Renin Angiotensin System Blockers and Risk of Mortality in Hypertensive Patients Hospitalized for COVID-19: An Italian Registry

Abstract

Background: It is uncertain whether exposure to renin-angiotensin system (RAS) modifiers affects the severity of the new coronavirus disease 2019 (COVID-19) because most of the available studies are retrospective.

Methods: We tested the prognostic value of exposure to RAS modifiers (either angiotensin-converting enzyme inhibitors [ACE-Is] or angiotensin receptor blockers [ARBs]) in a prospective study of hypertensive patients with COVID-19. We analyzed data from 566 patients (mean age 75 years, 54% males, 162 ACE-Is users, and 147 ARBs users) hospitalized in five Italian hospitals. The study used systematic prospective data collection according to a pre-specified protocol. All-cause mortality during hospitalization was the primary outcome.

Results: Sixty-six patients died during hospitalization. Exposure to RAS modifiers was associated with a significant reduction in the risk of in-hospital mortality when compared to other BP-lowering strategies (odds ratio [OR]: 0.54, 95% confidence interval [CI]: 0.32 to 0.90, p = 0.019). Exposure to ACE-Is was not significantly associated with a reduced risk of in-hospital mortality when compared with patients not treated with RAS modifiers (OR: 0.66, 95% CI: 0.36 to 1.20, p = 0.172). Conversely, ARBs users showed a 59% lower risk of death (OR: 0.41, 95% CI: 0.20 to 0.84, p = 0.016) even after allowance for several prognostic markers, including age, oxygen saturation, occurrence of severe hypotension during hospitalization, and lymphocyte count (adjusted OR: 0.37, 95% CI: 0.17 to 0.80, p = 0.012). The discontinuation of RAS modifiers during hospitalization did not exert a significant effect (p = 0.515).

Conclusions: This prospective study indicates that exposure to ARBs reduces mortality in hospitalized patients with COVID-19.

Keywords: ACE inhibitors; ACE2; COVID-19; SARS-CoV-2; angiotensin receptor blockers; angiotensin-converting enzyme inhibitors; renin–angiotensin system.

Figure 1

Risk of in-hospital death among hypertensive patients hospitalized for COVID-19 according to subgroups of antihypertensive therapy (upper panel). Survival curves (lower panel) were estimated using Kaplan–Meier product limit method and compared with the Mantel (log-rank) test. Legend: ACE-Is = ACE inhibitors; ARBs = angiotensin receptor blockers; BP = blood pressure; CI = confidence interval; OR = odds ratio.

Figure 2

Results of univariable analyses exploring predictors of in-hospital death. Legend: COPD = chronic obstructive pulmonary disease; CRP = C-reactive protein; eGFR = estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; WBC = white blood cell.

Figure 3

Effects of different blood pressure-lowering drugs on the probability (%) of in-hospital death according to different baseline risk strata (as identified by the presence of independent risk markers of prognosis).

Figure 4

Potential mechanisms of pharmacological modulation of the renin–angiotensin system to reduce the deleterious effects of angiotensin II accumulation. AI = angiotensin I; AII = angiotensin II; A_1,7 = angiotensin_1–7; ACE2 = angiotensin-converting enzyme 2; ACE-Is = ACE inhibitors; ARBs = angiotensin receptor blockers; ATR1 = angiotensin II type 1 receptor.