In reply— Association of Renin-Angiotensin System Blockers with Outcomes in Patients With COVID-19

To The Editor:

Current guidelines and health professional recommendations endorse the continuation of both antihypertensives angiotensin-converting-enzyme (ACE) inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for managing hypertension (HTN) during the COVID-19 pandemic. We have emphasized repeatedly that it is highly unlikely that the use of ACEIs and 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 and risk of severe disease were not increased among patients using ACEIs and 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 al⁴ retrospectively evaluated 965 patients diagnosed with COVID-19; 210 of these patients were using ACEI or ARB drugs. These authors also concluded that treatment with ACEIs and ARBs was not associated with mortality (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.17 to 2.26; P=.486), heart failure (OR, 1.37; 95% CI, 0.39 to 4.77; P=.622), rate of hospitalization (OR, 0.85; 95% CI, 0.45 to 1.64; P=.638), admission to intensive care units (OR, 0.87; 95% CI, 0.30 to 2.50; P=.798), or major acute cardiovascular events (OR, 1.06; 95% CI, 0.39 to 2.83; P=.915). In another observational study (NCT04331574) of 1591 patients, Iaccarino et al⁵ reported that ACEI and ARB therapy does not significantly contribute to increasing COVID-19 fatalities. Finally, in a recent systematic review, Nunes⁶ 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 that reported extremely high levels of AngII in patients with COVID-19,⁸ in our cohort of 30 patients with COVID-19, circulating AngII levels were normal regardless of COVID-19 severity, with no significant differences between patients with COVID-19 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. Although ACE2 expression is likely attenuated by severe acute respiratory syndrome (SARS-CoV-2) binding, these data suggest 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 or ARB use was found for COVID-19 severity or mortality, as would be expected, given the normal circulating levels of AngII. Hence, we suggest that the potential benefits of ACEIs and ARBs observed in some COVID-19 studies may be more attributable to effective intervention for a modifiable risk factor for poor COVID-19 outcomes (ie, 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 and ARBs in patients with COVID-19 have been conducted to date, and these findings need to be confirmed in prospective randomized controlled trials (RCTs). 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—such as the BRACE CORONA trial (NCT04364893), evaluating whether to continue or interrupt ACEI or ARB therapy—are underway. Results from this study will be presented at the forthcoming European Society of Cardiology meeting. Overall, owing to the lack of evidence on negative effects on mortality of ACEIs and ARBs in patients with COVID-19, we reaffirm our previous advice that discontinuing these drugs for managing HTN at the time of COVID-19 pandemic remains clinically unjustified.