key: cord-0869274-knz2pzqx
authors: Kerneis, Mathieu; Ferrante, Arnaud; Guedeney, Paul; Vicaut, Eric; Montalescot, Gilles
title: Severe acute respiratory syndrome coronavirus 2 and renin-angiotensin system blockers: A review and pooled analysis
date: 2020-10-22
journal: Arch Cardiovasc Dis
DOI: 10.1016/j.acvd.2020.09.002
sha: 7984c74833c35d2ddf1b835ee00f1e3b9c367488
doc_id: 869274
cord_uid: knz2pzqx

A novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing an international outbreak of respiratory illness described as coronavirus disease 2019 (COVID-19). SARS-CoV-2 infects human cells by binding to angiotensin-converting enzyme 2. Small studies suggest that renin-angiotensin system (RAS) blockers may upregulate the expression of angiotensin-converting enzyme 2, affecting susceptibility to SARS-CoV-2. This may be of great importance considering the large number of patients worldwide who are treated with RAS blockers, and the well-proven clinical benefit of these treatments in several cardiovascular conditions. In contrast, RAS blockers have also been associated with better outcomes in pneumonia models, and may be beneficial in COVID-19. This review sought to analyse the evidence regarding RAS blockers in the context of COVID-19 and to perform a pooled analysis of the published observational studies to guide clinical decision making. A total of 21 studies were included, comprising 11,539 patients, of whom 3417 (29.6%) were treated with RAS blockers. All-cause mortality occurred in 587/3417 (17.1%) patients with RAS blocker treatment and in 982/8122 (12.1%) patients without RAS blocker treatment (odds ratio 1.00, 95% confidence interval 0.69–1.45; P = 0.49; I² = 84%). As several hypotheses can be drawn from experimental analysis, we also present the ongoing randomized studies assessing the efficacy and safety of RAS blockers in patients with COVID-19. In conclusion, according to the current data and the results of the pooled analysis, there is no evidence supporting any harmful effect of RAS blockers on the course of patients with COVID-19, and it seems reasonable to recommend their continuation.

J o u r n a l P r e -p r o o f 4

Since December 2019, a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an international outbreak of respiratory illness described as coronavirus disease 2019 (COVID- 19) . The full spectrum of COVID-19 is still being depicted [1, 2] , but at least 20.5 million confirmed cases of COVID-19 and 740,000 deaths had been reported worldwide by the end of August 2020. First clinical reports from China noted that individuals with cardiovascular disease infected with SARS-CoV-2 may be at higher risk of developing severe forms of COVID-19 [1, [3] [4] [5] [6] [7] , with increased mortality [8] . Although the baseline medications of these patients were not reported, they would probably have included a renin-angiotensin system (RAS) blocker, such as angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) [9] . The main effect of these antihypertensive drugs is to reduce the angiotensin II vasoconstrictor effect [10] ; they may also cause upregulation of expression of angiotensin-converting enzyme 2 (ACE2) [11] . This may be important in the context of the COVID-19 pandemic, as SARS-CoV-2 infects human cells by binding to ACE2, which acts as a co-receptor for cellular viral entry [2, [12] [13] [14] [15] . In contrast, RAS blockers have been also associated with better outcomes in pneumonia models, and may be beneficial in COVID-19 [16] [17] [18] [19] . International scientific societies recommend continuing these treatments based on previous trials that demonstrated a clear benefit of RAS blockers in several cardiovascular conditions and the lack of evidence against their use in the particular setting of COVID-19 [20] . Recently, several large dedicated observational studies have demonstrated an absence of association between the use of RAS blockers and the risk of infection by SARS-CoV-2 or the severity of the infection [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] . These studies need to be confirmed by randomized trials, but provide reassuring data for clinicians.

The aims of this review were to report the updated evidence to guide physicians' clinical decision making, to present a pooled analysis of the published observational studies evaluating all-cause mortality of patients with COVID-19 according to treatment with RAS blockers and to provide the latest information on ongoing clinical research related to RAS blocker treatments in patients with J o u r n a l P r e -p r o o f 5 

The RAS regulates blood pressure and fluid and electrolyte balance [31, 32] . In response to a reduction in renal blood flow, a sympathetic nervous system stimulation or a diminution in sodium delivery to the macula densa, renin is secreted by the juxtaglomerular cells of the kidneys, converting angiotensinogen, produced in the liver, into angiotensin I (Fig. 1) . Angiotensin I, an inactive peptide, is then converted into angiotensin II by the angiotensin-converting enzyme (ACE) present on the surface of vascular endothelial cells, predominantly in the lungs. It should be noted that there are other ACE-independent pathways that produce angiotensin II:

angiotensin I can be converted by chymase or chymostatin-sensitive angiotensin II-generating enzyme (CAGE) [33] ; and angiotensinogen can be converted directly to angiotensin II by serine proteases, such as cathepsin-G or tissue plasminogen activator (t-PA) [34, 35] . Therefore, the plasma concentrations of angiotensin II remain normal in patients receiving chronic treatment with ACE-I [10] .

