Antivirals for adult patients hospitalised with SARS-CoV-2 infection: a randomised, phase II/III, multicentre, placebo-controlled, adaptive study, with multiple arms and stages. COALITION COVID-19 BRAZIL IX - REVOLUTIOn trial.

Background: Repurposed drugs for treatment of new onset disease may be an effective therapeutic shortcut. We aimed to evaluate the efficacy of repurposed antivirals compared to placebo in lowering SARS-CoV2 viral load of COVID-19 patients. Methods: REVOLUTIOn is a randomised, parallel, blinded, multistage, superiority and placebo controlled randomised trial conducted in 35 centres in Brazil. We include patients aged 18 years or older admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, symptoms onset 9 days or less and SpO2 94% or lower at room air were eligible. All participants were randomly allocated to receive either atazanavir, daclatasvir or sofosbuvir/daclatasvir or placebo for 10 days. The primary outcome was the decay rate (slope) of the SARS-CoV-2 viral load logarithm assessed in the modified intention to-treat population. This trial was registered with ClinicalTrials.gov, number NCT04468087. Findings: Between February 09, 2021, and August 04, 2021, 255 participants were enrolled and randomly assigned to atazanavir (n = 64), daclatasvir (n = 66), sofosbuvir/daclatasvir (n = 67) or placebo (n = 58). Compared to placebo group, the change from baseline to day 10 in log viral load was not significantly different for any of the treatment groups (0.05 [95% CI, -0.03 to 0.12], -0.02 [95% CI, -0.09 to 0.06], and -0.03 [95% CI, -0.11 to 0.04] for atazanavir, daclatasvir and sofosbuvir/daclatasvir groups respectively). There was no significant difference in the occurrence of serious adverse events between treatment groups. Interpretation: No significant reduction in viral load was observed from the use of atazanavir, daclatasvir or sofosbuvir/daclatasvir compared to placebo in hospitalised COVID-19 patients who need oxygen support with symptoms onset 9 days or less. Funding: Ministério da Ciência, Tecnologia e Inovação (MCTI) - Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ); Cia Latino-Americana de Medicamentos (Clamed); Cia Industrial H. Carlos Schneider (Ciser); Hospital Research Foundation Incorporation, Australia, HCor São Paulo; Blanver Farmoquímica; Instituto de Tecnologia em Fármacos (Farmanguinhos) da Fundação Oswaldo Cruz (Fiocruz); Coordenação Geral de Planejamento Estratégico (Cogeplan)/Fiocruz; and Fundação de apoio a Fiocruz (Fiotec, VPGDI-054-FIO-20-2-13).

Trends in Intensive Care Admissions and Outcomes of Stroke Patients Over 10 Years in Brazil: Impact of the COVID-19 Pandemic.

BACKGROUND: The coronavirus 2019 (COVID-19) pandemic affected stroke care worldwide. Data from low- and middle-income countries is limited. RESEARCH QUESTION: What was the impact of the pandemic in intensive care admissions and outcomes of patients with stroke, in comparison to trends over the last ten years? STUDY DESIGN AND METHODS: Retrospective cohort study including prospectively collected data from 165 ICUs in Brazil between 2011 and 2020. We analyzed clinical characteristics and mortality over a period of 10 years and evaluated the impact of the pandemic on stroke outcomes using the following approach: analyses of admissions for ischemic and hemorrhagic strokes and trends in in-hospital mortality over ten years; analysis of variable life-adjusted display (VLAD) during 2020; and a mixed-effects multivariable logistic regression model. RESULTS: 17,115 stroke admissions were analyzed, from which 13,634 were ischemic and 3,481 were hemorrhagic. In-hospital mortality was lower after ischemic stroke as compared to hemorrhagic (9% vs. 24%, respectively). Changes in VLAD across epidemiological weeks of 2020 showed that the rise in COVID-19 cases was accompanied by increased mortality, mainly after ischemic stroke. In logistic regression mixed models, mortality was higher in 2020 compared to 2019, 2018, and 2017 in patients with ischemic stroke, namely in those without altered mental status. In hemorrhagic stroke, the increased mortality in 2020 was observed in patients 50 years or younger, as compared to 2019. INTERPRETATION: Hospital outcomes of stroke admissions worsened during the COVID-19 pandemic, interrupting a trend of improvements in survival rates over 10 years. This effect was more pronounced during the surge of COVID-19 ICU admissions affecting predominantly patients with ischemic stroke without coma, and young patients with hemorrhagic stroke.

The resilient intensive care unit.

BACKGROUND: The COVID-19 pandemic tested the capacity of intensive care units (ICU) to respond to a crisis and demonstrated their fragility. Unsurprisingly, higher than usual mortality rates, lengths of stay (LOS), and ICU-acquired complications occurred during the pandemic. However, worse outcomes were not universal nor constant across ICUs and significant variation in outcomes was reported, demonstrating that some ICUs could adequately manage the surge of COVID-19. METHODS: In the present editorial, we discuss the concept of a resilient Intensive Care Unit, including which metrics can be used to address the capacity to respond, sustain results and incorporate new practices that lead to improvement. RESULTS: We believe that a resiliency analysis adds a component of preparedness to the usual ICU performance evaluation and outcomes metrics to be used during the crisis and in regular times. CONCLUSIONS: The COVID-19 pandemic demonstrated the need for a resilient health system. Although this concept has been discussed for health systems, it was not tested in intensive care. Future studies should evaluate this concept to improve ICU organization for standard and pandemic times.

