key: cord-329779-5sauq4gp
authors: Sanchis-Gomar, Fabian; Lavie, Carl J.; Perez-Quilis, Carme; Henry, Brandon M.; Lippi, Giuseppe
title: In Reply – Association of Renin Angiotensin System Blockers with Outcomes in Patients With COVID-19
date: 2020-09-14
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.09.011
sha: 
doc_id: 329779
cord_uid: 5sauq4gp

nan

To the Editor: Current guidelines and health professional recommendations endorse the continuation of both anti-hypertensives angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) for managing hypertension (HTN) during the COVID-19 pandemic. We have repeatedly emphasized that it is highly unlikely that the use of ACEI/ARBs would be associated with increased severity or mortality risk in patients with COVID-19. 1, 2 In the meta-analysis of Garg et al., 3 which included studies published until May 31, 2020, both mortality or severe disease risk were not increased among J o u r n a l P r e -p r o o f patients using ACEIs/ARBs. However, it was noted that administration of these drugs might reduce mortality in patients with HTN.

In a recent study, not included in their meta-analysis, López-Otero et al. 4 Finally, in a recent systematic review, Nunes 6 concluded that the use of ACEIs is not associated with higher rates of COVID-19 mortality, recommending additional clinical trials to confirm the safety profile of these drugs in this setting.

In a recent study performed by members of our group, the circulating levels of angiotensin II (AngII) were measured in patients with COVID-19. 7 Despite a case series from China which reported extremely high AngII in patients with COVID-19, 8 in our cohort of 30 COVID-19 patients, circulating AngII were normal regardless of COVID-19 severity, with no significant differences between COVID-19 patients and healthy controls. 7 Although circulating levels of AngII may not reflect the local lung milieu, it seems unlikely that AngII is a driver of systemic disease in COVID-19. Though ACE2 expression is likely attenuated by SARS-CoV-2 binding, this data suggests that AngII is readily metabolized in alternative metabolic pathways, resulting in normal circulating levels. This finding is consistent with the clinical study by López-Otero et al. 4 in which no beneficial association of ACEI/ARB use was found for COVID-19 severity or mortality, as would be expected given the normal circulating J o u r n a l P r e -p r o o f levels of AngII. We hence suggest that the potential benefits of ACEI/ARB usage observed in some COVID-19 studies may be more attributable to effective intervention for a modifiable risk factor for poor COVID-19 outcomes (i.e. HTN), with efficacious therapy minimizing HTN-induced endothelial dysfunction and end-organ injury that would otherwise be susceptible to further deterioration with SARS-CoV-2 infection.

Only retrospective observational studies regarding the potentially deleterious effects of ACEIs/ARBs in COVID-19 patients have been conducted to-date, and these findings need to be confirmed in prospective randomized controlled trials (RCT). To the best of our knowledge, there are several ongoing RCTs, and new and more reliable results will emerge shortly. Studies in randomized COVID-19 patients like the BRACE CORONA trial (NCT04364893), evaluating whether continuing or interrupting ACEI/ARB therapy, are underway; results from this study will be presented at the forthcoming European Society of Cardiology meeting. Overall, due to the lack of evidence on negative mortality effects of ACEI/ARB in COVID-19 patients, we reaffirm our previous advice that discontinuing these drugs for managing HTN at the time of COVID-19 pandemic remains clinically unjustified. 

In Reply -Angiotensin-Converting Enzyme 2 and the Resolution of Inflammation: In Support of Continuation of Prescribed Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers

Angiotensin-Converting Enzyme 2 and Anti-Hypertensives (Angiotensin Receptor Blockers and Angiotensin Converting Enzyme Inhibitors) in Coronavirus Disease 2019 (COVID-19)

Association of Renin Angiotensin System Blockers with Outcomes in Patients with Covid-19

Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on COVID-19 in a western population. CARDIOVID registry

Age and Multimorbidity Predict Death Among COVID-19 Patients: Results of the SARS-RAS Study of the Italian Society of Hypertension

Mortality and use of angiotensin converting enzyme inhibitors in Covid 19 disease -a systematic review

Circulating plasma levels of angiotensin II and aldosterone in patients with coronavirus disease 2019 (COVID-19): A preliminary report

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury