The Effects of ARBs, ACEis, and Statins on Clinical Outcomes of COVID-19 Infection Among Nursing Home Residents

Abstract

Objectives: Angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs), and HMG-CoA reductase inhibitors ("statins") have been hypothesized to affect COVID-19 severity. However, up to now, no studies investigating this association have been conducted in the most vulnerable and affected population groups (ie, older adults residing in nursing homes). The objective of this study was to explore the association of ACEi/ARB and/or statins with clinical manifestations in COVID-19-infected older adults residing in nursing homes.

Design: We undertook a retrospective multicenter cohort study to analyze the association between ACEi/ARB and/or statin use with clinical outcome of COVID-19. The outcomes were (1) serious COVID-19 defined as long-stay hospital admission or death within 14 days of disease onset, and (2) asymptomatic (ie, no disease symptoms in the whole study period while still being diagnosed by polymerase chain reaction).

Setting and participants: A total of 154 COVID-19-positive subjects were identified, residing in 1 of 2 Belgian nursing homes that experienced similar COVID-19 outbreaks.

Measures: Logistic regression models were applied with age, sex, functional status, diabetes, and hypertension as covariates.

Results: We found a statistically significant association between statin intake and the absence of symptoms during COVID-19 (odds ratio [OR] 2.91; confidence interval [CI] 1.27-6.71), which remained statistically significant after adjusting for covariates (OR 2.65; CI 1.13-6.68). Although the effects of statin intake on serious clinical outcome were in the same beneficial direction, these were not statistically significant (OR 0.75; CI 0.24-1.87). There was also no statistically significant association between ACEi/ARB and asymptomatic status (OR 2.72; CI 0.59-25.1) or serious clinical outcome (OR 0.48; CI 0.10-1.97).

Conclusions and implications: Our data indicate that statin intake in older, frail adults could be associated with a considerable beneficial effect on COVID-19 clinical symptoms. The role of statins and renin-angiotensin system drugs needs to be further explored in larger observational studies as well as randomized clinical trials.

Keywords: Angiotensin-converting enzyme inhibitors; COVID-19; angiotensin II receptor blockers; nursing home residents; statins.

Fig. 1

Three mechanisms suggested for the effects of statins and ACEis/ARBs in preventing severe pulmonary disease in COVID-19. (1) Under normal conditions the Tie-2 receptor is continuously activated by Angiopoetin-1 (Angpt-1), which in turn activates Akt-kinase, leading to phosphorylation and hence inhibition of the transcription factor Foxo1. Unphosphorylated or active Foxo1 initiates the transcription of genes leading to increased inflammation, decreased endothelial barrier integrity, and hypercoagulability. Angpt-2 is a partial antagonist of the Tie-2 receptor, stimulating inflammation, endothelial dysfunction and hypercoagulability. COVID-19 infection and ARDS are associated with increased Angpt-2 levels in blood, whereas statins simulate the Angpt-1 pathways. (2) The RAS system activates angiotensin-1 receptors (AT1R), stimulating inflammation, hypercoagulability, and endothelial permeability. The Ang II-ACE2-Ang(1–7)-Mas receptor pathway counteracts the effects of this RAS system. COVID-19 enters the cell through ACE2 receptors, thereby decreasing these membrane-bound receptors, and relatively stimulating the RAS system. ACEis/ARBs inhibit the RAS system, while concomitantly increasing ACE-2 expression, which protects against ARDS. Statins also increase ACE-2 expression. (3) In ARDS, there is an increase in the activation of the MyD88-NFkB inflammatory pathway. Statins preserve MyD88 at normal levels and downregulate NFkB. Black lines = stimulating effects; red lines = inhibiting effects.

Supplementary Fig. 1

(A) Monte Carlo simulations (10,000 simulations) for the association statin-asymptomatic status with feature hypertension as changing variable. Random samples of the total cohort (n = 154) were taken with change of the hypertension status for all subjects of this sample. For each sample, the OR for statin intake and asymptomatic status adjusted for age, gender, functional status, diabetes mellitus, and hypertension was calculated. The y-axis shows these ORs: boxplots represent median (midline), 25% and 75% percentiles (upper and lower perimeters) and 1.5× interquartile range (whiskers). The x-axis indicates the chosen sample size. A horizontal line at y = 1 represents the line of no effect. (B) Monte Carlo simulations (10,000 simulations) for the association statin-asymptomatic status with feature functional status as changing variable. Random samples of the residents with a Katz scale indicating a small decrease in functional status or unknown status (n = 56) were taken with change of the functional status for all subjects of this sample. For each sample, the OR for statin intake and asymptomatic status adjusted for age, gender, functional status, diabetes mellitus, and hypertension was calculated. The y-axis shows these ORs: boxplots represent median (midline), 25% and 75% percentiles (upper and lower perimeters), and 1.5× interquartile range (whiskers). The x-axis indicates the chosen sample size. A horizontal line at y = 1 represents the line of no effect.