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.

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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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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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Renin-angiotensin system antagonists are associated with lower mortality in hypertensive patients with COVID-19

Scottish Medical Journal ◽

10.1177/0036933020949219 ◽

2020 ◽

Vol 65 (4) ◽

pp. 123-126 ◽

Cited By ~ 3

Author(s):

Michael Megaly ◽

Mattew Glogoza

Keyword(s):

Enzyme Inhibitors ◽

Angiotensin Receptor Blockers ◽

Meta Analysis ◽

Renin Angiotensin System ◽

Angiotensin Converting Enzyme Inhibitors ◽

Lower Mortality ◽

Converting Enzyme Inhibitors ◽

Hypertensive Patients ◽

Risk Of Death ◽

Receptor Blockers

The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) in patients with Coronavirus 2019 (COVID-19) has been controversial. We performed a meta-analysis of all published studies that reported the outcomes of ACEIs/ARBs in patients with COVID-19. We included four observational studies (3,267 patients). The use of ACEIs/ARBs was associated with a similar risk of all-cause death (OR: 0.75, 95% CI [0.36, 1.57], p = 0.45). Sensitivity analysis including only hypertensive patients demonstrated a lower risk of death with ACEIs/ARBs use (OR: 0.57, 95% CI [0.32-0.98], p = 0.04). In conclusion, hypertensive patients with COVID-19 treated with ACEIs/ARBS have a lower mortality but further research is needed.

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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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Renin–angiotensin system blocker discontinuation and adverse outcomes in chronic kidney disease

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa300 ◽

2020 ◽

Author(s):

Carl P Walther ◽

Wolfgang C Winkelmayer ◽

Peter A Richardson ◽

Salim S Virani ◽

Sankar D Navaneethan

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Renin Angiotensin System ◽

Cox Proportional Hazards ◽

Adverse Outcomes ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Renin Angiotensin ◽

Risk Of Death ◽

Increased Risk

Abstract Background Treatment with renin–angiotensin system inhibitors (RASIs), angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) is the standard of care for those with chronic kidney disease (CKD) and albuminuria. However, ACEI/ARB treatment is often discontinued for various reasons. We investigated the association of ACEI/ARB discontinuation with outcomes among US veterans with non-dialysis-dependent CKD. Methods We performed a retrospective cohort study of patients in the Veterans Affairs healthcare system with non-dialysis-dependent CKD who subsequently were started on ACEI/ARB therapy (new user design). Discontinuation events were defined as a gap in ACEI/ARB therapy of ≥14 days and were classified further based on duration (14–30, 31–60, 61–90, 91–180 and >180 days). This was treated as a time-varying risk factor in adjusted Cox proportional hazards models for the outcomes of death and incident end-stage kidney disease (ESKD), which also adjusted for relevant confounders. Results We identified 141 252 people with CKD and incident ACEI/ARB use who met the inclusion criteria; these were followed for a mean 4.87 years. There were 135 356 discontinuation events, 68 699 deaths and 6152 incident ESKD events. Discontinuation of ACEI/ARB was associated with a higher risk of death [hazard ratio (HR) 2.3, 2.0, 1.99, 1.92 and 1.74 for those discontinued for 14–30, 31–60, 61–90, 91–180 and >180 days, respectively]. Similar associations were noted between ACEI and ARB discontinuation and ESKD (HR 1.64, 1.47, 1.54, 1.65 and 1.59 for those discontinued for 14–30, 31–60, 61–90, 91–180 and >180 days, respectively). Conclusions In a cohort of predominantly male veterans with CKD Stages 3 and 4, ACEI/ARB discontinuation was independently associated with an increased risk of subsequent death and ESKD. This may be due to the severity of illness factors that drive the decision to discontinue therapy. Further investigations to determine the causes of discontinuations and to provide an evidence base for discontinuation decisions are needed.

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

10.1101/2020.05.19.20106799 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jessica Barochiner ◽

Rocio Martinez

Keyword(s):

Angiotensin Receptor Blockers ◽

Meta Analysis ◽

Random Effect ◽

Renin Angiotensin System ◽

Cochrane Library ◽

Composite Outcome ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ras Inhibitors

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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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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Exposure to Renin-Angiotensin System Inhibitors Is Associated with Reduced Mortality of Older Hypertensive Covid-19 Patients

10.1101/2020.12.15.20247999 ◽

2020 ◽

Author(s):

Mauro Gori ◽

Carlo Berzuini ◽

Emilia D’Elia ◽

Arianna Ghirardi ◽

Luisa Bernardinelli ◽

...

Keyword(s):

Enzyme Inhibitors ◽

Renin Angiotensin System ◽

Angiotensin Converting Enzyme Inhibitors ◽

Converting Enzyme ◽

Converting Enzyme Inhibitors ◽

Angiotensin System ◽

Hypertensive Patients ◽

Renin Angiotensin ◽

Prior Use ◽

Receptor Blockers

Abstract From a cohort of 1352 consecutive patients admitted with coronavirus disease (Covid-19) to Papa Giovanni XXIII Hospital in Bergamo, Italy, between February and April 2020, we selected and studied 688 patients with arterial hypertension (254 deaths) to assess whether use of renin-angiotensin system inhibitors (RASIs) prior to hospital admission affects mortality from Covid-19. Prior use of RASIs was associated with a lower mortality in the over-68 group of patients, whereas no evidence of a similar effect (whether protective or adverse) was found in the younger group. There was positive relative excess due to a statistically significant (p =0.001) interaction between prior RASI exposure and an age greater than 68 years, corresponding to a positive relative excess risk. Next we used the subgroup of 411 hypertensive patients older than 68 yrs to separately assess the effects prior use of two RASI drug subclasses, angiotensin-converting enzyme inhibitors (ACEIs) and angiogiotensin receptor blockers (ARBs), by comparing these two exposures with no exposure to RASIs. We found both prior use of ACEIs and prior use of ARBs to be associated with a lower Covid-19 mortality, after adjusting for 32 medical history variables via propensity score matching. (ORACEI = 0.57, 95%CI 0.36 to 0.91, p =0.018) (ORARB = 0.49, 95%CI 0.29 to 0.82, p =0.006).

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