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      Losartan in hospitalized patients with COVID-19 in North America: An individual participant data meta-analysis

      research-article
      , MS a , , PhD b , c , , ScD d , , MD, PhD, MS e , , BS c , , PhD, MPH f , , MPH c , , MD, MSc g , , MD, MPH h , , PharmD i , , MD, MS j , k , , MD g , , PhD l , , MD, MS m , , RN, BS h , , MD n , o , , MD c , , MD h , p , * ,
      Medicine
      Lippincott Williams & Wilkins
      angiotensin receptor antagonists, angiotensin-converting enzyme inhibitors, COVID-19, individual participant data meta-analysis, losartan, SARS-CoV-2

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          Background:

          Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) have been hypothesized to benefit patients with COVID-19 via the inhibition of viral entry and other mechanisms. We conducted an individual participant data (IPD) meta-analysis assessing the effect of starting the ARB losartan in recently hospitalized COVID-19 patients.

          Methods:

          We searched ClinicalTrials.gov in January 2021 for U.S./Canada-based trials where an angiotensin-converting enzyme inhibitors/ARB was a treatment arm, targeted outcomes could be extrapolated, and data sharing was allowed. Our primary outcome was a 7-point COVID-19 ordinal score measured 13 to 16 days post-enrollment. We analyzed data by fitting multilevel Bayesian ordinal regression models and standardizing the resulting predictions.

          Results:

          325 participants (156 losartan vs 169 control) from 4 studies contributed IPD. Three were randomized trials; one used non-randomized concurrent and historical controls. Baseline covariates were reasonably balanced for the randomized trials. All studies evaluated losartan. We found equivocal evidence of a difference in ordinal scores 13-16 days post-enrollment (model-standardized odds ratio [OR] 1.10, 95% credible interval [CrI] 0.76–1.71; adjusted OR 1.15, 95% CrI 0.15–3.59) and no compelling evidence of treatment effect heterogeneity among prespecified subgroups. Losartan had worse effects for those taking corticosteroids at baseline after adjusting for covariates (ratio of adjusted ORs 0.29, 95% CrI 0.08–0.99). Hypotension serious adverse event rates were numerically higher with losartan.

          Conclusions:

          In this IPD meta-analysis of hospitalized COVID-19 patients, we found no convincing evidence for the benefit of losartan versus control treatment, but a higher rate of hypotension adverse events with losartan.

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          Most cited references31

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          RoB 2: a revised tool for assessing risk of bias in randomised trials

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            ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions

            Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomised Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.
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              Remdesivir for the Treatment of Covid-19 — Final Report

              Abstract Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)
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                Author and article information

                Contributors
                Journal
                Medicine (Baltimore)
                MD
                Medicine
                Lippincott Williams & Wilkins (Hagerstown, MD )
                0025-7974
                1536-5964
                09 June 2023
                09 June 2023
                09 June 2023
                : 102
                : 23
                : e33904
                Affiliations
                [a ] Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
                [b ] Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
                [c ] Division of Brain Injury Outcomes, Johns Hopkins School of Medicine, Baltimore, MD
                [d ] Division of Biostatistics, Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, UT
                [e ] University of Colorado Denver, Anschutz Medical Campus, Denver, CO
                [f ] Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
                [g ] Department of Internal Medicine, University of Kansas Medical Center, KS City, KS
                [h ] Bassett Research Institute, Bassett Medical Center, Cooperstown, NY
                [i ] Department of Research, Sharp Healthcare, San Diego, CA
                [j ] Department of Emergency Medicine, University of Minnesota, Minneapolis, MN
                [k ] Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, MN
                [l ] School of Population Health, University of New South Wales, The George Institute for Global Health, Sydney, NSW, Australia
                [m ] Department of Surgery, University of Minnesota, Minneapolis, MN
                [n ] Department of Medicine, Brigham and Women’s Hospital, Boston, MA
                [o ] Harvard Medical School, Boston, MA
                [p ] Department of Internal Medicine, Division of Infectious Diseases, Bassett Medical Center, Cooperstown, NY.
                Author notes
                * Correspondence: Daniel Freilich, Bassett Medical Center, 1 Atwell Road, Cooperstown, NY 13326 (e-mail: daniel.freilich@ 123456bassett.org ).
                Author information
                https://orcid.org/0000-0001-8366-9882
                https://orcid.org/0000-0002-2219-6900
                Article
                00039
                10.1097/MD.0000000000033904
                10256351
                0679f19f-62be-4759-aeb9-7d82d02e8b9b
                Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                : 30 December 2022
                : 10 May 2023
                : 11 May 2023
                Categories
                4900
                Research Article
                Systematic Review and Meta-Analysis
                Custom metadata
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                angiotensin receptor antagonists,angiotensin-converting enzyme inhibitors,covid-19,individual participant data meta-analysis,losartan,sars-cov-2

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