Abstract
BackgroundRetrospective studies on the use of Renin-Angiotensin-Aldosterone System blockade in patients with Coronavirus Disease 2019 (COVID-19) have been informative but conflicting, and prospective studies are required to demonstrate the safety, tolerability, and outcomes of initiating these agents in hospitalized patients with COVID-19 and hypertension.Methods and findingsThis is a single center feasibility study encompassing two cohorts: (1) prospective cohort (April 21, 2020 to May 29, 2020) and (2) retrospective cohort (March 7, 2020 to April 1, 2020) of hospitalized patients with real-time polymerase chain reaction (PCR) positive SARS-CoV-2 by nasopharyngeal swab. Key inclusion criteria include BP > 130/80 and a requirement of supplemental oxygen with FiO2 of 25% or higher to maintain SpO2 > 92%. Key exclusion criteria included hyperkalemia and acute kidney injury (AKI) at the time of enrollment. Prospective cohort consisted of de novo initiation of losartan and continuation for a minimum of 7 days and assessed for adverse events (AKI, hyperkalemia, transaminitis, hypotension) and clinical outcomes (change in SpO2/FiO2 and inflammatory markers, need for ICU admission and mechanical ventilation). Retrospective cohort consisted of continuation of losartan (prior-to-hospitalization) and assessment of similar outcomes. In the prospective cohort, a total of 250 hospitalized patients were screened and inclusion/exclusion criteria were met in 16/250 patients and in the retrospective cohort, a total of 317 hospitalized patients were screened and inclusion/exclusion criteria were met in 14/317 patients. Most common adverse event was hypotension, leading to discontinuation in 3/16 (19%) and 2/14 (14%) patients in the prospective and retrospective cohort. No patients developed AKI in the prospective cohort as compared to 1/14 (7%) patients in the retrospective cohort, requiring discontinuation of losartan. Hyperkalemia occurred in 1/16 (6%) and 0/14 patients in the prospective and retrospective cohorts, respectively. In the prospective cohort, 3/16 (19%) and 2/16 (13%) patients required ICU admission and mechanical ventilation. In comparison, 3/14 (21%) required ICU admission and mechanical ventilation in the retrospective cohort. A majority of patients in both cohorts (14/16 (88%) and 13/14 (93%) patients from the prospective and retrospective cohort) were discharged alive from the hospital. A total of 9/16 (prospective) and 5/14 (retrospective) patients completed a minimum 7 days of losartan. In these 9 patients in the prospective cohort, a significant improvement in SpO2/FiO2 ratio was observed from day 1 to 7. No significant changes in inflammatory markers (initiation, peak, and day 7) were observed in either cohort.ConclusionIn this pilot study we demonstrate that losartan was well-tolerated among hospitalized patients with COVID-19 and hypertension. We also demonstrate the feasibility of patient recruitment and the appropriate parameters to assess the outcomes and safety of losartan initiation or continuation, which provides a framework for future randomized clinical trials.
Highlights
To date, there are more than 20 million infected individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with more than 750,000 global deaths [1]
No significant changes in inflammatory markers were observed in either cohort. In this pilot study we demonstrate that losartan was well-tolerated among hospitalized patients with COVID-19 and hypertension
We demonstrate the feasibility of patient recruitment and the appropriate parameters to assess the outcomes and safety of losartan initiation or continuation, which provides a framework for future randomized clinical trials
Summary
There are more than 20 million infected individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with more than 750,000 global deaths [1]. In COVID-19, SARS-CoV-2 uses Angiotensin Converting Enzyme 2 (ACE2) as a receptor to gain viral entry into the host cell [5]. The use of ACE inhibitors (ACEi)/angiotensin receptor blockers (ARB) has been associated with increased expression of ACE2 receptor in some animal models [6], and, as such, was initially postulated to enhance viral entry into the host cell. It is postulated that binding of SARS-CoV-2 to ACE2 receptor enhances Angiotensin II (Ang II)-mediated activation of Angiotensin II Type 1 receptor (AT1R), leading to increased inflammation and fibrosis [9]. More recent studies in rodent models demonstrate that these antiinflammatory, anti-fibrotic, and vasodilatory effects are, in part, mediated via Ang 1–9 activation of the Angiotensin II Type 2 receptor (AT2R) [12, 13]. Retrospective studies on the use of Renin-Angiotensin-Aldosterone System blockade in patients with Coronavirus Disease 2019 (COVID-19) have been informative but conflicting, and prospective studies are required to demonstrate the safety, tolerability, and outcomes of initiating these agents in hospitalized patients with COVID-19 and hypertension
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