A randomized controlled trial of renin-angiotensin-aldosterone system inhibitor management in patients admitted in hospital with COVID-19

Abstract

Background: Renin-angiotensin aldosterone system inhibitors (RAASi) are commonly used among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection coronavirus disease 2019 (COVID-19). We evaluated whether continuation versus discontinuation of RAASi were associated with short term clinical or biochemical outcomes.

Methods: The RAAS-COVID-19 trial was a randomized, open label study in adult patients previously treated with RAASi who are hospitalized with COVID-19 (NCT04508985). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]) and the intention-to-treat principle.

Results: Overall, 46 participants were enrolled; 21 participants were randomized to discontinue RAASi and 25 to continue. Patients' mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a non-statistically different mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); P = .60). The negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.67 [95% CI 1.06-2.62]; P = .027); RAASi discontinuation increased brain natriuretic peptide levels (% change from baseline: +16.7% vs -27.5%; P = .024) and the incidence of acute heart failure (33% vs 4.2%, P = .016).

Conclusion: RAASi continuation in participants hospitalized with COVID-19 appears safe; discontinuation increased brain natriuretic peptide levels and may increase risk of acute heart failure; where possible, RAASi should be continued.

Copyright © 2022 Elsevier Inc. All rights reserved.

Figures

Figure 1

Clinical trial flow diagram. ACEi, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; EF, ejection fraction; eGFR, estimated glomerular filtration rate (mL/min/1.73m2); RAASi, renin-angiotensin-aldosterone system inhibitors.

Figure 2

Distribution of global rank scores between treatment arms. Lower score indicates clinical stability, higher scores indicate worsened outcomes. Boxes indicate the percentage of individuals at end of follow up with a specific score. Components of the global rank score includes: Components of the global rank score included: death; transfer to ICU for invasive ventilation or other indication; non-fatal major adverse cardiovascular events (any of: myocardial infarction, ischemic or hemorrhagic stroke, acute decompensated heart failure, or new onset atrial fibrillation); length of stay >4 days; development of acute kidney injury (>40% decline in eGFR or doubling of serum Cr from baseline); urgent intravenous treatment for high blood pressure/hypertensive crisis; or changes in biomarkers from baseline: >30% increase in high sensitivity troponin from baseline, >30% increase in BNP; >30% increase in CRP; or lymphocyte count drop >30%. The P-value for comparison using Wilcoxon test .6; P-value for comparison between the treatment arms with negative binomial .027. BNP, brain natriuretic peptide; CRP, c-reactive protein; eGFR, estimated glomerular filtration rate; ICU, intensive care unit.

Figure 3

Box plot of score by randomized group. Lower score indicates clinical stability, higher scores indicate worsened outcomes. Vertical line through the box indicates the median. Edge of the box indicates the quartiles. Whiskers indicate minimum and maximum. CI, confidence interval; IRR, incident rate ratio.

Figure 4

Relative change in biomarker changes across randomization groups, A) High-sensitivity troponin I, P-value for comparison using ANCOVA test .469. B) Brain natriuretic peptide, P-value for comparison using ANCOVA test .024. C) C-Reactive Protein, P-value for comparison using ANCOVA test .608. D) Lymphocyte count, P-value for comparison using ANCOVA test .925. ANCOVA, analysis of covariance.

Figure 5

Distribution of global rank score by randomized groups and ACEi/ARB at baseline. ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker.