Hypertension, renin-angiotensin-aldosterone-system-blocking agents, and COVID-19

Abstract Background There have been concerns regarding the safety of renin-angiotensin-aldosterone-system (RAAS)-blocking agents including angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) during the coronavirus disease 2019 (COVID-19) pandemic. This study sought to evaluate the impact of hypertension and the use of ACEI/ARB on clinical severity in patients with COVID-19. Methods A total of 3,788 patients aged 30 years or older who were confirmed with COVID-19 with real time reverse transcription polymerase chain reaction were identified from a claims-based cohort in Korea. The primary study outcome was severe clinical events, a composite of intensive care unit admission, need for ventilator care, and death. Results Patients with hypertension (n = 1,190, 31.4 %) were older and had higher prevalence of comorbidities than those without hypertension. The risk of the primary study outcome was significantly higher in the hypertension group, even after multivariable adjustment (adjusted odds ratio [aOR], 1.67; 95 % confidence interval [CI], 1.04 to 2.69). Among 1,044 patients with hypertensive medical treatment, 782 (74.9 %) were on ACEI or ARB. The ACEI/ARB subgroup had a lower risk of severe clinical outcomes compared to the no ACEI/ARB group, but this did not remain significant after multivariable adjustment (aOR, 0.68; 95 % CI, 0.41 to 1.15). Conclusions Patients with hypertension had worse COVID-19 outcomes than those without hypertension, while the use of RAAS-blocking agents was not associated with increased risk of any adverse study outcomes. The use of ACE inhibitors or ARBs did not increase the risk of adverse COVID-19 outcomes, supporting current guidance to continue these medications when indicated.

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Impact of hospitalised patients with COVID-19 taking Renin-Angiotensin-Aldosterone System inhibitors: a systematic review and meta-analysis

10.1101/2020.05.03.20089375 ◽

2020 ◽

Cited By ~ 1

Author(s):

Ranu Baral ◽

Maddie White ◽

Vassilios S Vassiliou

Keyword(s):

Systematic Review ◽

Angiotensin Receptor Blockers ◽

Meta Analysis ◽

Mortality Data ◽

Critical Events ◽

Converting Enzyme Inhibitors ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

Hospitalised Patients ◽

The Impact

AbstractInhibitors of the Renin-Angiotensin-Aldosterone System (RAAS) notably Angiotensin-Converting Enzyme inhibitors (ACEi) or Angiotensin Receptor Blockers (ARB) have been scrutinised in hypertensive patients hospitalised with coronavirus disease 2019 (COVID-19) following some initial data they might adversely affect prognosis. With an increasing number of COVID-19 cases worldwide and the likelihood of a “second wave” of infection it is imperative to better understand the impact RAAS inhibitor use in antihypertensive covid positive hospitalised patients.A systematic review and meta-analysis of ACEi or ARB in patients admitted with COVID-19 was conducted. PubMed and Embase were searched and six studies were included in the meta-analysis. Pooled analysis demonstrated that 18.3% of the patients admitted with COVID-19 were prescribed ACEi/ARBs (0.183, CI 0.129 to 0.238, p<0.001). The use of RAAS inhibitors did not show any association with ‘critical’ events (Pooled OR 0.833 CI 0.605 to 1.148, p=0.264) or death (Pooled OR 0.650, CI 0.356 to 1.187, p=0.161). In conclusion, our meta-analysis including ‘critical’ events and mortality data on patients prescribed ACEi/ARB and hospitalised with COVID-19, found no evidence to associate ACEi/ARB with death or adverse events.

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Cardiorenal disease development under chronic renin–angiotensin–aldosterone system suppression

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320312439140 ◽

2012 ◽

Vol 13 (1) ◽

pp. 217-219 ◽

Cited By ~ 8

Author(s):

Pantelis A Sarafidis ◽

Luis M Ruilope

Keyword(s):

Arterial Hypertension ◽

Enzyme Inhibitors ◽

Angiotensin Receptor Blockers ◽

Disease Development ◽

Converting Enzyme ◽

Angiotensin Receptor ◽

Converting Enzyme Inhibitors ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

Receptor Blockers

Drugs suppressing the renin-angiotensin-aldosterone system (RAAS) are now widely used to treat patients all along the cardiorenal continuum. It supposes that many patients, in particular those with arterial hypertension are treated with converting-enzyme inhibitors and angiotensin receptor blockers for years during which the development and prograssion of cardiorenal disease can be observed. The meaning of this progression in the presence of RAAS suppression requires to be clarified and to be treated in order to diminish the velocity of progression of cardiorenal disease.

