Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: A subgroup analysis of the SAVE-MORE randomised trial.

Background: The SAVE-MORE trial demonstrated that anakinra treatment in COVID-19 pneumonia with plasma soluble urokinase plasminogen activator (suPAR) levels of 6 ng/mL or more was associated with 0.36 odds for a worse outcome compared to placebo when expressed by the WHO-Clinical Progression Scale (CPS) at day 28. Herein, we report the results of subgroup analyses and long-term outcomes. Methods: This prospective, double-blind, randomised clinical trial, recruited patients with a confirmed SARS-CoV-2 infection, in need of hospitalisation, lower respiratory tract infection and plasma suPAR ≥6 ng/mL from 37 academic and community hospitals in Greece and Italy. Patients were 1:2 randomised to subcutaneous treatment with placebo or anakinra (100 mg) once daily for 10 days. Pre-defined subgroups of Charlson's comorbidity index (CCI), sex, age, level of suPAR, and time from symptom onset were analysed for the primary endpoint (overall comparison of distribution of frequencies of the scores from the WHO-CPS between treatments on day 28), by multivariable ordinal regression analysis in the intention to treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2020-005828-11) and ClinicalTrials.gov (NCT04680949). Findings: Patients were enrolled between 23 December 2020 and 31 March 2021; 189 patients in the placebo arm and 405 patients in the anakinra arm were the ITT population. Multivariable analysis showed that anakinra treatment was accompanied by significantly lower odds for worse outcome compared to placebo at day 28 for all studied subgroups (CCI ≥ 2, OR: 0.34, 95% confidence intervals [CI] 0.22-0.50; CCI < 2, OR: 0.38, 95% CI 0.21-0.68; suPAR > 9 ng/mL, OR: 0.35, 95% CI 0.19-0.66; suPAR 6-9 ng/mL, OR: 0.35, 95% CI 0.24-0.52; patients ≥65 years, OR: 0.41, 95% CI 0.25-0.66; and patients <65 years, OR: 0.29, 95% CI 0.19-0.45). The benefit was uniform, irrespective of the time from start of symptoms until the start of the study drug. At days 60 and 90, anakinra treatment had odds of 0.40 (95% CI 0.28-0.57) and 0.46 (95% CI 0.32-0.67) respectively, for a worse outcome compared to placebo. The costs of general ward stay, ICU stay, and drugs were lower with anakinra treatment. Interpretation: Anakinra represents an important therapeutic tool in the management of COVID-19 that may be administered in all subgroups of patients; benefits are maintained until day 90. Funding: Hellenic Institute for the Study of Sepsis; Swedish Orphan Biovitrum AB.

Risk Assessment of COVID-19 Cases in Emergency Departments and Clinics With the Use of Real-World Data and Artificial Intelligence: Observational Study.

BACKGROUND: The recent COVID-19 pandemic has highlighted the weaknesses of health care systems around the world. In the effort to improve the monitoring of cases admitted to emergency departments, it has become increasingly necessary to adopt new innovative technological solutions in clinical practice. Currently, the continuous monitoring of vital signs is only performed in patients admitted to the intensive care unit. OBJECTIVE: The study aimed to develop a smart system that will dynamically prioritize patients through the continuous monitoring of vital signs using a wearable biosensor device and recording of meaningful clinical records and estimate the likelihood of deterioration of each case using artificial intelligence models. METHODS: The data for the study were collected from the emergency department and COVID-19 inpatient unit of the Hippokration General Hospital of Thessaloniki. The study was carried out in the framework of the COVID-X H2020 project, which was funded by the European Union. For the training of the neural network, data collection was performed from COVID-19 cases hospitalized in the respective unit. A wearable biosensor device was placed on the wrist of each patient, which recorded the primary characteristics of the visual signal related to breathing assessment. RESULTS: A total of 157 adult patients diagnosed with COVID-19 were recruited. Lasso penalty function was used for selecting 18 out of 48 predictors and 2 random forest-based models were implemented for comparison. The high overall performance was maintained, if not improved, by feature selection, with random forest achieving accuracies of 80.9% and 82.1% when trained using all predictors and a subset of them, respectively. Preliminary results, although affected by pandemic limitations and restrictions, were promising regarding breathing pattern recognition. CONCLUSIONS: This study represents a novel approach that involves the use of machine learning methods and Edge artificial intelligence to assist the prioritization and continuous monitoring procedures of patients with COVID-19 in health departments. Although initial results appear to be promising, further studies are required to examine its actual effectiveness.

