Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19

Michael Pan, Alexi Vasbinder, Elizabeth Anderson, Toniemarie Catalan, Husam R Shadid, Hanna Berlin, Kishan Padalia, Patrick O'Hayer, Chelsea Meloche, Tariq U Azam, Ibrahim Khaleel, Erinleigh Michaud, Pennelope Blakely, Abbas Bitar, Yiyuan Huang, Lili Zhao, Rodica Pop-Busui, Sven H Loosen, Athanasios Chalkias, Frank Tacke, Evangelos J Giamarellos-Bourboulis, Jochen Reiser, Jesper Eugen-Olsen, Salim S Hayek, ISIC Group, Michael Pan, Alexi Vasbinder, Elizabeth Anderson, Toniemarie Catalan, Husam R Shadid, Hanna Berlin, Kishan Padalia, Patrick O'Hayer, Chelsea Meloche, Tariq U Azam, Ibrahim Khaleel, Erinleigh Michaud, Pennelope Blakely, Abbas Bitar, Yiyuan Huang, Lili Zhao, Rodica Pop-Busui, Sven H Loosen, Athanasios Chalkias, Frank Tacke, Evangelos J Giamarellos-Bourboulis, Jochen Reiser, Jesper Eugen-Olsen, Salim S Hayek, ISIC Group

Abstract

Background Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) is thought to affect COVID-19 through modulating levels of angiotensin-converting enzyme 2, the cell entry receptor for SARS-CoV2. We sought to assess the association between ACEi/ARB, biomarkers of inflammation, and outcomes in patients hospitalized for COVID-19. Methods and Results We leveraged the ISIC (International Study of Inflammation in COVID-19), identified patients admitted for symptomatic COVID-19 between February 1, 2020 and June 1, 2021 for COVID-19, and examined the association between in-hospital ACEi/ARB use and all-cause death, need for ventilation, and need for dialysis. We estimated the causal effect of ACEi/ARB on the composite outcomes using marginal structural models accounting for serial blood pressure and serum creatinine measures. Of 2044 patients in ISIC, 1686 patients met inclusion criteria, of whom 398 (23.6%) patients who were previously on ACEi/ARB received at least 1 dose during their hospitalization for COVID-19. There were 215 deaths, 407 patients requiring mechanical ventilation, and 124 patients who required dialysis during their hospitalization. Prior ACEi/ARB use was associated with lower levels of soluble urokinase plasminogen activator receptor and C-reactive protein. In multivariable analysis, in-hospital ACEi/ARB use was associated with a lower risk of the composite outcome of in-hospital death, mechanical ventilation, or dialysis (adjusted hazard ratio 0.49, 95% CI [0.36-0.65]). Conclusions In patients hospitalized for COVID-19, ACEi/ARB use was associated with lower levels of inflammation and lower risk of in-hospital outcomes. Clinical trials will define the role of ACEi/ARB in the treatment of COVID-19. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

Keywords: ACE inhibitors; COVID‐19; angiotensin receptor blockers; mortality; outcomes.

Figures

Figure 1. Cumulative incidence of outcomes by…
Figure 1. Cumulative incidence of outcomes by in‐hospital use of ACEi/ARB.
Bar graphs showing the cumulative incidence of death, need for mechanical ventilation, and need for renal replacement therapy by in‐hospital use of ACEi/ARB. ACEi/ARB indicates angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker.
Figure 2. In‐hospital ACEi/ARB use and risk…
Figure 2. In‐hospital ACEi/ARB use and risk of death, need for mechanical ventilation, and need for renal replacement therapy.
Bar graph depicting the odds ratio (OR) and 95% CI for the 3 different outcomes using 3 different models to calculate odds ratios. Model 0 was unadjusted. Model 1 was adjusted for age, sex, race, BMI, diabetes, hypertension, coronary artery disease, congestive heart failure, admission GFR, and institution. Model 2 incorporated the aforementioned variables in addition to mean arterial pressure on presentation. ACEi/ARB indicates angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker; BMI, body mass index; and GFR, glomerular filtration rate.
Figure 3. Weighted Kaplan‐Meier curve comparing survival…
Figure 3. Weighted Kaplan‐Meier curve comparing survival by in‐hospital ACEi/ARB use.
Weighted Kaplan‐Meier curve depicting survival probabilities of combined outcome of death, need for mechanical ventilation, or dialysis by in‐hospital ACEi/ARB over 30 days of hospitalization. Based on marginal structural model with weights accounting for age, sex, race, BMI, diabetes, hypertension, coronary artery disease, congestive heart failure, and serial measurements of blood pressure and serum creatinine. ACEi/ARB indicates angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker; and BMI, body mass index.
Figure 4. Hazard ratio of the combined…
Figure 4. Hazard ratio of the combined outcome of death, need for mechanical ventilation or dialysis for in‐hospital ACEi/ARB use stratified by subgroups.
Forest plot showing the hazard ratios for the combined outcome of death, need for mechanical ventilation, or dialysis for in‐hospital ACEi/ARB use stratified by subgroups using a time‐dependent Cox proportional hazards model. †P value for test of interaction. ACEi/ARB indicates angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker; and BMI, body mass index.

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