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

26 Pages Posted: 17 Feb 2021

See all articles by Michael Puskarich

Michael Puskarich

Hennepin County Medical Center - Emergency Medicine

Nathan W. Cummins

Mayo Clinic - Division of Infectious Diseases

Nicholas Ingraham

University of Minnesota - Minneapolis - Division of Pulmonary, Allergy, Critical Care and Sleep Medicine

David A. Wacker

University of Minnesota - Minneapolis - Division of Pulmonary, Allergy, Critical Care and Sleep Medicine

Ron Reilkoff

University of Minnesota - Minneapolis - Division of Pulmonary, Allergy, Critical Care and Sleep Medicine

Brian E. Driver

Hennepin County Medical Center - Department of Emergency Medicine

Michelle H. Biros

University of Minnesota - Minneapolis - Department of Emergency Medicine

Fernanda Bellolio

Mayo Clinic - Division of Infectious Diseases

Jeffrey G. Chipman

University of Minnesota - Minneapolis - Department of Surgery

Andrew C. Nelson

University of Minnesota - Minneapolis - Department of Laboratory Medicine and Pathology

Kenneth B. Beckman

University of Minnesota - Minneapolis - University of Minnesota Genomics Center

Ryan Langlois

University of Minnesota - Minneapolis - Department of Microbiology and Immunology

Tyler Bold

University of Minnesota - Minneapolis - Division of Infectious Diseases

Matthew T. Aliota

University of Minnesota - Twin Cities - Department of Veterinary and Biomedical Sciences

Timothy W. Schacker

University of Minnesota - Minneapolis - Division of Infectious Diseases

Helen T. Voelker

University of Minnesota - Minneapolis - Department of Biostatistics

Thomas A. Murray

University of Minnesota - Minneapolis - Division of Biostatistics

Joseph S. Koopmeiners

University of Minnesota - Minneapolis - Department of Biostatistics

Christopher Tignanelli

University of Minnesota - Minneapolis - Institute for Health Informatics; University of Minnesota - Minneapolis - Department of Surgery; North Memorial Health Hospital - Department of Surgery

More...

Abstract

Background: The SARS-CoV-2 virus enters cells via the ACE2 receptor, disrupting the renin-angiotensin-aldosterone axis, potentially contributing to lung injury. Treatment with angiotensin receptor blockers(ARBs) may mitigate these effects, though induction of ACE2 expression could increase viral entry, replication, and worsen disease.

Methods: This study represents a placebo-controlled blinded randomized clinical trial (RCT) to test the efficacy of losartan on outpatients with COVID-19 across three hospital systems in Minnesota, U.S. Participants included symptomatic outpatients with COVID-19 not already taking ACE-inhibitors or ARBs, enrolled within 7 days of symptom onset. Patients were randomized to losartan versus placebo for 10 days. The primary outcome was all-cause hospitalization within 15 days. Secondary outcomes included functional status, dyspnea, temperature, and viral load.

Findings: From April-November 2020, 117 participants were randomized 58 to losartan and 59 to placebo. The primary outcome did not differ significantly between the two arms based on Barnard’s test [losartan arm: 3 events (5.2%; 95% CI 1.8-14.1%) versus placebo arm: 1 event (1.7% 95% CI 0.01-9.0%); proportion difference -3.5% (95% CI -12.7-4.5%); p=0.32]. Functional status, self-reported dyspnea, maximum daily temperatures, and viral load were not significantly different between treatment groups. Due to a lower than expected hospitalization rate and low likelihood of a clinically important treatment effect, the trial was terminated early.

Interpretation: In this multicenter blinded RCT for outpatients with mild symptomatic COVID-19 disease, losartan did not significantly reduce hospitalizations, affect functional status or assessment of dyspnea. Viral load was not significantly affected by treatment. This study does not support initiation of losartan for low-risk outpatients.

Trial Registration: The trial was conducted under the authority of the Food and Drug Administration (IND 148365), was registered on clinicaltrials.gov prior to study initialization (NCT04311177).

Funding Statement: This study was supported by Minnesota Partnership for Biotechnology and Medical Genomics (CON000000076883)

Declaration of Interests: The authors have no financial conflicts of interest to disclose. MAP, MHN, TWS, and CJT have received additional funding from the Bill and Melinda Gates Foundation to conduct a clinical trial of losartan in inpatients with COVID-19.

Ethics Approval Statement: The protocol was approved by a central institutional review board and underwent local context review. The study was conducted following good clinical practice guidelines under the oversight of an independent data safety monitoring board (DSMB).

Keywords: COVID-19, clinical trial, RAAS, losartan, angiotensin receptor blocker, hospitalization, dyspnea, viral load

Suggested Citation

Puskarich, Michael and Cummins, Nathan W. and Ingraham, Nicholas and Wacker, David A. and Reilkoff, Ron and Driver, Brian E. and Biros, Michelle H. and Bellolio, Fernanda and Chipman, Jeffrey G. and Nelson, Andrew C. and Beckman, Kenneth B. and Langlois, Ryan and Bold, Tyler and Aliota, Matthew T. and Schacker, Timothy W. and Voelker, Helen T. and Murray, Thomas A. and Koopmeiners, Joseph S. and Tignanelli, Christopher, Effect of Losartan on Symptomatic Outpatients with COVID-19: A Randomized Clinical Trial. Available at SSRN: https://ssrn.com/abstract=3787463 or http://dx.doi.org/10.2139/ssrn.3787463

Michael Puskarich (Contact Author)

Hennepin County Medical Center - Emergency Medicine ( email )

Nathan W. Cummins

Mayo Clinic - Division of Infectious Diseases ( email )

200 First Street SW
Rochester, MN (507) 284-2511 55905
United States

Nicholas Ingraham

University of Minnesota - Minneapolis - Division of Pulmonary, Allergy, Critical Care and Sleep Medicine ( email )

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

David A. Wacker

University of Minnesota - Minneapolis - Division of Pulmonary, Allergy, Critical Care and Sleep Medicine ( email )

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Ron Reilkoff

University of Minnesota - Minneapolis - Division of Pulmonary, Allergy, Critical Care and Sleep Medicine ( email )

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Brian E. Driver

Hennepin County Medical Center - Department of Emergency Medicine ( email )

Michelle H. Biros

University of Minnesota - Minneapolis - Department of Emergency Medicine ( email )

United States

Fernanda Bellolio

Mayo Clinic - Division of Infectious Diseases ( email )

200 First Street SW
Rochester, MN (507) 284-2511 55905
United States

Jeffrey G. Chipman

University of Minnesota - Minneapolis - Department of Surgery ( email )

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Andrew C. Nelson

University of Minnesota - Minneapolis - Department of Laboratory Medicine and Pathology ( email )

Minneapolis, MN
United States

Kenneth B. Beckman

University of Minnesota - Minneapolis - University of Minnesota Genomics Center ( email )

Ryan Langlois

University of Minnesota - Minneapolis - Department of Microbiology and Immunology ( email )

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Tyler Bold

University of Minnesota - Minneapolis - Division of Infectious Diseases ( email )

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Matthew T. Aliota

University of Minnesota - Twin Cities - Department of Veterinary and Biomedical Sciences ( email )

420 Delaware St. SE
Minneapolis, MN 55455
United States

Timothy W. Schacker

University of Minnesota - Minneapolis - Division of Infectious Diseases ( email )

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Helen T. Voelker

University of Minnesota - Minneapolis - Department of Biostatistics ( email )

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Thomas A. Murray

University of Minnesota - Minneapolis - Division of Biostatistics ( email )

Joseph S. Koopmeiners

University of Minnesota - Minneapolis - Department of Biostatistics ( email )

110 Wulling Hall, 86 Pleasant St, S.E.
308 Harvard Street SE
Minneapolis, MN 55455
United States

Christopher Tignanelli

University of Minnesota - Minneapolis - Institute for Health Informatics

Minneapolis, MN
United States

University of Minnesota - Minneapolis - Department of Surgery ( email )

420 Delaware St. SE
Minneapolis, MN 55455
United States
(612) 625-7911 (Phone)

North Memorial Health Hospital - Department of Surgery

Robbinsdale, MN
United States