Continuing versus suspending angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Impact on adverse outcomes in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)--The BRACE CORONA Trial

Abstract

Angiotensin-converting enzyme-2 (ACE2) expression may increase due to upregulation in patients using angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs). Because renin-angiotensin system blockers increase levels of ACE2, a protein that facilitates coronavirus entry into cells, there is concern that these drugs could increase the risk of developing a severe and fatal form of COVID-19. The impact of discontinuing ACEI and ARBs in patients with COVID-19 remains uncertain. DESIGN: BRACE CORONA is a pragmatic, multicenter, randomized, phase IV, clinical trial that aims to enroll around 500 participants at 34 sites in Brazil. Participants will be identified from an ongoing national registry of suspected and confirmed cases of COVID-19. Eligible patients using renin-angiotensin system blockers (ACEI/ARBs) with a confirmed diagnosis of COVID-19 will be randomized to a strategy of continued ACEI/ARB treatment versus temporary discontinuation for 30 days. The primary outcome is the median days alive and out of the hospital at 30 days. Secondary outcomes include progression of COVID-19 disease, all-cause mortality, death from cardiovascular causes, myocardial infarction, stroke, transient ischemic attack, new or worsening heart failure, myocarditis, pericarditis, arrhythmias, thromboembolic events, hypertensive crisis, respiratory failure, hemodynamic decompensation, sepsis, renal failure, and troponin, B-type natriuretic peptide (BNP), N-terminal-proBNP, and D-dimer levels. SUMMARY: BRACE CORONA will evaluate whether the strategy of continued ACEI/ARB therapy compared with temporary discontinuation of these drugs impacts clinical outcomes among patients with COVID-19.

Graphical abstract

Figure 1

A) Renin angiotensin system and COVID-19: The spike proteins covering the coronavirus bind to ACE2 receptors primarily on type II alveolar cells, allowing the virus to inject its RNA. The host cell is destroyed in this process. After infection, type II cells release inflammatory signals to recruit immune cells. When the immune system attacks the area of infection it also kills healthy alveolar cells. This may result in alveolar collapse due to loss of surfactant from type II cells and acute lung injury. In the renin-angiotensin-aldosterone system (RAAS), angiotensin I (Ang I) is converted to angiotensin II (Ang II) by ACE. Ang II mediates vasoconstrictive, pro-inflammatory, pro-oxidative and pro-thrombotic effects (possibly by increasing levels of PAI-1) through agonism of the Ang II type 1 receptor (AT1R). ACE2 converts Ang II to angiotensin (1–7), which finally binds to Mas receptor (MasR) and mediates many beneficial actions, including vasodilation and anti-inflammatory, anti-oxidant and anti-apoptotic effects. Thus, ACE2/Ang (1–7)/MasR axis has opposite actions to ACE/Ang II/AT1R axis. ACE2 limits the adverse vasoconstrictor and profibrotic effects of Ang II through its degradation and by counteracting its actions through the formation of Ang (1–7). SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity as a consequence of increased internalization and shedding of ACE2 from the cell surface further tipping the ACE/ACE2 balance to a predominant ACE/Ang II/AT1 axis signaling, in which Ang II may then foster pulmonary vasoconstriction and inflammatory and oxidative organ damage, ultimately progressing towards acute lung injury. (B) Effects of RAAS inhibition in COVID-19: There are different postulated mechanisms by which inhibition of the RAAS with an ACEI or ARB might be dangerous or protective in COVID-19. Hypothesis 1 — RAAS inhibition is harmful in COVID-19 (left). ACEI and ARBs could theoretically increase the risk of SARS-CoV-2 infection and more severe COVID-19 owing to the role of ACE2 as the viral binding site. Although ACEI and ARBs do not directly affect ACE2 activity, this premise is based in part on the findings in some studies that ACEI and ARBs may increase ACE2 levels and thus enhance viral entry. Hypothesis 2 — RAAS inhibition is protective in COVID-19 (right). ACEI and ARBs may mitigate COVID-19 by attenuating Ang II-mediated acute lung impairment. Decreasing production of Ang II with an ACEI or blocking Ang II–AT1R actions with an ARB may reduce the levels of prothrombotic substances (such as PAI-1) and intensify the formation of Ang (1–7) by ACE2 and activation of the MasR, which attenuates inflammation and fibrosis and consequently may attenuate lung damage. Abbreviations: ACE = angiotensin-converting enzyme; ACE2 = angiotensin-converting enzyme-2; ACEI = ACE inhibitor; Ang (1–7)=angiotensin 1–7; Ang I = Angiotensin I; Ang II = angiotensin II; AT1R = Ang II type 1 receptor; AT2 = type II alveolar cells; ARBs = angiotensin receptor blockers; COVID-19 = coronavirus disease 2019; MasR = Mas receptor; PAI-1 = plasminogen activator inhibitor 1; RAAS = renin-angiotensin-aldosterone system; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Figure 2

Design of the BRACE CORONA trial.

Figure 3

Study flowchart.

Figure 4

Study timelines.