Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

Taurine effects on the occurrence of cardiac arrhythmias and QT interval dispersion in patients with postinfarction cardiosclerosis and chronic heart failure: a comparative randomised study

Aim. To study the effects of taurine therapy on the occurrence of cardiac arrhythmias and QT interval dispersion (dQT) among patients with postinfarction cardiosclerosis (PICS) and subsequent chronic heart failure (CHF). Material and methods. The study included 40 patients with previous myocardial infarction (MI), left ventricular ejection fraction (LVEF) <45 %, and Functional Class (FC) II-III CHF (NYHA). The participants were randomised into two groups: the main group (MG) included 20 patients receiving standard CHF treatment and taurine, while the control group (CG; n=20) was administered standard CHF treatment only. Both groups were comparable by the main clinical and anamnestic parameters. The therapy phase lasted 3 months. The analysis of taurine effects on the occurrence of cardiac arrhythmias and dQT was performed in the subgroups defined according to the CHF FC. dQT was assessed by 12-lead electrocardiography (ECG), while the arrhythmia occurrence was assessed by Holter ECG monitoring. The examined parameters were measured at baseline and after 3 months of the therapy. Results. In PICS patients with CHF, taurine demonstrated beneficial effects on the dynamics of dQT and cardiac arrhythmia occurrence. Conclusion. Taurine could be included in the complex treatment of PICS patients with FC II-III CHF

CYTOPROTECTION WITH TRIMETAZIDINE MB: RECENT DATA

The article focuses on new data on trimetazidine MB cytoprotection studies. The data provided on novel mechanisms of its effect including systemic action not related to myocardium. The results of epidemiological studies and meta-analysis are provided that confirm safety and efficacy of the medication in ischemic heart disease and chronic heart failure

ANTIOXIDANT EFFECT OF MILDRONATE IN PATIENTS AFTER CORONARY REVASCULARISATION

The study included 149 patients, aged 41–75 years, with Functional Class II-III stable angina, who underwent coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). Before the intervention, Group I (n=79) received standard therapy and mildronate (750 mg/d for 3 days, then 750 mg/d twice per week). Group II (n=70) did not receive any metabolic medications. Lipid peroxidation (LP) and antioxidant potential parameters were measured at baseline, 6 and 24 hours after the intervention in CABG patients; 10–15 days before, 2–3 days before and 1 day after the intervention in PCI participants. Pre-intervention mildronate therapy was associated with decreased blood levels of LP products, due to the activation of antioxidant enzymes – superoxide dismutase (SOD) and glutathione peroxidase (GP)

CYTOPROTECTOR MILDRONATE IN CORRECTING MYOCARDIAL DYSFUNCTION AMONG STABLE ANGINA PATIENTS AFTER CORONARY REVASCULARISATION

In total, 149 patients, aged 41–75 years, with Functional Class (FC) II-III stable angina, who underwent coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI), were examined. Group I (n=79) received standard therapy, as well as post-intervention mildronate therapy (750 mg/day for three days, then 750 mg per day twice a week). Group II (79 controls) did not receive any metabolic medications. Total and local left ventricular (LV) myocardial contractility was assessed by echocardiography 10–15 days before, 2–3 days before, and 10–12 days after the revascularisation. Mildronate therapy was associated with total and local myocardial contractility improvement, observed even before the intervention and further increasing after the operation. It was also linked to the reduction in post-revascularisation, reperfusionrelated LV myocardial dysfunction

Osteopontin in patients with chronic obstructive pulmonary disease and coronary heart disease

Background: Osteopontin is a protein expressed by various cell types, such as endothelial and epithelial cells, osteoclasts, hepatocytes, smooth muscle cells, activated macrophages, and T-cells. Cardiomyocytes, heart fibroblasts, endothelial cells of coronary arteries express osteopontin in response to hypoxia, inflammation, toxic factors, mechanical strain, and other stimuli. Aim: To study osteopontin levels in patients with chronic obstructive pulmonary disease (COPD) depending on concomitant ischemic heart disease (IHD), to identify an association between osteopontin levels with severity of COPD and functional lung test parameters. Materials and methods: This open-label, prospective, non-randomized comparative study with parallel groups included 99 patients with COPD grades AD by GOLD, with 49 of them having confirmed comorbid stable IHD. Serum osteopontin levels were measured by immunoenzyme assay (Human Osteopontin Platinum ELISA; Bender MedSystems, Austria). The data is given as medians and quartiles (Me [Q1; Q3]). In all patients we performed functional lung tests with bronchodilation, a 6-minute walking test, BODE index assessment, as well as CAT and mMRC questionnaires were used. Results: In the patients with COPD and IHD, the osteopontin levels were higher than in the patients with COPD without IHD (85.55 [46.86; 110.91] vs 55.43 [20.76; 89.64] ng/mL, respectively; p = 0.027). Osteopontin levels in the patients with all COPD grades and IHD were higher than in those without IHD, but the difference was significant only in GOLD grade B patients (91.28 [73.04; 110.91] vs 37.81 [22.54; 82.95] ng/mL, respectively, р = 0.028) and GOLD grade D patients (80.79 [34.65; 111.11] vs 37.46 [13.32; 109.5] ng/mL, respectively, р = 0.027). Conclusion: A significant increase of osteopontin levels in comorbid patients with COPD and stable IHD found in this study has not been previously known. It is necessary to perform further studies to identify a threshold level of osteopontin predictive of the risk of COPD exacerbations or cardiovascular events. This would help to improve medical treatment of COPD patients, as well as to identify the risk groups

VIKTOR A. LUSOV: DOCTOR, SCIENTIST, LEADER, AND TEACHER

The paper is focused on the importance of Viktor A. Lusov, as well as the department he had been heading for many years, for the Russian cardiology. The biographical information and the data on Professor Lusov’s students and colleagues are presented. The authors emphasise the important role of the clinical school maintained by Viktor A. Lusov — a talented doctor, scientist, leader, and teacher

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals