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Inhibitors of the ReninAngiotensin
Aldosterone System and Covid-19 in critically ill
elderly patients
Christian Jung (1), Raphael Romano Bruno (1), Bernhard Wernly (2), Michael Joannidis (3), Sandra Oeyen (4),
Tilemachos Zafeiridis (5), Brian Marsh (6), Finn H. Andersen (7), Rui Moreno (8), Ana Margarida Fernandes
(8) Antonio Artigas (9), Bernardo Bollen Pinto (10), Joerg Schefold (11), Georg Wolff (1), Malte Kelm (1),
Dylan W. De Lange (12), Bertrand Guidet (13), Hans Flaatten (14); Jesper Fjølner (15)
on behalf of the COVIP study group
Affiliations
1. Heinrich-Heine-University Duesseldorf, Medical Faculty, Department of Cardiology, Pulmonology and
Vascular Medicine, Düsseldorf, Germany
2. Department of Cardiology, Paracelsus Medical University, Salzburg, Austria
3. Division of Intensive Care and Emergency Medicine, Department of Internal Medicine, Medical
University Innsbruck, Innsbruck, Austria
4. Department of Intensive Care 1K12IC Ghent University Hospital, Ghent, Belgium
5. Intensive Care Unit General Hospital of Larissa, Larissa, Greece
6. Mater Misericordiae University Hospital, Dublin, Ireland
7. Dep. Of Anaesthesia and Intensive Care, Ålesund Hospital, Ålesund, Norway. Dep. of Circulation and
medical imaging, Norwegian university of Science and Technology, Trondheim, Norway
8. Unidade de Cuidados Intensivos Neurocríticos e Trauma. Hospital de São José, Centro Hospitalar
Universitário de Lisboa Central, Faculdade de Ciências Médicas de Lisboa, Nova Médical School,
Lisbon, Portugal
9. Department of Intensive Care Medecine, CIBER Enfermedades Respiratorias, Corporacion Sanitaria
Universitaria Parc Tauli, Autonomous University of Barcelona, Sabadell, Spain
Manuscript
© Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2020.
For permissions, please email: journals.permissions@oup.com
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10. Department of Acute Medicine, Geneva University Hospitals, Geneva, Switzerland
11. Department of Intensive Care Medicine, Inselspital, Universitätsspital, University of Bern, Bern,
Switzerland
12. Department of Intensive Care Medicine, University Medical Center, University Utrecht, the Netherlands
13. Assistance Publique - Hôpitaux de Paris, Hôpital Saint-Antoine, service de réanimation médicale, Paris,
F-75012, France
14. Department of Clinical Medecine,University of Bergen, Department of Anaestesia and Intensive Care,
Haukeland University Hospital , Bergen, Norway
15. Department of Intensive Care, Aarhus University Hospital, Aarhus, Denmark
Corresponding author:
Christian Jung, M.D. PhD
Division of Cardiology, Pulmonology, and Vascular Medicine
University Duesseldorf
Moorenstraße 5, 40225 Duesseldorf
Germany
Email: christian.jung@med.uni-duesseldorf.de
Word count: 609 (main text)
Conflict of Interests
The authors declare that they have no competing interests.
Financial Disclosure statement
No (industry) sponsorship has been received for this investigator-initiated study.
Acknowledgments
The support of the study in France by Assistance Publique-Hôpitaux de Paris is greatly appreciated.
Trial registration number
NCT04321265
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SARS-CoV-2, the coronavirus that causes COVID-19, uses the membrane-bound form of the
aminopeptidase angiotensin-converting enzyme 2 (ACE2) to enter cells. Since ACE2 is
centrally involved in the regulation of the renin-angiotensin-aldosterone system (RAAS), it has
been speculated that RAAS inhibitors influence clinical courses. Mehta et al. found no
association between use of RAAS inhibitors and likelihood of COVID-19 testing positivity in
18,472 patients. (1) Reynolds et al. performed a study based on data from electronic health
records (5,894 COVID-19 cases), where a Bayesian analysis showed no positive association of
RAAS inhibitors with either a positive test result or severe illness. Mancia et al. also found no
evidence in a population-based case-control study (6,272 case-patients) for RAAS inhibitors to
affect the risk of contracting COVID-19. (2)
However, although these retrospective studies report essential data, they are of limited use to
inform on elderly, co-morbid and severely ill patients, who represent the most vulnerable group
of patients affected by Covid-19 and are also most likely treated with RAAS inhibitors within
the general population. To investigate special clinical features in COVID-19, the COVIP study
(Very old intensive care patients, VIP-network; NCT04321265) is ongoing. COVIP
prospectively includes patients equal to or above 70 years of age with proven COVID-19 who
are admitted to an intensive care unit (ICU). A total of 244 ICUs in 38 countries are registered
to participate in COVIP. The primary endpoint is death after 30 days. Inclusion criteria are 1)
Age 70 years 2) ICU-Admission 3) Infection with SARS-CoV-2. Furthermore, a follow-up
will be performed after 3 months to assess death and quality of life. The prospective design
aims to create high-quality data about risk factors, comorbidities, pre-existing frailty, ICU-
treatment including treatment limitations, and the use of experimental drugs in this critically ill
patient collective of elderly patients. An interim analysis was performed on 7th of May with
respect to RAAS inhibitor use.
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In total, 324 patients were evaluated (Table 1): 157 (48%) were on RAAS inhibitors, 62 (19%)
on angiotensin-converting-enzyme (ACE) inhibitors (ACE-I) and 95 (29%) on angiotensin II
receptor blockers (ARB) before disease onset. Overall ICU-mortality was 45% and was similar
between patients with and without previous ARB (45% vs. 45%; p=0.98), but lower in patients
with previous ACE-I (31% vs. 49%; p=0.01). A propensity for being on ACE-I was calculated
using logistic regression, the covariates were age, body mass index, sex, sequential Organ
Failure Assessment (SOFA) score, as well as existing comorbidities of chronic heart failure,
ischemic heart disease, renal insufficiency, chronic pulmonary disease, arterial hypertension
and diabetes mellitus (Table 1). The primary endpoint was ICU mortality. Both univariable
(model 1) and multivariable (model 2, propensity score correction) logistic regression models
were built to evaluate associations with the primary endpoint. Odds ratios (OR, model 1, Table
1) and adjusted odds ratios (aOR, model 2) with respective 95% confidence intervals (CI) were
calculated. The univariate association of previous ACE-I with lower mortality (OR 0.46, 95%
CI 0.26-0.84; p=0.01; Table 1) remained statistically significant after propensity score
adjustment (aOR 0.32, 95%CI 0.15-0.67; p=0.002).
In conclusion, in a prospective study of elderly, critically ill and co-morbid patients, we do find
a beneficial association of previous ACE-I use with ICU survival. The current data confirms
the notion that there is either a positive or no effect of RAAS inhibitor use. In addition, our data
support the current view that continuation of RAAS inhibitor use should be recommended. (3)
In summary, this is the first prospective multinational study that demonstrates beneficial
associations of ACE-I in high risk Covid-19 patients and thus impact on daily practice.
However, further research evaluating potential causality is warranted.
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References
1. Mehta N, Kalra A, Nowacki AS, Anjewierden S, Han Z, Bhat P, Carmona-Rubio AE,
Jacob M, Procop GW, Harrington S, Milinovich A, Svensson LG, Jehi L, Young JB, Chung
MK. Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II
Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA
Cardiology 2020.
2. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-Angiotensin-
Aldosterone System Blockers and the Risk of Covid-19. N Engl J Med 2020.
3. Danser AHJ, Epstein M, Batlle D. Renin-Angiotensin System Blockers and the
COVID-19 Pandemic. Hypertension 2020; 75(6):1382-1385.
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Table legends
Table 1, title: Patient characteristics
Table 1, legend: Patient characteristics in all patients and in survivors and non-survivors,
respectively. All continuous variables were non-normally distributed, are presented as median
(range) and were compared using Mann-Whitney-U tests; categorical variables are presented
as n (%) and were compared using Chi² tests; p-values and Cochran-Mantel-Haenszel estimates
are reported, presented as odds ratios (OR) with 95% confidence intervals (CI); statistical
significance was assumed at p < 0.05 and is indicated by *.
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Table 1 Patient characteristics
All patients
(n = 324)
Survivors
(n = 177)
Non-Survivors
(n = 147)
p-values
OR (95% CI)
Age
74 (70-93)
77 (70-88)
<0.0001 *
-
BMI
26.9 (18.3-41.5)
26.5 (18.3-51.4)
0.65
-
Male/female sex
116/61 (52/61)
108/39 (48/39)
0.12
1.46 (0.90-2.35)
SOFA score
5 (2-13)
7 (1-17)
<0.0001 *
-
Chronic heart failure
20 (11.5)
25 (17.2)
0.14
1.60 (0.85-3.03)
Ischemic heart disease
31 (17.8)
32 (22.1)
0.40
1.31 (0.75-2.27)
Renal insufficiency
18 (10.2)
31 (21.1)
0.007 *
2.35 (1.25-4.40) *
Pulmonary disease
41 (23.3)
41 (28.3)
0.31
1.30 (0.79-2.15)
Arterial hypertension
115 (65.0)
96 (65.3)
0.95
1.02 (0.64-1.61)
Diabetes mellitus
48 (27.1)
47 (32.2)
0.32
1.28 (0.79-2.06)
ACE-I
43 (24.3)
19 (12.9)
0.01 *
0.46 (0.26-0.84) *
ARB
52 (29.4)
43 (29.3)
0.98
0.99 (0.62-1.61)
Table 1: Patient characteristics in all patients and in survivors and non-survivors, respectively. All continuous
variables were non-normally distributed, are presented as median (range) and were compared using Mann-
Whitney-U tests; categorical variables are presented as n (%) and were compared using Chi² tests; p-values and
Cochran-Mantel-Haenszel estimates are reported, presented as odds ratios (OR) with 95% confidence intervals
(CI); statistical significance was assumed at p < 0.05 and is indicated by *.
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... 21 Overall, Alvarez-Garcia et al. demonstrated that pre-existing heart failure was associated with an increased length of stay and mortality. Further, renin-angiotensin-aldosterone system inhibition did not affect clinical outcome, which is in line with a recent subgroup analysis of the COVIP study by Jung et al. 22 By contrast, Rey et al. found an increased mortality in CHF patients who stopped their guideline-directed medical therapy because of COVID-19. In a cohort of 152 patients, preexisting heart failure was associated with increased mortality. ...
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... The present study has some methodological limitations in common with the other COVIP-studies [11,26,[39][40][41][42]. COVIP did not contain a control group of younger COVID-19 ...
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Background: The SARS-CoV-2 coronavirus disease (COVID-19) pandemic is challenging health care systems globally. The disease disproportionately affects the elderly population, both in terms of disease severity and mortality risk. Objective: This study aimed to evaluate machine-learning based prognostication models for critically ill elderly COVID-19 patients, which dynamically incorporated multifaceted clinical information on the evolution of the disease. Methods: This multi-centre cohort study obtained patient data from 151 ICUs from 26 countries (COVIP study). Different models based on the Sequential Organ Failure Assessment (SOFA), Logistic Regression (LR), Random Forest (RF) and Extreme Gradient Boosting (XGBoost) were derived as baseline models that included admission variables only. We subsequently included clinical events and time-to-event as additional variables to derive the final models using the same algorithms and compared their performance with the baseline group. Furthermore, we derived baseline and final models on a European patient cohort and externally validated them on a non-European cohort that included Asian, African and American patients. Results: In total, 1,432 elderly (≥70 years) COVID-19 positive patients were admitted to an intensive care unit. Of these 809 (56.5%) patients survived up to 30 days after admission. The average length of stay was 21.6 (±18.2) days. Final models that incorporated clinical events and time-to-event provided superior performance with AUC of 0.81 (95% CI 0.804-0.811), with respect to both, the baseline models that used admission variables only and conventional ICU prediction models (SOFA-score, p<.001). The average precision increased from 0.65 (95% CI 0.650-0.655) to 0.77 (95% CI 0.759-0.770). Conclusions: Integrating important clinical events and time-to-event information led to a superior accuracy of 30-day mortality prediction compared with models based on the admission information and conventional ICU prediction models. The present study shows that machine-learning models provide additional information and may support complex decision-making in critically ill elderly COVID-19 patients. Clinicaltrial: Nct04321265.
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... In our study, as in many previous studies, the selection of hospitalized patients may generate a collider bias, whereby patients with RAAS blockers may be admitted for less severe disease and hence have better outcomes [28,[40][41][42]. This bias is much more likely to occur in even more specific settings (such as intensive care unit admission) [43], or in studies conducted in unrestricted populations (i.e., with no indication for RAAS blockers), due to a larger baseline imbalance, as explained above. Still, to account for potential different severity at inclusion between groups of exposure, we performed a separate adjustment for baseline severity, which did not modify the results. ...
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Background Renin‐angiotensin aldosterone system (RAAS) inhibitor—COVID‐19 studies, observational in design, appear to use biased methods that can distort the interaction between RAAS inhibitor use and COVID‐19 risk. This study assessed the extent of bias in that research and reevaluated RAAS inhibitor—COVID‐19 associations in studies without critical risk of bias. Methods and Results Searches were performed in MEDLINE, EMBASE, and CINAHL databases (December 1, 2019 to October 21, 2021) identifying studies that compared the risk of infection and/or severe COVID‐19 outcomes between those using or not using RAAS inhibitors (ie, angiotensin‐converting enzyme inhibitors or angiotensin II type‐I receptor blockers). Weighted hazard ratios (HR) and 95% CIs were extracted and pooled in fixed‐effects meta‐analyses, only from studies without critical risk of bias that assessed severe COVID‐19 outcomes. Of 169 relevant studies, 164 had critical risks of bias and were excluded. Ultimately, only two studies presented data relevant to the meta‐analysis. In 1 351 633 people with uncomplicated hypertension using a RAAS inhibitor, calcium channel blocker, or thiazide diuretic in monotherapy, the risk of hospitalization (angiotensin‐converting enzyme inhibitor: HR, 0.76; 95% CI, 0.66–0.87; P <0.001; angiotensin II type‐I receptor blockers: HR, 0.86; 95% CI, 0.77–0.97; P =0.015) and intubation or death (angiotensin‐converting enzyme inhibitor: HR, 0.64; 95% CI, 0.48–0.85; P =0.002; angiotensin II type‐I receptor blockers: HR, 0.74; 95% CI, 0.58–0.95; P =0.019) with COVID‐19 was lower in those using a RAAS inhibitor. However, these protective effects are probably not clinically relevant. Conclusions This study reveals the critical risk of bias that exists across almost an entire body of COVID‐19 research, raising an important question: Were research methods and/or peer‐review processes temporarily weakened during the surge of COVID‐19 research or is this lack of rigor a systemic problem that also exists outside pandemic‐based research? Registration URL: www.crd.york.ac.uk/prospero/ ; Unique identifier: CRD42021237859.
