IMPORTANT: This site is undergoing maintenance on May 28, 2024 from 2:00 AM EST to 4:00 PM EST. Individual users will not be able to log into their accounts to comment on articles or take CME. Institutional administrators will not be able to make changes. Contact [email protected] with questions.
IMPORTANT: This site is undergoing maintenance on May 28, 2024 from 2:00 AM EST to 4:00 PM EST. Individual users will not be able to log into their accounts to comment on articles or take CME. Institutional administrators will not be able to make changes. Contact [email protected] with questions.
Reviews
15 May 2020

Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review

Publication: Annals of Internal Medicine
Volume 173, Number 3

Abstract

An update is available for this article.

Background:

The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) in coronavirus disease 2019 (COVID-19) susceptibility, severity, and treatment is unclear.

Purpose:

To evaluate, on an ongoing basis, whether use of ACEIs or ARBs either increases risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or is associated with worse COVID-19 disease outcomes, and to assess the efficacy of these medications for COVID-19 treatment.

Data Sources:

MEDLINE (Ovid) and Cochrane Database of Systematic Reviews from 2003 to 4 May 2020, with planned ongoing surveillance for 1 year; the World Health Organization database of COVID-19 publications and medRxiv.org through 17 April 2020; and ClinicalTrials.gov to 24 April 2020, with planned ongoing surveillance.

Study Selection:

Observational studies and trials in adults that examined associations and effects of ACEIs or ARBs on risk for SARS-CoV-2 infection and COVID-19 disease severity and mortality.

Data Extraction:

Single-reviewer abstraction confirmed by another reviewer, independent evaluation by 2 reviewers of study quality, and collective assessment of certainty of evidence.

Data Synthesis:

Two retrospective cohort studies found that ACEI and ARB use was not associated with a higher likelihood of receiving a positive SARS-CoV-2 test result, and 1 case–control study found no association with COVID-19 illness in a large community (moderate-certainty evidence). Fourteen observational studies, involving a total of 23 565 adults with COVID-19, showed consistent evidence that neither medication was associated with more severe COVID-19 illness (high-certainty evidence). Four registered randomized trials plan to evaluate ACEIs and ARBs for treatment of COVID-19.

Limitation:

Half the studies were small and did not adjust for important confounding variables.

Conclusion:

High-certainty evidence suggests that ACEI or ARB use is not associated with more severe COVID-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain.

Primary Funding Source:

None. (PROSPERO: registration number pending)
Concerns exist that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) increase susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the viral agent that causes coronavirus disease 2019 [COVID-19]) and the likelihood of severe COVID-19 illness (1). Early reports from Wuhan, China, showed that hypertension and diabetes were common among patients with COVID-19 and were associated with worse outcomes (2). Although these early studies did not specify whether patients were using ACEIs or ARBs before becoming infected, these medications are widely used to treat hypertension and diabetes (3, 4).
The proposed mechanism by which ACEIs and ARBs may play a role in COVID-19 is through upregulation of angiotensin-converting enzyme 2 (ACE2), which is presumed to act as a functional receptor for SARS-CoV-2 to gain entry to host cells (5) (Figure 1). Angiotensin-converting enzyme 2 exists primarily as a membrane-bound monocarboxypeptidase with robust expression in such tissues as lung, vasculature, intestine, and kidney (5). A soluble or circulating form of ACE2 (sACE2) has cardiovascular effects in the renin–angiotensin system (6–8). Related to viral pathogenesis, sACE2 was shown to block SARS viral entry into cells (9) and is now being considered as a potential therapy (10).
Figure 1. ACE2, the RAS, and SARS-CoV-2 infection. As part of the RAS, ACE2 (green) regulates the levels of angiotensin II. As the functional receptor for SARS-CoV-2, ACE2 may facilitate viral entry into cells. This figure illustrates the role of ACE2 in the RAS and how pharmacologic RAS blockade with ACEIs or ARBs (red) could theoretically increase the amount of ACE2 available for viral binding. ACE2 = angiotensin-converting enzyme 2; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; AT1 = type 1 angiotensin receptor; RAS = renin–angiotensin system; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
Figure 1. ACE2, the RAS, and SARS-CoV-2 infection.
As part of the RAS, ACE2 (green) regulates the levels of angiotensin II. As the functional receptor for SARS-CoV-2, ACE2 may facilitate viral entry into cells. This figure illustrates the role of ACE2 in the RAS and how pharmacologic RAS blockade with ACEIs or ARBs (red) could theoretically increase the amount of ACE2 available for viral binding. ACE2 = angiotensin-converting enzyme 2; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; AT1 = type 1 angiotensin receptor; RAS = renin–angiotensin system; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.
Angiotensin-converting enzyme 2 is distinct and not directly related to the clinical use of ACEIs or ARBs, or to their mechanisms of action. Angiotensin-converting enzyme inhibitors target angiotensin-converting enzyme 1 (ACE) to inhibit conversion of angiotensin I to angiotensin II, thereby reducing levels of angiotensin II available to bind and activate the type 1 angiotensin receptor (AT1), which mediates most of the vasopressor effects of angiotensin II (11). Angiotensin-receptor blockers work by binding to AT1 receptors and directly blocking the actions of angiotensin II. In contrast to ACE, which acts to generate angiotensin II, ACE2 degrades angiotensin II into angiotensin (1–7) and is thus a negative regulator of the renin–angiotensin system (Figure 1) (12).
Although postulated as a mechanism for increased susceptibility to SARS-CoV-2 (13), upregulation of ACE2 due to ACEIs or ARBs has not been consistently demonstrated in human and animal studies (14). In addition to ACEI and ARB exposure, several other mechanisms of ACE2 upregulation are being explored, including exposure to nonsteroidal anti-inflammatory agents (2) and thiazide diuretics (15), tobacco use (16), diabetes (17), and cytokines produced by the body in response to viral infections (18). Finally, polymorphisms in the Ace2 gene in humans previously were associated with hypertension and diabetes, suggesting that there is some genetic determination of ACE2 levels and function (19).
Paradoxically, mechanisms by which ACEIs and ARBs may be protective in SARS-CoV-2 infection are also being proposed (12, 20). Animal studies have found that direct angiotensin II suppression with ACEIs and AT1 receptor antagonism with ARBs may promote and stabilize cell membrane complexes between ACE2 and AT1 receptors (21). In theory, these complexes may reduce the ability of the virus to enter host cells (14). Suppression of angiotensin II may also prevent virus-mediated acute lung injury (22) and other organ dysfunction, which is another proposed mechanism by which use of ACEIs and ARBs may be beneficial in COVID-19.
Uncertainty regarding the role of ACEIs and ARBs in the COVID-19 disease course has generated several questions for clinicians. The aims of this living systematic review are to synthesize evidence related to the following questions: Does use of ACEIs or ARBs among adults before infection with SARS-CoV-2 increase the risk for COVID-19? Is the use of these medications before infection associated with more severe COVID-19 disease and worse outcomes? Finally, what are the benefits and harms of initiating these drugs as treatment for patients with COVID-19?

Methods

This is a living systematic review with ongoing literature surveillance and critical appraisal. It was originally conducted in response to a request from the World Health Organization. We registered the review with PROSPERO (registration number pending) and followed standard methods and reporting guidelines for systematic reviews (23, 24). Key questions were developed by World Health Organization staff and revised with input from authors (D.K., V.J.K., and K.M.). Methods of the review included searches and review of data related to SARS-CoV-2 and 2 other coronaviruses associated with earlier pneumonia outbreaks: SARS-CoV-1, causing severe acute respiratory syndrome (SARS), and MERS-CoV, causing Middle East respiratory syndrome (MERS). This report and the ongoing surveillance focus on questions and data related to SARS-CoV-2 and disease from SARS-CoV-2 (COVID-19).

Data Sources and Searches

We searched, without language restrictions, the following databases: MEDLINE (Ovid) and the Cochrane Database of Systematic Reviews from 1 January 2003 to 4 May 2020, the World Health Organization database of COVID-19 publications (25) and medRxiv.org from inception to 17 April 2020, and ClinicalTrials.gov to 24 April 2020. (See the Supplement for search strategy and terms.) We also identified additional citations through hand-searching of reference lists.

Study Selection

Selection criteria were as follows: observational studies of adults in any setting examining associations between use of ACEIs or ARBs and risks for acquiring SARS-CoV-2 and COVID-19, SARS, or MERS; observational studies of adults with COVID-19, SARS, or MERS, in any setting, examining associations between ACEI or ARB use and risks for a broad range of clinical outcomes, including death, severity of illness (mechanical ventilation, intensive care unit [ICU] admission, length of stay, need for noninvasive ventilation, hospitalization, organ dysfunction), cardiovascular events, and radiologic findings; and trials in adults with COVID-19, in any setting, comparing laboratory or clinical outcomes between patients treated with either ACEIs or ARBs and those receiving “usual care,” placebo, or other treatments. We did not limit selection criteria by language. We excluded case reports and case series with fewer than 10 patients. One author (V.J.K. or D.K.) examined titles and abstracts for potential relevance, and 2 authors (D.K. and K.M.) independently reviewed full-text articles for inclusion.

Data Extraction and Quality Assessment

One author (M.K. or E.L.) abstracted details of study setting, population, exposures, and outcomes of interest, and a second author (K.M. or D.K.) checked entries for accuracy. Two authors (V.J.K., K.M., or D.K.) independently assessed the quality of observational studies by using the Newcastle–Ottawa Quality Assessment Scale (26).

Data Synthesis and Analysis

We synthesized evidence qualitatively. We collectively rated the certainty of the body of evidence by using criteria that assessed study limitations, directness of the population studied and the outcomes measured, consistency of results across studies, and precision of effect estimates (27).

Literature Surveillance

We plan weekly literature surveillance of MEDLINE and the Cochrane Database of Systematic Reviews for studies about SARS-CoV-2 and COVID-19 through March 2021 by using the search strategy presented in the Supplement. We will use the selection, data abstraction, and quality assessment methods described earlier. If we identify clinical trials, we will use the Cochrane Risk of Bias Tool for quality assessment (28). New evidence that does not substantively change our review conclusions will be summarized briefly on a monthly basis; a major update will be performed when new evidence changes the nature or strength of the conclusions.

Role of the Funding Source

Authors did not receive funding for this study outside of salary support.

Results

The PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) (23) flowchart (Figure 2) summarizes the results of the search and study selection processes. As of 4 May 2020, we included 14 observational studies (29–42).
Figure 2. Evidence search and selection based on the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) approach (as of 4 May 2020). COVID-19 = coronavirus disease 2019; WHO = World Health Organization.
Figure 2. Evidence search and selection based on the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) approach (as of 4 May 2020).
COVID-19 = coronavirus disease 2019; WHO = World Health Organization.

Key Question 1: Does the Use of ACEIs and ARBs Before Infection With SARS-CoV-2 Increase the Risk for COVID-19?

Three studies (33, 36, 37), which included a total of 8766 patients with COVID-19 and presented analyses adjusted for important confounding factors, had consistent results and provide moderate-certainty evidence that ACEIs or ARBs are not associated with a higher likelihood of positive SARS-CoV-2 test results among symptomatic patients (Table 1). Two U.S. studies examined patients tested for SARS-CoV-2. A Veterans Health Administration study found that prior ACEI or ARB use was not associated with an increased likelihood of a positive SARS-CoV-2 test result (adjusted odds ratio [aOR], 0.98 [95% CI, 0.78 to 1.23]) (36). A study from the New York University Langone Health System found that the proportion of patients with positive SARS-CoV-2 test results was similar between patients treated and those not treated with ACEIs or ARBs (adjusted median difference, −0.5 [CI, −2.6 to 3.6]) (37).
Table 1. Use of ACEIs or ARBs and Odds of Receiving a Positive COVID-19 Test Result
Table 1. Use of ACEIs or ARBs and Odds of Receiving a Positive COVID-19 Test Result
A community-based case–control study from the Lombardy region of Italy included all patients older than 40 years with diagnosed COVID-19 (33). The study found that patients with COVID-19 were not more likely to have been receiving ACEIs (aOR, 0.96 [CI, 0.87 to 1.07]) or ARBs (aOR, 0.95 [CI, 0.86 to 1.05]).
These results may not apply to patients with mild or no symptoms, because most of the patients included in these studies were probably symptomatic and had undergone testing before widespread testing of asymptomatic or mildly symptomatic patients was available.

Key Question 2: Is Use of ACEIs and ARBs Associated With More Severe COVID-19 Illness?

We found 13 retrospective cohort studies (29–32, 34, 36–42) and 1 case–control study (33) that examined whether a history of ACEI or ARB use was associated with severity of illness in patients with COVID-19. Overall, these studies included a total of 23 565 patients with COVID-19, had consistent results, and provided high-certainty evidence that a history of ACEI or ARB use is not associated with increased severity of COVID-19 illness. Eight studies were conducted in China (32–37, 39–41), 2 in Italy (33, 38), 1 in the United Kingdom (29), 2 in the United States (36, 37), and 1 in several countries (34) (Table 2). Nine studies included only hospitalized patients; the outcome of interest for most of these studies was death or severe or critical illness, defined as hypoxemic respiratory distress with or without the need for intensive care. One multicenter study from northern Italy included patients with symptomatic COVID-19 and examined hospitalization as an outcome (38). One U.S. study (36), conducted in the Veterans Health Administration, examined hospitalization and ICU admission as outcomes in all birth cohort veterans (ages 54 to 75 years) tested for COVID-19. The other U.S. study included patients with COVID-19 in the New York University health system and examined ICU admission, assisted ventilation, and death as outcomes (37).
Table 2. Use of ACEIs or ARBs and Odds of Severe COVID-19 Illness
Table 2. Use of ACEIs or ARBs and Odds of Severe COVID-19 Illness
Seven studies, each including more than 200 patients with COVID-19, found that a history of ACEI or ARB use was not associated with more severe illness in analyses adjusted for important confounders, such as age and comorbid cardiovascular conditions (29, 33, 34, 36–38, 42). In an Italian study, the unadjusted odds of severe illness were higher among patients with a history of ACEI or ARB use, but the differences were no longer evident in adjusted analyses restricted to those with cardiovascular disease (adjusted hazard ratio, 1.12 [CI, 0.82 to 1.54]) (38). Likewise, in the Veterans Health Administration study, the unadjusted odds of hospitalization or ICU admission were higher among patients with ACEI or ARB exposure (36). When analyses were adjusted for age, race, comorbid conditions, and a composite of physiologic injury, this difference was no longer statistically significant for hospitalization risk (aOR, 1.24 [CI, 0.79 to 1.95]), and the observed increase in ICU admission risk was reduced after adjustment for confounders, although it remained statistically significant (aOR, 1.69 [CI, 1.01 to 2.84]). Three studies found that a history of ACEI or ARB use was actually associated with lower odds of severe illness or death (29, 34, 42).
The 7 other studies either included small samples of patients with COVID-19 or had few patients with a history of ACEI or ARB use, or they did not adjust for important confounding factors (30, 32, 35, 39–41). Unadjusted analyses of the data presented in these studies consistently showed that the odds of severe illness were not higher among patients with a history of ACEI or ARB use. These smaller studies commonly did not include detailed information on how baseline use of ACEIs and ARBs was verified. Most studies did not specify the exact duration of follow-up for outcomes, although this probably would not have altered the results substantially because the outcomes of interest were typically short-term, hospital-based outcomes.
Of note, a trial in Ireland is enrolling patients with COVID-19 who are receiving ACEIs or ARBs for hypertension and is randomly assigning them to continue this treatment or switch to an alternate antihypertensive therapy (43). The primary outcomes of this study are the number of patients with COVID-19 who die, require intubation in the ICU, or require hospitalization for noninvasive ventilation, and the time from randomization to the first occurrence of any of these outcomes (43). The study criteria exclude patients who have an indication for ACEI or ARB therapy other than essential hypertension, such as heart failure or diabetes.

Key Question 3: What Are the Benefits and Harms of Initiating ACEI or ARB Treatment for Patients With COVID-19?

Although we found no completed studies addressing this key question, we discovered 4 potentially pertinent trials that are registered in the ClinicalTrials.gov database of the U.S. National Institutes of Health:
Efficacy of Captopril Nebulization in COVID-19 Patients Suffering of SARS-CoV-2 Pneumonia. A Randomized Phase II Study (NCT04355429 [France; not yet recruiting]) (44)
Randomized Trial of ACEIs in Treatment of COVID-19 (NCT04345406 [Egypt; not yet recruiting]) (45)
Randomized Controlled Trial of Losartan for Patients With COVID-19 Not Requiring Hospitalization (NCT04311177 [University of Minnesota; patient enrollment started, completion expected April 2021]) (46)
Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization (NCT04312009 [University of Minnesota; patient enrollment started, completion expected April 2021]) (47)

Discussion

We conducted a systematic review examining the relationship between ACEI or ARB use and COVID-19 illness. We found moderate-certainty evidence from 3 studies (33, 36, 37) that ACEI or ARB use was not associated with an increased likelihood of a positive SARS-CoV-2 test result among symptomatic patients, but we found no studies that examined whether ACEI or ARB use is associated with a higher likelihood of acquiring mild or asymptomatic SARS-CoV-2 infection. We found no studies examining the efficacy of ACEIs or ARBs in reducing the risk for complications in COVID-19 illness, although trials examining this question are under way (43–47). Fourteen studies across several countries provided high-certainty evidence consistently showing that ACEIs and ARBs do not increase the risk for more severe illness in patients with COVID-19.
As expected and appropriate, the body of evidence examining the question of potential harm related to ACEI or ARB use in patients with COVID-19 consists only of observational studies. Our confidence in these findings is strengthened by several factors. The lack of association between ACEI or ARB use and illness severity is consistent across all studies, across several continents. These studies included more than 23 000 patients with COVID-19, and all studies included consecutive series of patients, which makes it unlikely that large cohorts of patients with COVID-19 exist that are substantially different from those represented in these 14 studies. Although initial studies addressing this question were smaller and had methodologic limitations, the rapidly expanding evidence base now includes large, methodologically sound observational studies.
These larger studies have accounted for confounding factors, which is important because the factors that might compel ACEI or ARB use, such as comorbid cardiovascular conditions or diabetes, might also contribute to more severe COVID-19 illness. We would expect this type of “confounding by indication” to contribute to spuriously elevated odds of severe illness. Unmeasured, or residual, confounding is a concern in interpreting any body of observational evidence. In this case, residual confounding factors would tend to inflate the association between ACEI or ARB treatment and COVID-19 outcomes; that studies still did not show an association of ACEIs or ARBs with severe COVID-19 illness strengthens our confidence in the findings.
Likewise, the factors contributing to our confidence in the lack of association between ACEI or ARB use and the likelihood of positive SARS-CoV-2 test results include the consistency of findings, as well as the size and quality of these 3 studies (33, 36, 37). However, our confidence in these findings is not as strong as for the question about severity of illness, because far fewer studies exist and we cannot draw conclusions about the association between ACEI or ARB use and the risk for mild COVID-19 illness or asymptomatic SARS-CoV-2 infection.
In 5 studies (29, 30, 32, 34, 42), ACEI or ARB use was associated with a lower risk for severe illness. Although these results are intriguing, they do not provide enough evidence to draw conclusions about the potential efficacy of these medications in treating COVID-19. However, several trials are under way that are designed to examine this question.
The concern about ACEI or ARB use in patients with COVID-19 stemmed largely from arguments of biologic plausibility, particularly the observation that ACEIs and ARBs have the potential to upregulate ACE2 receptors (which seem to be the cellular entry point for SARS-CoV-2) (5). However, even this observation has not been consistent across animal and human models, and biologic plausibility arguments suggest that ARBs may be helpful in treating COVID-19 (14, 20).
On the basis of the findings from this rapidly expanding literature, no indication exists to prophylactically stop ACEI or ARB treatment because of concerns about COVID-19. Indeed, withdrawal of long-term ACEIs or ARBs may be harmful, especially in patients with heart failure because observational studies and trials have suggested that discontinuation of ACEI or ARB therapy is associated with worse outcomes (48–50). The potential harms of not initiating ACEI or ARB therapy in patients with a compelling indication also may be important to consider.
Limitations of our review methods include searching the ClinicalTrials.gov and medRxiv.org databases by using keywords and the possibility that we missed relevant studies. However, we anticipate that many studies currently available in preprint form will eventually be published and that we will identify them through ongoing electronic literature surveillance.
In conclusion, high-certainty evidence exists that patients receiving long-term ACEI or ARB therapy are not at increased risk for poor outcomes from COVID-19 illness. Moderate-certainty evidence also exists that ACEI or ARB use is not associated with a greater likelihood of positive SARS-CoV-2 test results among symptomatic patients. Whether these medications are beneficial in COVID-19 treatment remains uncertain.

Supplemental Material

Supplement. Supplemental Appendices

References

1.
Watkins J. Preventing a covid-19 pandemic [Editorial]. BMJ. 2020;368:m810. [PMID: 32111649]  doi: 10.1136/bmj.m810
2.
Fang LKarakiulakis GRoth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? [Letter]. Lancet Respir Med. 2020;8:e21. [PMID: 32171062]  doi: 10.1016/S2213-2600(20)30116-8
3.
Gauer RLaRocque J. JNC 8: relaxing the standards [Editorial]. Am Fam Physician. 2014;90:449-52. [PMID: 25369620]
4.
American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2020. Diabetes Care. 2020;43:S111-S134. [PMID: 31862753]  doi: 10.2337/dc20-S010
5.
Wan YShang JGraham Ret al. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020;94. [PMID: 31996437]  doi: 10.1128/JVI.00127-20
6.
Liu PWysocki JSouma Tet al. Novel ACE2-Fc chimeric fusion provides long-lasting hypertension control and organ protection in mouse models of systemic renin angiotensin system activation. Kidney Int. 2018;94:114-125. [PMID: 29691064]  doi: 10.1016/j.kint.2018.01.029
7.
Epelman STang WHChen SYet al. Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensin-aldosterone system. J Am Coll Cardiol. 2008;52:750-4. [PMID: 18718423]  doi: 10.1016/j.jacc.2008.02.088
8.
Xia HSriramula SChhabra KHet al. Brain angiotensin-converting enzyme type 2 shedding contributes to the development of neurogenic hypertension. Circ Res. 2013;113:1087-1096. [PMID: 24014829]  doi: 10.1161/CIRCRESAHA.113.301811
9.
Li WMoore MJVasilieva Net al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature. 2003;426:450-4. [PMID: 14647384]
10.
Batlle DWysocki JSatchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? [Letter]. Clin Sci (Lond). 2020;134:543-545. [PMID: 32167153]  doi: 10.1042/CS20200163
11.
Sparks MACrowley SDGurley SBet al. Classical renin-angiotensin system in kidney physiology. Compr Physiol. 2014;4:1201-28. [PMID: 24944035]  doi: 10.1002/cphy.c130040
12.
Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res. 2020. [PMID: 32129518]  doi: 10.1002/ddr.21656
13.
Diaz JH. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Travel Med. 2020. [PMID: 32186711]  doi: 10.1093/jtm/taaa041
14.
Sparks M, Hiremath S. The Coronavirus Conundrum: ACE2 and Hypertension. Accessed at www.nephjc.com/news/covidace2 on 25 March 2020.
15.
Jessup JABrosnihan KBGallagher PEet al. Differential effect of low dose thiazides on the renin angiotensin system in genetically hypertensive and normotensive rats. J Am Soc Hypertens. 2008 Mar-Apr;2:106-15. [PMID: 19343087]  doi: 10.1016/j.jash.2007.10.005
16.
Cai G. Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov. medRxiv. Preprint posted online 28 February 2020. doi: 10.1101/2020.02.05.20020107
17.
Rao S, Lau A, So HC. Exploring diseases/traits and blood proteins causally related to expression of ACE2, the putative receptor of 2019-nCov: A Mendelian randomization analysis. medRxiv. Preprint posted online 12 May 2020. doi: 10.1101/2020.03.04.20031237
18.
Wang PH, Cheng Y. Increasing host cellular receptor—angiotensin-converting enzyme 2 (ACE2) expression by coronavirus may facilitate 2019-nCoV infection. bioRxiv. Preprint posted online 27 February 2020. doi: 10.1101/2020.02.24.963348
19.
Burrell LMHarrap SBVelkoska Eet al. The ACE2 gene: its potential as a functional candidate for cardiovascular disease. Clin Sci (Lond). 2013;124:65-76. [PMID: 23013041]
20.
Vaduganathan MVardeny OMichel Tet al. Renin-angiotensin-aldosterone system inhibitors in patients with covid-19. N Engl J Med. 2020;382:1653-1659. [PMID: 32227760]  doi: 10.1056/NEJMsr2005760
21.
Deshotels MRXia HSriramula Set al. Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism. Hypertension. 2014;64:1368-1375. [PMID: 25225202]  doi: 10.1161/HYPERTENSIONAHA.114.03743
22.
Yang PGu HZhao Zet al. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep. 2014;4:7027. [PMID: 25391767]  doi: 10.1038/srep07027
23.
Moher DLiberati ATetzlaff Jet alPRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264-9, W64. [PMID: 19622511]
24.
U.S. Department of Health and Human Services. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Accessed at www.effectivehealthcare.ahrq.gov on 11 May 2020.
25.
World Health Organization. Global research on coronavirus disease (COVID-19) Accessed at www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov on 5 May 2020.
26.
Newcastle–Ottawa Quality Assessment Scale Case Control and Cohort Studies. Accessed at www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf on 25 March 2020.
27.
Berkman NDLohr KNAnsari MTet al. Grading the strength of a body of evidence when assessing health care interventions: an EPC update. J Clin Epidemiol. 2015;68:1312-24. [PMID: 25721570]  doi: 10.1016/j.jclinepi.2014.11.023
28.
Sterne JACSavovic JPage MJet al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. [PMID: 31462531]  doi: 10.1136/bmj.l4898
29.
Bean D, Kraljevic Z, Searle T, et al. Treatment with ACE-inhibitors is associated with less severe disease with SARS-Covid-19 infection in a multi-site UK acute Hospital Trust. medRxiv. Preprint posted online 12 May 2020. doi: 10.1101/2020.04.07.20056788
30.
Feng YLing YBai Tet al. COVID-19 with different severity: a multi-center study of clinical features. Am J Respir Crit Care Med. 2020. [PMID: 32275452]  doi: 10.1164/rccm.202002-0445OC
31.
Li JWang XChen Jet al. Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) infection in Wuhan, China. JAMA Cardiol. 2020. [PMID: 32324209]  doi: 10.1001/jamacardio.2020.1624
32.
Liu Y, Huang F, Xu J, et al. Anti-hypertensive angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients. medRxiv. Preprint posted online 27 March 2020. doi: 10.1101/2020.03.20.20039586
33.
Mancia GRea FLudergnani Met al. Renin-angiotensin-aldosterone system blockers and the risk of covid-19. N Engl J Med. 2020. [PMID: 32356627]  doi: 10.1056/NEJMoa2006923
34.
Mehra MRDesai SSKuy Set al. Cardiovascular disease, drug therapy, and mortality in covid-19. N Engl J Med. 2020. [PMID: 32356626]  doi: 10.1056/NEJMoa2007621
35.
Meng JXiao GZhang Jet al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension [Letter]. Emerg Microbes Infect. 2020;9:757-760. [PMID: 32228222]  doi: 10.1080/22221751.2020.1746200
36.
Rentsch CT, Kidwai-Khan F, Tate JP, et al. Covid-19 testing, hospital admission, and intensive care among 2,026,227 United States veterans aged 54-75 years. medRxiv. Preprint posted online 14 April 2020. doi: 10.1101/2020.04.09.20059964
37.
Reynolds HRAdhikari SPulgarin Cet al. Renin-angiotensin-aldosterone system inhibitors and risk of covid-19. N Engl J Med. 2020. [PMID: 32356628]  doi: 10.1056/NEJMoa2008975
38.
Giorgi Rossi P, Marino M, Formisano D, et al. Characteristics and outcomes of a cohort of SARS-CoV-2 patients in the province of Reggio Emilia, Italy. medRxiv. Preprint posted online 16 April 2020. doi: 10.1101/2020.04.13.20063545
39.
Yang G, Tan Z, Zhou L, et al. Angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors usage is associated with improved inflammatory status and clinical outcomes in COVID-19 patients with hypertension. medRxiv. Preprint posted online 4 April 2020. doi: 10.1101/2020.03.31.20038935
40.
Peng YDMeng KGuan HQet al. [Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV]. Zhonghua Xin Xue Guan Bing Za Zhi. 2020;48:E004. [PMID: 32120458]  doi: 10.3760/cma.j.cn112148-20200220-00105
41.
Zeng Z, Sha T, Zhang Y, et al. Hypertension in patients hospitalized with COVID-19 in Wuhan, China: a single-center retrospective observational study. medRxiv. Preprint posted online 11 April 2020. doi: 10.1101/2020.04.06.20054825
42.
Zhang PZhu LCai Jet al. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020. [PMID: 32302265]  doi: 10.1161/CIRCRESAHA.120.317134
43.
U.S. National Library of Medicine. Coronavirus (COVID-19) ACEi/ARB Investigation (CORONACION). ClinicalTrials.gov Identifier: NCT04330300 [updated 13 April 2020]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04330300?term=NCT04330300&draw=2&rank=1 on 29 April 2020.
44.
U.S. National Library of Medicine. Efficacy of Captopril in Covid-19 Patients With Severe Acute Respiratory Syndrome (SARS) CoV-2 Pneumonia (CAPTOCOVID). ClinicalTrials.gov Identifier: NCT04355429 [updated 28 April 2020]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04355429?term=NCT04355429&draw=2&rank=1 on 29 April 2020.
45.
U.S. National Library of Medicine. Angiotensin Converting Enzyme Inhibitors in Treatment of Covid 19. ClinicalTrials.gov Identifier: NCT04345406 [updated 14 April 2020]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04345406?term=NCT04345406&draw=2&rank=1 on 29 April 2020.
46.
U.S. National Library of Medicine. Losartan for Patients With COVID-19 Not Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04311177 2020 [updated March 23, 2020]. Accessed at https://clinicaltrials.gov/ct2/show/results/NCT04311177 on 25 March 2020.
47.
U.S. National Library of Medicine. Losartan for Patients With COVID-19 Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04312009 2020 [updated 23 March 2020]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04312009 on 25 March 2020.
48.
Pflugfelder PWBaird MGTonkon MJet al. Clinical consequences of angiotensin-converting enzyme inhibitor withdrawal in chronic heart failure: a double-blind, placebo-controlled study of quinapril. The Quinapril Heart Failure Trial Investigators. J Am Coll Cardiol. 1993;22:1557-63. [PMID: 8227822]
49.
Gilstrap LGFonarow GCDesai ASet al. Initiation, continuation, or withdrawal of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and outcomes in patients hospitalized with heart failure with reduced ejection fraction. J Am Heart Assoc. 2017;6. [PMID: 28189999]  doi: 10.1161/JAHA.116.004675
50.
Halliday BPWassall RLota ASet al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet. 2019;393:61-73. [PMID: 30429050]  doi: 10.1016/S0140-6736(18)32484-X

Comments

0 Comments
Sign In to Submit A Comment
Tomoyuki Kawada24 June 2020
Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and coronavirus disease 2019 infection

Mackey et al. reported that ACEI or ARB use was not associated with more severe COVID-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients (1). I agree that the authors mentioned that conclusion cannot be made whether these medications increase the risk of disease or are beneficial in COVID-19 treatment. Fosbøl et al. and Kai et al. reported the same conclusion (2,3), and I want to present two recent reports about this association. Guo et al. conducted a meta-analysis regarding mortality of COVID-19 infection in patients with hypertension by treatment of renin-angiotensin-aldosterone system inhibitors (4). Pooled odds ratio (OR) (95% confidence interval [CI]) of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (ACEI/ARB) treatment for disease severity was 0.71 (0.46-1.08).

In addition, pooled OR (95% CI) of ACEI/ARB treatment for mortality was 0.57 (CI 0.38-0.84). As there was no significant association between ACEI/ARB treatment and disease severity, significant lowering effect of ACEI/ARB treatment on mortality needs adequate explanations. Additionally, there are many factors for selecting appropriate combinations of hypertension medication. As there are information that different ARB presents different infectious mechanism on COVID-19 (5), sub-analysis by classifying types of ACEI/ARB use should also be conducted for the risk assessment.

REFERENCES

1. Mackey K, King VJ, Gurley S, et al. Risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults. Ann Intern Med 2020;M20-1515. doi:10.7326/M20-1515

2. Fosbøl EL, Butt JH, Østergaard L, et al. Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use With COVID-19 diagnosis and mortality. JAMA 2020;e2011301. doi:10.1001/jama.2020.11301

3. Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hypertens Res 2020;43(7):648-654.

4. Guo X, Zhu Y, Hong Y. Decreased mortality of COVID-19 with renin-angiotensin-aldosterone system inhibitors therapy in patients with Hypertension: A meta-analysis. Hypertension 2020 May 27 doi:10.1161/HYPERTENSIONAHA.120.15572

5. Magrone T, Magrone M, Jirillo E. Focus on receptors for coronaviruses with special reference to angiotensin-converting enzyme 2 as a potential drug target - A perspective. Endocr Metab Immune Disord Drug Targets 2020 Apr 27 doi:10.2174/1871530320666200427112902

Devan Kansagara, Katherine Mackey, Kathryn Vela1 July 2020
Update Alert: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults

In this first monthly update of our living review (1), we searched MEDLINE (Ovid) weekly from 4 May to 8 June 2020 using the same search strategy described in the original review, and we also identified additional citations from consultation with content experts. Searches yielded 138 results; independent dual review of these records identified 4 new studies (see Supplement Tables 1 and 2) and 2 in-progress trials for inclusion.

 

New Evidence

One new retrospective cohort study examined the association between angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blocker (ARB) use and the likelihood of testing positive for COVID-19 (2). This study included all patients who had testing in 1 health system in 2 different states; patients with symptoms were prioritized for testing at the time so most patients were likely to have been symptomatic. As in the previous review that identified 3 similar studies, neither ACEI nor ARB use was associated with likelihood of testing positive for COVID-19.

This study also examined the association between ACEI or ARB use and COVID-19 illness severity. It found use of these medications was associated with a moderate increase in hospitalization and intensive care unit admission risk but not risk for mechanical ventilation (2). We found an additional 3 new studies evaluating the association between ACEI or ARB use and COVID-19 illness severity. Two were small single-center retrospective cohort studies from China that found that ACEI or ARB use was not associated with an increased risk for death or severe COVID-19 illness (3, 4). A nationwide retrospective cohort study from Korea similarly found that these medications were not associated with severity of illness after adjustment for demographic characteristics, comorbid conditions, and hospital type (5).

The 2 studies from China included small, highly select patient populations and did not describe in detail how ACEI or ARB exposure was determined. The 2 larger studies were generally methodologically sound, although 1 study cautioned that the number of patients treated with ACEI or ARBs who had the outcomes of intensive care unit admission or mechanical ventilation was small (2). (See Supplement Table 3 for methodological strengths and weaknesses of the studies.)

Of note, 1 international study that examined the association between ACEI or ARBs and severity of COVID-19 illness has since been retracted by the journal in which it was published (6). We will no longer consider results of this study in determining overall effects or certainty of evidence.

Overall, the addition of the new studies and the retraction of 1 prior study does not change the findings or certainty of evidence ratings we reported in the original review.

 

In-Progress Trials

We identified 2 randomized controlled trials, currently in progress, that will compare the effects of continuing or withdrawing ACEI or ARB treatment on clinical outcomes in patients hospitalized with COVID-19. One is a U.S. study (7) and the other is a Brazilian study (8), and both are expected to be completed by the end of 2020.

Supplemental Information can be viewed at https://www.acpjournals.org/doi/suppl/10.7326/L20-0887

This article was published at Annals.org on 25 June 2020.

 

References 

1. Mackey K, King VJ, Gurley S, et al. Risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults. Ann Intern Med. 15 May 2020. [Epub ahead of print]. [PMID: 32422062] doi:10.7326/M20-151

2. Mehta N, Kalra A, Nowacki AS, et al. Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020. [PMID: 32369097] doi:10.1001/jamacardio.2020.1855

3. Chen Y, Yang D, Cheng B, et al. Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication. Diabetes Care. 2020;43:1399-1407. [PMID: 32409498] doi:10.2337/dc20-0660

4. Huang Z, Cao J, Yao Y, et al. The effect of RAS blockers on the clinical characteristics of COVID-19 patients with hypertension. Ann Transl Med. 2020;8:430. [PMID: 32395474] doi:10.21037/atm.2020.03.229

5. Jung SY, Choi JC, You SH, et al. Association of renin-angiotensin-aldosterone system inhibitors with COVID-19-related outcomes in Korea: a nationwide population-based cohort study. Clin Infect Dis. 2020. [PMID: 32442285] doi:10.1093/cid/ciaa624

6. Mehra MR, Desai SS, Kuy S, et al. Retraction: cardiovascular disease, drug therapy, and mortality in covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621 [Letter]. N Engl J Med. 2020. [PMID: 32501665] doi:10.1056/NEJMc2021225

7. Elimination or Prolongation of ACE Inhibitors and ARB in Coronavirus Disease 2019 (REPLACECOVID). ClinicalTrials.gov: NCT04338009. Updated 24 April 2020. Accessed at https://clinicaltrials.gov/ct2/show/NCT04338009on 18 June 2020.

8. Angiotensin Receptor Blockers and Angiotensin-converting Enzyme Inhibitors and Adverse Outcomes in Patients With COVID19 (BRACE-CORONA). ClinicalTrials.gov: NCT04364893. Updated 28 April 2020. Accessed at https://clinicaltrials.gov/ct2/show/NCT04364893 on 18 June 2020.

Katherine Mackey, MD; MPP, Devan Kansagara, MD; MCR, Kathryn Vela, MLIS, AHIP28 August 2020
Update Alert 3: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults

We searched MEDLINE (Ovid) weekly from 7 July to 3 August 2020 using the same search strategy as described in the original review (1). We did not limit the search by language. This search update yielded 67 results (de-duplicated), and after an independent dual-review process, we identified 2 new meta-analyses and 1 reestimated meta-analysis (2–4), interim results from 1 randomized controlled trial (5), and 13 new observational studies (6–18).

New Evidence

Results of 2 meta-analyses found that angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB) use was not associated with coronavirus disease 2019 (COVID-19) disease severity (2, 3). In 1 of these meta-analyses of 9 primary studies with a total of 3936 patients with hypertension, use of ACEIs or ARBs was associated with a lower mortality in COVID-19 (2). In the other meta-analysis of 15 studies of 7410 patients with hypertension, subgroup analysis found that ARB use, but not ACEI use, was associated with lower mortality (3). A third meta-analysis reestimated data from studies included in a prior review and found that exclusion of a retracted study by Mehra and colleagues did not change the prior review's finding of a lack of association with ACEI and ARB use and COVID-19 mortality (4, 19).

In addition, interim findings from an ongoing randomized controlled trial (started in 2018) on the use of ramipril among patients with aortic stenosis treated with transcatheter aortic valve replacement found that the use of ramipril was not associated with the incidence or severity of COVID-19 (20). To our knowledge, this is the first study to report findings from a randomized controlled trial on the association between ACEI use and COVID-19.

We also identified 13 new observational studies (6–18). One of these observational studies that was based on analysis of insurance data in Korea addressed our first key question regarding the use of ACEIs and ARBs and COVID-19 risk, finding that increased adherence to ACEI and ARB treatment was associated with a lower incidence of COVID-19 (10). Twelve studies addressed our second key question about ACEI and ARB use and COVID-19 disease severity, and 11 of these studies found a lack of association with ACEIs or ARBs and more severe disease (6–9, 11–13, 15–18). Moreover, 3 of these 11 studies found that use of ACEIs or ARBs was associated with less severe COVID-19 illness (11, 16, 18). The exception was a French study of 149 patients hospitalized with severe COVID-19 illness (defined by an oxygen saturation of 94% or less while the patient was breathing ambient air or receiving oxygen support), 44 of whom were receiving ACEIs or ARBs (14). This study found that ACEI and ARB use was associated with a higher risk for acute kidney injury. However, this study did not examine whether ACEI or ARB use was independently associated with respiratory failure or death.

Overall, inclusion of 17 studies from this search update does not change the certainty of evidence rating we reported in the original article for key questions 1 or 2. Although there is a signal toward improved outcomes among patients with COVID-19 who continue use of ACEIs or ARBs, the benefits and harms of initiating ACEIs or ARBs (that is, new users) in COVID-19 treatment remains unclear.

 

Citation Update

A study by Bean and colleagues that was included in our original manuscript as a preprint has now been published (20).

Also of note, we attempted to register our review protocol with PROSPERO, but registration was not accepted given the stage of our review at the time. We followed standard methods and reporting guidelines for systematic reviews (21, 22). We have posted a copy of our protocol to OSF (https://osf.io/qm6h9/).

This article was published at Annals.org on 26 August 2020

References 

1. Mackey K, King VJ, Gurley S, et al. Risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults. A living systematic review. Ann Intern Med. 2020;173:195-203. [PMID: 32422062] doi:10.7326/M20-1515

2. Guo X, Zhu Y, Hong Y. Decreased mortality of COVID-19 with renin-angiotensin-aldosterone system inhibitors therapy in patients with hypertension: a meta-analysis [Letter]. Hypertension. 2020;76:e13-e14. [PMID: 32458694] doi:10.1161/HYPERTENSIONAHA.120.15572

3. Pranata R, Permana H, Huang I, et al. The use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. Diabetes Metab Syndr. 2020;14:983-990. [PMID: 32615377] doi:10.1016/j.dsx.2020.06.047

4. Alamer A, Abraham I. Mortality in COVID-19 patients treated with ACEIs/ARBs: re-estimated meta-analysis results following the Mehra et al. retraction [Letter]. Pharmacol Res. 2020;160:105053. [PMID: 32619721] doi:10.1016/j.phrs.2020.105053

5. Amat-Santos IJ, Santos-Martinez S, López-Otero D, et al. Ramipril in high-risk patients with COVID-19. J Am Coll Cardiol. 2020;76:268-276. [PMID: 32470515] doi:10.1016/j.jacc.2020.05.040

6. Andrea C, Francesco M, Antonio N, et al. Renin-angiotensin-aldosterone system inhibitors and outcome in patients with SARS-CoV-2 pneumonia: a case series study [Letter]. Hypertension. 2020;76:e10-e12. [PMID: 32383626] doi:10.1161/HYPERTENSIONAHA.120.15312

7. De Spiegeleer A, Bronselaer A, Teo JT, et al. The effects of ARBs, ACEIs, and statins on clinical outcomes of COVID-19 infection among nursing home residents. J Am Med Dir Assoc. 2020;21:909-914.e2. [PMID: 32674818] doi:10.1016/j.jamda.2020.06.018

8. Golpe R, Pérez-de-Llano LA, Dacal D, et al; Lugo Covid-19 team. Risk of severe COVID-19 in hypertensive patients treated with renin-angiotensin-aldosterone system inhibitors. Med Clin (Barc). 2020. [PMID: 32651067] doi:10.1016/j.medcli.2020.06.013

9. Iaccarino G, Grassi G, Borghi C, et al; SARS-RAS Investigators. Age and multimorbidity predict death among COVID-19 patients: results of the SARS-RAS study of the Italian Society of Hypertension. Hypertension. 2020;76:366-372. [PMID: 32564693] doi:10.1161/HYPERTENSIONAHA.120.15324

10. Kim J, Kim DW, Kim KI, et al; Korean Society of Hypertension. Compliance of antihypertensive medication and risk of coronavirus disease 2019: a cohort study using big data from the Korean National Health Insurance Service. J Korean Med Sci. 2020;35:e232. [PMID: 32597045] doi:10.3346/jkms.2020.35.e232

11. Lam KW, Chow KW, Vo J, et al. Continued in-hospital ACE inhibitor and ARB use in hypertensive COVID-19 patients is associated with positive clinical outcomes. J Infect Dis. 2020. [PMID: 32702098] doi:10.1093/infdis/jiaa447

12. Liu X, Liu Y, Chen K, et al. Efficacy of ACEIs/ARBs versus CCBs on the progression of COVID-19 patients with hypertension in Wuhan: a hospital-based retrospective cohort study. J Med Virol. 2020. [PMID: 32687223] doi:10.1002/jmv.26315

13. Parigi TL, Vespa E, Pugliese N. COVID-19, ACEI/ARBs and gastrointestinal symptoms: the jury is still out on the association [Letter]. Gastroenterology. 2020. [PMID: 32682762] doi:10.1053/j.gastro.2020.06.095

14. Oussalah A, Gleye S, Clerc Urmes I, et al. Long-term ACE inhibitor/ARB use is associated with severe renal dysfunction and acute kidney injury in patients with severe COVID-19: results from a referral center cohort in the north east of France. Clin Infect Dis. 2020. [PMID: 32623470] doi:10.1093/cid/ciaa677

15. Sardu C, Maggi P, Messina V, et al. Could anti-hypertensive drug therapy affect the clinical prognosis of hypertensive patients with COVID-19 infection? Data from centers of southern Italy. J Am Heart Assoc. 2020:e016948. [PMID: 32633594] doi:10.1161/JAHA.120.016948

16. Senkal N, Meral R, Medetalibeyoglu A, et al. Association between chronic ACE inhibitor exposure and decreased odds of severe disease in patients with COVID-19. Anatol J Cardiol. 2020;24:21-29. [PMID: 32628137] doi:10.14744/AnatolJCardiol.2020.57431

17. Xu J, Huang C, Fan G, et al. Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis. Front Med. 2020. [PMID: 32621202] doi:10.1007/s11684-020-0800-y

18. Zhou F, Liu YM, Xie J, et al. Comparative impacts of ACE (angiotensin-converting enzyme) inhibitors versus angiotensin II receptor blockers on the risk of COVID-19 mortality [Letter]. Hypertension. 2020;76:e15-e17. [PMID: 32493070] doi:10.1161/HYPERTENSIONAHA.120.15622

19. Zhang X, Yu J, Pan LY, et al. ACEI/ARB use and risk of infection or severity or mortality of COVID-19: a systematic review and meta-analysis. Pharmacol Res. 2020;158:104927. [PMID: 32422341] doi:10.1016/j.phrs.2020.104927

20. Bean DM, Kraljevic Z, Searle T, et al. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are not associated with severe COVID-19 infection in a multi-site UK acute hospital trust. Eur J Heart Fail. 2020;22:967-974. [PMID: 32485082] doi:10.1002/ejhf.1924

21. Moher D, Liberati A, Tetzlaff J, et al; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264-9, W64. [PMID: 19622511]

22. U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Accessed at https://effectivehealthcare.ahrq.gov/products/cer-methods-guide/overview on 11 May 2020

Disclosures:

Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1068.

