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).

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.

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.

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.).

Predictors of subclinical carotid atherosclerosis in middle-aged women.

BACKGROUND: Traditional strategies for primary cardiovascular prevention have been insufficient in reducing the high rates of coronary ischemic events in women, probably because these women are often stratified into low-risk groups. However, cardiovascular diseases continue to be the main cause of morbidity and mortality in women worldwide. We hypothesized that carotid atherosclerosis (CA) is common in middle-aged women. METHODS: We prospectively evaluated asymptomatic peri- and post-menopausal women with no cardiovascular diseases or the use of hormone therapy from two gynecologic clinics. All the patients underwent full clinical and laboratory evaluation and underwent a B-mode ultrasound for carotid evaluations. The presence of CA was defined as the presence of plaque and/or carotid intima-media thickness (CIMT)>1.00 mm. We performed logistic regression to evaluate independent predictors of CA. RESULTS: We studied 823 women (age: 54.4±5.4 years; body mass index-BMI: 28.5±4.9 kg/m2; diabetes:10%; hypertension: 58%). The prevalence of CA was 12.7% for the entire population and 11% for the low-risk sub-group as defined by a Framingham risk score <5%. In the multivariate model, age: odds ratio (OR) = 1.54, 95% confidence interval (CI) = 1.25-1.89,p<0.001; current smoker status: OR = 2.69, 95% CI = 1.48-4.91, p = 0.001; total cholesterol: OR = 1.13, 95% CI = 1.03-1.24, p = 0.008; and systolic blood pressure: OR = 1.01, 95% CI = 1.00-1.02, p = 0.030 remained independently associated with CA. CONCLUSION: Subclinical CA is common among asymptomatic middle-aged women, and traditional risk factors are independently associated with CA. These findings are particularly relevant for improving cardiovascular health in women.

Case report: a rare cause of metabolic alkalosis.

A case of a 66-year-old white man with recent onset of oedema, hypertension, metabolic alkalosis and profound hypokalaemia is described. The initial laboratorial workup showed that urinary chloride concentration and potassium excretion were increased, suggesting a state of hyperaldosteronism. Nonetheless, renin activity was low and aldosterone levels were normal. The metabolic alkalosis seen in this case was due to a rare cause, the ectopic adrenocorticotropic hormone syndrome. A literature review in the subject is presented.

Estratificação de risco de doença coronária em mulheres / Cardiovascular disease in women: risk stratification

As doenças cardiovasculares representam a principal causa de morte nas mulheres. Apesar de os fatores de risco como dislipidemia, hipertensão, diabetes, tabagismo e história familiar serem os mesmos para ambos os sexos, a estratificação de risco com mulheres apresenta algumas peculiaridades. O escore de Framingham, classicamente utilizado para avaliação de risco cardiovascular, apresenta várias limitações no que se refere às mulheres, pois raramente uma mulher é classificada como de alto risco com o uso dessa escala. Para melhor estratificação, é preciso considerar que a presença de pelo menos um fator de risco para aterosclerose já pode indicar maior risco no longo prazo. Marcadores de aterosclerose subclínica e proteína C-reativa ultra-sensível podem ser úteis para melhor acurácia na estratificação de risco da mulher.

Metabolic syndrome, abdominal obesity, and cardiovascular risk in elderly women.

BACKGROUND: Metabolic syndrome and abdominal obesity are risk factors for cardiovascular diseases in middle age women but, not completely understood in older people. In this study we analyzed the association between metabolic syndrome and abdominal obesity and the occurrence of cardiovascular events in these elderly women. METHODS: A prospective follow-up study included 516 consecutive women aged 60-84 years who sought medical care at a geriatric outpatient facility. The presence of metabolic syndrome and higher quartiles of waist circumference and waist-to-hip ratio were analyzed as predictive variables, and were adjusted for age, smoking, and previous cardiovascular diseases. The outcomes were the occurrence of stroke, myocardial infarction, evidence of coronary artery disease, or cardiovascular death. RESULTS: During a mean follow-up of 6.6 years, 94 (18.2%) cardiovascular events were observed (48 fatal and 46 non-fatal). Metabolic syndrome was diagnosed in 206 women (39.9%). After adjustments for confounding variables, metabolic syndrome and waist-to-hip ratio above the 75th percentile (>0.98) were predictors of the outcomes, but greater waist circumference (>96 cm) was not. Adjusted hazard ratios for these variables were: metabolic syndrome, 1.66, 95% CI -1.11 to 2.47, p=0.01; waist-to-hip ratio, 1.72, 95% CI -1.05 to 2.82; p=0.03 and waist circumference, 1.37, 95% CI -0.91 to 2.07, p=0.12. CONCLUSION: Metabolic syndrome and high waist-to-hip ratio were associated with increased risk of cardiovascular events in the studied sample.

[Exercise stress test: prognostic value for elderly patients with stable coronary atherosclerosis]. / Teste ergométrico: valor prognóstico em pacientes idosos com doença aterosclerótica coronariana estável.

OBJECTIVE: To study the prognostic value of exercise stress test variables in elderly patients with coronary atherosclerosis and exercise-induced ischemia. METHODS: Sixty-four elderly patients (61 men, 73 +/- 5 years old) with coronary atherosclerosis, verified by cardiac catheterization, that were clinically stable, had a left ventricle ejection fraction greater than or equal to 0.40 and developed myocardial ischemia during the exercise stress test were studied. The patients were evaluated every six months for cardiac events (death, myocardial infarction, unstable angina, angioplasty and myocardial revascularization). RESULTS: After a mean follow-up period of 48 months, 23 (36%) patients suffered cardiac events. There was no clinical or angiographical differences among the patients that suffered cardiac events and those that did not. Using multivariate analysis, the presence of chest pain during the exercise stress test (relative risk 2.668, p = 0.031) and the heart rate at the onset of ischemia (relative risk 0.966, p = 0.009) were associated with cardiac events. CONCLUSION: In this elderly population, the presence of chest pain during the exercise stress test and the heart rate at the onset of ischemia were associated with cardiac events. These variables could be useful for risk evaluation in patients with stable coronary atherosclerosis.

Teste ergométrico: valor prognóstico em pacientes idosos com doença aterosclerótica coronariana estável / Exercise stress test: prognostic value for elderly patients with stable coronary atherosclerosis

OBJETIVO: Estudar o valor prognóstico das variáveis do teste ergométrico em pacientes idosos com doença aterosclerótica coronariana e isquemia induzida pelo esforço. MÉTODOS: Foram estudados 64 pacientes idosos (61 homens, idade de 73 ± 5 anos) com doença aterosclerótica coronariana, comprovada por coronariografia, clinicamente estável, fração de ejeção de ventrículo esquerdo maior ou igual a 0,40 e isquemia miocárdica durante o teste ergométrico. A cada seis meses, os pacientes foram avaliados para eventos cardíacos (morte, infarto do miocárdio, angina instável, angioplastia e revascularização do miocárdio). RESULTADOS: Após seguimento médio de 48 meses, 23 (36 por cento) pacientes sofreram eventos cardíacos. Não houve diferença clínica e angiográfica entre os pacientes que sofreram o evento e os que não o sofreram. Pela análise multivariada, a presença de dor precordial durante o teste ergométrico (risco relativo de 2,668 e p = 0,031) e a freqüência cardíaca no início da isquemia (risco relativo de 0,966 e p = 0,009) foram associadas a eventos cardíacos. CONCLUSÃO: Nessa população idosa, a presença de dor precordial durante o teste ergométrico e a freqüência cardíaca no início da isquemia foram associadas a eventos cardíacos. Essas variáveis podem ser úteis para avaliação do risco de pacientes com doença aterosclerótica coronariana estável.

Relação do índice de massa corporal, da relação cintura-quadril e da circunferência abdominal com a mortalidade em mulheres idosas: seguimento de 5 anos / Relationship between body mass index, waist circumference, and waist-to-hip ratio and mortality in elderly women: a 5-year follow-up study

Este estudo analisa a associação entre a relação cintura-quadril (RCQ), a circunferência abdominal (CA) e o índice de massa corporal (IMC) com a mortalidade total e cardiovascular em 575 mulheres idosas ambulatoriais por um seguimento de cinco anos. Os maiores quartis de RCQ, CA e IMC, bem como as categorias pré-determinadas de IMC, foram analisados como variáveis preditivas e analisada a interferência de algumas variáveis confundidoras. Oitenta e oito mulheres morreram durante o seguimento (15,4 por cento). As mulheres com baixo peso (IMC < 18,5kg/m²) apresentavam uma associação positiva com a mortalidade total nas análises uni e multivariadas, independentemente da estratificação etária. Nas curvas de sobrevida e na análise univariada, o maior quartil de RCQ (> 0,97) estava associado com a maior mortalidade total, entretanto, na análise multivariada o aumento de RCQ apresentou uma associação independente com a mortalidade total, apenas entre as mulheres de 60 a 80 anos. Nenhuma medida antropométrica apresentou uma associação significativa com a mortalidade cardiovascular. Os resultados identificaram o baixo peso e a RCQ como preditores de mortalidade total em idosas, principalmente entre as mulheres com até 80 anos.

[Relationship between body mass index, waist circumference, and waist-to-hip ratio and mortality in elderly women: a 5-year follow-up study]. / Relação do índice de massa corporal, da relação cintura-quadril e da circunferência abdominal com a mortalidade em mulheres idosas: seguimento de 5 anos.

This study examines the association between body mass index (BMI), waist-to-hip ratio (WHR), and waist circumference (WC) and all-cause and cardiovascular mortality in elderly women in a 5-year longitudinal study of 575 female outpatients 60 years and over. The highest BMI, WHR, and WC quartiles and predefined BMI categories were analyzed as predictive variables. Death occurred in 88 (15.4%). Underweight (BMI < 18.5 kg/m2) was associated with all-cause mortality in uni- and multivariate analyses, regardless of age bracket. The survival curves and univariate analysis showed that the highest WHR quartile (> or = 0.97) was associated with all-cause mortality. However, after adjustment for age, smoking, and previous cardiovascular diseases, the increase in WHR was positively associated only in women from 60 to 80 years of age. None of the anthropometric measurements was associated with cardiovascular mortality. The results indicate that underweight and increased waist-to-hip ratio were predictors of all-cause mortality in elderly women, mainly among those under 80 years.