Prescribing Trend of Renin-Angiotensin System Blocking Drugs during COVID-19 Pandemic: a Retrospective Cohort Study

It is known from a recent study that SARS-COV2 (COVID 19) virus had a high affinity for an-giotensin converting enzyme 2 (ACE2), which increased human-to-human transmission. Users of angiotensin converting enzyme inhibitors (ACEI) have higher ACE2 receptor expression, raising concerns about ACEI safety in COVID19 patients and whether their use predisposes to the disease. The aim of this study was to test the pattern of prescriptions for these drugs in the United Kingdom. This retrospective cohort study observed renin-angiotensin system (RAS) blocking drug prescribing patterns in the United Kingdom. From April 2018 to December 2021, primary care prescribing data for RAS blocking drugs were collected in England, Wales, and Northern Ireland. Before April 2020, the rate of RAS blocking drugs prescribing was similar to the rate after April 2020 in England (median difference = 0.651, p value = 0.607) and Wales (median difference = 6.508, p value = 0.591). However, after April 2020, the prescribing rate in Northern Ireland was significantly lower (median difference = 36.136, p value = 0.002). Except for Northern Ireland, there was no difference in the use of renin-angiotensin system blocking drugs following the April 2020 study. Other studies using patient-level data should be conducted to investigate why Northern Ireland differs from the rest of the UK.

In the SARS-CoV-2 Pandora Pandemic: Can the Stance of Premorbid Intestinal Innate Immune System as Measured by Fecal Adnab-9 Binding of p87:Blood Ferritin, Yielding the FERAD Ratio, Predict COVID-19 Susceptibility and Survival in a Prospective Population Database?

SARS-CoV-2 severity predictions are feasible, though individual susceptibility is not. The latter prediction allows for planning vaccination strategies and the quarantine of vulnerable targets. Ironically, the innate immune response (InImS) is both an antiviral defense and the potential cause of adverse immune outcomes. The competition for iron has been recognized between both the immune system and invading pathogens and expressed in a ratio of ferritin divided by p87 (as defined by the Adnab-9 ELISA stool-binding optical density, minus the background), known as the FERAD ratio. Associations with the FERAD ratio may allow predictive modeling for the susceptibility and severity of disease. We evaluated other potential COVID-19 biomarkers prospectively. Patients with PCR+ COVID-19 tests (Group 1; n = 28) were compared to three other groups. In Group 2 (n = 36), and 13 patients displayed COVID-19-like symptoms but had negative PCR or negative antibody tests. Group 3 (n = 90) had no symptoms and were negative when routinely PCR-tested before medical procedures. Group 4 (n = 2129) comprised a pool of patients who had stool tests and symptoms, but their COVID-19 diagnoses were unknown; therefore, they were chosen to represent the general population. Twenty percent of the Group 4 patients (n = 432) had sufficient data to calculate their FERAD ratios, which were inversely correlated with the risk of COVID-19 in the future. In a case report of a neonate, we studied three biomarkers implicated in COVID-19, including p87, Src (cellular-p60-sarcoma antigen), and Abl (ABL-proto-oncogene 2). The InImS of the first two were positively correlated. An inverse correlation was found between ferritin and lysozyme in serum (p < 0.05), suggesting that iron could have impaired an important innate immune system anti-viral effector and could partially explain future COVID-19 susceptibility.

Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers and outcomes in hospitalized patients with COVID-19: an updated systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Our prior analysis demonstrated no significant difference in risk of mortality or disease progression among patients with COVID-19. With the availability of findings from randomized controlled trials (RCTs), we provide an updated review of RCTs which explored the outcomes among hospitalized patients with COVID-19 treated with Angiotensin Converting Enzyme inhibitor (ACEis)/Angiotensin Receptor Blockers (ARBs) versus control. RESEARCH DESIGN AND METHODS: This systematic review and meta-analysis covers RCTs exploring mortality, intensive care unit admission, and mechanical ventilation outcomes among hospitalized COVID-19 patients treated with ACEi/ARBs. RESULTS: Ten studies were included in this meta-analysis. For mortality with ACEi/ARB utilization among hospitalized COVID-19 patients, the pooled risk ratio (RR) was 0.97 (95% CI 0.64-1.47, p = 0.89) with heterogeneity of 26%. Further, the pooled RR for ACEi/ARB use on ICU admission and mechanical ventilation were 0.55 (0.55-1.08, p = 0.13) with a heterogeneity of 0% and 1.02 (0.78-1.32, p = 0.91) with a heterogeneity of 0%, respectively. CONCLUSION: Among hospitalized patients with COVID-19, the use of ACEi/ARB was not associated with increased risk of mortality, ICU admission, or mechanical ventilation compared to control. These findings support continuation of ACEi/ARB for whom baseline clinical indications for these agents exist.

Treating COVID-19: Targeting the Host Response, Not the Virus.

In low- and middle-income countries (LMICs), inexpensive generic drugs like statins, ACE inhibitors, and ARBs, especially if used in combination, might be the only practical way to save the lives of patients with severe COVID-19. These drugs will already be available in all countries on the first pandemic day. Because they target the host response to infection instead of the virus, they could be used to save lives during any pandemic. Observational studies show that inpatient statin treatment reduces 28-30-day mortality but randomized controlled trials have failed to show this benefit. Combination treatment has been tested for antivirals and dexamethasone but, with the exception of one observational study in Belgium, not for inexpensive generic drugs. Future pandemic research must include testing combination generic drug treatments that could be used in LMICs.

An audit comparing management of patients with HFrEF at a DGH before and during the COVID-19 pandemic.

This audit compared the management of patients with heart failure with reduced ejection fraction (HFrEF) admitted to a district general hospital (DGH) during comparative eight month periods before and during the COVID-19 pandemic. The periods studied were from 1st February 2019 to 30th September 2019 and between the same dates in 2020. We investigated differences in mortality and patient characteristics (age, gender and new or prior diagnosis). For patients who survived to discharge and who were not referred to palliative care, we also investigated whether there were differences in rates of echocardiography and prescription of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists and beta blockers. We found that the number of cases was lower during the pandemic and there was a lower mortality rate that was not statistically significant. There was a higher proportion of new cases (odds ratio [OR] 2.21, 95% confidence interval [CI] 1.24 to 3.94, p=0.008) and of female patients (OR 2.03, 95%CI 1.14 to 3.61, p=0.019). For survivors, there was a non-significant decrease in prescription rates for ACE inhibitors and angiotensin II receptor antagonists (81.6% vs. 71.4%, p=0.137) that was not seen for beta blockers. The length of stay was increased and there was also an increase in the interval between admission and echocardiography in patients who were newly diagnosed. Regardless of time period, the time before echocardiography was significantly associated with length of stay.

Thymus vulgaris, a natural pharmacy against COVID-19: A molecular review.

Introduction: A worldwide pandemic infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a deadly disease called COVID-19. Interaction of the virus and the Angiotensin converting-enzyme 2 (ACE2) receptor leads to an inflammatory-induced tissue damage. Thymus vulgaris L. (TvL) is a plant with a long history in traditional medicine that has antimicrobial, antiseptic, and antiviral properties. Thymol and Carvacrol are two important biological components in Thyme that have anti-inflammatory, antioxidant, and immunomodulatory properties. This study is a molecular review on the potential effects of TvL and its active compounds on SARS-COV2 infection. Method: This is a narrative review in which using PubMed, Scopus, ISI, Cochrane, ScienceDirect, Google scholar, and Arxiv preprint databases, the molecular mechanisms of therapeutic and protective effects of TvL and its active compounds have been discussed regarding the molecular pathogenesis in COVID-19. Results: Thyme could suppress TNF-alpha, IL-6, and other inflammatory cytokines. It also enhances the anti-inflammatory cytokines like TGF-beta and IL-10. Thyme extract acts also as an inhibitor of cytokines IL-1-beta and IL-8, at both mRNA and protein levels. Thymol may also control the progression of neuro-inflammation toward neurological disease by reducing some factors. Thyme and its active ingredients, especially Thymol and Carvacrol, have also positive effects on the renin-angiotensin system (RAS) and intestinal microbiota. Conclusions: Accordingly, TvL and its bioactive components may prevent COVID-19 complications and has a potential protective role against the deleterious consequences of the disease.

The role of membrane and circulating forms of ACE 2 in pathological processes in COVID-19 infection

The review analyzes milestone information about the function and pathogenic significance of human angiotensin-converting enzyme 2 (ACE 2). ACE 2 is involved in the development of diseases such as hypertension, malabsorption of certain amino acids in the intestine, and a new type of pneumonia COVID-19 caused by the SARS-CoV-2 virus. Based on the latest literary sources, an assessment is made of the role of differential expression of receptor and soluble forms of this protein in the functioning of the renin-angiotensin-aldosterone system, as well as the mechanisms of ACE 2 participation in the sequential chemical conversion of angiotensin II and its effect on the function of the cardiovascular system. The role of ACE 2 in the development of inflammatory processes in the intestine and its effect on the composition of the intestinal microbiota are also discussed. In addition, the review presents most general data on the proteolytic activation of the S-glycoprotein of the SARS-CoV-2 virus and its participation, together with ACE 2, in the process of virus introduction into the host cell. In conclusion, the hypothesis about autoimmune complications of COVID-19 associated with the formation of the S-glycoprotein-ACE 2 immune complex and the production of autoantibodies is considered. Copyright © 2021 All-Russian Public Organization Antihypertensive League. All rights reserved.

ACE inhibitors on ACE1, ACE2, and TMPRSS2 expression and spheroid attachment on human endometrial Ishikawa cells.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells via receptor angiotensin-converting enzyme 2 (ACE2) and co-receptor transmembrane serine protease 2 (TMPRSS2). However, patients with SARS-CoV-2 infection receiving ACE1 inhibitors had higher ACE2 expression and were prone to poorer prognostic outcomes. Until now, information on the expression of ACE1, ACE2, and TMPRSS2 in human endometrial tissues, and the effects of ACE inhibitors on embryo implantation are limited. We found human endometria expressed ACE1, ACE2, and TMPRSS2 transcripts and proteins. Lower ACE1, but higher ACE2 transcripts were found at the secretory than in the proliferative endometria. ACE1 proteins were weakly expressed in endometrial epithelial and stromal cells, whereas ACE2 and TMPRSS2 proteins were highly expressed in luminal and glandular epithelial cells. However, ACE1 and TMPRSS4 were highly expressed in receptive human endometrial epithelial (Ishikawa and RL95-2) cells, but not in non-receptive AN3CA and HEC1-B cells. Treatment of human endometrial epithelial cells with ACE1 (Captopril, Enalaprilat, and Zofenopril) or ACE2 (DX600) inhibitors did not significantly alter the expression of ACE1, ACE2 and TMPRSS2 transcripts and spheroid (blastocyst surrogate) attachment onto Ishikawa cells in vitro. Taken together, our data suggest that higher ACE2 expression was found in mid-secretory endometrium and the use of ACE inhibitors did not alter endometrial receptivity for embryo implantation.

Association of outpatient use of renin-angiotensin-aldosterone system blockers on outcomes of acute respiratory illness during the COVID-19 pandemic: a cohort study.

OBJECTIVES: Evaluate the associations between patients taking ACE inhibitors and angiotensin receptor blockers (ARBs) and their clinical outcomes after an acute viral respiratory illness (AVRI) due to COVID-19. DESIGN: Retrospective cohort. SETTING: The USA; 2017-2018 influenza season, 2018-2019 influenza season, and 2019-2020 influenza/COVID-19 season. PARTICIPANTS: People with hypertension (HTN) taking an ACEi, ARB or other HTN medications, and experiencing AVRI. MAIN OUTCOME MEASURES: Change in hospital admission, intensive care unit (ICU) or coronary care unit (CCU), acute respiratory distress (ARD), ARD syndrome (ARDS) and all-cause mortality, comparing COVID-19 to pre-COVID-19 influenza seasons. RESULTS: The cohort included 1 059 474 episodes of AVRI (653 797 filled an ACEi or ARB, and 405 677 other HTN medications). 58.6% were women and 72.9% with age ≥65. The ACEi/ARB cohort saw a larger increase in risk in the COVID-19 influenza season than the other HTN medication cohort for four out of five outcomes, with an additional 1.5 percentage point (pp) increase in risk of an inpatient stay (95% CI 1.2 to 1.9 pp) and of ICU/CCU use (95% CI 0.3 to 2.7 pp) as well as a 0.7 pp (0.1 to 1.2 pp) additional increase in risk of ARD and 0.9 pp (0.4 to 1.3 pp) additional increase in risk of ARDS. There was no statistically significant difference in the absolute risk of death (-0.2 pp, 95% CI -0.4 to 0.1 pp). However, the relative risk of death in 2019/2020 versus 2017/2018 for the ACEi/ARB group was larger (1.40 (1.36 to 1.44)) than for the other HTN medication cohort (1.24 (1.21 to 1.28)). CONCLUSIONS: People with AVRI using ACEi/ARBs for HTN had a greater increase in poor outcomes during the COVID-19 pandemic than those using other medications to treat HTN. The small absolute magnitude of the differences likely does not support changes in clinical practice.

The role of angiotensin-converting enzyme 2 in the pathogenesis of COVID-19: the villain or the hero?

Angiotensin-converting enzyme 2 (ACE 2) is the entry receptor for the novel coronavirus SARS-CoV-2, the aetiological agent of COVID-19. At the same time, ACE 2 expression decreases during COVID-19. Two seemingly contradictory relationships between the expression of ACE 2 and COVID-19 have been reported. Increased level of expression of ACE 2 may be a risk factor for the development of COVID-19 infection, while reduced ACE 2 expression during COVID-19 leads to acute respiratory distress syndrome. This article provides a comprehensive overview of available scientific knowledge about the role of ACE 2 in the pathogenesis of COVID-19, which is available up to current day. Also, it discusses unknown factors that we will have to reveal in order to understand the whole role of ACE 2 in the pathogenesis of COVID-19.

Sartans and ACE Inhibitors: Mortality in Patients Hospitalized with COVID-19. Retrospective Study in Patients on Long-Term Treatment Who Died in the Italian Hospitals of Area Vasta n.5-Marche Region.

INTRODUCTION: During the 2019 Coronavirus pandemic (COVID-19), a concern emerged regarding a possible correlation between the severe form of SARS-CoV-2 infection and administration of ACE-Inhibitors (ACE-I) and Sartans (ARB), since long-term use of these drugs may potentially result in an adaptive response with up-regulation of the ACE 2 receptor. Given the crucial role of ACE2, being the main target for virus entry into the cell, the potential consequences of ACE2 up-regulation have been a source of debate. The aim of this retrospective cohort study on COVID-19-positive patients who died is to investigate whether previous long-term exposure to ACE-I and/or ARB was associated with higher mortality due to COVID-19 infection, compared to all other types of drug treatment. METHODS: We analysed the clinical and demographic data of 615 patients hospitalized for COVID-19 at the two hospitals of the Vasta Area n.5, between March 2020 and April 2021. Among them, 86 patients, treated with ACE-Is and/0 ARBs for about 12 months, died during hospitalization following a diagnosis of acute respiratory failure. Several quantitative and qualitative variables were recorded for all patients by reading their medical records. RESULTS: The logistic model showed that the variables that increase mortality are age and comorbid diseases. There were no demonstrable mortality effects with ACE-I and ARB intake. CONCLUSIONS: The apparent increase in morbidity in patients with COVID-19 who received long-term treatment with ACE-I or ARB is not due to the drugs themselves, but to the conditions associated with their use.