Effect of Empagliflozin and Dapagliflozin on Ambulatory Arterial Stiffness in Patients with Type 2 Diabetes Mellitus and Cardiovascular Co-Morbidities: A Prospective, Observational Study.

Background and Objectives: Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease. Arterial stiffness is an independent prognostic marker for cardiovascular disease development. We aimed at determining the effect of two different sodium-glucose co-transporter-2 (SGLT-2) inhibitors on ambulatory arterial stiffness in individuals with T2DM. Materials and Methods: In this single-center, single-arm, prospective study performed from January 2020 to August 2021, we planned to enroll adult subjects with T2DM and stable antidiabetic and antihypertensive treatment, assigned either to empagliflozin or dapagliflozin for 6 months. All eligible subjects underwent ambulatory blood pressure monitoring. We set as the primary efficacy outcome the change in ambulatory pulse wave velocity (PWV) from baseline to week 24. Results: We finally enrolled 46 diabetic subjects, with a mean age of 62.89 (8.53) years and mean T2DM duration of 9.72 (6.37) years. Thirty patients received dapagliflozin, while sixteen patients received empagliflozin. Due to COVID-19 pandemic restrictive measures during the study, the mean follow-up period extended from 6 months to 9.98 (3.27) months. Regarding the prespecified primary efficacy outcome, we found that the SGLT-2 inhibitor treatment did not have a significant effect on PWV (p = 0.65). Prior history of cardiovascular disease did not significantly affect the observed effects. Other indices of arterial stiffness, such as augmentation index and central pulse pressure, were not significantly affected, neither by empagliflozin nor by dapagliflozin. Conclusions: SGLT-2 inhibitor treatment with empagliflozin or dapagliflozin in subjects with T2DM failed to improve ambulatory PWV over a mean follow-up of 10 months. Registration number: ISRCTN88851713.

Hypertensive urgencies during the first wave of the COVID-19 pandemic in a tertiary hospital setting: a U-shaped alarming curve.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic provoked unprecedented disturbance in hypertension care, while alarming concerns arose about its long-term consequences. We investigated the trends of emergency visits and admissions regarding uncontrolled hypertension in order to assess the impact of COVID-19 spread on population behavior towards hypertension urgencies during its first wave. Material and methods: Data from daily unscheduled visits and admission counts in the Cardiology sector were collected from the Emergency Department database of a tertiary General Hospital in Athens, Greece for the period January 15th to July 15th 2020. These data were compared with those from the previous year. Cases of patients who presented with hypertensive urgency or who were admitted due to uncontrolled hypertension were separately analyzed. Results: A total of 7,373 patient records were analyzed. Hypertension urgency cases demonstrated a U-shaped distribution in 2020, showing a declining trend during the rapid virus spread, an image that was reversed after the transmission rate's decline. COVID-19 incidence in Greece was inversely associated with uncontrolled hypertension admissions during its declining phase (r = -0.64, p = 0.009), whereas total attendance exhibited a similar correlation during the first and the following months of the pandemic (r = 0.677, p = 0.031, r = -0.789, p = 0.001). Uncontrolled hypertension rate on admission was positively related to the national incidence of COVID-19 cases during the first months of 2020 (r = 0.82, p = 0.045). Conclusions: Hypertensive urgency-related visits followed a U-shape distribution during the pandemic's first wave with the attendance nadir coinciding with the virus spread peak. This is a complex phenomenon, closely related to increased levels of public stress, disruptions in health care services and to a lesser extent to the imposed restrictions in transportation. The initial relative increase in uncontrolled hypertension-related admissions rate, combined with the later increase of hypertensive urgencies may be indicative of blood pressure deregulation among the studied population, which is multifactorial and potentially detrimental.

Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial.

Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/ß inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml-1, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.

Janus kinase inhibitors and major COVID-19 outcomes: time to forget the two faces of Janus! A meta-analysis of randomized controlled trials.

