Effect of Adding Losartan to Standard of Care Treatment on the Risk of Death and Icu Admission Among Hospitalized COVID-19 Patients: A Randomized Trial

Abstract

Background: Angiotensin-converting enzyme 2 (ACE2) is the host receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recognizing that angiotensin receptor blockers upregulate the expression of ACE2, it has been proposed that these drugs may have a beneficial effect in Covid-19.

Methods: We did an open-label randomized controlled trial to test whether addition of losartan to standard of care lowers the risk of death or intensive care unit (ICU) admission in patients with confirmed SARS-CoV-2 infection. The trial was run in a secondary hospital in Stockholm, Sweden between October 5th 2020 and June 21st 2021. Included patients were randomized using a 1:1 allocation ratio, to receive standard care or losartan in addition to standard care, using an electronic tool. The study was not blinded. The primary outcome was a composite of ICU admission or death within 28 days of admission.

Findings: The study was terminated for futility after a planned interim analysis. A total of 302 patients were included of whom 151 were assigned to each group. The primary outcome occurred in 12 (7·9%) in the intervention group and 17 (11·4%) in the standard-of-care group (risk difference, 3·5 percentage points; 95% confidence interval, −3·5-11). Among secondary outcomes, there were no differences between the groups in the occurrence of death (p=1·00), ICU admission (p=0·24), or the National Early Warning Scale 2 (NEWS2) score levels (p=0·15), but patients randomized to losartan treatment had a 6·7 percentage points lower risk of mechanical ventilation (95% confidence interval, 1·6-12·7) and 12·5 mg/L lower c-reactive protein concentration (95% confidence interval, 2·8-22 mg/L; p=0·01).

Interpretation: Addition of losartan to standard care treatment did not result in a lower occurrence of the primary outcome of death or ICU admission.

Trial Registration Details: ISCRTN register number: ISRCTN48734830 (2020-07-10). EudraCT number: 2020-002040-22.

Funding Information: No specific funding was acquired for the conduct of this study. Dr Edgren is supported by grants from Swedish Research Council (2017-01954), Region Stockholm (2020-0125) and clinical research appointment from Region Stockholm.

Declaration of Interests: All authors declare that they have no conflicts of interest.

Ethics Approval Statement: This was a single-center, investigator-initiated, open-label randomized controlled trial, performed at Södersjukhuset Hospital in Stockholm, Sweden. The research protocol (link to research protocol: ISRCTN48734830_Protocol_v5_22Jun2020 Alice[2103].pdf) was approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency (EudraCT number: 2020-002040-22) prior to enrolment of the first patient. The study was conducted following good clinical practice guidelines under the oversight of a data safety monitoring board. The study was designed in the spring of 2020, at a time when less data was available on the prognosis of hospitalized patients with Covid-19.

Keywords: COVID-19, losartan, angiotensin receptor blocker, ARB, hospitalized, in-hospital, SARS-CoV-2, RECOVER study, pandemic, RCT, randomized clinical trial