≥18 years old undergoing PCI for ≥1 lesion in native coronaries of 2.25 to 4.00 mm in diameter were randomized 1:1:1 to OCT-, IVUS-, or angiography-guided PCI. Predetermined guidance protocols were applied in all groups. An external elastic membrane–based protocol was used for stent sizing by OCT and IVUS. The primary end point was noninferiority of stent expansion (minimum stent area ≥90% of the average reference lumen area), measured by post-PCI OCT, in OCT-guided versus IVUS-guided PCI (noninferiority margin, 6.5%). Results: One hundred fifty-one patients (156 lesions) were randomly allocated to OCT (51 lesions [32.7%]), IVUS (52 lesions [33.3%]), or angiography (53 lesions [34.0%]). Stent expansion with OCT guidance (98.01±16.14%) was noninferior to IVUS (91.69±15.75%; 1-sided lower 95% CI, 0.55 mm 2 ; P non-inferiority P =0.041). IVUS and angiography obtained similar stent expansions ( P =0.921). Stent edge dissection and periprocedural complication rates were not significantly different among the groups. Conclusions: Stent expansion with OCT guidance using a dedicated external elastic membrane–based sizing strategy was noninferior to that achieved with IVUS and superior to an optimized angiographic strategy. Registration: URL: plataformabrasil.saude.gov.br ; Unique identifier: 69968417.8.0000.5462.

Introduction Ventricular arrhythmias (VAs) are a major cause of morbidity and mortality in patients with heart disease. Recent studies evaluated the effect of renal denervation (RDN) on the occurrence of VAs. We conducted a systematic review and meta-analysis to determine the efficacy and safety of this procedure. Methods and results A systematic search of the literature was performed to identify studies that evaluated the use of RDN for the management of VAs. Primary outcomes were reduction in the number of VAs and implantable cardioverter-defibrillator (ICD) therapies. Secondary outcomes were changes in blood pressure and renal function. Ten studies (152 patients) were included in the meta-analysis. RDN was associated with a reduction in the number of VAs, ATP (antitachycardia pacing), ICD shocks and overall ICD therapies of 3.53events/patient/month (95%CI=-5.48 to -1.57), 2.86events/patient/month (95%CI=-4.09 to -1.63), 2.04events/patient/month (95%CI=-2.12 to -1.97), and 2.68events/patient/month (95%CI=-3.58 to -1.78), respectively. Periprocedural adverse events occurred in 1.23% of patients and no significant changes were seen in blood pressure or renal function. Conclusions In patients with refractory VAs, RDN was associated with a reduction in the number of VAs and ICD therapies, and was shown to be a safe procedure. KEYWORDS: Renal denervation, ventricular arrhythmias, implantable cardioverter-defibrillator, antitachycardia pacing, ICD shocks.

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 .

Introduction: Moving toward evidence-based care protocols is key to reduce the burden of cardiovascular diseases. Hypothesis: We assessed the hypothesis that a multifaceted intervention could improve the adherence to evidence-based therapies for coronary artery disease patients. Methods: The BRIDGE Cardiovascular Prevention study was a cluster randomized trial including 1,619 patients with ischemic stroke, coronary artery disease or peripheral artery disease from 40 outpatient clinics in Brazil. Clusters were randomized to receive a multifaceted quality improvement intervention or to routine practice. The intervention included reminders, care algorithms, training of a case manager, audit and feedback reports, and distribution of educational materials to health care providers. The primary endpoint was the adherence to combined use of statins, antiplatelets and ACEi or ARBs, using an “all or none” approach at 12 months in patients without contra-indications. Results: Among the 1619 patients enrolled in the original sample, 1327 (81.9%) were coronary artery disease patients. The mean age was 65.7 (SD=10.4) and 880 (66.3 %) were men. There was a significant difference in the combined prescription of evidence-based therapies between the intervention and the control groups (75.4% versus 61.8 % respectively, Odds Ratio, 2.33 [95% CI, 1.29 - 4.21], p Conclusions: Among coronary artery disease patients treated in Brazil, a quality improvement intervention resulted in improved prescription of evidence-based therapies for cardiovascular prevention.

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

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

Submitted by DSpace Unilasalle (dspace@unilasalle.edu.br) on 2021-07-30T17:29:03Z No. of bitstreams: 1 Hydroxychloroquine with or without Azithromycin_NEJM.pdf: 657905 bytes, checksum: abd774ed0fca84d1bf82fc915cc48491 (MD5) Made available in DSpace on 2021-07-30T17:29:03Z (GMT). No. of bitstreams: 1 Hydroxychloroquine with or without Azithromycin_NEJM.pdf: 657905 bytes, checksum: abd774ed0fca84d1bf82fc915cc48491 (MD5) Previous issue date: 2020 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.)

RESUMO Objetivo: A infecção causada pelo coronavírus da síndrome respiratória aguda grave 2 (SARS-CoV-2) disseminou-se por todo o mundo e foi categorizada como pandemia. As manifestações mais comuns da infecção pelo SARS-CoV-2 (doença pelo coronavírus 2019 - COVID-19) se referem a uma pneumonia viral com graus variáveis de comprometimento respiratório e até 40% dos pacientes hospitalizados, que podem desenvolver uma síndrome do desconforto respiratório agudo. Diferentes ensaios clínicos avaliaram o papel dos corticosteroides na síndrome do desconforto respiratório agudo não relacionada com COVID-19, obtendo resultados conflitantes. Delineamos o presente estudo para avaliar a eficácia da administração endovenosa precoce de dexametasona no número de dias vivo e sem ventilação mecânica nos 28 dias após a randomização, em pacientes adultos com quadro moderado ou grave de síndrome do desconforto respiratório agudo causada por COVID-19 provável ou confirmada. Métodos: Este é um ensaio pragmático, prospectivo, randomizado, estratificado, multicêntrico, aberto e controlado que incluirá 350 pacientes com quadro inicial (menos de 48 horas antes da randomização) de síndrome do desconforto respiratório agudo moderada ou grave, definida segundo os critérios de Berlim, causada por COVID-19. Os pacientes elegíveis serão alocados de forma aleatória para tratamento padrão mais dexametasona (Grupo Intervenção) ou tratamento padrão sem dexametasona (Grupo Controle). Os pacientes no Grupo Intervenção receberão dexametasona 20mg por via endovenosa uma vez ao dia, por 5 dias, e, a seguir, dexametasona por via endovenosa 10mg ao dia por mais 5 dias, ou até receber alta da unidade de terapia intensiva, o que ocorrer antes. O desfecho primário será o número de dias livres de ventilação mecânica nos 28 dias após a randomização, definido como o número de dias vivo e livres de ventilação mecânica invasiva. Os desfechos secundários serão a taxa de mortalidade por todas as causas no dia 28, a condição clínica no dia 15 avaliada com utilização de uma escala ordinal de seis níveis, a duração da ventilação mecânica desde a randomização até o dia 28, a avaliação com o Sequential Organ Failure Assessment Score após 48 horas, 72 horas e 7 dias, e o número de dias fora da unidade de terapia intensiva nos 28 dias após a randomização. Abstract Objective: The infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads worldwide and is considered a pandemic. The most common manifestation of SARS-CoV-2 infection (coronavirus disease 2019 - COVID-19) is viral pneumonia with varying degrees of respiratory compromise and up to 40% of hospitalized patients might develop acute respiratory distress syndrome. Several clinical trials evaluated the role of corticosteroids in non-COVID-19 acute respiratory distress syndrome with conflicting results. We designed a trial to evaluate the effectiveness of early intravenous dexamethasone administration on the number of days alive and free of mechanical ventilation within 28 days after randomization in adult patients with moderate or severe acute respiratory distress syndrome due to confirmed or probable COVID-19. Methods: This is a pragmatic, prospective, randomized, stratified, multicenter, open-label, controlled trial including 350 patients with early-onset (less than 48 hours before randomization) moderate or severe acute respiratory distress syndrome, defined by the Berlin criteria, due to COVID-19. Eligible patients will be randomly allocated to either standard treatment plus dexamethasone (Intervention Group) or standard treatment without dexamethasone (Control Group). Patients in the intervention group will receive dexamethasone 20mg intravenous once daily for 5 days, followed by dexamethasone 10mg IV once daily for additional 5 days or until intensive care unit discharge, whichever occurs first. The primary outcome is ventilator-free days within 28 days after randomization, defined as days alive and free from invasive mechanical ventilation. Secondary outcomes are all-cause mortality rates at day 28, evaluation of the clinical status at day 15 assessed with a 6-level ordinal scale, mechanical ventilation duration from randomization to day 28, Sequential Organ Failure Assessment Score evaluation at 48 hours, 72 hours and 7 days and intensive care unit -free days within 28.