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Association of Renin--Angiotensin--Aldosterone System Blocker use with Covid-19 Hospitalization and All-cause Mortality in the UK Biobank

10.22541/au.163252572.25645081/v1 ◽

2021 ◽

Author(s):

Fatemeh Safizadeh ◽

Thi Ngoc Mai Nguyen ◽

Hermann Brenner ◽

Ben Schöttker

Keyword(s):

Angiotensin Receptor Blockers ◽

Multivariable Logistic Regression Analysis ◽

Protective Effects ◽

Uk Biobank ◽

Antihypertensive Medications ◽

Converting Enzyme Inhibitors ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

Wide Range ◽

The Uk

Aim: The risk-benefit profile of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in coronavirus disease 2019 (Covid-19) is still a matter of debate. With growing evidence on the protective effect of this group of commonly used antihypertensives in Covid-19, we aimed to thoroughly investigate the association between the use of major classes of antihypertensive medications and Covid-19 outcomes in comparison with the use of ACEIs and ARBs. Methods: We conducted a population-based study in patients with pre-existing hypertension in the UK Biobank. Multivariable logistic regression analysis was performed adjusting for a wide range of confounders. Results: The use of either beta-blockers (BBs), calcium-channel blockers (CCBs), or diuretics was associated with a higher risk of Covid-19 hospitalization compared to ACEI use (adjusted OR, 1.63; 95% CI, 1.40 to 1.90) and ARB use (adjusted OR, 1.50; 95% CI, 1.27 to 1.77). The risk of 28-day mortality among Covid-19 patients was also increased among users of BBs, CCBs or diuretics when compared to ACEI users (adjusted OR, 1.64; 95% CI, 1.23 to 2.19) but not when compared to ARB users (adjusted OR, 1.18; 95% CI, 0.87 to 1.59). However, no associations were observed when the same analysis was conducted among hospitalized Covid-19 patients only. Conclusion: Our results suggest protective effects of blocking of the renin-angiotensin-aldosterone system on Covid-19 hospitalization and mortality among patients with pharmaceutically treated hypertension, which should be addressed by randomized controlled trials. If confirmed, this finding could have high clinical relevance for treating hypertension during the SARS-CoV-2 pandemic.

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Renin-Angiotensin-Aldosterone System Blockade Strategies and the Risk of Acute Kidney Injury in Septic and Critically Ill Patients

10.21203/rs.2.22152/v1 ◽

2020 ◽

Author(s):

Ruey-Hsing Chou ◽

Shang-Feng Yang ◽

Cheng-Hsueh Wu ◽

Yi-Lin Tsai ◽

Ya-Wen Lu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Angiotensin Receptor Blockers ◽

Kidney Injury ◽

Secondary Outcome ◽

Converting Enzyme Inhibitors ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin ◽

Raas Blockade ◽

Icu Admission

Abstract Background: Renin-angiotensin-aldosterone system (RAAS) blockers are widely used for the treatment of hypertension and heart failure, but the usage of angiotensin- converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARB) demands caution due to a potential risk of causing acute kidney injury (AKI). Whether long-term RAAS blockade increases AKI risk and should be withdrawn during critical illness remains inconclusive. This study aimed to investigate the associations between RAAS blockade strategies and AKI incidence in patients admitted to intensive care units (ICUs). Methods: Twenty-four hundred dialysis-free patients admitted to ICUs during December 2015–July 2017 were enrolled. Patients with pre-ICU AKI (n=568) were excluded when examining in-ICU AKI events. Patients using ACEi or ARB for more than 1 month before hospitalization were defined as long-term ACEi/ARB users. ACEi/ARB users were further grouped by ACEi/ARB continuation/withdrawal at ICU admission. Daily urine output and serum creatinine were measured in ICU. The primary outcome was occurrence of AKI within 48 hours after ICU admission, and the secondary outcome was all-cause mortality within 1 year. Results: Totally 1181 (49.2%) AKI cases and 895 (37.3%) deaths within 1 year occurred. ACEis/ARBs were continued for 122 patients and withdrawn for 239 patients. ACEi/ARB users were older and had lower initial estimated glomerular filtration rates (eGFRs). Compared with non-use, long-term ACEi/ARB use [odds ratio (OR) 1.03, 95% confidence interval (CI) 0.85–1.26, p=0.741] and continued ICU use (OR 1.14, 95% CI 0.78–1.68, p=0.491) were not associated with increased AKI risk. ACEi/ARB use was associated with less 1-year mortality. However, compared with withdrawal, continued ACEi/ARB use in ICUs was associated with higher AKI incidence among patients with sepsis (OR 2.89, 95% CI 1.35–6.20, p=0.006). Conclusions: Long-term RAAS blockade was not associated with a higher AKI or mortality incidence during acute illness. Continued ACEi/ARB use in ICUs may increase AKI risk in septic patients. Long-term and continued ACEi/ARB use are recommended, with cautious evaluation at ICU admission.

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The Impact of Transitions of Care Pharmacist Services and Identification of Risk Predictors in Heart Failure Readmission

Journal of Pharmacy Practice ◽

10.1177/0897190019884173 ◽

2019 ◽

pp. 089719001988417 ◽

Cited By ~ 2

Author(s):

Marci Wood ◽

Tracey Sweeney ◽

Molly Trayah ◽

Maria Civalier ◽

Wesley McMillian

Keyword(s):

Risk Factors ◽

Heart Failure ◽

Angiotensin Receptor Blockers ◽

Significant Risk ◽

Retrospective Chart Review ◽

Transitions Of Care ◽

Converting Enzyme Inhibitors ◽

Increased Risk ◽

Risk Predictors ◽

The Impact

Background: Heart failure (HF) is a prevalent and costly disease state for adult Americans, with 30-day readmissions rates for patients with HF utilized to limit hospital compensation. Objective: To determine the impact of the transitions of care (TOC) service at our institution on 30-day all-cause and HF readmissions and identify predictive risk factors for 30-day all-cause readmission. Methods: Retrospective chart review of patients aged 18 years and older admitted with HF and all subsequent readmissions between October 1, 2015, and September 30, 2017. A weighted logistic regression model was developed to determine risk factors for 30-day all-cause readmission. Results: There were no significant differences in all-cause or HF readmission rates analyzed by TOC service involvement. Significant risk predictors for 30-day all-cause readmission included discharge to a rehabilitation facility (odds ratio [OR] = 9.3) or home with home health (OR = 1.6) versus home with self-care. Comorbidities associated with an increased risk of 30-day all-cause readmission included diabetes, coronary artery disease, and aortic stenosis. Use of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and spironolactone was associated with decreased risk of 30-day all-cause readmission. Conclusion: Identified predictors in the patient population with HF at our institution may be used to target patients at increased risk of all-cause readmission within 30 days.

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Diabetic Kidney Disease: A Renin-Angiotensin-Aldosterone System Focused Review

Journal of Pharmacy Practice ◽

10.1177/0897190009333163 ◽

2009 ◽

Vol 22 (6) ◽

pp. 560-570 ◽

Cited By ~ 1

Author(s):

Pamela F. Hite ◽

Heather F. DeBellis

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Angiotensin Receptor Blockers ◽

The United States ◽

Diabetic Patients ◽

Converting Enzyme Inhibitors ◽

Renin Angiotensin Aldosterone System ◽

Diabetic Kidney ◽

Renin Angiotensin ◽

Renin Inhibitors

Diabetic nephropathy, also referred to as diabetic kidney disease, is a multifaceted complication of one of the largest epidemics in the United States. Diabetic patients currently represent approximately 8% of the US population. Aggressive screening and control of diabetes, hypertension, and dyslipidemia as well as dietary protein restriction are vital to the prevention and management of diabetic kidney disease. Because there are no direct pharmacologic options for diabetic kidney disease, treatment is focused on controlling comorbidities that exacerbate the development and progression of diabetic kidney disease. This article will provide an overview of structural renal alterations during the progression of diabetic kidney disease as well as a concise review of current diabetic kidney disease management guidelines with a focus on agents that affect the renin-angiotensin-aldosterone system. At this point in time, the mainstays of therapy are angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. More research is currently needed to determine if renin inhibitors will have an active role in the management of diabetic kidney disease.

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The Role of Renin-Angiotensin-Aldosterone System in the Heart and Lung: Focus on COVID-19

Frontiers in Pharmacology ◽

10.3389/fphar.2021.667254 ◽

2021 ◽

Vol 12 ◽

Author(s):

Annamaria Mascolo ◽

Cristina Scavone ◽

Concetta Rafaniello ◽

Antonella De Angelis ◽

Konrad Urbanek ◽

...