The association of the COVID-19 pandemic and short-term outcomes of non-COVID-19 critically ill patients: an observational cohort study in Brazilian ICUs.

PURPOSE: To assess whether intensive care unit (ICU) outcomes for patients not affected by coronavirus disease 2019 (COVID-19) worsened during the COVID-19 pandemic. METHODS: Retrospective cohort study including prospectively collected information of patients admitted to 165 ICUs in a hospital network in Brazil between 2011 and 2020. Association between admission in 2020 and worse hospital outcomes was performed using different techniques, including assessment of changes in illness severity of admitted patients, a variable life-adjusted display of mortality during 2020, a multivariate mixed regression model with admission year as both fixed effect and random slope adjusted for SAPS 3 score, an analysis of trends in performance using standardized mortality ratio (SMR) and standardized resource use (SRU), and perturbation analysis. RESULTS: A total of 644,644 admissions were considered. After excluding readmissions and patients with COVID-19, 514,219 patients were available for analysis. Non-COVID-19 patients admitted in 2020 had slightly lower age and SAPS 3 score but a higher mortality (6.4%) when compared with previous years (2019: 5.6%; 2018: 6.1%). Variable-adjusted life display (VLAD) in 2020 increased but started to decrease as the number of COVID-19 cases increased; this trend reversed as number of COVID cases reduced but recurred on the second wave. After logistic regression, being admitted in 2020 was associated with higher mortality when compared to previous years from 2016 and 2019. Individual ICUs standardized mortality ratio also increased during 2020 (higher SMR) while resource use remained constant, suggesting worsening performance. A perturbation analysis further confirmed changes in ICU outcomes for non-COVID-19 patients. CONCLUSION: Hospital outcomes of non-COVID-19 critically ill patients worsened during the pandemic in 2020, possibly resulting in an increased number of deaths in critically ill non-COVID patients.

Evolving changes in mortality of 13,301 critically ill adult patients with COVID-19 over 8 months.

PURPOSE: Clinical characteristics and management of COVID-19 patients have evolved during the pandemic, potentially changing their outcomes. We analyzed the associations of changes in mortality rates with clinical profiles and respiratory support strategies in COVID-19 critically ill patients. METHODS: A multicenter cohort of RT-PCR-confirmed COVID-19 patients admitted at 126 Brazilian intensive care units between February 27th and October 28th, 2020. Assessing temporal changes in deaths, we identified distinct time periods. We evaluated the association of characteristics and respiratory support strategies with 60-day in-hospital mortality using random-effects multivariable Cox regression with inverse probability weighting. RESULTS: Among the 13,301 confirmed-COVID-19 patients, 60-day in-hospital mortality was 13%. Across four time periods identified, younger patients were progressively more common, non-invasive respiratory support was increasingly used, and the 60-day in-hospital mortality decreased in the last two periods. 4188 patients received advanced respiratory support (non-invasive or invasive), from which 42% underwent only invasive mechanical ventilation, 37% only non-invasive respiratory support and 21% failed non-invasive support and were intubated. After adjusting for organ dysfunction scores and premorbid conditions, we found that younger age, absence of frailty and the use of non-invasive respiratory support (NIRS) as first support strategy were independently associated with improved survival (hazard ratio for NIRS first [95% confidence interval], 0.59 [0.54-0.65], p < 0.001). CONCLUSION: Age and mortality rates have declined over the first 8 months of the pandemic. The use of NIRS as the first respiratory support measure was associated with survival, but causal inference is limited by the observational nature of our data.

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

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.

Guiding Principles for the Conduct of Observational Critical Care Research for Coronavirus Disease 2019 Pandemics and Beyond: The Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study Registry.

OBJECTIVES: Use of observational data to inform the response and care of patients during a pandemic faces unique challenges. DESIGN: The Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study COVID 2019 Registry Core data and research methodology team convened over virtual meetings throughout March to June 2020 to determine best practice goals for development of a pandemic disease registry to support rapid data collection and analysis. SETTING: International, multi-center registry of hospitalized patients. PATIENTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Large-scale observational data collection requires: 1) quality assurance and harmonization across many sites; 2) a transparent process for selecting from among many potential research questions; 3) the use of best practices in design of descriptive, predictive, and inferential studies; (4) innovative approaches to characterize random error in the setting of constantly updated data; (5) rapid peer-review and reporting; and (6) transitions from a focus on discovery to implementation. Herein, we describe the guiding principles to best practices and suggestions for innovations to study design and reporting within the coronavirus disease 2019 Viral Infection and Respiratory Illness Universal Study pandemic registry. CONCLUSIONS: Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study coronavirus disease 2019 registry sought to develop and implement prespecified best practices combined with grassroots efforts from clinical sites worldwide in order to develop clinically useful knowledge in response to a pandemic.

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.

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.

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.

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.

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

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.).