key: cord-0279515-o6mxd0tv
authors: Puskarich, M. A.; Ingraham, N. E.; Merck, L. H.; Driver, B. E.; Wacker, D. A.; Black, L. P.; Jones, A. E.; Fletcher, C. V.; South, A. M.; Nelson, A. C.; Murray, T. A.; Lewandowski, C.; Farhat, J.; Benoit, J. L.; Bryne, D.; Hall, A.; Reilkoff, R. A.; Biros, M. H.; Cherabuddi, K.; Chipman, J. G.; Schacker, T. W.; Bold, T.; Beckman, K. B.; Langlois, R.; Aliota, M.; Guirgis, F.; Galbraith, J.; Beyer, M.; Salmen, C.; Roberts, B. W.; Wright, D. W.; Voelker, H.; Koopmeiners, J. S.; Tignanelli, C. J.
title: Effect of losartan on hospitalized patients with COVID-19-induced lung injury: A randomized clinical trial
date: 2021-08-28
journal: nan
DOI: 10.1101/2021.08.25.21262623
sha: fae9b6d1c86f93a7e208014078e2cee2545c97e4
doc_id: 279515
cord_uid: o6mxd0tv

Background: SARS-CoV-2 viral entry may disrupt angiotensin II (Ang II) homeostasis in part via ACE2 downregulation, potentially contributing to COVID-19 induced lung injury. Preclinical models of viral pneumonias that utilize ACE2 demonstrate Ang II type 1 receptor (AT1R) blockade mitigates lung injury, though observational COVID-19 data addressing the effect of AT1R blockade remain mixed. Methods: Multicenter, blinded, placebo-controlled randomized trial of losartan (50 mg PO twice daily for 10 days) versus placebo. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already taking a renin-angiotensin-aldosterone system (RAAS) inhibitor were eligible. The primary outcome was the imputed partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio at 7 days. Secondary outcomes included ordinal COVID-19 severity, oxygen, ventilator, and vasopressor-free days, and mortality. Losartan pharmacokinetics (PK) and RAAS components [Ang II, angiotensin-(1-7) (Ang-(1-7)), ACE, ACE2] were measured in a subgroup of participants. Findings: From April 2020 - February 2021, 205 participants were randomized, 101 to losartan and 104 to placebo. Compared to placebo, losartan did not significantly affect PaO2/FiO2 ratio at 7 days [difference of -24.8 (95% -55.6 to 6.1; p=0.12)]. Losartan did not improve any secondary clinical outcome, but worsened vasopressor-free days. PK data were consistent with appropriate steady-state concentrations, but we observed no significant effect of losartan on RAAS components. Interpretation: Initiation of orally administered losartan to hospitalized patients with COVID-19 and acute lung injury does not improve PaO2 / FiO2 ratio at 7 days. These data may have implications for ongoing clinical trials.

Background: SARS-CoV-2 viral entry may disrupt angiotensin II (Ang II) homeostasis in part via ACE2 downregulation, potentially contributing to COVID-19 induced lung injury. Preclinical models of viral pneumonias that utilize ACE2 demonstrate Ang II type 1 receptor (AT1R) blockade mitigates lung injury, though observational COVID-19 data addressing the effect of AT1R blockade remain mixed.

Methods: Multicenter, blinded, placebo-controlled randomized trial of losartan (50 mg PO twice daily for 10 days) versus placebo. Hospitalized patients with COVID-19 and a respiratory sequential organ failure assessment score of at least 1 and not already taking a reninangiotensin-aldosterone system (RAAS) inhibitor were eligible. The primary outcome was the imputed partial pressure of oxygen to fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio at 7 days.

Secondary outcomes included ordinal COVID-19 severity, oxygen, ventilator, and vasopressorfree days, and mortality. Losartan pharmacokinetics (PK) and RAAS components [Ang II, angiotensin-(1-7) (Ang-(1-7)), ACE, ACE2] were measured in a subgroup of participants.

Findings: From April 2020 -February 2021, 205 participants were randomized, 101 to losartan and 104 to placebo. Compared to placebo, losartan did not significantly affect PaO 2 /FiO 2 ratio at 7 days [difference of -24.8 (95% -55.6 to 6.1; p=0. 12) ]. Losartan did not improve any secondary clinical outcome, but worsened vasopressor-free days. PK data were consistent with appropriate steady-state concentrations, but we observed no significant effect of losartan on RAAS components. (1) (2) (3) (4) (5) (6) (7) (8) (9) , which generally oppose Ang II's effects. 2, 4 Early data suggested Ang II levels may be associated with viral load and degree of lung injury in COVID-19 patients, 4 though more recent and methodologically robust data demonstrate mixed findings. [5] [6] [7] Preclinical models of viral pneumonias affecting ACE2, including severe acute respiratory syndrome coronavirus (SARS-CoV), demonstrate Ang II type 1 receptor (AT1R) blockade reduces lung injury and death. [8] [9] [10] Observational studies of antecedent angiotensinconverting enzyme inhibitor (ACE-i) or AT1R blocker (ARB) use and disease severity and mortality in COVID-19, meanwhile, demonstrate mixed results. [11] [12] [13] [14] [15] [16] [17] RAAS inhibition in COVID-19, therefore, remains an ongoing area of controversy.

We hypothesized losartan treatment might reduce lung injury and improve clinical outcomes in hospitalized patients with COVID-19 by restoring Ang II and Ang- (1) (2) (3) (4) (5) (6) (7) homeostasis. To test this hypothesis, we conducted a multicenter blinded randomized placebocontrolled clinical trial of patients hospitalized with COVID-19 not already taking a RAAS inhibitor. The primary objective was to test if losartan improves the PaO 2 /FiO 2 (P/F) ratio at 7 days. We also sought to determine if losartan affects biochemical markers (including RAAS components), severity of illness, and mortality.

We conducted a prospective multicenter blinded randomized placebocontrolled trial of hospitalized patients with COVID-19 at 13 hospitals in the United States from April 2020 to February 2021 following CONSORT guidelines. 18 The protocol was approved by a All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Exclusion criteria included: active outpatient treatment with an ACE-i, ARB, or aliskiren; prior adverse reaction to ACE-i/ARB; pregnancy, breastfeeding, or lack of contraception; history of dialysis, stage IV chronic kidney disease, or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m 2 ; potassium >5.0 mmol/L; history of severe liver disease; enrollment in another blinded clinical trial for COVID-19; lack of informed consent; inability to randomize within 48 hours of admission or positive test; oxygen saturation at baseline; or respiratory sequential organ failure assessment (SOFA) score of <1 (defined as P/F of <400, utilizing SaO2 if PaO2 is unavailable). 20, 21 Screening and consent: Electronic health records (EHR) were screened by manual chart review by trained research personnel. Due to limitations in personal protective equipment, informed consent was typically conducted remotely via telephone or video teleconference, and documentation was maintained using a 21 CFR part 11 compliant electronic consent (eConsent) platform (REDCap). 22 Randomization and blinding: Enrolled participants were randomized using permuted blocks of randomly varying sizes (2, 4, or 6) stratified by site and age (>=60 or <60 years). A central randomization website generated treatment allocations in a 1:1 ratio. All participants and All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262623 doi: medRxiv preprint study personnel were blinded except statisticians preparing the randomization and investigational pharmacists.

Intervention: The intervention was losartan 50 mg PO twice daily (100 mg daily total) versus equally appearing placebo, yielding an expected 70% inhibition of AT1R. 23 Study drug was shipped to sites as pills and prepared locally by an unblinded pharmacist in suspension per the manufacturer's package insert. Study drug was administered for 10 days if eGFR >60 mL/min/1.73 m 2 , once daily for eGFR 30-60, and discontinued if eGFR decreased below 30, following discharge, or by a blinded investigator if a drug-related serious adverse effect (SAE) was suspected.

Primary efficacy outcome: The primary outcome was the PaO 2 /FiO 2 ratio on day 7. If lacking, PaO 2 was imputed using the method of Pandharipande (for positive pressure ventilation) or Gadrey (no positive pressure). 21, 24 Participants discharged prior to day 7 were provided a home pulse oximeter and contacted via phone.

Secondary outcomes: Oxygen, ventilator, and vasopressor-free days (to 10 days), time to discharge, 7-point ordinal scale of COVID-19 severity, 25 and 28-day mortality were measured.

A subset of participants (limited by local biohazard capacity) underwent biospecimen collection.

Safety monitoring: Creatinine and potassium were measured on days 0, 1, 3, and 7.

Acute kidney injury was defined as an increase in serum creatinine of 0.3 mg/dL or 1.5-times baseline. 26 Blood pressures and medical charts were reviewed daily for up to 15 days postrandomization.

Pharmacokinetic measurements: Blood samples were obtained at 2, 4, and 6 hours after a dose of losartan or placebo (50 mg) in a subgroup blinded to treatment allocation. Plasma concentrations of losartan and its active carboxy metabolite, carboxylosartan (LCA) were quantified by a validated LC-MS/MS assay with a lower limit of quantification of 3 ng/mL at the University of Nebraska Medical Center. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262623 doi: medRxiv preprint RAAS measurements: Blood was collected in an EDTA tube containing a cocktail of protease inhibitors validated with the intended assays and red-top tubes per best practices. [27] [28] [29] Extracted plasma and serum were stored at -80°C and sent to the CLIA-certified Biomarker Analytical Core at Atrium Health Wake Forest Baptist for analysis. The plasma was thawed on ice, extracted on Sep-Pak C18 columns (Waters Corp., Milford, Massachusetts, USA), and the eluted fractions analyzed with radioimmunoassays. 28 Plasma Ang II was measured using the Immuno-Biological Lab, Inc. kit (IBL America, Minneapolis, MN 55432), while plasma Ang-(1-7)

was measured using an antibody produced by the laboratory and validated with LC-MS/MS. Serum ACE and ACE2 activity were analyzed using established methods. 27, 28 Viral load: Consistent with our prior work, we report normalized Ct value for SARS-CoV-2 targets compared to human RP internal sample control, providing a relative value to compensate for sampling and extraction quality. 30 Statistical analysis: Statistical analyses were performed using SAS (version 9.4 or newer) or R (version 4.0.3 or newer). 31 All statistical tests were two-tailed with p-values less than 0.05 considered statistically significant. Baseline clinical characteristics are summarized using descriptive statistics. All analyses were conducted using intent-to-treat principles. We tested the effect of losartan on P/F ratio at Day 7 using predictive modeling, imputing zero for participants that died early to penalize for death. Missing values in alive participants were multiply imputed 20 times using predictive mean matching. The predictive models included study arm, location of enrollment, baseline hypertension, assigned sex, age, body mass index, baseline P/F ratio, and days from randomization to discharge. Secondary unadjusted analysis of the primary outcome was carried out using Welch's t-test.

Longitudinal secondary endpoints were analyzed using generalized linear mixed models or generalized estimating equations, adjusting for corresponding baseline measurements.

Mortality was summarized using Kaplan-Meier plots and compared using the log-rank test and unadjusted Cox models to estimate hazard ratios. Time to hospital discharge, with death in All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262623 doi: medRxiv preprint hospital or discharge to comfort care as a competing risk, was evaluated using cumulative incidence plots and Fine-Gray's test (rho = 0), the competing risks' analog to the log-rank test.

Ordinal outcomes were analyzed using proportional odds regression.

Pharmacokinetic characteristics were determined using the trapezoidal rule and linear regression (Phoenix WinNonLin v8.3, Certara, Princeton, NJ, USA). RAAS data were analyzed by jointly modeling RAAS components and time-to-discharge using the 'JM' package in R on the natural-log scale using linear mixed effects models with terms for treatment assignment, baseline values, and a linear term for day. Viral load was analyzed using linear mixed models with a visit-by-treatment group interaction and a global Wald test for overall treatment statistical significance.

Power and sample size: Due to a paucity of data at study design, we based expected variance of P/F on prior studies of viral-induced acute lung injury, considering standard deviations (SD) between 50-125. [32] [33] [34] [35] At a sample size of 200 with a 1:1 allocation ratio, we calculated 90% power to detect a difference of 70 in the P/F ratio assuming SD 150, and 80% to detect a 50-unit difference, assuming SD 125.

Of the 4,113 patients screened, 3,672 met exclusion criteria (Figure 1) . Of those eligible, 47% (208) provided consent to participate. Three developed post-enrollment exclusions, leaving 205 randomized participants (104 placebo and 101 losartan), representing the intent-to-treat cohort. All participants were followed until completion or withdrawal.

Demographics and clinical characteristics were fairly well matched ( Table 1) , though more patients in the losartan arm were enrolled in the ICU (16.8% vs 8.7%). Participants were middle aged (mean age 55 years) and racially and ethnically diverse (33% Black and 21% Hispanic). A high proportion were overweight (89%) or obese (63%), while almost half carried a preexisting diagnosis of hypertension (40%). All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Primary outcome data were missing in 15.4% of the placebo arm and 9.9% of the losartan arm, due to an inability to contact the participant on day 7 or participant failure to record pulse oximetry values. This difference reflects a higher proportion of participants discharged prior to day 7 in the placebo arm (59.6% vs. 48.5%). Three participants (2.9%) in the placebo arm and 2 (2.0%) in the intervention arm died prior to day 7.

Based on raw data, P/F ratio did not differ between the placebo and intervention arms We observed no difference in time to hospital discharge or in-hospital mortality ( Figure   3 ). By day 28, 11 participants in the intervention arm died vs 9 in the placebo arm, equilibrating to 11 in each group by day 90. There were no differences in freedom from oxygen or mechanical ventilation in the first 10 days following randomization, and the ordinal outcome did not differ between treatment groups (data not shown).

More patients in the losartan arm required vasopressors (20 versus 11, p = 0.08), contributing to fewer vasopressor-free days in the intervention group (8.7 versus 9.4, p = 0.04, Table 2 ). Adverse events did not differ significantly by treatment allocation (Supplementary Viral load did not differ by treatment (Supplementary Figure 1) . We detected no losartan or LCA in any placebo treated participant (n=3), while losartan and LCA pharmacokinetics were consistent with expected values in those treated with losartan (n=7;

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table 4 ).

In this multicenter, blinded, randomized, placebo-controlled clinical trial, 205 hospitalized participants with COVID-19 and acute lung injury not already taking RAAS inhibitors were randomized to oral losartan at its maximal FDA-approved dose to test the hypothesis that AT1R blockade improves pulmonary function. Despite a moderate to severely ill cohort, well matched P/F ratios, and pharmacologically relevant steady-state concentrations, we found no evidence that treatment with losartan improves lung injury or clinical outcomes, nor significantly affects major circulating RAAS components. We recently published our experience in an analogous trial in the outpatient setting. 30 Though this trial was terminated early, losartan did not reduce hospital admissions, dyspnea, nor quality of life. Given a relatively healthy cohort, a low prevalence of hypertension, and a low event rate, it remained unclear whether more severely ill patients with hypothetically greater Ang II expression relative to Ang-(1-7) might benefit from losartan. This trial advances those findings. Specifically, our results do not support the hypothesis that losartan effectively mitigates viral-induced acute lung injury in COVID-19, with uncertain implications for other, potentially more potent, agents that target the RAAS.