Angiotensin II can bind with two types of receptors: mostly angiotensin II type 1 (AT1), but also angiotensin II type 2 (AT2). The AT2 receptor-mediated effects are physiologically antagonistic to those mediated by the AT1 receptor (Table 1) . After binding to AT1, angiotensin II induces vasoconstriction of arterioles and secretion of aldosterone and vasopressin, leading to an increase in blood pressure, mainly through vasoconstriction, promotion of fibrosis and water and sodium reabsorption [36] . Angiotensin II may also contribute to endothelial dysfunction and enhance the oxidation and uptake of low-density lipoprotein by macrophages and endothelial cells, thus promoting atherosclerosis [36] . Conversely, when binding to AT2 receptors, angiotensin II may lead to vasodilation and natriuresis, and prevent inflammation or fibrosis [37] .

Finally, ACE2, a homologue of ACE that is highly expressed in the cardiovascular, renal, testicular and gastrointestinal systems, as well as in lung cells [38] [39] [40] [41] , negatively regulates the RAS, converting angiotensin I into angiotensin (1-9) and angiotensin II into angiotensin (1-7), with potent vasodilatory, anti-inflammatory, has been hypothesized that the increase in angiotensin II levels following therapy with ARBs (but not ACE-I), by increasing the substrate load on ACE2, is responsible for its upregulation [57] . This hypothesis is unlikely, given the number of ACE2 substrates and the low level of angiotensin II variations. It has been demonstrated in murine neuroblastoma cells that treatment with angiotensin II is associated with an acute decrease in ACE2 activity, which was prevented by treatment with losartan, suggesting that AT1 receptor blockade potentially plays a role [58] . The less consistent effect of ACE-I on ACE2 also seems to be tissue dependent, as they have been demonstrated to increase ACE2 activity in kidneys in a murine model [59] , and to increase intestinal ACE2 mRNA levels in patients treated with ACE-I compared with in those on ARBs [60] . Nevertheless, discrepancies between ACE2 mRNA levels and ACE2 activity have been reported [11, 59, 61] , and the circulating and urinary levels of ACE2 are not a good indicator of the activity of the membrane-bound form. Thus, ACE-I and ARBs may have different influences on the course of SARS-CoV-2 infection. In addition, data regarding the effect of RAS blockers on ACE2 expression in lungs are lacking. It should be noted however, that SARS-CoV infection was reported in in vitro models of ACE2-negative cells, whereas some ACE2-positive cells were spared, suggesting that other receptors, co-receptors or mechanisms are involved in the interaction between cells and virus [62] .

Finally, the concerns about the use of RAS blockers in the context of COVID-19 are also based on observational studies. Individuals infected with SARS-CoV-2 with a history of diabetes, hypertension or cardiovascular disease appear to have a higher risk of developing a severe form of COVID-19, with higher mortality [1, [3] [4] [5] [6] [7] . In the landmark Chinese cohort study (n = 1099 patients), 23.7% of the individuals with confirmed COVID-19 had hypertension, 16.2% had diabetes and 8% had ischaemic heart disease or cerebrovascular disease [4] . In another study from Wuhan, China, the most common co-morbidities of 32 nonsurvivors from a group of 52 patients with COVID-19 admitted to an intensive care unit were diabetes (22%) and cardiovascular disease (22%) [8] . In another Chinese case series of 187 patients with confirmed COVID-19, 35 .3% had underlying cardiovascular disease, including hypertension, coronary heart disease and cardiomyopathy. The mortality rate of patients treated with RAS blockers was numerically higher compared with patients without ACE-I or ARBs (36.8% vs 25.6%, respectively), albeit not reaching statistical significance [63] . The continuation of RAS blockers could also enhance acute kidney injury, a frequent complication (3-15%) among individuals with severe COVID-19 [1, 4, 7, [64] [65] [66] . Major drawbacks of these studies were that adjusted multivariable analyses were not performed, and that confounding factors, such as age or a coexisting condition J o u r n a l P r e -p r o o f 8 (e.g. hypertension, diabetes, obesity or chronic organ failure), can explain these results. Finally, whereas chronic medications of individuals infected with COVID-19 were not reported in the vast majority of these observational studies [1, 4, 7, 8, [64] [65] [66] , the Patient-Centered Evaluative Assessment of Cardiac Events (PEACE) study on 1.7 million adults in China recently reported that 30.1% of the Chinese adults aged 35-75 years with systemic hypertension received antihypertensive medication, with RAS blockers being the second most commonly used treatment, concerning 28.5% of patients [9] .

Hypotheses regarding the facilitating role of RAS blockers in SARS-CoV-2 infection should be analysed cautiously because they come from non-randomized trials with many confounding factors or from small in vitro or animal studies. In contrast, RAS blockers may also have several beneficial effects in patients with COVID-19.

ACE2 has been shown to reduce inflammation [46] and RAS blockers have been associated, in animal studies, with a reduction in severe lung injury in the setting of viral pneumonias [16] [17] [18] [19] . The binding of the SARS-CoV-2 spike protein to ACE2 leads to ACE2 downregulation in the infected cells, leading to an increased effect of angiotensin II, which induces pulmonary vasoconstriction and increases pulmonary vascular permeability by overstimulation of AT1 receptor, thus promoting lung injury [17, 18, 67] . Interestingly, high levels of plasma angiotensin II were reported in patients with COVID-19, and were associated with total viral load and degree of lung injury [68] . Therefore, AT1 receptor blockade, by increasing ACE2 expression and angiotensin (1) (2) (3) (4) (5) (6) (7) production and reducing angiotensin II deleterious effects, could have the potential to prevent lung injury [16, 19, 69] .

Recently, dedicated observational studies have reported reassuring findings. In a Chinese cohort enrolling 1128 adult patients with hypertension (including 188 patients taking ACE-I or ARBs) and hospitalized for COVID-19, RAS blockers were independently associated with a reduction in the 28-day all-cause mortality rate compared with other antihypertensive drugs (adjusted hazard ratio 0.42, 95% confidence interval [CI] 0.19-0.92; P = 0.03) [29] . In another study from the Wuhan region, among 1178 patients, 30.7% were hypertensive, of whom 31.8% were taking ACE-I or ARBs. No association was found between the use of RAS blockers and the severity of COVID-19 or the fatality rate [23] . An Italian case-control study among 6272 patients with SARS-CoV-2 infection demonstrated that cases were more likely to be treated with ACE-I or ARBs than controls, but also with other antihypertensive drugs, because of a higher prevalence of cardiovascular observational study in New York, among 12,594 patients tested for COVID-19, 5894 (46.8%) had a positive test, 1002 (17.0%) had a severe form and 4357 (34.6%) were hypertensive, of whom 634 (24.6%) had a severe illness. Previous treatment with RAS blockers was not associated with a higher risk of testing positive for COVID-19 or of a severe form of the disease [27] . In another study, among 1705 patients with SARS-CoV-2 infection, eight deaths occurred in the ACE-I/ARBs group (3.8%) and 34 in the control group (2.1%) [25] . Finally, a UK study involving 1200 patients with COVID-19 reported a lower rate of death or transfer to a critical illness unit among those treated with ACE-I or ARBs (odds ratio 0.63, 95% CI 0.47-0.84; P < 0.01) [21] .

Finally, RAS blocker treatment is beneficial in case of heart failure, type 1 or 2 myocardial infarction or myocarditis, which are common complications of COVID-19, where the presence of acute cardiac injury has been reported in up to 10% of patients [6, 7] . In an autopsy study of patients who died from SARS infection, viral RNA was present in heart samples from 35% of the patients, and was associated with marked reductions in ACE2 protein expression [70] . In one murine model, ACE2 deficiency was associated with adverse left ventricular remodelling after myocardial infarction by potentiation of angiotensin II effects [71] . As a result, it may be hypothesized that although the heart may be particularly affected by SARS-CoV strains, discontinuation of RAS blockers in patients with COVID-10 could render them even more vulnerable to early and late complications.