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Background: Antecedent use of renin angiotensin aldosterone inhibitors (RAASi) appears crucial to prevent clinical deterioration and protect against cardiovascular and/or thrombotic complications of Coronavirus Disease (COVID-19), for indicated patients. Doubts have been raised about continuing treatment throughout infection, and nothing is known regarding its effect with concomitant medications. Hence, the purpose of this paper is to evaluate the differential effect of RAASi continuation in patients hospitalized with COVID-19 according to diuretic use. Methods: We used the Coracle (epidemiology, clinical characteristics, and therapy in real life patients affected by Sars-Cov-2) multi-center registry, which contains data of hospitalized patients with COVID-19 from 4 regions of Italy. We performed analyses on adult (50+ years) records with admission on/after February 22, 2020 with a known mortality or discharge status as of April 1, 2020. We constructed a multivariable Firth logistic regression model to complete our objective. Results: There were 286 patients in this analysis. Overall, 100 (35.0%) patients continued RAASi and 186 (65%) discontinued. There were 98 patients who were treated with a diuretic; 51 (52%) of those continued RAASi. The in-hospital mortality rates among patients treated with a diuretic and continued vs. discontinued RAASi were 7.8% vs 25.5% (p = 0.0179). There were 188 patients who were not treated with a diuretic; 49 (26.1%) of those continued RAASi. The in-hospital mortality rates among patients who were not treated with a diuretic and continued vs. discontinued RAASi were 16.3% vs 9.4% (p = 0.1827). After accounting for age, congestive heart failure, and coronary heart disease/ischemic heart disease, continuing RAASi decreased the risk of mortality by approximately 72% (OR = 0.28, 95% CI = 0.08 – 0.94, p = 0.0391) for patients treated with diuretics, but did not alter the risk in patients who were not treated with diuretics. Conclusion: Diuretic use in hospitalized patients with COVID-19 who were on RAASi prior to admission was associated with increased risk of in-hospital mortality. Whether this combined therapy increases risk or is the reflection of a more severe presentation deserves further investigation. Continuing RAASi therapy in patients concomitantly treated with diuretics was associated with reduced in-hospital mortality.
Article
Importance The role of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in the setting of the coronavirus disease 2019 (COVID-19) pandemic is hotly debated. There have been recommendations to discontinue these medications, which are essential in the treatment of several chronic disease conditions, while, in the absence of clinical evidence, professional societies have advocated their continued use. Objective To study the association between use of ACEIs/ARBs with the likelihood of testing positive for COVID-19 and to study outcome data in subsets of patients taking ACEIs/ARBs who tested positive with severity of clinical outcomes of COVID-19 (eg, hospitalization, intensive care unit admission, and requirement for mechanical ventilation). Design, Setting, and Participants Retrospective cohort study with overlap propensity score weighting was conducted at the Cleveland Clinic Health System in Ohio and Florida. All patients tested for COVID-19 between March 8 and April 12, 2020, were included. Exposures History of taking ACEIs or ARBs at the time of COVID-19 testing. Main Outcomes and Measures Results of COVID-19 testing in the entire cohort, number of patients requiring hospitalizations, intensive care unit admissions, and mechanical ventilation among those who tested positive. Results A total of 18 472 patients tested for COVID-19. The mean (SD) age was 49 (21) years, 7384 (40%) were male, and 12 725 (69%) were white. Of 18 472 patients who underwent COVID-19 testing, 2285 (12.4%) were taking either ACEIs or ARBs. A positive COVID-19 test result was observed in 1735 of 18 472 patients (9.4%). Among patients who tested positive, 421 (24.3%) were admitted to the hospital, 161 (9.3%) were admitted to an intensive care unit, and 111 (6.4%) required mechanical ventilation. Overlap propensity score weighting showed no significant association of ACEI and/or ARB use with COVID-19 test positivity (overlap propensity score–weighted odds ratio, 0.97; 95% CI, 0.81-1.15). Conclusions and Relevance This study found no association between ACEI or ARB use and COVID-19 test positivity. These clinical data support current professional society guidelines to not discontinue ACEIs or ARBs in the setting of the COVID-19 pandemic. However, further study in larger numbers of hospitalized patients receiving ACEI and ARB therapy is needed to determine the association with clinical measures of COVID-19 severity.
Article
Background A potential association between the use of angiotensin-receptor blockers (ARBs) and angiotensin-converting–enzyme (ACE) inhibitors and the risk of coronavirus disease 2019 (Covid-19) has not been well studied. Methods We carried out a population-based case–control study in the Lombardy region of Italy. A total of 6272 case patients in whom infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was confirmed between February 21 and March 11, 2020, were matched to 30,759 beneficiaries of the Regional Health Service (controls) according to sex, age, and municipality of residence. Information about the use of selected drugs and patients’ clinical profiles was obtained from regional databases of health care use. Odds ratios and 95% confidence intervals for associations between drugs and infection, with adjustment for confounders, were estimated by means of logistic regression. Results Among both case patients and controls, the mean (±SD) age was 68±13 years, and 37% were women. The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile. Use of ARBs or ACE inhibitors did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86 to 1.05] for ARBs and 0.96 [95% CI, 0.87 to 1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63 to 1.10] for ARBs and 0.91 [95% CI, 0.69 to 1.21] for ACE inhibitors), and no association between these variables was found according to sex. Conclusions In this large, population-based study, the use of ACE inhibitors and ARBs was more frequent among patients with Covid-19 than among controls because of their higher prevalence of cardiovascular disease. However, there was no evidence that ACE inhibitors or ARBs affected the risk of COVID-19.
Article
Background There is concern about the potential of an increased risk related to medications that act on the renin–angiotensin–aldosterone system in patients exposed to coronavirus disease 2019 (Covid-19), because the viral receptor is angiotensin-converting enzyme 2 (ACE2). Methods We assessed the relation between previous treatment with ACE inhibitors, angiotensin-receptor blockers, beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative result on Covid-19 testing as well as the likelihood of severe illness (defined as intensive care, mechanical ventilation, or death) among patients who tested positive. Using Bayesian methods, we compared outcomes in patients who had been treated with these medications and in untreated patients, overall and in those with hypertension, after propensity-score matching for receipt of each medication class. A difference of at least 10 percentage points was prespecified as a substantial difference. Results Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness. There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive. Conclusions We found no substantial increase in the likelihood of a positive test for Covid-19 or in the risk of severe Covid-19 among patients who tested positive in association with five common classes of antihypertensive medications.
Article
During the spread of the severe acute respiratory syndrome coronavirus-2, some reports of data still emerging and in need of full analysis indicate that certain groups of patients are at risk of COVID-19. This includes patients with hypertension, heart disease, diabetes mellitus, and clearly the elderly. Many of those patients are treated with reninangiotensin system blockers. Because the ACE2 (angiotensin-converting enzyme 2) protein is the receptor that facilitates coronavirus entry into cells, the notion has been popularized that treatment with renin-angiotensin system blockers might increase the risk of developing a severe and fatal severe acute respiratory syndrome coronavirus-2 infection. The present article discusses this concept. ACE2 in its full-length form is a membrane-bound enzyme, whereas its shorter (soluble) form circulates in blood at very low levels. As a mono-carboxypeptidase, ACE2 contributes to the degradation of several substrates including angiotensins I and II. ACE (angiotensin-converting enzyme) inhibitors do not inhibit ACE2 because ACE and ACE2 are different enzymes. Although angiotensin II type 1 receptor blockers have been shown to upregulate ACE2 in experimental animals, the evidence is not always consistent and differs among the diverse angiotensin II type 1 receptor blockers and differing organs. Moreover, there are no data to support the notion that ACE inhibitor or angiotensin II type 1 receptor blocker administration facilitates coronavirus entry by increasing ACE2 expression in either animals or humans. Indeed, animal data support elevated ACE2 expression as conferring potential protective pulmonary and cardiovascular effects. In summary, based on the currently available evidence, treatment with renin-angiotensin system blockers should not be discontinued because of concerns with coronavirus infection.
Aldosterone System Blockers and the Risk of Covid-19
Aldosterone System Blockers and the Risk of Covid-19. N Engl J Med 2020.