Renin–Angiotensin–Aldosterone System Inhibitors in Patients with COVID-19: General Considerations and Clinical Implications

Initially reported in China at the end of 2019, the coronavirus pandemic has now reached an international scale with more than 1.5 million cases worldwide and more than 80,000 deaths by April 8th of this year. Recent studies have shown that the virus invades host cells by the angiotensin-converting enzyme 2 receptor, making it essential to viral transmission. Concerns have been raised about possible benefits and harms associated with the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptors blockers in these patients. However, there is lack of evidence to recommend even temporarily discontinuing reninangiotensin system inhibitors/blockers in patients infected with the SARS-CoV-2.


INTRODUCTION
Initially reported in China at the end of 2019, the coronavirus pandemic has now reached an international scale with more than 1.5 million cases worldwide and more than 80,000 deaths by April 8 th of this year 1 . Most patients who end up in the intensive care unit (ICU) have significant lung deterioration and require mechanical ventilation.
However, cardiac complications including myocardial ischemia, myocarditis and cardiac dysfunction have also been described and can substantially increase the mortality rate 2 .
Recent studies showed that COVID-19 virus invades host cells by the angiotensin-converting enzyme 2 (ACE2) receptor, making it essential to viral transmission 3 . The virus uses the ACE2 receptor, downregulating the reninangiotensin-aldosterone system (RAS) and thus, the modulation of this process could have implications in disease progression 4 .

COVID-19, SARS and ACE2
ACE2 is present in multiple organs and is directly associated with heart function and the development of diabetes and hypertension 5 . As is known from classic previous studies, ACE inhibitors (ACEIs) have an important role in the treatment of cardiovascular disease, significantly reducing morbidity and mortality in patients with heart failure 6-9 , for which the same is seen with the use of renin-angiotensin system (RAS) antagonist medications 10,11 .
Because of this association of COVID-19 with the ACE2 receptor, there are concerns of possible benefits and harms associated with the use of ACE inhibitors and angiotensin receptors blockers (ARBs) in infected patients.
Since the first outbreak of SARS-related coronavirus in 2003, the ACE2 protein was known as a receptor for the SARS-CoV virus 12 . Due to this association, when scientists initially isolated the new virus (SARS-CoV-2) and published the genome sequence collected from the first five patients in Wuhan, China, the hypothesis of ACE2 being a cellular entry receptor was formulated. The results confirmed that only cells expressing ACE2 receptor could be infected 13 . Given this mechanism, a concern about the use of RAS antagonists, which can potentially increase the expression of ACE2 leading to an increased virus infection, was raised in the medical community. The correlation between elevated plasma levels of ACE2 and the severity of lung injury in COVID-19 infected patients 14 also corroborated this concern. Despite the existence of a feasible and plausible mechanism, there is no evidence to support this potential effect in humans. Many studies have investigated elevated ACE2 levels in patients with cardiovascular diseases including poor biventricular performance 15 , left atrium remodeling 16 and myocardial fibrosis among patients with severe aortic stenosis 17 , yet, none were able to demonstrate that ACEI/ARB use had any influence. Only one study assessed the long-term effect of ACEIs/ARBs on the treatment of patients with hypertension: Olmesartan is the only drug found to have an increased ACE2 level in the urine 18 .
All this data was produced using animal experiments, preclinical observation studies and trials of patients not infected with the new SARS-CoV-2. Nearly four months after the first cases described in December 2019, and the worldwide spread of the virus, initial retrospective cohorts show a high prevalence of hypertension from 13% in nonsevere patients 19 up to 30% among hospitalized patients 20,21 . Based on this, a considerable number of patients are expected to be taking ACEIs and ARBs. Meng and colleagues retrospectively analyzed 42 patients (17 of them on ACEIs or ARBs) admitted to a single center in China for which both groups had an equal number of severe disease presentations and baseline characteristics. Considering the limitations of a small retrospective analysis, the RAS group had better clinical and laboratorial outcomes than the non-RAS group 13 . Another retrospective analysis of 112 patients with SARS-CoV-2 performed in Wuhan found that the use of ACEIs or ARBs had no effect on mortality and morbidity 22 . These findings reinforce the idea presented by Liu et al. who proposed that in patients infected with the COVID-19, angiotensin II plasma levels are directly correlated with viral load and lung injury -suggesting the use of ARBs as a potential treatment for these patients 14 .

ACEIs/ARBs and GUIDELINES
ACEIs and ARBs have been widely used worldwide for decades. Their benefits in heart disease, hypertension and kidney disease are well known.
ACEIs have shown decreasing mortality, morbidity and hospitalizations regardless of the etiology and severity of the heart failure with reduced ejection fraction (HFrEF) 23 recommend ACEIs for all patients with HFrEF unless contraindicated [25][26][27] . ACEIs should be started as soon as the patient is diagnosed with HFrEF and should not be discontinued even if left ventricle function improves 28 . Therefore, in times of pandemic, when access to the healthcare system is limited, changing ACEI long term treatment is risky and can be fatal in patients with HFrEF.

CONCLUSION
In summary, based on the evidence presented by current studies up until April 8 th of 2020, there is lack of evidence to recommend even temporarily discontinuing RAS antagonists in patients infected with the SARS-CoV-2 as well as to prescribe them for all patients. The use of this class of drugs as potential treatment to modulate plasma ACE2 levels is not yet clearly elucidated and requires further clinical trials for before such conclusions can be made.