Any potential risk associated with ACE-I should also be balanced by the well-described adverse impact of discontinuing RAS blockers in individual patients with systemic hypertension or established cardiovascular disease [72] [73] [74] [75] . In the Get With The Guidelines Heart Failure (GWTG-HF) registry, discontinuation of RAS blockers among patients hospitalized for acute heart failure with reduced ejection fraction was associated with high rates of mortality or readmission after discharge [73] . The Withdrawal of Pharmacological Treatment for Heart Failure in Patients with Recovered Dilated Cardiomyopathy (TRED-HF) trial demonstrated clinical worsening 6 months after withdrawal of heart failure medications (including RAS blockers) among patients with recovered dilated cardiomyopathy [74] . In a study including African Americans with heart failure with reduced ejection fraction, RAS blocker dose reduction or discontinuation was associated with a longer median length of hospital stay [76] . In a study evaluating ACE-I treatment following myocardial infarction, a high incidence of ischaemia-related events occurred after ACE-I withdrawal, suggesting a rebound phenomenon [77] . In a study evaluating haemodynamic and hormonal responses to captopril therapy among seven patients, captopril withdrawal resulted in abrupt increases in circulating angiotensin II levels, arterial pressure, pulse rate and plasma norepinephrine, but without a decrease in cardiac function [78] .

RAS blockers have also demonstrated some benefits in several conditions in major clinical trials ( 

We conducted a pooled analysis to evaluate the effect of ACE-I/ARBs on all-cause mortality in patients with A total of 21 studies were included, comprising a total of 11,539 patients, of whom 3417 (29.6%) were treated with RAS blockers (Fig. A.2 ). The main characteristics of the included studies are detailed in Table A. 3.

All-cause mortality occurred in 587/3417 (17.1%) and 982/8122 (12.1%) patients with and without RAS blocker treatment, respectively (odds ratio 1.00, 95% CI 0.69-1.45; P = 0.49; I² = 84%) (Fig. 3) . Consistent results were found using a fixed-effect model (Fig. A.1 ).

observational. Second, the populations were heterogenous, as some studies included all patients treated with RAS blockers, whereas others included only patients with hypertension or diabetes. Third, this analysis was not conducted using patient-level data. Nevertheless, these results support the current international society recommendation to continue ACE-I or ARBs during the COVID-19 pandemic [20] .

It remains crucial to prospectively determine the effect of RAS blocker continuation or discontinuation on outcomes in patients infected with SARS-CoV-2. Several scientific societies have wisely advised not to stop such treatments in patients with an underlying indication, in the setting of COVID-19 [20] . Despite the considerable challenge of running a randomized controlled trial during a major health crisis, several upcoming or already ongoing studies will assess the efficacy and safety of RAS blockers in patients with COVID-19 (Table 2 and 

There is a great deal of interest in the potential role of the RAS and RAS blockers in the development of SARS-CoV-2 infection. This review and the results of the pooled analysis of observational studies support the continuation of RAS blockers during the COVID-19 pandemic. Despite the major challenges of conducting randomized trials during the COVID-19 pandemic, several ongoing prospective studies will provide evidence with respect to the safety and efficacy of RAS blocker treatment in this setting. Before the results of these studies, and based on large cohort analysis and this pooled analysis, it is reasonable to recommend continuing RAS blockers.

None. The other authors declare that they have no conflicts of interest concerning this article. ARBs: angiotensin II receptor blockers; AT1/AT2 receptor, angiotensin II type 1/2 receptor. 

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

Clinical Characteristics of Coronavirus Disease 2019 in China

Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China

COVID-19 and the cardiovascular system

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study

Prevalence, awareness, treatment, and control of hypertension in China: data from 1.7 million adults in a population-based screening study (China PEACE Million Persons Project)

Effects of ARB or ACE-inhibitor administration on plasma levels of aldosterone and adiponectin in hypertension

Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

Angiotensin-converting enzyme 2 protects from severe acute lung failure

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target

HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are not associated with severe COVID-19 infection in a multisite UK acute hospital trust

Renin-Angiotensin-Aldosterone System Inhibitors and Outcome in Patients With SARS-CoV-2 Pneumonia. A Case Series Study

Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China

Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19

Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19)

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19

Effects of Angiotensin II Receptor Blockers and ACE (Angiotensin-Converting Enzyme) Inhibitors on Virus Infection, Inflammatory Status, and Clinical Outcomes in Patients With COVID-19 and Hypertension: A Single-Center Retrospective Study

Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19

Clinical characteristics of coronavirus disease 2019 (COVID-19) patients with hypertension on renin-angiotensin system inhibitors