Katherine Mackey, MD, MPP; Kathryn Vela, MLIS, AHIP; Devan Kansagara, MD, MCR22 September 2020
Update Alert 4: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults

In this fourth monthly update of our living review (1), we searched MEDLINE (Ovid) weekly from 4 August to 31 August 2020 using the same search strategy as described in the original review. We did not limit the search by language. This search update yielded 82 results (de-duplicated), and after an independent dual-review process, we identified 24 new studies meeting our inclusion criteria—19 observational studies, 4 meta-analyses, and 1 systematic review (2–25).

New Evidence

Findings from the 19 observational studies are overall consistent with prior evidence that found a lack of association between angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB) use and more severe coronavirus disease 2019 (COVID-19) (2–20). Several studies suggest that use of ACEIs or ARBs before developing COVID-19 may be associated with improved outcomes (3, 4, 7, 11, 12).

Two meta-analyses addressed our first key question about use of ACEIs and ARBs and COVID-19 risk, finding that neither ACEI nor ARB use is significantly associated with the odds of COVID-19 disease (22, 24). Three meta-analyses addressed our second key question about ACEI and ARB use and COVID-19 disease severity, finding that use of these medications was not associated with the risk for more severe disease (21–23).

Overall, inclusion of 24 studies from this search update does not change the certainty of evidence rating we reported in the original manuscript for key questions 1 or 2. Studies have not examined the benefits and harms of initiating ACEIs and ARBs (that is, new users) in COVID-19 treatment; therefore, evidence for key question 3 remains unclear.

This article was published at Annals.org on 22 September 2020

References 

1. Mackey K, King VJ, Gurley S, et al. Risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults. A living systematic review. Ann Intern Med. 2020;173:195-203. [PMID: 32422062] doi:10.7326/M20-1515

2. Bae DJ, Tehrani DM, Rabadia SV, et al. Angiotensin converting enzyme inhibitor and angiotensin II receptor blocker use among outpatients diagnosed with COVID-19. Am J Cardiol. 2020;132:150-157. [PMID: 32819683] doi:10.1016/j.amjcard.2020.07.007

3. Barochiner J, Martínez R. Use of inhibitors of the renin-angiotensin system in hypertensive patients and COVID-19 severity: a systematic review and meta-analysis. J Clin Pharm Ther. 2020. [PMID: 32767823] doi:10.1111/jcpt.13246

4. Chen FF, Zhong M, Liu Y, et al. The characteristics and outcomes of 681 severe cases with COVID-19 in China. J Crit Care. 2020;60:32-37. [PMID: 32736197] doi:10.1016/j.jcrc.2020.07.003

5. Dalan R, Ang LW, Tan WYT, et al. The association of hypertension and diabetes pharmacotherapy with COVID-19 severity and immune signatures: an observational study. Eur Heart J Cardiovasc Pharmacother. 2020. [PMID: 32766831] doi:10.1093/ehjcvp/pvaa098

6. Gormez S, Ekicibasi E, Degirmencioglu A, et al. Association between renin-angiotensin-aldosterone system inhibitor treatment, neutrophil-lymphocyte ratio, D-Dimer and clinical severity of COVID-19 in hospitalized patients: a multicenter, observational study. J Hum Hypertens. 2020. [PMID: 32839534] doi:10.1038/s41371-020-00405-3

7. Hippisley-Cox J, Young D, Coupland C, et al. Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people. Heart. 2020;106:1503-1511. [PMID: 32737124] doi:10.1136/heartjnl-2020-317393

8. Huang W, Li T, Ling Y, et al. Effects of angiotensin converting enzyme inhibitor/angiotensin receptor blocker on clinical characteristics of coronavirus disease 2019 patients with hypertension. Zhonghua Nei Ke Za Zhi. 2020;59:689-694. [PMID: 32838499] doi:10.3760/cma.j.cn112138-20200229-00155

9. Martínez-Del Río J, Piqueras-Flores J, Nieto-Sandoval Martín de la Sierra P, et al. Comparative analysis between the use of renin-angiotensin system antagonists and clinical outcomes of hospitalized patients with COVID-19 respiratory infection. Med Clin (Barc). 2020. [PMID: 32782110] doi:10.1016/j.medcli.2020.07.004

10. Matsuzawa Y, Ogawa H, Kimura K, et al. Renin-angiotensin system inhibitors and the severity of coronavirus disease 2019 in Kanagawa, Japan: a retrospective cohort study. Hypertens Res. 2020. [PMID: 32820236] doi:10.1038/s41440-020-00535-8

11. Megaly M, Glogoza M. Renin-angiotensin system antagonists are associated with lower mortality in hypertensive patients with COVID-19 [Letter]. Scott Med J. 2020:36933020949219. [PMID: 32807019] doi:10.1177/0036933020949219

12. Pan W, Zhang J, Wang M, et al. Clinical features of COVID-19 in patients with essential hypertension and the impacts of renin-angiotensin-aldosterone system inhibitors on the prognosis of COVID-19 patients. Hypertension. 2020;76:732-741. [PMID: 32654555] doi:10.1161/HYPERTENSIONAHA.120.15289

13. Raisi-Estabragh Z, McCracken C, Ardissino M, et al. Renin-angiotensin-aldosterone system blockers are not associated with coronavirus disease 2019 (COVID-19) hospitalization: study of 1,439 UK Biobank cases. Front Cardiovasc Med. 2020;7:138. [PMID: 32766285] doi:10.3389/fcvm.2020.00138

14. Ran J, Song Y, Zhuang Z, et al. Blood pressure control and adverse outcomes of COVID-19 infection in patients with concomitant hypertension in Wuhan, China. Hypertens Res. 2020. [PMID: 32855527] doi:10.1038/s41440-020-00541-w

15. Rey JR, Caro-Codón J, Rosillo SO, et al. Heart failure in covid-19 patients: prevalence, incidence and prognostic implications. Eur J Heart Fail. 2020. [PMID: 32833283] doi:10.1002/ejhf.1990

16. Shah P, Owens J, Franklin J, et al. Baseline use of angiotensin-converting enzyme inhibitor/AT1 blocker and outcomes in hospitalized coronavirus disease 2019 African-American patients. J Hypertens. 2020. [PMID: 32740406] doi:10.1097/HJH.0000000000002584

17. Son M, Seo J, Yang S. Association between renin-angiotensin-aldosterone system inhibitors and COVID-19 infection in South Korea. Hypertension. 2020;76:742-749. [PMID: 32654557] doi:10.1161/HYPERTENSIONAHA.120.15464

18. Tan ND, Qiu Y, Xing XB, et al. Associations between angiotensin-converting enzyme inhibitors and angiotensin II receptor blocker use, gastrointestinal symptoms, and mortality among patients with COVID-19. Gastroenterology. 2020;159:1170-1172.e1. [PMID: 32422208] doi:10.1053/j.gastro.2020.05.034

19. Trifirò G, Massari M, Da Cas R, et al; ITA-COVID-19: RAAS Inhibitor Group. Renin-angiotensin-aldosterone system inhibitors and risk of death in patients hospitalised with COVID-19: a retrospective Italian cohort study of 43,000 patients. Drug Saf. 2020. [PMID: 32852721] doi:10.1007/s40264-020-00994-5

20. Yuan Y, Liu D, Zeng S, et al. In-hospital use of ACEI/ARB is associated with lower risk of mortality and critic illness in COVID-19 patients with hypertension [Letter]. J Infect. 2020. [PMID: 32800800] doi:10.1016/j.jinf.2020.08.014

21. Baral R, White M, Vassiliou VS. Effect of renin-angiotensin-aldosterone system inhibitors in patients with COVID-19: a systematic review and meta-analysis of 28,872 patients. Curr Atheroscler Rep. 2020;22:61. [PMID: 32830286] doi:10.1007/s11883-020-00880-6

22. Liu X, Long C, Xiong Q, et al. Association of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with risk of COVID-19, inflammation level, severity, and death in patients with COVID-19: a rapid systematic review and meta-analysis. Clin Cardiol. 2020. [PMID: 32757246] doi:10.1002/clc.23421

23. Salah HM, Calcaterra G, Mehta JL. Renin-angiotensin system blockade and mortality in patients with hypertension and COVID-19 infection. J Cardiovasc Pharmacol Ther. 2020:1074248420947628. [PMID: 32748634] doi:10.1177/1074248420947628

24. Usman MS, Siddiqi TJ, Khan MS, et al. A meta-analysis of the relationship between renin-angiotensin-aldosterone system inhibitors and COVID-19 [Letter]. Am J Cardiol. 2020;130:159-161. [PMID: 32624189] doi:10.1016/j.amjcard.2020.05.038

25. Singh AK, Gupta R, Misra A. Comorbidities in COVID-19: outcomes in hypertensive cohort and controversies with renin angiotensin system blockers. Diabetes Metab Syndr. 2020;14:283-287. [PMID: 32283499] doi:10.1016/j.dsx.2020.03.016

Disclosures:

Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1177.

Katherine Mackey, MD, MPP; Devan Kansagara, MD, MCR; Kathryn Vela, MLIS, AHIP28 October 2020
Update Alert 5 of Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review

Literature search update and yield

We searched MEDLINE (Ovid) weekly from September 1 to September 28, 2020 using the same search strategy as described in the original review (1). We did not limit the search by language. This search update yielded 77 results (de-duplicated), and after an independent dual review process, we identified 15 new studies meeting our inclusion criteria – 8 observational studies, 6 systematic reviews with meta-analyses, and 1 clinical trial protocol.

 

New evidence

Findings from 2 observational studies, one of which is an update of a previously published retrospective analysis of insurance data in South Korea, found no evidence of an association with ACEI/ARB use and risk of COVID-19 disease. (2-3). This South Korean study and an additional 6 observational studies found no association between the use of ACEI/ARBs and COVID-19 disease severity. (3-9) These studies include a retrospective analysis of the association of ACEI/ARB use on need for mechanical ventilation and mortality among a predominantly Hispanic/Latino and African American population in New York City treated for COVID-19 in March 2020 which, like prior studies, found no difference. (4)

These findings are supported by 6 new systematic reviews with meta-analyses, except for one review finding a mildly increased risk of infection among patients younger than age 60 using ARBs (aOR, 1.09 [95% CI, 1.01 to 1.18]. (10-15)

Overall, inclusion of 15 studies from this search update does not change the certainty of evidence rating we reported in the original manuscript for key question 1 or key question 2. Studies have not examined the benefits and harms of initiating ACEI/ARB (i.e. new users) in COVID-19 treatment and therefore evidence for key question 3 remains unclear.

In-progress trial

We identified one new in-progress trial evaluating hospital-related outcomes between adults admitted with COVID-19 who continued or discontinued ACEI/ARBs. (16)

 

References

  1. Mackey K, King VJ, Gurley S, Kiefer M, Liederbauer E, Vela K, Sonnen P, Kansagara D. Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults. Ann Intern Med. 2020 May 15:M20-1515. doi: 10.7326/M20-1515. Epub ahead of print. PMID: 32422062; PMCID: PMC7249560.
  1. Chodick G, Nutman A, Yiekutiel N, Shalev V. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers are not associated with increased risk of SARS-CoV-2 infection. J Travel Med. 2020 Aug 20;27(5):taaa069. doi: 10.1093/jtm/taaa069. PMID: 32406512; PMCID: PMC7239115.
  1. Seo J, Son M. Update on association between exposure to renin-angiotensin-aldosterone system inhibitors and coronavirus disease 2019 in South Korea. Korean J Intern Med. 2020 Aug 21. doi: 10.3904/kjim.2020.380. Epub ahead of print. PMID: 32872736.
  1. Adrish M, Chilimuri S, Sun H, Mantri N, Yugay A, Zahid M. The Association of Renin-Angiotensin-Aldosterone System Inhibitors With Outcomes Among a Predominantly Ethnic Minority Patient Population Hospitalized With COVID-19: The Bronx Experience. Cureus. 2020 Sep 3;12(9):e10217. doi: 10.7759/cureus.10217. PMID: 32905551; PMCID: PMC7473610.
  1. Anzola GP, Bartolaminelli C, Gregorini GA, Coazzoli C, Gatti F, Mora A, Charalampakis D, Palmigiano A, De Simone M, Comini A, Dellaglio E, Cassetti S, Chiesa M, Spedini F, d'Ottavi P, Savio MC. Neither ACEIs nor ARBs are associated with respiratory distress or mortality in COVID-19 results of a prospective study on a hospital-based cohort. Intern Emerg Med. 2020 Sep 23:1–8. doi: 10.1007/s11739-020-02500-2. Epub ahead of print. PMID: 32965603; PMCID: PMC7508677.
  1. Kocayigit I, Kocayigit H, Yaylaci S, Can Y, Erdem AF, Karabay O. Impact of antihypertensive agents on clinical course and in-hospital mortality: analysis of 169 hypertensive patients hospitalized for COVID-19. Rev Assoc Med Bras (1992). 2020 Sep 21;66Suppl 2(Suppl 2):71-76. doi: 10.1590/1806-9282.66.S2.71. PMID: 32965360.
  1. Negreira-Caamaño M, Piqueras-Flores J, Martínez-DelRio J, Nieto-Sandoval-Martin-DeLaSierra P, Aguila-Gordo D, Mateo-Gomez C, Salas-Bravo D, Rodriguez-Martinez M, Negreira-Caamaño M. Impact of Treatment with Renin-Angiotensin System Inhibitors on Clinical Outcomes in Hypertensive Patients Hospitalized with COVID-19. High Blood Press Cardiovasc Prev. 2020 Sep 19:1–8. doi: 10.1007/s40292-020-00409-7. Epub ahead of print. PMID: 32949380; PMCID: PMC7501502.
  1. Soleimani A, Kazemian S, Karbalai Saleh S, Aminorroaya A, Shajari Z, Hadadi A, Talebpour M, Sadeghian H, Payandemehr P, Sotoodehnia M, Bahreini M, Najmeddin F, Heidarzadeh A, Zivari E, Ashraf H. Effects of angiotensin receptor blockers (ARBs) on in-hospital outcomes of patients with hypertension and confirmed or clinically suspected COVID-19. Am J Hypertens. 2020 Sep 12:hpaa149. doi: 10.1093/ajh/hpaa149. Epub ahead of print. PMID: 32920644; PMCID: PMC7543264.
  1. Wang Z, Zhang D, Wang S, Jin Y, Huan J, Wu Y, Xia C, Li Z, Qi X, Zhang D, Han X, Zhu X, Qu Y, Wang Q. A Retrospective Study from 2 Centers in China on the Effects of Continued Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Patients with Hypertension and COVID-19. Med Sci Monit. 2020 Sep 24;26:e926651. doi: 10.12659/MSM.926651. PMID: 32969367; PMCID: PMC7523417.
  1. Caldeira D, Alves M, Gouveia E Melo R, Silvério António P, Cunha N, Nunes-Ferreira A, Prada L, Costa J, Pinto FJ. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: Systematic review and meta-analysis. Int J Cardiol Heart Vasc. 2020 Dec;31:100627. doi: 10.1016/j.ijcha.2020.100627. Epub 2020 Aug 27. PMID: 32875060; PMCID: PMC7451091.
  1. Chan CK, Huang YS, Liao HW, Tsai IJ, Sun CY, Pan HC, Chueh JS, Wang JT, Wu VC, Chu TS; National Taiwan University Hospital Study Group of ARF, the Taiwan Primary Aldosteronism Investigators and the Taiwan Consortium for Acute Kidney Injury and Renal Diseases. Renin-Angiotensin-Aldosterone System Inhibitors and Risks of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Systematic Review and Meta-Analysis. Hypertension. 2020 Nov;76(5):1563-1571. doi: 10.1161/HYPERTENSIONAHA.120.15989. Epub 2020 Sep 1. PMID: 32869673; PMCID: PMC7485525.
  1. Greco A, Buccheri S, D'Arrigo P, Calderone D, Agnello F, Monte M, Milluzzo RP, Franchina AG, Ingala S, Capodanno D. Outcomes of renin-angiotensin-aldosterone system blockers in patients with COVID-19: a systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2020 Sep 1;6(5):335-337. doi: 10.1093/ehjcvp/pvaa074. PMID: 32671399; PMCID: PMC7454531.
  1. Hasan SS, Kow CS, Hadi MA, Zaidi STR, Merchant HA. Mortality and Disease Severity Among COVID-19 Patients Receiving Renin-Angiotensin System Inhibitors: A Systematic Review and Meta-analysis. Am J Cardiovasc Drugs. 2020 Sep 12:1–20. doi: 10.1007/s40256-020-00439-5. Epub ahead of print. PMID: 32918209; PMCID: PMC7486167.
  1. Lo KB, Bhargav R, Salacup G, Pelayo J, Albano J, McCullough PA, Rangaswami J. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers and outcomes in patients with COVID-19: a systematic review and meta-analysis. Expert Rev Cardiovasc Ther. 2020 Oct 5:1-12. doi: 10.1080/14779072.2020.1826308. Epub ahead of print. PMID: 32945216.
  1. Patoulias D, Katsimardou A, Stavropoulos K, Imprialos K, Kalogirou MS, Doumas M. Renin-Angiotensin System Inhibitors and COVID-19: a Systematic Review and Meta-Analysis. Evidence for Significant Geographical Disparities. Curr Hypertens Rep. 2020 Sep 10;22(11):90. doi: 10.1007/s11906-020-01101-w. PMID: 32910274; PMCID: PMC7481766.
  1. Cohen JB, Hanff TC, Corrales-Medina V, William P, Renna N, Rosado-Santander NR, Rodriguez-Mori JE, Spaak J, Andrade-Villanueva J, Chang TI, Barbagelata A, Alfonso CE, Bernales-Salas E, Coacalla J, Castro-Callirgos CA, Tupayachi-Venero KE, Medina C, Valdivia R, Villavicencio M, Vasquez CR, Harhay MO, Chittams J, Sharkoski T, Byrd JB, Edmonston DL, Sweitzer N, Chirinos JA. Randomized elimination and prolongation of ACE inhibitors and ARBs in coronavirus 2019 (REPLACE COVID) Trial Protocol. J Clin Hypertens (Greenwich). 2020 Sep 16. doi: 10.1111/jch.14011. Epub ahead of print. PMID: 32937008.

Disclosures:

Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1293.