Introduction Hydroxychloroquine and its combination with azithromycin have been suggested to improve viral clearance in patients with COVID-19, but its effect on clinical outcomes remains uncertain. Methods and analysis We describe the rationale and design of an open-label pragmatic multicentre randomised (concealed) clinical trial of 7 days of hydroxychloroquine (400 mg BID) plus azithromycin (500 mg once daily), hydroxychloroquine 400 mg BID, or standard of care for moderately severe hospitalised patients with suspected or confirmed COVID-19 (in-patients with up to 4L/minute oxygen supply through nasal catheter). Patients are randomised in around 50 recruiting sites and we plan to enrol 630 patients with COVID-19. The primary endpoint is a 7-level ordinal scale measured at 15-days: 1)not hospitalised, without limitations on activities; 2)not hospitalised, with limitations on activities; 3)hospitalised, not using supplementary oxygen; 4)hospitalised, using supplementary oxygen; 5)hospitalised, using high-flow nasal cannula or non-invasive ventilation; 6)hospitalised, on mechanical ventilation; 7)death. Secondary endpoints are the ordinal scale at 7 days, need for mechanical ventilation and rescue therapies during 15 days, need of high-flow nasal cannula or non-invasive ventilation during 15 days, length of hospital stay, in-hospital mortality, thromboembolic events, occurrence of acute kidney injury, and number of days free of respiratory support at 15 days. Secondary safety outcomes include prolongation of QT interval on electrocardiogram, ventricular arrhythmias, and liver toxicity. The main analysis will consider all patients with confirmed COVID-19 in the groups they were randomly assigned. Ethics and dissemination This study has been approved by Brazil’s National Ethic Committee (CONEP) and National Health Surveillance Agency (ANVISA). An independent data monitoring committee will perform interim analyses and evaluate adverse events throughout the trial. Results will be submitted for publication after enrolment and follow-up are complete, as well as presented and reported to local health agencies. ClinicalTrials.gov identifier NCT04322123 Strengths and limitations of this study Pragmatic randomised controlled trial of 7 days of hydroxychloroquine plus azithromycin, hydroxychloroquine or standard of care for moderately severe in-patients with suspected or confirmed COVID-19 Multicentre: around 50 recruiting sites in Brazil with planned enrolment of 630 patients (1:1:1) The primary endpoint is a 7-level ordinal scale ([1] not hospitalised, without limitations on activities; [2] not hospitalised, with limitations on activities; [3] hospitalised, not using supplementary oxygen; [4] hospitalised, using supplementary oxygen; [5] hospitalised, using high-flow nasal cannula or non-invasive ventilation; [6] hospitalised, on mechanical ventilation; [7] death) measured at 15 days. Open label design (no placebo)

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.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).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/mRYGB is an attractive strategy for mid-term OSA remission or decrease moderate-to-severe forms of OSA in patients with obesity grade 1-2.

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.

Background The safety and efficacy of ticagrelor in patients with ST-elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remain uncertain. Objectives The primary objective of the TicagRElor in pAtients with ST elevation myocardial infarction treated with Thrombolysis (TREAT) trial is to evaluate the short-term safety of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy. Key secondary objectives are to assess the safety and efficacy of ticagrelor compared with clopidogrel at 12-months. Design The TREAT trial is a multicenter, randomized, phase III, Prospective randomized open blinded end-point (PROBE) study that enrolled 3,799 patients in 152 sites from 10 countries. Following administration of fibrinolytic therapy patients were randomized to a loading dose of ticagrelor 180 mg or clopidogrel 300 mg followed by a maintenance dose of ticagrelor 90 mg twice daily or clopidogrel 75 mg/day for 12-months. The primary outcome is the rate of TIMI major bleeding at 30-days and will be assessed for non-inferiority using an intention-to-treat analysis. Co-treatments include aspirin and anticoagulants. Other evidence based therapies are also recommended. Secondary efficacy outcome include a composite of death from vascular causes, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack or other arterial thrombotic event. All-cause mortality as well as individual components of the combined efficacy endpoint will also be ascertained. Summary TREAT is an international randomized controlled trial comparing ticagrelor with clopidogrel in STEMI patients treated with fibrinolytic therapy. The results of this trial will inform clinical practice and international guidelines.

Background Previous evidence suggests that acute treatment with statins reduce atherosclerotic complications, including periprocedural myocardial infarction, but currently, there are no large, adequately powered studies to define the effects of early, high-dose statins in patients with acute coronary syndrome (ACS) and planned invasive management. Objectives The main goal of Statins Evaluation in Coronary procedUres and REvascularization (SECURE-PCI) Trial is to determine whether the early use of a loading dose of 80 mg of atorvastatin before an intended percutaneous coronary intervention followed by an additional dose of 80 mg 24 hours after the procedure will be able to reduce the rates of major cardiovascular events at 30 days in patients with an ACS. Design The SECURE-PCI study is a pragmatic, multicenter, double-blind, placebo-controlled randomized trial planned to enroll around 4,200 patients in 58 different sites in Brazil. The primary outcome is the rate of major cardiovascular events at 30 days defined as a composite of all-cause mortality, nonfatal acute myocardial infarction, nonfatal stroke, and coronary revascularization. Summary The SECURE PCI is a large randomized trial testing a strategy of early, high-dose statin in patients with ACS and will provide important information about the acute treatment of this patient population.

