Effect of weight-adjusted intermediate-dose versus fixed-dose prophylactic anticoagulation with low-molecular-weight heparin on venous thromboembolism among noncritically and critically ill patients with COVID-19: the COVI-DOSE trial, a multicenter, randomised, open-label, phase 4 trial.

Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients. Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707). Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034). Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens. Funding: French Ministry of Health, CAPNET, Grand-Est Region, Grand-Nancy Métropole.

Risk factors of long term symptoms and outcomes among patients discharged after covid-19: prospective, multicentre observational study

Objective To investigate risk factors and subphenotypes associated with long term symptoms and outcomes after hospital admission for covid-19. Design Prospective, multicentre observational study. Setting 93 hospitals in France. Participants Data from 2187 adults admitted to hospital with covid-19 in France between 1 February 2020 and 30 June 2021. Main outcome measures Primary endpoint was the total number of persistent symptoms at six months after hospital admission that were not present before admission. Outcomes examined at six months were persistent symptoms, Hospital Anxiety and Depression Scale, six minute walk test distances, 36-Item Short Form Health Survey scores, and ability to resume previous professional activities and self-care. Secondary endpoints included vital status at six months, and results of standardised quality-of-life scores. Additionally, an unsupervised consensus clustering algorithm was used to identify subphenotypes based on the severity of hospital course received by patients. Results 1109 (50.7%) of 2187 participants had at least one persistent symptom. Factors associated with an increased number of persistent symptoms were in-hospital supplemental oxygen (odds ratio 1.12, 95% confidence interval 1 to 1.24), no intensive care unit admission (1.15, 1.01 to 1.32), female sex (1.33, 1.22 to 1.45), gastrointestinal haemorrhage (1.51, 1.02 to 2.23), a thromboembolic event (1.66, 1.17 to 2.34), and congestive heart failure (1.76, 1.27 to 2.43). Three subphenotypes were identified: including patients with the least severe hospital course (based on ventilatory support requirements). Although Hospital Anxiety and Depression Scale scores were within normal values for all groups, patients of intermediate severity and more comorbidities had a higher median Hospital Anxiety and Depression Scale score than did the other subphenotypes. Patients in the subphenotype with most severe hospital course had worse short form-36 scores and were less able to resume their professional activity or care for themselves as before compared with other subphenotypes. Conclusions Persistent symptoms after hospital admission were frequent, regardless of acute covid-19 severity. However, patients in more severe subphenotypes had a significantly worse functional status and were less likely to resume their professional activity or able to take care of themselves as before. Trial registration NCT04262921.

Spironolactone effect on the blood pressure of patients at risk of developing heart failure: an analysis from the HOMAGE trial.

AIMS: Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined. To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone's effect. METHODS AND RESULTS: HOMAGE (Heart OMics in Aging) was a prospective multicentre randomized open-label blinded endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25-50 mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, Months 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations was used. The median (percentile25-75) age was 73 (69-79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by -10.3 (-13.0 to -7.5) mmHg and DBP by -3.2 (-4.8 to -1.7) mmHg (P < 0.001 for both). A higher proportion of patients on spironolactone had controlled BP <130/80 mmHg (36 vs. 26%; P = 0.014). Lower baseline renin levels predicted a greater response to spironolactone (interactionP = 0.041). CONCLUSION: Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.

Digital health and artificial intelligence in kidney research: a report from the 2020 Kidney Disease Clinical Trialists (KDCT) meeting.