Coronavirus disease-2019 (COVID-19) represents a global public health nightmare. The "cytokine storm," the most prominent underlying pathophysiologic mechanism of this disease, can theoretically be targeted at several stages. Janus kinase (JAK) inhibitors constitute a drug class that could ameliorate the inflammatory response and enhance antibody production. Herein, we aimed to evaluate the efficacy of JAK inhibitors in patients with COVID-19, performing the most updated relevant meta-analysis. We searched two major databases for randomized controlled trials (RCTs) enrolling adult patients with documented COVID-19 in the in-hospital setting, assigned either to JAK inhibitor treatment plus standard of care or standard of care alone. We set as primary efficacy outcome the endpoint of COVID-19 death on day 28 and as secondary efficacy composite outcome that of mechanical ventilation or initiation of extracorporeal membrane oxygenation (ECMO). We finally pooled data of interest from 4 RCTs in a total of 1338 subjects with documented COVID-19 infection, utilizing the following JAK inhibitors: baricitinib, ruxolitinib, tofacitinib, and nezulcitinib. Treatment with JAK inhibitor compared to control resulted in a significant reduction in the risk for COVID-19 death by 43%, while it also led to a significant decrease in the risk for mechanical ventilation or ECMO initiation by 36%. Herein, we demonstrate a clear benefit with JAK inhibitors added to standard of care in patients with COVID-19 in terms of risk reduction concerning major outcomes. Larger RCTs will elucidate their place in treatment armamentarium against COVID-19.

Dipeptidyl Peptidase-4 Inhibitors and COVID-19-Related Deaths among Patients with Type 2 Diabetes Mellitus: A Meta-Analysis of Observational Studies.

The coronavirus disease 2019 (COVID-19) pandemic remains an unbeaten enemy. Unfortunately, no targeted treatment option is available. Patients with type 2 diabetes mellitus (T2DM) have increased odds for severe or fatal disease, as demonstrated in recent observational studies. There is an ongoing discussion regarding the impact of different antidiabetic drug classes on outcomes of interest among affected subjects. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been placed at the epicenter, since the DPP-4 enzyme seems to be implicated in the disease pathogenesis. Herein we present an updated meta-analysis of observational studies addressing the risk of COVID-19 death among patients with T2DM on prior DPP-4 inhibitor treatment. We pooled data from 10 observational studies, showing that DPP-4 inhibitors produce a non-significant decrease in the risk for COVID-19-related death. However, when administered in the inpatient setting, DPP-4 inhibitors decrease the risk for COVID-19-related death by 50%. Ongoing randomized controlled trials will shed further light.

Renin-Angiotensin System Inhibitors and COVID-19: a Systematic Review and Meta-Analysis. Evidence for Significant Geographical Disparities.

PURPOSE OF REVIEW: While the COVID-19 pandemic is constantly evolving, it remains unclear whether the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) affects the clinical course of SARS-CoV-2 infection. For this meta-analysis, PubMed, CENTRAL, and grey literature were searched from their inception to 19 May 2020 for randomized, controlled trials or observational studies that evaluate the association between the use of either ACE inhibitors or ARBs and the risk for major clinical endpoints (infection, hospitalization, admission to ICU, death) in adult patients during the COVID-19 pandemic. In addition, a subgroup geographical analysis of outcomes was performed. Studies including less than 100 subjects were excluded from our analysis. RECENT FINDINGS: In total, 25 observational studies were included. ACE inhibitors and ARBs were not associated with increased odds for SARS-CoV-2 infection, admission to hospital, severe or critical illness, admission to ICU, and SARS-CoV-2-related death. In Asian countries, the use of ACE inhibitors/ARBs decreased the odds for severe or critical illness and death (OR = 0.37, 95% CI 0.16-0.89, I2 = 83%, and OR = 0.62, 95% CI 0.39-0.99, I2 = 0%, respectively), whereas they increased the odds for ICU admission in North America and death in Europe (OR = 1.75, 95% CI 1.37-2.23, I2 = 0%, and OR = 1.68, 95% CI 1.05-2.70, I2 = 82%, respectively). ACE inhibitors might be marginally protective regarding SARS-CoV-2-related death compared with ARBs (OR = 0.86, 95% CI 0.74-1.00, I2 = 0%). Randomized controlled trials are needed to confirm the aforementioned associations between ACE inhibitors, ARBs, and SARS-CoV-2.