Takotsubo Cardiomyopathy: A COVID-19 Complication.

COVID-19 started as an unknown viral illness and has been a challenging pandemic to overcome. The virus has been associated with multiple organ involvement, including the heart. Takotsubo cardiomyopathy (TSCM), a stress cardiomyopathy, is an uncommon complication in patients diagnosed with COVID-19. The pathogenesis is historically a result of stress onto the body that leads to a catecholamine surge. However, COVID-19 may cause direct damage to the cardiac myocytes via spike protein and angiotensin-converting enzyme 2 (ACE2) receptors which can further exacerbate the stressful insult on the patient and lower the threshold for developing TSCM. In this case report, we discuss a 94-year-old female who presented with signs and symptoms of acute coronary syndrome but, upon cardiac catheterization, was found to have basal hypercontraction with apical ballooning, consistent with TSCM.

Sex Differences and COVID-19.

Biological sex and psychosocial gender both play a role in many disease outcomes, and the novel coronavirus disease (COVID-19) is no different. Clinical observations in COVID-19 patient data delineate clear disparities between males and females, indicating males are at a higher risk for poorer disease outcomes. Although we are yet to understand the sex and gender-based disparities specific to COVID-19, there is evidence for sex-based differences in the endocrine, immune and renin-angiotensin system, all systems implicated in COVID-19 outcomes. Such disparities are largely thought to be driven by sex chromosomes and modulating sex hormones, which are known to vary between sex, and across the reproductive lifespan. Understanding and exploiting these driving factors are critical to understanding the pathobiology of SARS-CoV-2 virus and may lead to the development of novel therapies and increase the efficacy of preventative vaccine strategies currently under development. This chapter focuses on the endocrine, immune and renin-angiotensin system and genetic sex-based differences that could account for the meaningful differences observed in the outcomes of the SARS-CoV-2 infection.

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and COVID-19-related outcomes: A patient-level analysis of the PCORnet blood pressure control lab.

SARS-CoV-2 accesses host cells via angiotensin-converting enzyme-2, which is also affected by commonly used angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), raising concerns that ACEI or ARB exposure may portend differential COVID-19 outcomes. In parallel cohort studies of outpatient and inpatient COVID-19-diagnosed adults with hypertension, we assessed associations between antihypertensive exposure (ACEI/ARB vs. non-ACEI/ARB antihypertensives, as well as between ACEI- vs. ARB) at the time of COVID-19 diagnosis, using electronic health record data from PCORnet health systems. The primary outcomes were all-cause hospitalization or death (outpatient cohort) or all-cause death (inpatient), analyzed via Cox regression weighted by inverse probability of treatment weights. From February 2020 through December 9, 2020, 11,246 patients (3477 person-years) and 2200 patients (777 person-years) were included from 17 health systems in outpatient and inpatient cohorts, respectively. There were 1015 all-cause hospitalization or deaths in the outpatient cohort (incidence, 29.2 events per 100 person-years), with no significant difference by ACEI/ARB use (adjusted HR 1.01; 95% CI 0.88, 1.15). In the inpatient cohort, there were 218 all-cause deaths (incidence, 28.1 per 100 person-years) and ACEI/ARB exposure was associated with reduced death (adjusted HR, 0.76; 95% CI, 0.57, 0.99). ACEI, versus ARB exposure, was associated with higher risk of hospitalization in the outpatient cohort, but no difference in all-cause death in either cohort. There was no evidence of effect modification across pre-specified baseline characteristics. Our results suggest ACEI and ARB exposure have no detrimental effect on hospitalizations and may reduce death among hypertensive patients diagnosed with COVID-19.

Angiotensin Converting Enzyme Inhibitors May Increase While Active Vitamin D May Decrease the Risk of Severe Pneumonia in SARS-CoV-2 Infected Patients with Chronic Kidney Disease on Maintenance Hemodialysis.

The group most at risk of death due to COVID-19 are patients on maintenance hemodialysis (HD). The study aims to describe the clinical course of the early phase of SARS-CoV-2 infection and find predictors of the development of COVID-19 severe pneumonia in this population. This is a case series of HD nonvaccinated patients with COVID-19 stratified into mild pneumonia and severe pneumonia group according to the chest computed tomography (CT) pneumonia total severity score (TSS) on admission. Epidemiological, demographic, clinical, and laboratory data were obtained from hospital records. 85 HD patients with a mean age of 69.74 (13.19) years and dialysis vintage of 38 (14-84) months were included. On admission, 29.14% of patients had no symptoms, 70.59% reported fatigue followed by fever-44.71%, shortness of breath-40.0%, and cough-30.59%. 20% of the patients had finger oxygen saturation less than 90%. In 28.81% of patients, pulmonary parenchyma was involved in at least 25%. The factors associated with severe pneumonia include fever, low oxygen saturation and arterial partial pressure of oxygen, increased C-reactive protein and ferritin serum levels, low blood count of lymphocytes as well as chronic treatment with angiotensin converting enzyme inhibitors; while the chronic active vitamin D treatment was associated with mild pneumonia. In conclusion, even though nearly one-third of the patients were completely asymptomatic, while the remaining usually reported only single symptoms, a large percentage of them had extensive inflammatory changes at diagnosis with SARS-CoV-2 infection. We identified potential predictors of severe pneumonia, which might help individualize pharmacological treatment and improve clinical outcomes.

EFFECT OF RAAS INHIBITORS ON OUTCOMES OF HOSPITALIZED PATIENTS WITH SARS-COV-2 INFECTION

B Conclusions: b Patients on RAAS inhibitors prior to hospitalization for SARS-CoV-2 infection had higher mortality and complications than those not on these medications. B Introduction: b The aim of our study was to determine the effect of prior use of renin-angiotensin-aldosterone system (RAAS) inhibitors on mortality and outcomes in hospitalized patients with laboratory-confirmed SARS-CoV-2 infection. [Extracted from the article] Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Renin Angiotensin System Blockers and Risk of Mortality in Hypertensive Patients Hospitalized for COVID-19: An Italian Registry.

BACKGROUND: It is uncertain whether exposure to renin-angiotensin system (RAS) modifiers affects the severity of the new coronavirus disease 2019 (COVID-19) because most of the available studies are retrospective. METHODS: We tested the prognostic value of exposure to RAS modifiers (either angiotensin-converting enzyme inhibitors [ACE-Is] or angiotensin receptor blockers [ARBs]) in a prospective study of hypertensive patients with COVID-19. We analyzed data from 566 patients (mean age 75 years, 54% males, 162 ACE-Is users, and 147 ARBs users) hospitalized in five Italian hospitals. The study used systematic prospective data collection according to a pre-specified protocol. All-cause mortality during hospitalization was the primary outcome. RESULTS: Sixty-six patients died during hospitalization. Exposure to RAS modifiers was associated with a significant reduction in the risk of in-hospital mortality when compared to other BP-lowering strategies (odds ratio [OR]: 0.54, 95% confidence interval [CI]: 0.32 to 0.90, p = 0.019). Exposure to ACE-Is was not significantly associated with a reduced risk of in-hospital mortality when compared with patients not treated with RAS modifiers (OR: 0.66, 95% CI: 0.36 to 1.20, p = 0.172). Conversely, ARBs users showed a 59% lower risk of death (OR: 0.41, 95% CI: 0.20 to 0.84, p = 0.016) even after allowance for several prognostic markers, including age, oxygen saturation, occurrence of severe hypotension during hospitalization, and lymphocyte count (adjusted OR: 0.37, 95% CI: 0.17 to 0.80, p = 0.012). The discontinuation of RAS modifiers during hospitalization did not exert a significant effect (p = 0.515). CONCLUSIONS: This prospective study indicates that exposure to ARBs reduces mortality in hospitalized patients with COVID-19.