It is important to note that we observed two potentially harmful effects of losartan on hemodynamics and kidney function. However, a higher proportion of participants in the intervention arm were enrolled in the ICU, indicating potential small imbalances in severity of illness at enrollment. Further, while the losartan group was more likely to meet acute kidney injury criteria by KDIGO, this finding may indicate expected physiologic changes in intraglomerular blood flow rather than actual tissue injury per se. Nevertheless, in the absence of benefit and potential for harm, we conclude losartan treatment is not indicated in this setting. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In light of our results, it is important to consider the pharmacology and biochemical effects of the intervention. The observed pharmacokinetics of losartan and LCA are consistent with reported values 23 and maximal AT1R blockade. 39 As the half-lives of losartan and LCA are ~2 and 6 hours, and time to maximal concentrations were 1 and 4 hours, steady-state was achieved in the first day of dosing. Despite this, plasma Ang II and Ang-(1-7) concentrations and serum ACE and ACE2 activities were not affected. This may be interpreted that the intervention window was simply too narrow to observe the hypothesized biochemical effects.

Alternative explanations include poor specificity of circulatory RAAS (unknown tissue source) or relative lack of RAAS dysregulation at baseline in this population. 4 More recent observations may suggest SARS-CoV-2 does not induce unique, clinically relevant RAAS alterations, even in those who develop severe disease. Future analyses could investigate whether the circulatory RAAS is a mediator for treatment-induced effects on the outcomes. 40 These results stand in contrast to an open-label trial of telmisartan that demonstrated significantly reduced 30-day mortality in the treatment arm (4.3% vs 22.5%). 31, 36 However, that study was powered to detect a reduction in C-reactive protein, was unblinded, excluded ICU patients, and was terminated early due to slow recruitment, limiting the interpretation of the observed mortality reduction. Two additional trials, meanwhile, examined discontinuation versus continuation of RAAS inhibitors on admission for COVID-19, and found no significant differences between groups, further supporting current guidelines against routine discontinuation of these medications. 37, 38 Our study complements and advances these findings.

There are several limitations to consider with this study. The trial was initiated early in the pandemic, and temporal changes in clinical care including introduction of dexamethasone and remdesivir may have biased the trial towards the null. Our findings may also be consistent with the hypothesis that the RAAS does not play a significant role in SARS-CoV-2-related acute lung injury relative to other inflammatory pathways. Our choice of primary efficacy outcome required differential imputation methods based on whether or not the participant was treated All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262623 doi: medRxiv preprint with positive pressure ventilation, potentially affecting the results. However, the lack of effect on oxygen or mechanical ventilation-free days decreases the likelihood a larger study would identify clinically meaningful effects. While we detected sufficient concentrations of losartan, it remains possible lung parenchymal penetration is limited, mitigating potential efficacy. The relatively small sub-group undergoing RAAS measurement may have been underpowered to detect treatment effects. It remains possible that certain subgroups may benefit from ARB treatment that we could not identify due to inadequate subgroup sample size, including patients who may have RAAS dysregulation at baseline prior to infection. Finally, we cannot necessarily generalize these findings to other ARBs, ACE inhibitors, or other agents that modulate the RAAS. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262623 doi: medRxiv preprint Figure 3 -Time-to-event curves of hospital discharge and survival, comparing placebo (red lines) and losartan (blue lines). No statistically differences between groups were observed (p=0.258) All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262623 doi: medRxiv preprint Other/Unknown 6 (5.8%) 3 (3%) All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262623 doi: medRxiv preprint curve to 6 hours post dose; AUC 0-12h , estimated area under the concentration time curve to 12 hours post dose; CL/F, apparent oral clearance.

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. activity; Ang-(1-7) -angiotensin-(1-7) concentration; Ang II -angiotensin II concentration All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262623 doi: medRxiv preprint Supplementary Figure 1 -Effect of losartan on relative viral load (log10 scale); (relative viral load (RVL) is corrected to human marker DNA to control for specimen quality. Placebo is in red lines and losartan in blue lines with 95% CIs at each assessment. Losartan did not statistically significantly affect the cycle threshold or relative viral load overall or at any time point.

All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 28, 2021. ; https://doi.org/10.1101/2021.08.25.21262623 doi: medRxiv preprint

Live): 86,321,500 Cases and 1,865,798 Deaths from COVID-19 Virus Pandemic -Worldometer

Understanding the renin-angiotensinaldosterone-SARS-CoV axis: a comprehensive review

Immunomodulation in COVID-19

COVID-19, ACE2, and the cardiovascular consequences

Expression of ACE2, Soluble ACE2, Angiotensin I, Angiotensin II and Angiotensin-(1-7) Is Modulated in COVID-19 Patients

A pilot study to assess the circulating reninangiotensin system in COVID-19 acute respiratory failure

Letter to the Editor -Circulating plasma levels of angiotensin II and aldosterone in patients with coronavirus disease 2019 (COVID-19): A preliminary report

Angiotensin-converting enzyme 2 protects from severe acute lung failure

The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice

Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections

The Interplay between the Immune System, the Renin Angiotensin Aldosterone System (RAAS) and RAAS Inhibitors May Modulate the Outcome of COVID 19: A Systematic Review

Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19

Publish Ahead of Print

Mortality and Disease Severity Among COVID-19 Patients Receiving Renin-Angiotensin System Inhibitors: A Systematic Review and Meta-analysis

Angiotensin-converting enzyme inhibitors All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted

COVID-19 RISk and Treatments (CORIST) Collaboration. RAAS inhibitors are not associated with mortality in COVID-19 patients: Findings from an observational multicenter study in Italy and a meta-analysis of 19 studies

Cardiovascular Therapies, and COVID-19 Mortality: A Nationwide

Antihypertensive Drugs and COVID-19 Risk: A Cohort Study of 2 Million Hypertensive Patients

CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials

CDC. Symptoms of Coronavirus

Serial Evaluation of the SOFA Score to Predict Outcome in Critically Ill Patients

Derivation and validation of Spo2/Fio2 ratio to impute for Pao2/Fio2 ratio in the respiratory component of the Sequential Organ Failure Assessment score

The REDCap consortium: Building an international community of software platform partners

Clinical pharmacokinetics of losartan

Imputation of partial pressures of arterial oxygen using oximetry and its impact on sepsis diagnosis

Remdesivir for the Treatment of Covid-19 -Final Report

Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary

Severe Acute Respiratory Syndrome Coronavirus 2, COVID-19, and the Renin-Angiotensin System: Pressing Needs and Best Research Practices

Association between preterm birth and the reninangiotensin system in adolescence: influence of sex and obesity

Measurement of Angiotensin Peptides: HPLC-RIA. Methods All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity

Effect of Losartan on Symptomatic Outpatients with COVID-19: A Randomized Clinical Trial

R: A language and environment for statistical computing. R Foundation for Statistical Computing

The National Heart, Lung, and Blood Institute PETAL Clinical Trials Network. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome

An assessment of H1N1 influenza-associated acute respiratory distress syndrome severity after adjustment for treatment characteristics

Registry Group. Early corticosteroids in severe influenza A/H1N1 pneumonia and acute respiratory distress syndrome

H1N1 influenza A virus-associated acute lung injury: response to combination oseltamivir and prolonged corticosteroid treatment

Telmisartan for treatment of Covid-19 patients: an open randomized clinical trial

Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial

Continuation versus discontinuation of reninangiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial

Drug concentration response relationships in normal volunteers after oral administration of losartan, an angiotensin II receptor antagonist

Evaluating sources of bias in observational studies of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use during COVID-19: beyond confounding