The exponential growth in digital technology coupled with the global coronavirus disease 2019 pandemic is driving a profound change in the delivery of medical care and research conduct. The growing availability of electronic monitoring, electronic health records, smartphones and other devices and access to ever greater computational power provides not only new opportunities, but also new challenges. Artificial intelligence (AI) exemplifies the potential of this digital revolution, which also includes other tools such as mobile health (mHealth) services and wearables. Despite digital technology becoming commonplace, its use in medicine and medical research is still in its infancy, with many clinicians and researchers having limited experience with such tools in their usual practice. This article, derived from the 'Digital Health and Artificial Intelligence' session of the Kidney Disease Clinical Trialists virtual workshop held in September 2020, aims to illustrate the breadth of applications to which digital tools and AI can be applied in clinical medicine and research. It highlights several innovative projects incorporating digital technology that range from streamlining medical care of those with acute kidney injury to the use of AI to navigate the vast genomic and proteomic data gathered in kidney disease. Important considerations relating to any new digital health project are presented, with a view to encouraging the further evolution and refinement of these new tools in a manner that fosters collaboration and the generation of robust evidence.

Beneficial Effects of Mineralocorticoid Receptor Pathway Blockade against Endothelial Inflammation Induced by SARS-CoV-2 Spike Protein.

BACKGROUND: Vascular endothelial cells activation and dysfunction mediate inflammation and abnormal coagulation in COVID-19 patients. Mineralocorticoid receptor (MR) signaling and its downstream target Galectin-3 (Gal-3) are known to mediate cardiovascular inflammation and might be involved in the pathogenesis of COVID-19 complications. Accordingly, we aimed to investigate the potential beneficial effects of MR antagonism and Gal-3 inhibition on the inflammatory response induced by SARS-CoV-2 Spike protein in human aortic endothelial cells (HAECs). METHODS: HAECs were treated with recombinant SARS-COV2 Spike (S) protein. MR antagonists (namely spironolactone and eplerenone) or the Gal-3 inhibitor G3P-01 were supplemented before and after S protein challenge. HAECs supernatants were assessed by ELISA or Western blotting. RESULTS: HAECs treated with recombinant S protein resulted in enhanced secretion of inflammatory molecules (interleukin-6, monocyte chemoattractant protein-1, interleukin-18, interleukin-27, and interferon-γ) as well as in the thrombosis marker plasminogen activator inhibitor (PAI)-1. This was prevented and reversed by both MR antagonists and G3P-01. CONCLUSIONS: These findings indicate that MR/Gal-3 pathway blockade could be a promising option to reduce endothelial inflammation in SARS-CoV-2 infection.

Chronic use of renin-angiotensin-aldosterone system blockers and mortality in COVID-19: A multicenter prospective cohort and literature review.

AIMS: The role of renin-angiotensin-aldosterone system (RAAS) blockers on the course of coronavirus disease 2019 (COVID-19) is debated. We assessed the association between chronic use of RAAS blockers and mortality among inpatients with COVID-19 and explored reasons for discrepancies in the literature. METHODS AND RESULTS: We included adult hypertensive patients from a prospective nationwide cohort of 3512 inpatients with COVID-19 up to June 30, 2020. Cox proportional hazard models with various adjustment or propensity weighting methods were used to estimate the hazard ratios (HR) of 30-day mortality for chronic users versus non-users of RAAS blockers. We analyzed data of 1160 hypertensive patients: 719 (62%) were male and 777 (67%) were older than 65 years. The main comorbidities were diabetes (n = 416, 36%), chronic cardiac disease (n = 401, 35%), and obesity (n = 340, 29%); 705 (61%) received oxygen therapy. We recorded 135 (11.6%) deaths within 30 days of diagnosis. We found no association between chronic use of RAAS blockers and mortality (unadjusted HR = 1.13, 95% CI [0.8-1.6]; propensity inverse probability treatment weighted HR = 1.09 [0.86-1.39]; propensity standardized mortality ratio weighted HR = 1.08 [0.79-1.47]). Our comprehensive review of previous studies highlighted that significant associations were mostly found in unrestricted populations with inappropriate adjustment, or with biased in-hospital exposure measurement. CONCLUSION: Our results do not support previous concerns regarding these drugs, nor a potential protective effect as reported in previous poorly designed studies and meta-analyses. RAAS blockers should not be discontinued during the pandemic, while in-hospital management of these drugs will be clarified by randomized trials. NCT04262921.