Comparison of infection risks and clinical outcomes in patients with and without SARS-CoV-2 lung infection under renin-angiotensin-aldosterone system blockade: Systematic review and meta-analysis

Abstract

Aims: Angiotensin-converting enzyme-2 (ACE2) is the receptor for SARS-CoV-2. Animal studies suggest that renin-angiotensin-aldosterone system (RAAS) blockers might increase the expression of ACE2 and potentially increase the risk of SARS-CoV-2 infection.

Methods and results: The effect of ACE inhibitor (ACEI) treatment on the pneumonia incidence in non-COVID-19 patients (25 studies, 330 780 patients) was associated with a 26% reduction of pneumonia risk (odds ratio [OR]: 0.74, P < .001). Pneumonia-related death cases in ACEI-treated non-COVID-19 patients were reduced by 27% (OR: 0.73, P = .004). However, angiotensin II receptor blockers (ARB) treatment (10 studies, 275 621 non-COVID-19 patients) did not alter pneumonia risk in patients. Pneumonia-related death cases in ARB-treated non-COVID-19 patients was analysed only in 1 study and was significantly reduced (OR, 0.47; 95% confidence interval, 0.30 to 0.72). Results from 11 studies (8.4 million patients) showed that the risk of getting infected with the SARS-CoV-2 virus was reduced by 13% (OR: 0.87, P = .014) in patients treated with ACEI, whereas analysis from 10 studies (8.4 million patients) treated with ARBs showed no effect (OR, 0.92, P = .354). Results from 34 studies in 67 644 COVID-19 patients showed that RAAS blockade reduces all-cause mortality by 24% (OR = 0.76, P = .04).

Conclusion: ACEIs reduce the risk of getting infected with the SARS-CoV-2 virus. Blocking the RAAS may decrease all-cause mortality in COVID-19 patients. ACEIs also reduce the risk of non-COVID pneumonia. All-cause mortality due to non-COVID pneumonia is reduced by ACEI and potentially by ARBs.

Keywords: ACE inhibitors; ACE2; SARS-CoV-2; angiotensin II receptor blockers.

FIGURE 1

In patients with severe pneumonia, there is likewise a compensatory activation of the RAAS, resulting in tachycardia and an elevation of SVR that may be deleterious in this setting. Tachycardia, which shortens the duration of diastole, impairs the filling of the left ventricle. An elevated SVR increases left ventricular afterload (wall stress), increasing myocardial oxygen demand. These changes can lead to a further increase in left ventricular end‐diastolic pressure and more edema formation. To the degree that pulmonary edema results in hypoxia, there maybe a further worsening of myocardial function. Besides these haemodynamic effects of an activated RAAS in critically ill patients with pneumonia, an activated RAAS promotes also inflammation in the lung and heart likewise contributing to impaired heart and lung function in these patients. This might explain our finding that all‐cause mortality in non‐COVID‐19 pneumonia patients was significantly reduced when blocking the RAAS in general either with ACEI or ARBs. ACEIs do have an additional effect that might be of clinical impact. They increase levels of substance P and bradykinins which can sensitise the sensory nerves of the airways and enhance the cough reflex which may have a protective role on the tracheobronchial tree. ACE2 is expressed in human lungs and COVID‐19 spike (S) protein seems to use it as a cellular entry receptor. It is still a research question whether age and the use of ACE inhibitors and/or ARBs could impact on ACE2 expression and consequently affect the infection pattern of COVID‐19. Another aspect is that ARBs might stabilize the ACE2‐AT1 receptor interaction and might prevent viral S protein‐ACE2 interaction and internalization. Clinical data indicated that SARS‐CoV‐2 infection related myocarditis and heart failure may negatively influence outcome of SARS‐CoV‐2 pneumonia. ACE inhibitor treatment reduces the risk of pneumonia and pneumonia related mortality, whereas ARBs do not reduce the risk of pneumonia in non‐COVID‐19 patients. RAAS blockade reduces severe adverse clinical outcomes and all‐cause mortality in COVID‐19 patients. RAAS = renin–angiotensin–aldosterone system, SVR = systemic vascular resistance; Ang = angiotensin, ACE = angiotensin converting enzyme, AT1 receptors = angiotensin 1 receptors, ARBs = angiotensin receptor blockers, MCRA = mineralocorticoid receptor antagonists, COVID‐19 = coronavirus disease 19

FIGURE 2

Forest plots for association between renin–angiotensin–aldosterone system inhibitors and risk of COVID‐19 infection

FIGURE 3

Forest plots for association between renin–angiotensin–aldosterone system inhibitors and risk of all‐cause mortality in COVID‐19 patients

FIGURE 4

Forest plots for association between renin–angiotensin–aldosterone system inhibitors and COVID‐19 related severe adverse clinical outcomes defined as admission to the intensive care unit, the use of assisted ventilation, or death