Use of inhibitors of the renin angiotensin system and COVID-19 prognosis: a systematic review and meta-analysis

Background: controversy has arisen in the scientific community on whether the use of renin angiotensin system (RAS) inhibitors in the context of COVID-19 would be of benefit or harmful. A meta-analysis of eligible studies comparing the occurrence of severe and fatal COVID-19 in infected patients who were under treatment with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) vs no treatment or other antihypertensives was conducted. Methods: PubMed, Google Scholar, the Cochrane Library, MedRxiv and BioRxiv were searched for relevant studies. Fixed-effect models or random-effect models were used depending on the heterogeneity between estimates. Results: a total of fifteen studies with 21,614 patients were included. The use of RAS inhibitors was associated with a non-significant 20% decreased risk of the composite outcome (death, admission to intensive care unit, mechanical ventilation requirement or progression to severe or critical pneumonia): RR 0.81 (95%CI: 0.63-1.04), p=0.10, I2=82%. In a subgroup analysis that included hypertensive subjects only, ACEI/ARB were associated with a 27% significant decrease in the risk of the composite outcome (RR 0.73 (95%CI: 0.56-0.96), p=0.02, I2=65%). Conclusion: the results of this pooled analysis suggest that the use of ACEI/ARB does not worsen the prognosis, and could even be protective in hypertensive subjects. Patients should continue these drugs during their COVID-19 illness.

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Mortality and Pre‐Hospitalization use of Renin‐Angiotensin System Inhibitors in Hypertensive COVID‐19 Patients

Journal of the American Heart Association ◽

10.1161/jaha.120.017736 ◽

2020 ◽

Vol 9 (21) ◽

Cited By ~ 3

Author(s):

Chen Chen ◽

Feng Wang ◽

Peng Chen ◽

Jiangang Jiang ◽

Guanglin Cui ◽

...

Keyword(s):

Protective Effect ◽

Angiotensin Receptor Blockers ◽

Meta Analysis ◽

Renin Angiotensin System ◽

Published Data ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Hypertensive Patients ◽

Renin Angiotensin ◽

Ras Inhibitors

Abstract Background There has been significant controversy regarding the effects of pre‐hospitalization use of renin‐angiotensin system (RAS) inhibitors on the prognosis of hypertensive COVID‐19 patients. Methods and Results We retrospectively assessed 2,297 hospitalized COVID‐19 patients at Tongji Hospital in Wuhan, China, from January 10 th to March 30 th , 2020; and identified 1,182 patients with known hypertension on pre‐hospitalization therapy. We compared the baseline characteristics and in‐hospital mortality between hypertensive patients taking RAS inhibitors (N=355) versus non‐RAS inhibitors (N=827). Of the 1,182 hypertensive patients (median age 68 years, 49.1% male), 12/355 (3.4%) patients died in the RAS inhibitors group vs. 95/827 (11.5%) patients in the non‐RAS inhibitors group (p<0.0001). Adjusted hazard ratio for mortality was 0.28 (95% CI 0.15‐0.52, p<0.0001) at 45 days in the RAS inhibitors group compared with non‐RAS inhibitors group. Similar findings were observed when patients taking angiotensin receptor blockers (N=289) or angiotensin converting enzyme inhibitors (N=66) were separately compared with non‐RAS inhibitors group. The RAS inhibitors group compared with non‐RAS inhibitors group had lower levels of C‐reactive protein (median 13.5 vs. 24.4 pg/mL; p=0.007) and interleukin‐6 (median 6.0 vs. 8.5 pg/mL; p=0.026) on admission. The protective effect of RAS inhibitors on mortality was confirmed in a meta‐analysis of published data when our data were added to previous studies (odd ratio 0.44, 95% CI 0.29–0.65, p<0.0001). Conclusions In a large single center retrospective analysis we observed a protective effect of pre‐hospitalization use of RAS inhibitors on mortality in hypertensive COVID‐19 patients; which might be associated with reduced inflammatory response.

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Discontinuation of the renin–angiotensin system inhibitors improves erythropoiesis in patients with lower-risk myelodysplastic syndromes

Therapeutic Advances in Hematology ◽

10.1177/2040620720958299 ◽

2021 ◽

Vol 12 ◽

pp. 204062072095829

Author(s):

George Pavlidis ◽

Sotirios G. Papageorgiou ◽

Efthimia Bazani ◽

Anthi Bouchla ◽

Eirini Glezou ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Lower Risk ◽

Angiotensin Receptor Blockers ◽

Renin Angiotensin System ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Renin Angiotensin ◽

Group A ◽

Group B ◽

Ras Inhibitors

Renin–angiotensin system (RAS) blockade by angiotensin-converting enzyme inhibitors (ACEis) or angiotensin-receptor blockers (ARBs) has been related to anemia in various situations. We aimed to investigate whether discontinuation of RAS inhibitors improves erythropoiesis in patients with lower-risk myelodysplastic syndromes (LR-MDSs). Seventy-four patients with LR-MDS were divided into three groups matched for gender and age. Group A consisted of 20 hypertensive patients who discontinued RAS inhibitors and received alternative medications. Group B consisted of 26 patients who continued to receive ACEi/ARB and Group C included 28 patients (50% hypertensive) never exposed to ACEi/ARB. Half of the patients in each group were under treatment with recombinant human erythropoietin (rHuEPO). Data were collected at baseline and after 3, 6 and 12 months. Group A showed a significant increase in hemoglobin from 10.4 ± 1g/dL at baseline to 12.6 ± 1.2 g/dL after 12 months ( p = 0.035) and in hematocrit (31.4 ± 3% versus 37.9 ± 4%, p = 0.002). Incident anemia decreased from 100% at baseline to 60% at 12 months ( p = 0.043) despite a concomitant dose reduction in rHuEPO by 18% ( p = 0.035). No changes in hemoglobin and hematocrit were observed in both Group B and Group C. In the subset of patients not treated with rHuEPO, improvement of erythropoiesis was found only in Group A, as measured by changes in hemoglobin (11.5 ± 1 g/dL versus 12.4 ± 1.3 g/dL, p = 0.041) and hematocrit (34.5 ± 3% versus 37.1 ± 4%, p = 0.038) after 12 months. In contrast, Group B and Group C decreased hemoglobin and hematocrit after 12 months ( p < 0.05). In conclusion, discontinuation of ACEi/ARB in LR-MDS patients is followed by a significant recovery of erythropoiesis after 12 months.

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HFrEF pharmacological treatment: ACEIs and/or ARBs

ESC CardioMed ◽

10.1093/med/9780198784906.003.0424 ◽

2018 ◽

pp. 1844-1848

Author(s):

Marc A. Pfeffer

Keyword(s):

Heart Failure ◽

Angiotensin Receptor Blockers ◽

Antihypertensive Agents ◽

Drug Effects ◽

Renin Angiotensin System ◽

Angiotensin Converting Enzyme Inhibitors ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Renin Angiotensin ◽

Reduced Ejection Fraction

Several classes of inhibitors of the renin–angiotensin system were developed as antihypertensive agents. Following the early observations of favourable haemodynamic effects of angiotensin-converting enzyme inhibitors (ACEIs) in patients with congestive heart failure, a series of major randomized outcome trials demonstrated morbidity and mortality benefits of these agents across the spectrum of patients with heart failure with reduced ejection fraction (HFrEF). Angiotensin receptor blockers (ARBs) were then also shown to have similar benefits with a suggestion of some incremental improvements when used together. However, in the trials that randomized patients to a proven dose of an ACEI plus either placebo or an ARB, the combination of the two inhibitors of the renin–angiotensin system resulted in more adverse drug effects without a meaningful improvement in clinical outcomes. This chapter reviews the fundamental underpinnings for use of either an ACEI or ARB to improve prognosis of patients with HFrEF.

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Use of Renin-Angiotensin System Antagonists in Patients with Hypertension and COVID-19 Infection: A Rapid Review and Meta-analysis

Acta Medica Philippina ◽

10.47895/amp.v54i0.1867 ◽

2020 ◽

Vol 54 ◽

Author(s):

Rowena Natividad S. Flores-Genuino ◽

Charissa Mia Salud-Gnilo ◽

Evelyn Osio-Salido

Keyword(s):

Heart Failure ◽

Angiotensin Receptor Blockers ◽

Severe Disease ◽

Renin Angiotensin System ◽

Rapid Review ◽

Insufficient Evidence ◽

Converting Enzyme Inhibitors ◽

Cross Sectional ◽

Angiotensin System ◽

Renin Angiotensin

KEY FINDINGSAmong patients with confirmed COVID-19 infection and hypertension, there is insufficient evidence that RASantagonists are associated with mortality or severe COVID-19 disease.• There is uncertainty with regards to the safe use of renin-angiotensin system (RAS) antagonists, such asangiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), for COVID-19 patientswith hypertension and other comorbidities (heart failure, chronic kidney disease) because of two possiblecontradictory mechanisms 1) upregulation of ACE2 receptors that may facilitate the virus entry into the lung.and 2) control of unabated angiotensin II levels reducing acute lung injury.• Based on very low-quality retrospective cohort studies, there is insufficient evidence that RAS antagonists areassociated with increased mortality (6 studies) or severe disease (10 studies) among patients with confirmedCOVID-19 infection and hypertension.• There are 36 ongoing studies (21 RCTs, 1 single-arm trial, 4 prospective cohorts, 4 retrospective cohorts, 4 casecontrol, and 2 cross-sectional) on this topic.• The European Society of Cardiology (ESC) Council on Hypertension, the International Society of Hypertension(ISH) and the joint statement by the American College of Cardiology (ACC), American Heart Association (AHA),and Heart Failure Society of America (HFSA) all caution against discontinuing RAS-related treatments inpatients with hypertension who become infected with COVID-19.

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Dual Blockade of the Renin-Angiotensin System: A Strategy that Should Be Reconsidered in Cardiorenal Diseases?

Nephron ◽

10.1159/000513119 ◽

2021 ◽

pp. 1-8

Author(s):

Mei Mei ◽

Zulian Zhou ◽

Qian Zhang ◽

Yi Chen ◽

Hongwen Zhao ◽

...

Keyword(s):

Enzyme Inhibitors ◽

Angiotensin Receptor Blockers ◽

Renin Angiotensin System ◽

Angiotensin Converting Enzyme Inhibitors ◽

Individualized Therapy ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Renin Angiotensin ◽

System A ◽

Receptor Blockers

Studies on pharmacological mechanisms demonstrated that a strategy of dual renin-angiotensin system (RAS) blockade may have a synergistic effect in the treatment of cardiorenal diseases and may reduce adverse reactions. However, some previous clinical studies reported that dual RAS blockade did not significantly benefit many patients with cardiorenal diseases and increased the risk of hyperkalemia, hypotension and renal function damage. Therefore, the current clinical guidelines suggest that the combined use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) should be used with caution in the clinic. However, these studies enrolled older patients with cardiovascular risk factors, and the results of these trials may not be generalized to the overall population. Some clinical evidence suggests that the combination of low-dose ACEIs and ARBs leads to more effective RAS blockade with few adverse effects. The advent of new RAS inhibitors with superior pharmacological effects provides a more suitable drug choice for individualized therapy for dual RAS blockade. Therefore, the choice of appropriate ARBs/ACEIs for individualized therapy based on patient condition may be a better way to improve the efficiency and safety of the dual RAS blockade strategy.

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Mechanisms linking the renin-angiotensin system, obesity, and breast cancer

Endocrine Related Cancer ◽

10.1530/erc-19-0314 ◽

2019 ◽

Vol 26 (12) ◽

pp. R653-R672 ◽

Cited By ~ 10

Author(s):

Fahmida Rasha ◽

Latha Ramalingam ◽

Lauren Gollahon ◽

Rakshanda Layeequr Rahman ◽

Shaikh Mizanoor Rahman ◽

...

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Complex Disease ◽

Angiotensin Receptor Blockers ◽

Renin Angiotensin System ◽

Ang Ii ◽

Angiotensin System ◽

Renin Angiotensin ◽

Breast Adipose Tissue ◽

Ras Inhibitors

Obesity is a complex disease and a global epidemic. It is a risk factor for other chronic diseases including breast cancer, especially in women after menopause. Diverse etiologies underlie the relationship between obesity and breast cancer. Adipose tissue is in part responsible for these interactions. In obesity, adipose tissue undergoes several metabolic dysregulations resulting in the secretion of many pro-inflammatory cytokines, growth factors, and hormones which in turn, can promote tumor microenvironment (TME) formation and cancer progression within the breast tissue. Angiotensin II (Ang II) is a well-known hypertensive hormone produced systemically and locally by the renin-angiotensin system (RAS). Activation of this system in obesity is a potential contributor to local and systemic inflammation in breast adipose tissue. Ang II actions are primarily mediated through binding to its two receptors, type 1 (AT1R) and type 2 (AT2R). RAS inhibitors include angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) which are currently prescribed as safe antihypertensive therapies. Recent studies have explored the potential use of ACE-I and ARBs in breast cancer patients as anti-tumor agents. Therefore, it is vital to understand the role of RAS in breast cancer and identify mechanisms of Ang II and RAS inhibitors in the TME and in obesity and breast cancer crosstalk. In this review, we performed a detailed analysis and discussed mechanisms of Ang II-AT1R interactions in breast cancer with emphasis on obesity-associated breast cancer. We further summarized recent in vitro, in vivo and human studies that used ACE-I/ARB interventions to improve breast cancer outcomes.

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Comparative efficacy of different renin angiotensin system blockade therapies in patients with IgA nephropathy: a Bayesian network meta-analysis of 17 RCTs

PeerJ ◽

10.7717/peerj.11661 ◽

2021 ◽

Vol 9 ◽

pp. e11661

Author(s):

Zhihao Huo ◽

Huizhen Ye ◽

Peiyi Ye ◽

Guanqing Xiao ◽

Zhe Zhang ◽

...

Keyword(s):

Blood Pressure ◽

Network Analysis ◽

Bayesian Network ◽

Iga Nephropathy ◽

Kidney Function ◽

Meta Analysis ◽

Renin Angiotensin System ◽

Cochrane Library ◽

Angiotensin System ◽

Renin Angiotensin

Background IgA nephropathy (IgAN) is still one of the most prevalent forms of primary glomerulonephritis globally. However, no guidelines have clearly indicated which kinds of renin angiotensin system blockade therapies (ACEIs or ARBs or their combination) in patients with IgAN result in a greater reduction in proteinuria and a better preservation of kidney function. Thus, we conducted a Bayesian network analysis to evaluate the relative effects of these three therapy regimens in patients with IgAN. Methods The protocol was registered in PROSPERO with ID CRD42017073726. We comprehensively searched the PubMed, the Cochrane Library, Embase, China Biology Medicine disc, WanFang and CNKI databases for studies published since 1993 as well as some grey literature according to PICOS strategies. Pairwise meta-analysis and Bayesian network analysis were conducted to evaluate the effect of different regimens. Results Seventeen randomized controlled trials (RCTs) involving 1,006 patients were analyzed. Co-administration of ACEIs and ARBs had the highest probability (92%) of being the most effective therapy for reducing proteinuria and blood pressure, but ACEIs would be the most appropriate choice for protecting kidney function in IgAN. Conclusion The combination of ACEIs and ARBs seems to have a significantly better antiproteinuric effect and a greater reduction of blood pressure than ACEI or ARB monotherapy in IgAN. ACEIs appear to be a more renoprotective therapy regimen among three therapies.

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Renin Angiotensin System Inhibition and Susceptibility and Outcomes from COVID-19: A Systematic Review and Meta-analysis of 69,200 COVID-19 Patients

10.1101/2020.10.03.20206375 ◽

2020 ◽

Author(s):

Yi Zhang ◽

Shikai Yu ◽

Yawei Xu ◽

Bryan Williams

Keyword(s):

Systematic Review ◽

Observational Studies ◽

Meta Analysis ◽

Renin Angiotensin System ◽

Risk Of Infection ◽

Angiotensin System ◽

Renin Angiotensin ◽

Significant Difference ◽

The Impact ◽

Ras Inhibitors

ABSTRACTBackgroundEarly observational studies suggested that the use of the renin angiotensin system (RAS) inhibitors, specifically angiotensin converting enzyme inhibitors or angiotensin receptor blockers, may increase the risk of infection with SARS-CoV-2 and adversely affect the prognosis or survival of infected patients. To explore the impact of RAS inhibitor use on the risk of SARS-CoV-2 infection and the prognosis of SARS-CoV-2 infected patients, from all published studies.Methods and FindingsA systematic review and meta-analysis of the use of RAS inhibitors in relation to infection with SARS-CoV-2 and/or the severity and mortality associated with COVID-19 was conducted. English language bibliographic databases PubMed, Web of Science, OVID Embase, Scopus, MedRxiv, BioRxiv, searched from Jan 1st, 2020 to July 20th, 2020. 58 observational studies (69,200 COVID-19 patients and 3,103,335 controls) were included. There was no difference in the susceptibility to SARS-CoV-2 infection between RAS inhibitor users and non-users (unadjusted OR 1.05, 95% CI 0.90 to 1.21), (adjusted OR 0.93, 95% CI 0.85 to 1.02), (adjusted HR 1.07, 95% CI 0.87 to 1.31). There was no significant difference in the severe Covid-19 case rate between RAS inhibitor users and non-users (unadjusted OR 1.05, 95% CI 0.81 to 1.36), (adjusted OR 0.76, 95% CI 0.52 to 1.12), or in mortality due to COVID-19 between RAS inhibitor users and non-users (unadjusted OR 1.12, 95% CI 0.88 to 1.44), (adjusted OR 0.97, 95% CI 0.77 to 1.23), (adjusted HR 0.62, 95% CI 0.34 to 1.14).ConclusionsIn the most comprehensive analysis of all available data to date, treatment with RAS inhibitors was not associated with increased risk of infection, severity of disease, or mortality due to COVID-19. The best available evidence suggests that these treatments should not be discontinued on the basis of concern about risk associated with COVID-19.

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Cessation of Renin-Angiotensin System Antagonists During the SARS-CoV-2 Pandemic – Do We Have the Evidence?

Journal of Interdisciplinary Medicine ◽

10.2478/jim-2020-0022 ◽

2020 ◽

Vol 5 (3) ◽

pp. 105-109

Author(s):

Emanuel Blîndu ◽

Renata Gerculy ◽

Diana Opincariu ◽

Daniel Cernica ◽

Imre Benedek

Keyword(s):

Angiotensin Converting Enzyme ◽

Angiotensin Receptor Blockers ◽

Healthcare Providers ◽

Age Groups ◽

Renin Angiotensin System ◽

Host Cells ◽

Converting Enzyme ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Renin Angiotensin

AbstractThe aim of this review is to provide a short update on whether treatment with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) has beneficial or harmful effects in patients infected with SARS-CoV-2. Epidemiological studies have shown that SARS-CoV-2 infects all age groups, presenting a higher incidence in elderly patients with various comorbidities such as hypertension, diabetes mellitus, and cardiovascular diseases. A large proportion of these patients are treated with ACEIs and ARBs. Since it has been demonstrated that SARS-CoV-2 uses angiotensin converting enzyme type 2 (ACE2) as an entry point into host cells, it is important to know whether ACEIs and ARBs could modify the expression of this enzyme, and thus promote the viral infection. Animal studies and a few studies in humans have shown that renin angiotensin system (RAS) inhibitors increase tissue expression of ACE2, but with potentially beneficial effects. In this context, it is imperative to provide appropriate guidance for clinicians and patients. The major cardiology associations across the world have released statements in which they recommend healthcare providers and patients to continue their treatments for hyper-tension and heart failure as prescribed.

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