By 1 April 1, 2020, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),1–4 known as COVID-19 (coronavirus disease 2019), had spread to over 200 countries, infecting more than 1 million people, and was designated a global pandemic by the World Health Organization.5

Although the infection can cause severe disease in anyone, one of the largest analyses conducted to date,6 reported more severe outcomes (intensive care unit [ICU] admission, mechanical ventilation, and death) in patients with hypertension, coronary artery disease, and diabetes.

The interaction of SARS-CoV-2 and the renin-angiotensin-aldosterone system is a cornerstone in COVID-19 infection. The virus links to membrane-bound angiotensin-converting enzyme 2 (ACE2) and is internalized in the cells by transmembrane proteases.7,8 Angiotensin I upregulates a metalloprotease (ADAM-17) that increases the solubility of ACE2 (a form not valid for SARS-CoV-2 binding)9,10 and also releases proinflammatory cytokines that downregulate ACE2 cell surface expression, reducing the ability of SARS-CoV-2 to cause damage.11

Given the possible increased susceptibility of patients taking ACEI in the COVID-19 pandemic, it has been proposed that they should discontinue this medication.12 At this moment, the impact of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) on the clinical course of COVID-19 is controversial.3,7,13–17 When the current study was being performed, scientific societies and government agencies were recommending continuing with this treatment, due to the lack of evidence for the hypothesis.18,19

There is a lack of evidence in this field, and most of the available data are based on observational studies conducted in China; none have been based on a whole population, and there is little information on how the virus affects the western population.

From 10 March to 6 April, 965 patients (0.22%) were diagnosed with COVID-19 out of the 447 979 inhabitants of the area covering the university hospital. Of COVID-19 patients, 234 (24.25%) needed hospitalization; among these patients, 33 (14.1%) required ICU admission. During the study period, 38 patients died (3.94%), of whom 35 (3.6%) had heart failure (figure 1, figure 2 and figure 3).

Figure 1.

Events in the COVID-19 positive cohort depending on the type of treatment. ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.

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Figure 2.

Events in the COVID-19 hospitalized cohort depending on the type of treatment. ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers.

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Figure 3.

Hospital admissions according to type of treatment. ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; ICU, intensive care unit.

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Of the total population, 72 527 (16.19%) were under chronic treatment with ACEI (26 617 [36.7%] or ARB (48 085 [66.3%]). Of the COVID-19 patients, 210 (21.8%) were under ACEI or ARB treatment at the time of diagnosis; of these, 165 (78.57%) were taking them for more than 1 year. The age and sex distribution of the population with COVID-19 involvement are summarized in table 1.

Table 2 summarizes the baseline characteristics of COVID-19 patients and provides a comparison of the cohort under ACEI/ARB treatment and that not receiving this treatment. The cohort of patients under ACEI/ARB was older (72.1± 13.2 vs 56.0± 20.5; P <.01) and had more cardiovascular risk factors (hypertension, diabetes, smoking, and dyslipidemia) and cardiovascular comorbidities (coronary artery diseases and ventricular dysfunction) than the cohort without ACEI/ARB. There were fewer women in the ACEI/ARB group (43.8% vs 59.5%; P <.01). Renal impairment and peripheral vasculopathy were also more prevalent in patients taking ACEI/ARB. On admission, patients with previous treatment with ACEI/ARB had lower oxygenation (peripheral O2 saturation under 95% in 31.9% vs 19.7%; P <.01; respiratory insufficiency in 43.9% vs 26.9%, P <.01) and had higher creatinine and troponin levels. Figure 1 and figure 2 show the events in all COVID-19 patients and in those who were admitted. Figure 3 shows hospital admissions according to type of treatment.

Table 3 shows that, on univariate analysis, treatment with ACEI/ARB (combined and individually) significantly increased in the risk of hospitalization, but this association disappeared both in the multivariate analysis with logistic regression and in that performed in the model created with propensity score matching to adjust for potential risk arguments. Hospitalized patients under ACEI/ARB showed more frequent need for more ICU admissions.