An Update on the Tissue Renin Angiotensin System and Its Role in Physiology and Pathology

The reninangiotensin system: going beyond the classical paradigms

Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system

Angiotensin II-generating enzymes

Multiple pathways of angiotensin production in the blood vessel wall: evidence, possibilities and hypotheses

The potential role of AT(1)-receptor blockade in the prevention and reversal of atherosclerosis

AT2 receptor activities and pathophysiological implications

A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9

Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme

A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism

Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse

ACE2 deficiency modifies renoprotection afforded by ACE inhibition in experimental diabetes

Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease

ACE2: from vasopeptidase to SARS virus receptor

Angiotensin II-mediated oxidative stress and inflammation mediate the age-dependent cardiomyopathy in ACE2 null mice

Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndromecoronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2)

Clinical Relevance and Role of Neuronal AT1 Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS

Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19

Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker

Interaction between RAAS inhibitors and ACE2 in the context of COVID-19

Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors

Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression

Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?

Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism

Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors

Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors

Discrepancy between intrarenal messenger RNA and protein expression of ACE and ACE2 in human diabetic nephropathy

Pathology and pathogenesis of severe acute respiratory syndrome

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Clinical Characteristics of 138 Hospitalized Patients With

Novel Coronavirus-Infected Pneumonia in Wuhan, China

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

Modulation of TNF-alpha-converting enzyme by the spike protein of SARS-CoV and ACE2 induces TNF-alpha production and facilitates viral entry

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19?

SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS

Loss of angiotensin-converting enzyme 2 accelerates maladaptive left ventricular remodeling in response to myocardial infarction

Initiation, Continuation, Switching, and Withdrawal of Heart Failure Medical Therapies During Hospitalization

Initiation, Continuation, or Withdrawal of

Enzyme Inhibitors/Angiotensin Receptor Blockers and Outcomes in Patients Hospitalized With Heart Failure With Reduced Ejection Fraction

Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial

Clinical consequences of angiotensin-converting enzyme inhibitor withdrawal in chronic heart failure: a double-blind, placebo-controlled study of quinapril. The Quinapril Heart Failure Trial Investigators

Discontinuation/Dose Reduction of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers during Acute Decompensated Heart Failure in African-American Patients with Reduced Left-Ventricular Ejection Fraction

Long-term anti-ischemic effects of angiotensin-converting enzyme inhibition in patients after myocardial infarction. The Captopril and Thrombolysis Study (CATS) Investigators

Hemodynamic and hormonal responses during captopril therapy for heart failure: acute, chronic and withdrawal studies

Interrupting the renin-angiotensin system: the role of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of hypertension

Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)

Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure

Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions

Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure

A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure

Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-convertingenzyme inhibitors: the CHARM-Alternative trial

Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-convertingenzyme inhibitors: the CHARM-Added trial

Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure

The perindopril in elderly people with chronic heart failure (PEP-CHF) study

Irbesartan in patients with heart failure and preserved ejection fraction

Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial

The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study)

The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients

Angiotensin-converting-enzyme inhibition in stable coronary artery disease

Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators

ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group

Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction. Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II)

The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure

A clinical trial of the angiotensin-convertingenzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group

Effects of angiotensin-converting enzyme inhibition with perindopril on left ventricular remodeling and clinical outcome: results of the randomized Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) Study

Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both

Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial

Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study

Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol

Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project

Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators

Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes

Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy

Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy

Further Evolution of the ACC/AHA Clinical Practice Guideline Recommendation Classification System: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines

Ramipril in High-Risk Patients With COVID-19

Clinical Characteristics and Outcomes of Patients With Diabetes and COVID-19 in Association With Glucose-Lowering Medication

Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives

Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study

The effect of RAS blockers on the clinical characteristics of COVID-19 patients with hypertension

Age and Multimorbidity Predict Death Among COVID-19 Patients: Results of the SARS-RAS Study of the Italian Society of Hypertension

Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy

Association of renin-angiotensin-aldosterone system inhibitors with COVID-19-related outcomes in Korea: a nationwide population-based cohort study

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area

Is the use of ACE inb/ARBs associated with higher inhospital mortality in Covid-19 pneumonia patients?

Clinical Impact of Renin-angiotensin System Inhibitors on In-hospital Mortality of Patients With Hypertension Hospitalized for Coronavirus Disease

Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis

ICU: intensive care unit; NCT number: ClinicalTrials.gov identifier; RAS: renin-angiotensin system; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SOFA: sepsis-related organ failure assessment