Angiotensin II receptor blocker intake associates with reduced markers of inflammatory activation and decreased mortality in patients with cardiovascular comorbidities and COVID-19 disease

Abstract

Aims: Patients with cardiovascular comorbidities have a significantly increased risk for a critical course of COVID-19. As the SARS-CoV2 virus enters cells via the angiotensin-converting enzyme receptor II (ACE2), drugs which interact with the renin angiotensin aldosterone system (RAAS) were suspected to influence disease severity.

Methods and results: We analyzed 1946 consecutive patients with cardiovascular comorbidities or hypertension enrolled in one of the largest European COVID-19 registries, the Lean European Open Survey on SARS-CoV-2 (LEOSS) registry. Here, we show that angiotensin II receptor blocker intake is associated with decreased mortality in patients with COVID-19 [OR 0.75 (95% CI 0,59-0.96; p = 0.013)]. This effect was mainly driven by patients, who presented in an early phase of COVID-19 at baseline [OR 0,64 (95% CI 0,43-0,96; p = 0.029)]. Kaplan-Meier analysis revealed a significantly lower incidence of death in patients on an angiotensin receptor blocker (ARB) (n = 33/318;10,4%) compared to patients using an angiotensin-converting enzyme inhibitor (ACEi) (n = 60/348;17,2%) or patients who received neither an ACE-inhibitor nor an ARB at baseline in the uncomplicated phase (n = 90/466; 19,3%; p<0.034). Patients taking an ARB were significantly less frequently reaching the mortality predicting threshold for leukocytes (p<0.001), neutrophils (p = 0.002) and the inflammatory markers CRP (p = 0.021), procalcitonin (p = 0.001) and IL-6 (p = 0.049). ACE2 expression levels in human lung samples were not altered in patients taking RAAS modulators.

Conclusion: These data suggest a beneficial effect of ARBs on disease severity in patients with cardiovascular comorbidities and COVID-19, which is linked to dampened systemic inflammatory activity.

Fig 1. Mortality risk in patients with CVD and hypertension.

Forrest plots of univariate and multivariate analysis for mortality risk for the given clinical characteristics of all included patients (A) and patients who presented in the uncomplicated phase at baseline (n = 1132) (B).

Fig 2. Mortality risk in patients with CVD and hypertension—Advanced disease.

Forrest plots of univariate and multivariate analysis for mortality risk for the given clinical characteristics of patients who presented in the complicated phase (n = 620) (A) and those who presented in the critical phase (n = 194) (B).

Fig 3. Kaplan-Meier analysis, patients with CVD and/or hypertension, baseline uncomplicated.

Association between intake of RAAS- modulating drugs and mortality by Kaplan–Meier analysis in patients in the uncomplicated phase. P-value is for log-rank test, n = 1132.

Fig 4. Biomarkers in all patients with CVD/Hypertension.

Percentage of patients above the mortality predicting threshold for biomarkers calculated by ROC analysis in all patients with cardiovascular disease or hypertension irrespective of disease phase at baseline for patients without RAAS-modulation, patients on ACE-inhibitors and patients taking ARBs. n-numbers and p-values are depicted above each panel.

Fig 5. Biomarkers in uncomplicated patients with CVD/Hypertension.

Percentage of patients above the mortality predicting threshold for biomarkers calculated by ROC analysis in patients in an uncomplicated stage of COVID-19 at baseline with cardiovascular disease for patients without RAAS-modulation, patients on ACEi and patients taking ARBs. n-numbers and p-values are depicted above each panel.

Fig 6. ACEi or ARB do not affect expression of ACE2 in lung epithelial cells.

(A) Lung stainings of patients without RAAS modulators, with ACEi treatment and ARB medication for ACE-2 (red), Hoechst (blue) and Ulex (white). (B) Quantification of ACE-2 expression mean intensity, arbitrary units. mean±SEM; Kruskal-Wallis-test.