Background: Recent research efforts on bariatric surgery have focused on metabolic and diabetes mellitus resolution. Randomized trials designed to assess the impact of bariatric surgery in patients with obesity and hypertension are needed. Methods: In this randomized, single-center, nonblinded trial, we included patients with hypertension (using ≥2 medications at maximum doses or >2 at moderate doses) and a body mass index between 30.0 and 39.9 kg/m 2 . Patients were randomized to Roux-en-Y gastric bypass plus medical therapy or medical therapy alone. The primary end point was reduction of ≥30% of the total number of antihypertensive medications while maintaining systolic and diastolic blood pressure Results: We included 100 patients (76% female, mean age 43.8±9.2 years, mean body mass index 36.9±2.7 kg/m2), and 96% completed follow-up. Reduction of ≥30% of the total number of antihypertensive medications while maintaining controlled blood pressure occurred in 41 of 49 patients from the gastric bypass group (83.7%) compared with 6 of 47 patients (12.8%) from the control group with a rate ratio of 6.6 (95% confidence interval, 3.1–14.0; P P =0.005). Eleven patients (22.4%) from the gastric bypass group and none in the control group were able to achieve SPRINT levels without antihypertensives. Waist circumference, body mass index, fasting plasma glucose, glycohemoglobin, low-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein, and 10-year Framingham risk score were lower in the gastric bypass than in the control group. Conclusions: Bariatric surgery represents an effective strategy for blood pressure control in a broad population of patients with obesity and hypertension. Clinical Trial Registration: URL: https://clinicaltrials.gov . Unique identifier: NCT01784848.

BACKGROUND Human morbid obesity is increasing worldwide in an alarming way. The hypothalamus is known to mediate its mechanisms. Deep brain stimulation (DBS) of the ventromedial hypothalamus (VMH) may be an alternative to treat patients refractory to standard medical and surgical therapies. OBJECTIVE To assess the safety, identify possible side effects, and to optimize stimulation parameters of continuous VMH-DBS. Additionally, this study aims to determine if continuous VMH-DBS will lead to weight loss by causing changes in body composition, basal metabolism, or food intake control. METHODS The BLESS study is a feasibility study, single-center open-label trial. Six patients (body mass index > 40) will undergo low-frequency VMH-DBS. Data concerning timing, duration, frequency, severity, causal relationships, and associated electrical stimulation patterns regarding side effects or weight changes will be recorded. EXPECTED OUTCOMES We expect to demonstrate the safety, identify possible side effects, and to optimize electrophysiological parameters related to VMH-DBS. No clinical or behavioral adverse changes are expected. Weight loss ≥ 3% of the basal weight after 3 mo of electrical stimulation will be considered adequate. Changes in body composition and increase in basal metabolism are expected. The amount of food intake is likely to remain unchanged. DISCUSSION The design of this study protocol is to define the safety of the procedure, the surgical parameters important for target localization, and additionally the safety of long-term stimulation of the VMH in morbidly obese patients. Novel neurosurgical approaches to treat metabolic and autonomic diseases can be developed based on the data made available by this investigation.

ANDROMEDA-SHOCK is an international, multicenter, randomized controlled trial comparing peripheral perfusion-targeted resuscitation to lactate-targeted resuscitation in patients with septic shock in order to test the hypothesis that resuscitation targeting peripheral perfusion will be associated with lower morbidity and mortality.To report the statistical analysis plan for the ANDROMEDA-SHOCK trial.We describe the trial design, primary and secondary objectives, patients, methods of randomization, interventions, outcomes, and sample size. We describe our planned statistical analysis for the primary, secondary and tertiary outcomes. We also describe the subgroup and sensitivity analyses. Finally, we provide details for presenting our results, including mock tables showing baseline characteristics, the evolution of hemodynamic and perfusion variables, and the effects of treatments on outcomes.According to the best trial practice, we report our statistical analysis plan and data management plan prior to locking the database and initiating the analyses. We anticipate that this procedure will prevent analysis bias and enhance the utility of the reported results.O estudo ANDROMEDA-SHOCK é um estudo internacional, multicêntrico, randomizado e controlado comparando ressuscitação guiada pela perfusão periférica com ressuscitação guiada pelo lactato em pacientes com choque séptico, com a finalidade de testar a hipótese de que a ressuscitação guiada pela perfusão periférica associa-se a menor morbidade e mortalidade.Relatar o plano de análise estatística para o estudo ANDROMEDA-SHOCK.Descrevemos o delineamento do estudo, os objetivos primário e secundários, pacientes, métodos de randomização, intervenções, desfechos e tamanho da amostra. Descrevemos nossos planos de análise estatística para os desfechos primários, secundários e terciários. Também descrevemos as análises de subgrupos e sensibilidade. Finalmente, fornecemos detalhes para a apresentação dos resultados, inclusive modelos de tabelas para apresentar as características basais, a evolução das variáveis de hemodinâmica e perfusão, e os efeitos dos tratamentos nos desfechos.Segundo as melhores práticas de pesquisa, relatamos nosso plano de análise estatística e plano de gestão de dados antes do fechamento da base de dados e do início da análise dos dados. Nossa expectativa é que este procedimento previna a ocorrência de vieses na análise e incremente a utilidade dos resultados relatados.

Sao Paulo Research Foundation, Sao Paulo, Brazil [FAPESP 2012/51692-7] AstraZeneca [ESR 14-10726] Background: Early reperfusion of the occluded coronary artery during acute myocardial infarction is considered crucial for reduction of infarcted mass and recovery of ventricular function. Effective microcirculation and the balance between protective and harmful lymphocytes may have roles in reperfusion injury and may affect final ventricular remodeling. Methods/design: BATTLE-AMI is an open-label, randomized trial comparing the effects of four therapeutic strategies (rosuvastatin/ticagrelor, rosuvastatin/clopidogrel, simvastatin plus ezetimibe/ticagrelor, or simvastatin plus ezetimibe/clopidogrel) on infarcted mass and left ventricular ejection fraction (LVEF) (blinded endpoints) in patients with ST-segment elevation myocardial infarction submitted to fibrinolytic therapy before coronary angiogram (pharmacoinvasive strategy). All patients (n = 300, 75 per arm) will be followed up for six months. The effects of treatment on subsets of B and T lymphocytes will be determined by flow-cytometry/ELISPOT and will be correlated with the infarcted mass, LVEF, and microcirculation perfusion obtained by cardiac magnetic resonance imaging. The primary hypothesis is that the combined rosuvastatin/ticagrelor therapy will be superior to other therapies (particularly for the comparison with simvastatin plus ezetimibe/clopidogrel) for the achievement of better LVEF at 30 days (primary endpoint) and smaller infarcted mass (secondary endpoint) at 30 days and six months. The trial will also evaluate the improvement in the immune/inflammatory responses mediated by B and T lymphocytes. Omics field (metabolomics and proteomics) will help to understand these responses by molecular events. Discussion: BATTLE-AMI is aimed to (1) evaluate the role of subsets of lymphocytes on microcirculation improvement and (2) show how the choice of statin/antiplatelet therapy may affect cardiac remodeling after acute myocardial infarction with ST elevation. Univ Fed Sao Paulo, Rua Loefgren 1350, BR-04040001 Sao Paulo, SP, Brazil Hosp Coracao, Rua Desembargador Eliseu Guilherme,147, Sao Paulo, Brazil Inst Dante Pazzanese Cardiol, Ave Dante Pazzanese 500, Sao Paulo, Brazil Univ Santo Amaro, Rua Prof Eneas de Siqueira 340, Sao Paulo, Brazil Univ Sao Paulo, Ave Prof Lineu Prestes,748, Sao Paulo, Brazil Univ Fed Sao Paulo, Rua Loefgren 1350, BR-04040001 Sao Paulo, SP, Brazil FAPESP 2012/51692-7 Web of Science

Feline injection site sarcoma is a malignant neoplasm with digitiform projections into muscular planes that are ill recognized during physical examination and may compromise tumor margin demarcation. This study compared tumoral size of 32 cats measured by different methods, and evaluated the CT density of 10 tumoral tissues (Hounsfield unit) based on histograms. Tumor axes were measured by physical examination and CT images. Larger craniocaudal axis measurements were obtained following multiplanar reconstruction of pre- and post-contrast CT images (p=0.049 and p=0.041 respectively); dorsoventral axis measurements taken from post-contrast CT images were also larger (p=0.010). Tumor volume estimates increased following contrast-enhancement. Histograms tended to produce two peaks: one in the fat and another in the soft tissue attenuation range. Multiplanar reconstructed post-contrast CT images provided clearer definition of tumor margins and more judicious determination of tumor size. A tendency of common FISS attenuation profile could be described. RESUMO: O sarcoma de aplicação felino (SAF) é uma neoplasia maligna que geralmente apresenta projeções digitiformes para planos musculares adjacentes, dificilmente reconhecidos ao exame físico, o que pode comprometer a real identificação das suas margens. Este estudo comparou as dimensões tumorais de 32 SAFs mensurados por diferentes métodos (exame físico e por imagens de tomografia computadorizada) e avaliou a densidade tomográfica em unidades Hounsfield de 10 dessas neoplasias, com base em histogramas. As medidas no eixo craniocaudal foram maiores quando obtidas após reconstrução multiplanar de imagens tomográficas, tanto na fases pré como após administração de meio de contraste (p=0,049 e p=0,041, respectivamente). As medições tomográficas no eixo dorsoventral obtidas na fase pós-contraste também foram maiores, quando comparadas com as imagens pré-contraste (p=0,010). Estimativas do volume tumoral foram maiores após a fase contrastada. Os histogramas das densidades tumorais tenderam a produzir dois picos: o primeiro no intervalo de valores de densidade gordura e o segundo no intervalo correspondente a tecidos moles. As imagens tomográficas pós-contraste com reconstrução multiplanar demarcaram com mais clareza as margens do tumor e definiram de forma mais criteriosa o seu tamanho. Uma tendência de perfil de atenuação comum para o SAF pôde ser descrita com esse estudo.

Rationale: Evidence from observational studies suggests that driving pressure is strongly associated with pulmonary injury and mortality, regardless of positive end-expiratory pressure (PEEP) level...

Rationale: 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 la...

BackgroundHighly active antiretroviral therapy (HAART) has reduced HIV-related morbidity and mortality at all stages of infection and reduced transmission of HIV. Currently, the immediate start of HAART is recommended for all HIV patients, regardless of the CD4 count. There are several concerns, however, about starting treatment in critically ill patients. Unpredictable absorption of medication by the gastrointestinal tract, drug toxicity, drug interactions, limited reserve to tolerate the dysfunction of other organs resulting from hypersensitivity to drugs or immune reconstitution syndrome, and the possibility that subtherapeutic levels of drug may lead to viral resistance are the main concerns. The objective of our study was to compare the early onset (up to 5 days) with late onset (after discharge from the ICU) of HAART in HIV-infected patients admitted to the ICU.MethodsThis was a randomized, open-label clinical trial enrolling HIV-infected patients admitted to the ICU of a public hospital in southern Brazil. Patients randomized to the intervention group had to start treatment with HAART within 5 days of ICU admission. For patients in the control group, treatment should begin after discharge from the ICU. The patients were followed up to determine mortality in the ICU, in the hospital and at 6 months. The primary outcome was hospital mortality. The secondary outcome was mortality at 6 months.ResultsThe calculated sample size was 344 patients. Unfortunately, we decided to discontinue the study due to a progressively slower recruitment rate. A total of 115 patients were randomized. The majority of admissions were for AIDS-defining illnesses and low CD4. The main cause of admission was respiratory failure. Regarding the early and late study groups, there was no difference in hospital (66.7% and 63.8%, p = 0.75) or 6-month (68.4% and 79.2%, p = 0.20) mortality. After multivariate analysis, the only independent predictors of in-hospital mortality were shock and dialysis during the ICU stay. For the mortality outcome at 6 months, the independent variables were shock and dialysis during the ICU stay and tuberculosis at ICU admission.ConclusionsAlthough the early termination of the study precludes definitive conclusions being made, early HAART administration for HIV-infected patients admitted to the ICU compared to late administration did not show benefit in hospital mortality or 6-month mortality. ClinicalTrials.gov, NCT01455688. Registered 20 October 2011, https://clinicaltrials.gov/show/NCT01455688.

To report the statistical analysis plan (first version) for the Balanced Solutions versus Saline in Intensive Care Study (BaSICS).BaSICS is a multicenter factorial randomized controlled trial that will assess the effects of Plasma-Lyte 148 versus 0.9% saline as the fluid of choice in critically ill patients, as well as the effects of a slow (333mL/h) versus rapid (999mL/h) infusion speed during fluid challenges, on important patient outcomes. The fluid type will be blinded for investigators, patients and the analyses. No blinding will be possible for the infusion speed for the investigators, but all analyses will be kept blinded during the analysis procedure.BaSICS will have 90-day mortality as its primary endpoint, which will be tested using mixed-effects Cox proportional hazard models, considering sites as a random variable (frailty models) adjusted for age, organ dysfunction and admission type. Important secondary endpoints include renal replacement therapy up to 90 days, acute renal failure, organ dysfunction at days 3 and 7, and mechanical ventilation-free days within 28 days.This manuscript provides details on the first version of the statistical analysis plan for the BaSICS trial and will guide the study's analysis when follow-up is finished.Relatar o plano de análise estatística (primeira versão) para o estudo Balanced Solutions versus Saline in Intensive Care Study (BaSICS).O estudo BaSICS é um ensaio multicêntrico fatorial e randomizado que avaliará os efeitos da administração dos fluidos Plasma-Lyte 148 em comparação com solução salina 0,9% como fluido de escolha em pacientes críticos, assim como os efeitos de uma velocidade de infusão lenta (333mL/hora) em comparação com uma velocidade de infusão rápida (999mL/hora) durante desafios com volume, em importantes desfechos do paciente. O tipo de fluido será mantido cego para os investigadores, pacientes e nas análises. Não será possível, entretanto, ocultar dos investigadores a velocidade de infusão, mas os procedimentos de análise serão mantidos cegos quanto a esse aspecto.O estudo BaSICS terá como parâmetro primário a mortalidade em 90 dias, que será testada com utilização de modelos de risco proporcional de Cox de efeitos mistos, considerando os centros de estudo como variável randômica (modelos de fragilidade) ajustada por idade, disfunção de órgãos e tipo de admissão. Os parâmetros secundários importantes incluem terapia de substituição renal até 90 dias, insuficiência renal aguda, disfunção de órgãos nos dias 3 e 7 e dias sem ventilação mecânica em 28 dias.Este artigo fornece detalhes referentes à primeira versão do plano de análise estatística para o estudo BaSICS e orientará a análise do estudo após a conclusão do seguimento.

RESUMO Introdução: Os marcadores pró-inflamatórios desempenham papel importante na severidade de pacientes com COVID-19. Assim, terapêuticas anti-inflamatórias são agentes interessantes para potencialmente combater a cascata inflamatória descontrolada em tais pacientes. Delineamos um ensaio para testar tocilizumabe em comparação com o tratamento padrão, tendo como objetivo melhorar os desfechos por meio da inibição da interleucina 6, um importante mediador inflamatório na COVID-19. Métodos e análises: Este será um estudo aberto multicêntrico, randomizado e controlado, que comparará os desfechos de pacientes tratados com tocilizumabe mais tratamento padrão com o tratamento padrão isoladamente em pacientes com COVID-19 moderada a grave. Como critérios de inclusão, serão exigidos dois dos quatro critérios a seguir: dosagens de dímero D acima de 1.000ng/mL, proteína C-reativa acima de 5mg/dL, ferritina acima de 300mg/dL e desidrogenase lática acima do limite superior do normal. O objetivo primário será comparar a condição clínica no dia 15, conforme avaliação por meio de escala ordinal de 7 pontos aplicada nos estudos de COVID-19 em todo o mundo. O desfecho primário será avaliado por regressão logística ordinal assumindo razões de propensão proporcionais ajustadas pelas variáveis de estratificação (idade e sexo). Ética e disseminação: O TOCIBRAS foi aprovado pelos comitês de ética locais e central (nacional) do Brasil em conformidade com as atuais diretrizes e orientações nacionais e internacionais. Cada centro participante obteve aprovação do estudo por parte de seu comitê de ética em pesquisa, antes de iniciar as inscrições no protocolo. Os dados derivados deste ensaio serão publicados independentemente de seus resultados. Se tiver sua efetividade comprovada, esta estratégia terapêutica poderá aliviar as consequências da resposta inflamatória na COVID-19 e melhorar os resultados clínicos. ABSTRACT Introduction: Pro-inflammatory markers play a significant role in the disease severity of patients with COVID-19. Thus, anti-inflammatory therapies are attractive agents for potentially combating the uncontrolled inflammatory cascade in these patients. We designed a trial testing tocilizumab versus standard of care intending to improve the outcomes by inhibiting interleukin-6, an important inflammatory mediator in COVID-19. Methods and analysis: This open-label multicentre randomized controlled trial will compare clinical outcomes of tocilizumab plus standard of care versus standard of care alone in patients with moderate to severe COVID-19. Two of the following four criteria are required for protocol enrolment: D-dimer > 1,000ng/mL; C reactive protein > 5mg/dL, ferritin > 300mg/dL, and lactate dehydrogenase > upper limit of normal. The primary objective will be to compare the clinical status on day 15, as measured by a 7-point ordinal scale applied in COVID-19 trials worldwide. The primary endpoint will be assessed by an ordinal logistic regression assuming proportional odds ratios adjusted for stratification variables (age and sex). Ethics and dissemination: The TOCIBRAS protocol was approved by local and central (national) ethical committees in Brazil following current national and international guidelines/directives. Each participating center had the study protocol approved by their institutional review boards before initiating protocol enrolment. The data derived from this trial will be published regardless of the results. If proven active, this strategy could alleviate the consequences of the inflammatory response in COVID-19 patients and improve their clinical outcomes.

Importance Translating evidence into clinical practice in the management of acute ischemic stroke (AIS) and transient ischemic attack (TIA) is challenging, especially in low- and middle-income countries. Objective To assess the effect of a multifaceted quality improvement intervention on adherence to evidence-based therapies for care of patients with AIS and TIA. Design, Setting and Participants This 2-arm cluster-randomized clinical trial assessed 45 hospitals and 2336 patients with AIS and TIA for eligibility before randomization. Eligible hospitals were able to provide care for patients with AIS and TIA in Brazil, Argentina, and Peru. Recruitment started September 12, 2016, and ended February 26, 2018; follow-up ended June 29, 2018. Data were analyzed using the intention-to-treat principle. Interventions The multifaceted quality improvement intervention included case management, reminders, a roadmap and checklist for the therapeutic plan, educational materials, and periodic audit and feedback reports to each intervention cluster. Main Outcomes and Measures The primary outcome was a composite adherence score for AIS and TIA performance measures. Secondary outcomes included an all-or-none composite end point of performance measures, the individual process measure components of the composite end points, and clinical outcomes at 90 days after admission (stroke recurrence, death, and disability measured by the modified Rankin scale). Results A total of 36 hospitals and 1624 patients underwent randomization. Nineteen hospitals were randomized to the quality improvement intervention and 17 to routine care. The overall mean (SD) age of patients enrolled in the study was 69.4 (13.5) years, and 913 (56.2%) were men. Overall mean (SD) composite adherence score for the 10 performance measures in the intervention group hospitals compared with control group hospitals was 85.3% (20.1%) vs 77.8% (18.4%) (mean difference, 4.2%; 95% CI, −3.8% to 12.2%). As a secondary end point, 402 of 817 patients (49.2%) at intervention hospitals received all the therapies that they were eligible for vs 203 of 807 (25.2%) in the control hospitals (odds ratio, 2.59; 95% CI, 1.22-5.53;P = .01). Conclusions and Relevance A multifaceted quality improvement intervention did not result in a significant increase in composite adherence score for evidence-based therapies in patients with AIS or TIA. However, when using an all-or-none approach, the intervention resulted in improved adherence to evidence-based therapies. Trial Registration ClinicalTrials.gov identifier:NCT02223273

Background Preliminary evidence suggests that statins may prevent major perioperative vascular complications. Methods We randomized 648 statin-naive patients who were scheduled for noncardiac surgery and were at risk for a major vascular complication. Patients were randomized to a loading dose of atorvastatin or placebo (80 mg anytime within 18hours before surgery), followed by a maintenance dose of 40 mg (or placebo), started at least 12hours after the surgery, and then 40 mg/d (or placebo) for 7days. The primary outcome was a composite of all-cause mortality, nonfatal myocardial injury after noncardiac surgery, and stroke at 30days. Results The primary outcome was observed in 54 (16.6%) of 326 patients in the atorvastatin group and 59 (18.7%) of 316 patients in the placebo group (hazard ratio [HR] 0.87, 95% CI 0.60-1.26, P =.46). No significant effect was observed on the 30-day secondary outcomes of all-cause mortality (4.3% vs 4.1%, respectively; HR 1.14, 95% CI 0.53-2.47, P =.74), nonfatal myocardial infarction (3.4% vs 4.4%, respectively; HR 0.76, 95% CI 0.35-1.68, P =.50), myocardial injury after noncardiac surgery (13.2% vs 16.5%; HR 0.79, 95% CI 0.53-1.19, P =.26), and stroke (0.9% vs 0%, P =.25). Conclusion In contrast to the prior observational and trial data, the LOAD trial has neutral results and did not demonstrate a reduction in major cardiovascular complications after a short-term perioperative course of statin in statin-naive patients undergoing noncardiac surgery. We demonstrated, however, that a large multicenter blinded perioperative statin trial for high-risk statin-naive patients is feasible and should be done to definitely establish the efficacy and safety of statin in this patient population.

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 or2 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

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.

Background Translating evidence into clinical practice in the management of acute ischemic stroke (AIS) and transient ischemic attack (TIA) is challenging especially in low- and middle-income countries. Objectives The aim of this study is to assess the effect of a multifaceted quality improvement intervention on adherence to evidence-based therapies for AIS and TIA patients care. Design We designed a pragmatic, 2-arm cluster-randomized trial involving 36 clusters and 1624 patients from Brazil, Argentina, and Peru. Hospitals are randomized to receive a multifaceted quality improvement intervention (intervention group) or to routine care (control group). The BRIDGE Stroke multifaceted quality improvement intervention includes case management, reminders, health care providers’ educational materials (including treatment algorithms), interactive workshops, and audit and feedback reports. Primary outcome is a composite adherence score to AIS and TIA performance measures. Secondary outcomes include an “all or none” composite end point to performance measures, the individual components of the composite end points, and clinical outcomes at 90 days following admission (stroke recurrence, death, and disability measured by the modified Rankin scale). Summary The BRIDGE Stroke Trial is an international pragmatic evaluation of a multifaceted quality improvement intervention. If effective, this intervention could be potentially extended widely to improve the quality of care and outcomes of patients with AIS or TIA.