Previous treatment with ACEI/ARB (combined and individually) showed no impact on mortality or on heart failure, either in the multivariate analysis or in the propensity score-adjusted model. Taking the treatment for more than 1 year also had no effect (table 4). When we analyzed only the subgroup of patients requiring hospitalization, the absence of an impact on mortality and on heart failure remained both in the multivariate analysis and in the propensity score model, including in the evaluation of treatment taken for more than 1 year (table 5). The lack of effect remained when we applied the same models to the combined endpoint of mortality and heart failure (table 6).

To our knowledge, this is one of the few studies that analyzes the impact of ACEI/ARB on COVID-19 prognosis based on a large western-world population that includes all positive cases in a health area. This is also the largest cohort of patients studied to date.

The main findings are the neutral effect of ACEI/ARB on mortality, heart failure, and the combination of mortality and heart failure. Previous treatment with ACEI/ARB in patients with COVID-19 showed no association with the need for hospitalization or ICU admission. Taking ACEI/ARB for more than 1 year also had no effect. All these findings were confirmed, both in the overall analysis of the sample and in the propensity score model. Based on these data, withdrawal of chronic treatment with ACEI/ARB in patients testing positive for COVID-19 would not be justified. The available data on the effect of ACEI/ARB on mortality in patients with COVID-19 have focused mainly on cohorts of admitted patients and especially on hypertensive patients.22,23

SARS-CoV-2 enters the cells through a glycoprotein of its crown, which binds to the ACE2 of the alveoli pneumocytes,7,13 leading to its internalization after priming by the transmembrane protease, serine 2.7,8 After the virus enters the cell, it releases its RNA and proteins, leading to the development of new viral particles. ACE2 is 2% in a soluble form—not valid for SARS-CoV-2 binding—, after cleavage by ADAM-17. Angiotensin I upregulates ADAM-17, thus increasing soluble ACE2 levels.9,10 Furthermore, ADAM-17 also mediates the release of membrane-bound precursors of proinflammatory cytokines (tumor necrosis factor-α, interferon-γ, and interleukin-4) into the circulation. The interaction between SARS-CoV-2 and ACE2 triggers a massive production of proinflammatory cytokines, which attracts leucocytes and hyperactive macrophages that release more cytokines, inducing the obliteration of the alveoli and developing the characteristic hyaline membranes of acute respiratory distress syndrome.3,7,13,17 Therefore, downregulation of ACE2 cell surface expression reduces the ability of ARS-CoV-2 to cause damage.11 ACE inhibitors and ARB are highly recommended drugs for patients with cardiovascular diseases, such as refractory hypertension, heart failure, and coronary artery disease.18,19 Chronic treatment with these medications increases the expression of ACE.24–26 Based on this mechanism, some authors have hypothesized that persistent downregulation of the renin-angiotensin-aldosterone system may cause harm by increasing ACE2 expression.12,14 On the other hand, angiotensin II takes part in the immune response to acute respiratory distress syndrome, so its depuration though ACE2 may be beneficial.15–17 When this study was being performed, scientific societies and government agencies were recommending continuing with this treatment.18,19 This advice is supported by the results of this study, upgrading the expert-consensus recommendation to an evidence-based one according to a registry with all cases of COVID-19 infection from a western health area. An ongoing randomized clinical trial with losartan in these patients will help us to make a stronger recommendation (NCT04312009 and NCT04311177).27

To obtain an overall picture of the relevance of these results, we highlight that in the area where the study was conducted, 72 527 (16.19%) of the inhabitants were under chronic treatment with ACEI or ARB. Out of the COVID-19 patients, 210 (21.8%) were under ACEI or ARB at the time of diagnosis. According to the latest estimates, it is likely that by the end of the year, up to 70% of the Spanish population will have been infected by this new coronavirus,28 hence the importance of identifying the effects of these widely used drugs on the prognosis of this new disease.

Withdrawal of chronic treatment with ACEI/ARB in patients testing positive for COVID-19 would not be justified. In line with the recommendations of scientific societies and government agencies, this study supports continuation of this treatment.

The authors declare that there is no conflict of interest regarding the publication of this article.