Keyword(s):

Lung Injury ◽

Angiotensin Converting Enzyme ◽

Angiotensin Receptor Blockers ◽

Protective Action ◽

Angiotensin Converting Enzyme Inhibitors ◽

Converting Enzyme ◽

Converting Enzyme Inhibitors ◽

Renin Angiotensin Aldosterone System ◽

Renin Angiotensin

The renin-angiotensin-aldosterone system (RAAS) firstly considered as a cardiovascular circulating hormonal system, it is now accepted as a local tissue system that works synergistically or independently with the circulating one. Evidence states that tissue RAAS locally generates mediators with regulatory homeostatic functions, thus contributing, at some extent, to organ dysfunction or disease. Specifically, RAAS can be divided into the traditional RAAS pathway (or classic RAAS) mediated by angiotensin II (AII), and the non-classic RAAS pathway mediated by angiotensin 1–7. Both pathways operate in the heart and lung. In the heart, the classic RAAS plays a role in both hemodynamics and tissue remodeling associated with cardiomyocyte and endothelial dysfunction, leading to progressive functional impairment. Moreover, the local classic RAAS may predispose the onset of atrial fibrillation through different biological mechanisms involving inflammation, accumulation of epicardial adipose tissue, and electrical cardiac remodeling. In the lung, the classic RAAS regulates cell proliferation, immune-inflammatory response, hypoxia, and angiogenesis, contributing to lung injury and different pulmonary diseases (including COVID-19). Instead, the local non-classic RAAS counteracts the classic RAAS effects exerting a protective action on both heart and lung. Moreover, the non-classic RAAS, through the angiotensin-converting enzyme 2 (ACE2), mediates the entry of the etiological agent of COVID-19 (SARS-CoV-2) into cells. This may cause a reduction in ACE2 and an imbalance between angiotensins in favor of AII that may be responsible for the lung and heart damage. Drugs blocking the classic RAAS (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) are well known to exert a cardiovascular benefit. They are recently under evaluation for COVID-19 for their ability to block AII-induced lung injury altogether with drugs stimulating the non-classic RAAS. Herein, we discuss the available evidence on the role of RAAS in the heart and lung, summarizing all clinical data related to the use of drugs acting either by blocking the classic RAAS or stimulating the non-classic RAAS.

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Controversial Roles of the Renin Angiotensin System and Its Modulators During the COVID-19 Pandemic

Frontiers in Physiology ◽

10.3389/fphys.2021.624052 ◽

2021 ◽

Vol 12 ◽

Author(s):

Simon B. Gressens ◽

Georges Leftheriotis ◽

Jean-Claude Dussaule ◽

Martin Flamant ◽

Bernard I. Levy ◽

...

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Enzyme Inhibitors ◽

Angiotensin Receptor Blockers ◽

Renin Angiotensin System ◽

Angiotensin Converting Enzyme Inhibitors ◽

Converting Enzyme ◽

Converting Enzyme Inhibitors ◽

Renin Angiotensin ◽

The Impact

Since December 2019, the coronavirus 2019 (COVID-19) pandemic has rapidly spread and overwhelmed healthcare systems worldwide, urging physicians to understand how to manage this novel infection. Early in the pandemic, more severe forms of COVID-19 have been observed in patients with cardiovascular comorbidities, who are often treated with renin-angiotensin aldosterone system (RAAS)-blockers, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), but whether these are indeed independent risk factors is unknown. The cellular receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the membrane-bound angiotensin converting enzyme 2 (ACE2), as for SARS-CoV(-1). Experimental data suggest that expression of ACE2 may be increased by RAAS-blockers, raising concerns that these drugs may facilitate viral cell entry. On the other hand, ACE2 is a key counter-regulator of the RAAS, by degrading angiotensin II into angiotensin (1-7), and may thereby mediate beneficial effects in COVID-19. These considerations have raised concerns about the management of these drugs, and early comments shed vivid controversy among physicians. This review will describe the homeostatic balance between ACE-angiotensin II and ACE2-angiotensin (1-7) and summarize the pathophysiological rationale underlying the debated role of the RAAS and its modulators in the context of the pandemic. In addition, we will review available evidence investigating the impact of RAAS blockers on the course and prognosis of COVID-19 and discuss why retrospective observational studies should be interpreted with caution. These considerations highlight the importance of solid evidence-based data in order to guide physicians in the management of RAAS-interfering drugs in the general population as well as in patients with more or less severe forms of SARS-CoV-2 infection.

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Renin-Angiotensin System Blockade after Acute Kidney Injury (AKI) and Risk of Recurrent AKI

Clinical Journal of the American Society of Nephrology ◽

10.2215/cjn.05800519 ◽

2019 ◽

Vol 15 (1) ◽

pp. 26-34 ◽

Cited By ~ 10

Author(s):

Chi-yuan Hsu ◽

Kathleen D. Liu ◽

Jingrong Yang ◽

David V. Glidden ◽

Thida C. Tan ◽

...

Keyword(s):

Heart Failure ◽

Care Delivery ◽

Angiotensin Receptor Blockers ◽

Renin Angiotensin System ◽

Time Dependent ◽

Converting Enzyme Inhibitors ◽

Inference Models ◽

Angiotensin System ◽

Renin Angiotensin ◽

Increased Risk

Background and objectivesHow to best medically manage patients who survived hospitalized AKI is unclear. Use of renin-angiotensin system blockers in this setting may increase risk of recurrent AKI.Design, setting, participants, & measurementsThis is a cohort study of 10,242 members of an integrated health care delivery system in Northern California who experienced AKI and survived a hospitalization between January 1, 2006 and December 31, 2013. All study participants did not have prior heart failure or use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) up to 5 years prior. New receipt and time-updated exposure of ACE-Is/ARBs was identified on the basis of dispensed prescriptions found in outpatient health plan pharmacy databases. The main outcome of interest was subsequent episode of hospitalized AKI after discharge from an initial index hospitalization complicated by AKI. Recurrent AKI episode was defined using acute changes in serum creatinine concentrations. Marginal structural models were used to adjust for baseline and potential time-dependent confounders.ResultsForty-seven percent of the study population had a documented eGFR<60 ml/min per 1.73 m2 or documented proteinuria before hospitalization. With a median of 3 (interquartile range, 1–5) years of follow-up, 1853 (18%) patients initiated use of ACE-Is/ARBs and 2124 (21%) patients experienced recurrent AKI. Crude rate of recurrent AKI was 6.1 (95% confidence interval [95% CI], 5.9 to 6.4) per 100 person-years off ACE-Is/ARBs and 5.7 (95% CI, 4.9 to 6.5) per 100 person-years on ACE-Is/ARBs. In marginal structural causal inference models that adjusted for baseline and potential time-dependent confounders, exposure to ACE-I/ARB use was not associated with higher incidence of recurrent AKI (adjusted odds ratio, 0.71; 95% CI, 0.45 to 1.12).ConclusionsIn this study of AKI survivors without heart failure, new use of ACE-I/ARB therapy was not independently associated with increased risk of recurrent hospitalized AKI.

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Impact of Renin-Angiotensin-Aldosterone-System Inhibitor Drugs on Mortality in Patients with Atrial Fibrillation and Hypertension

10.21203/rs.3.rs-1188151/v1 ◽

2021 ◽

Author(s):

Wei Xu ◽

Yan-Min Yang ◽

Jun Zhu ◽

Shuang Wu ◽

Juan Wang ◽

...

Keyword(s):

Atrial Fibrillation ◽

Cox Regression ◽

Angiotensin Receptor Blockers ◽

Cardiovascular Death ◽

Renin Angiotensin Aldosterone System ◽

Cox Regression Analysis ◽

Renin Angiotensin ◽

The Impact ◽

Reduced Risk

Abstract Background Renin-angiotensin-aldosterone-system inhibitors markedly played an active role in the primary and secondary prevention of atrial fibrillation (AF), but the impact of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) on the mortality of patients with AF remains unclear. This study aimed to examine the relationship between treatment with ACEIs or ARBs and the mortality in emergency department (ED) patients with AF and hypertension. Methods This multicenter study enrolled 2016 ED patients from September 2008 to April 2011; Total 1110 patients with AF and hypertension were analyzed. Patients were grouped according to whether they were treated with ACEI/ARB or not and completed a 1-year follow-up to evaluate outcomes including all-cause death, cardiovascular death, stroke, and major adverse events (MAEs). Results Among the 1110 patients with AF and hypertension, 574 (51.7%) received ACEI/ARB treatment. During the 1-year follow-up, 169 all-cause deaths (15.2%) and 100 cardiovascular deaths (9.0%) occurred, while 98 strokes (8.8%) and 255 MAEs (23.0%) occurred. According to the multivariate Cox regression analysis, ACEI/ARB therapy was significantly associated with a reduced risk of all-cause death (HR, 0.642; 95% CI, 0.466–0.884; P = 0.007). Moreover, ACEI/ARB therapy was independently associated with a reduced risk of cardiovascular death (HR, 0.649; 95% CI, 0.424–0.993; P = 0.046) and MAEs (HR: 0.701, 95% CI 0.541–0.907, P = 0.007) after adjusting for other risk factors. Conclusions Our results revealed that ACEI/ARB therapy was independently associated with a reduced risk of all-cause death, cardiovascular death, and MAEs in ED patients with AF and hypertension. These results provide evidence for a tertiary preventive treatment for patients with atrial fibrillation and hypertension.

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