Katherine Mackey MD MPP, Devan Kansagara MD MCR, Kathryn Vela MLIS AHIP17 November 2020
Update Alert 6 of Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review

Literature search update and yield

We searched MEDLINE (Ovid) weekly from September 29 to October 26, 2020 using the same search strategy as described in the original review (1). We did not limit the search by language. This search update yielded 64 results (de-duplicated), and after an independent dual review process, we identified 15 new studies meeting our inclusion criteria – 12 observational studies and 3 systematic reviews with meta-analyses

New evidence

Findings from 1 new observational study found no evidence of an association with ACEI/ARB use and risk of COVID-19 disease. (7). Findings from an additional 12 new observational studies did not demonstrate an association between use of ACEI/ARB and worse outcomes in COVID-19. (2-6, 8-13) These findings are supported by 4 new systematic reviews with meta-analyses. (14-16)

Overall, inclusion of 15 studies from this search update does not change the certainty of evidence rating we reported in the original manuscript for key question 1 or key question 2. Studies have not examined the benefits and harms of initiating ACEI/ARB (i.e. new users) in COVID-19 treatment and therefore evidence for key question 3 remains unclear.

References

  1. Mackey K, King VJ, Gurley S, Kiefer M, Liederbauer E, Vela K, Sonnen P, Kansagara D. Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults. Ann Intern Med. 2020 May 15:M20-1515. doi: 10.7326/M20-1515. Epub ahead of print. PMID: 32422062; PMCID: PMC7249560.
  1. Braude P, Carter B, Short R, Vilches-Moraga A, Verduri A, Pearce L, Price A, Quinn TJ, Stechman M, Collins J, Bruce E, Einarsson A, Rickard F, Mitchell E, Holloway M, Hesford J, Barlow-Pay F, Clini E, Myint PK, Moug S, McCarthy K, Hewitt J. The influence of ACE inhibitors and ARBs on hospital length of stay and survival in people with COVID-19. Int J Cardiol Heart Vasc. 2020 Dec;31:100660. doi: 10.1016/j.ijcha.2020.100660. Epub 2020 Oct 15. PMID: 33083516; PMCID: PMC7561344.
  1. Covino M, De Matteis G, Burzo ML, Santoro M, Fuorlo M, Sabia L, Sandroni C, Gasbarrini A Prof, Franceschi F Prof, Gambassi G Prof; GEMELLI AGAINST COVID-19 Group. Angiotensin-Converting Enzyme Inhibitors Or Angiotensin Ii Receptor Blockers And Prognosis Of Hypertensive Patients Hospitalized With Covid-19. Intern Med J. 2020 Oct 6. doi: 10.1111/imj.15078. Epub ahead of print. PMID: 33022124.
  1. Cui H, Wu F, Fan Z, Cheng X, Cheng J, Fan M. The effects of renin-angiotensin system inhibitors (RASI) in coronavirus disease (COVID-19) with hypertension: A retrospective, single-center trial. Med Clin (Engl Ed). 2020 Oct 9;155(7):295-298. doi: 10.1016/j.medcle.2020.06.007. Epub 2020 Oct 5. PMID: 33043142; PMCID: PMC7533685.
  1. Desai A, Voza G, Paiardi S, Teofilo FI, Caltagirone G, Pons MR, Aloise M, Kogan M, Tommasini T, Savevski V, Stefanini G, Angelini C, Ciccarelli M, Badalamenti S, De Nalda AL, Aghemo A, Cecconi M, Martinelli Boneschi F, Voza A; Humanitas COVID-19 task force. The role of anti-hypertensive treatment, comorbidities and early introduction of LMWH in the setting of COVID-19: A retrospective, observational study in Northern Italy. Int J Cardiol. 2020 Sep 25:S0167-5273(20)33843-2. doi: 10.1016/j.ijcard.2020.09.062. Epub ahead of print. PMID: 32980434; PMCID: PMC7516574.
  1. Di Castelnuovo A, Costanzo S, Antinori A, Berselli N, Blandi L, Bonaccio M, Cauda R, Gialluisi A, Guaraldi G, Menicanti L, Mennuni M, Mussinelli R, My I, Parruti G, Patti G, Perlini S, Santilli F, Signorelli C, Stefanini GG, Vergori A, Abete P, Ageno W, Agostoni P, Aiello L, Al Moghazi S, Arboretti R, Aucella F, Barbieri G, Barchitta M, Bartoloni A, Bonfanti P, Cacciatore F, Caiano L, Carrozzi L, Cascio A, Castiglione G, Cianfrone S, Ciccullo A, Cingolani A, Cipollone F, Colomba C, Colombo C, Cozzi O, Crisetti A, Crosta F, Danzi GB, D'Ardes D, de Gaetano Donati K, Di Gennaro F, Di Tano G, D'Offizi G, Fusco FM, Gentile I, Graziani E, Guarnieri G, Larizza G, Leone A, Lio V, Lucia MB, Maccagni G, Madaro F, Maitan S, Mancarella S, Manuele R, Mapelli M, Maragna R, Marcucci R, Maresca G, Marongiu S, Marotta C, Marra L, Mastroianni F, Mazzitelli M, Mengozzi A, Menichetti F, Meschiari M, Milic J, Minutolo F, Molena B, Mussini C, Musso M, Odone A, Olivieri M, Palimodde A, Pasi E, Pesavento R, Petri F, Pinchera B, Pivato CA, Poletti V, Ravaglia C, Rossato M, Rossi M, Sabena A, Salinaro F, Sangiovanni V, Sanrocco C, Scoppettuolo G, Scorzolini L, Sgariglia R, Simeone PG, Trecarichi EM, Vettor R, Vianello A, Vinceti M, Virano A, Vocciante L, Iacoviello L, Caterina. RAAS inhibitors are not associated with mortality in COVID-19 patients: findings from an observational multicenter study in Italy and a meta-analysis of 19 studies. Vascul Pharmacol. 2020 Sep 26:106805. doi: 10.1016/j.vph.2020.106805. Epub ahead of print. PMID: 32992048;PMCID: PMC7521934.
  1. Dublin S, Walker R, Floyd JS, Shortreed SM, Fuller S, Albertson-Junkans L, Harrington LB, Greenwood-Hickman MA, Green BB, Psaty BM. Renin-angiotensin-aldosterone system inhibitors and COVID-19 infection or hospitalization: a cohort study. Am J Hypertens. 2020 Oct 13:hpaa168. doi: 10.1093/ajh/hpaa168. Epub ahead of print. PMID: 33048112.
  1. Georges JL, Cochet H, Roger G, Ben Jemaa H, Soltani J, Azowa JB, Mamou R, Gilles F, Saba J, Prevot A, Pasqualini M, Monguillon V, De Tournemire M, Bertrand A, Koukabi-Fradelizi M, Beressi JP, Livarek B. Association entre l’hypertension artérielle, les traitements inhibiteurs du système rénine angiotensine et les formes graves de COVID-19. Étude prospective monocentrique française [Association of hypertension and antihypertensive agents and the severity of COVID-19 pneumonia. A monocentric French prospective study]. Ann Cardiol Angeiol (Paris). 2020 Nov;69(5):247-254. French. doi: 10.1016/j.ancard.2020.09.030. Epub 2020 Sep 29. PMID: 33039120; PMCID: PMC7522617.
  1. Feng Z, Li J, Yao S, Yu Q, Zhou W, Mao X, Li H, Kang W, Ouyang X, Mei J, Zeng Q, Liu J, Ma X, Rong P, Wang W. Clinical Factors Associated with Progression and Prolonged Viral Shedding in COVID-19 Patients: A Multicenter Study. Aging Dis. 2020 Oct 1;11(5):1069-1081. doi: 10.14336/AD.2020.0630. PMID: 33014523; PMCID: PMC7505267.
  1. Hu J, Zhang X, Zhang X, Zhao H, Lian J, Hao S, Jia H, Yang M, Lu Y, Xiang D, Cai H, Zhang S, Gu J, Ye C, Yu G, Jin C, Zheng L, Yang Y, Sheng J. COVID-19 is more severe in patients with hypertension; ACEI/ARB treatment does not influence clinical severity and outcome. J Infect. 2020 May 28:S0163-4453(20)30334-0. doi: 10.1016/j.jinf.2020.05.056. Epub ahead of print. PMID: 32474032; PMCID: PMC7255723.
  1. Palazzuoli A, Mancone M, De Ferrari GM, Forleo G, Secco GG, Ruocco GM, D'Ascenzo F, Monticone S, Paggi A, Vicenzi M, Palazzo AG, Landolina M, Taravelli E, Tavazzi G, Blasi F, Infusino F, Fedele F, De Rosa FG, Emmett M, Schussler JM, Tecson KM, McCullough PA. Antecedent Administration of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Antagonists and Survival After Hospitalization for COVID-19 Syndrome. J Am Heart Assoc. 2020 Oct 7:e017364. doi: 10.1161/JAHA.120.017364. Epub ahead of print. PMID: 33023356.
  1. Rodilla E, Saura A, Jiménez I, Mendizábal A, Pineda-Cantero A, Lorenzo-Hernández E, Fidalgo-Montero MDP, López-Cuervo JF, Gil-Sánchez R, Rabadán-Pejenaute E, Abella-Vázquez L, Giner-Galvañ V, Solís-Marquínez MN, Boixeda R, Peña-Fernández A, Carrasco-Sánchez FJ, González-Moraleja J, Torres-Peña JD, Guisado-Espartero ME, Escobar-Sevilla J, Guzmán-García M, Martín-Escalante MD, Martínez-González ÁL, Casas-Rojo JM, Gómez-Huelgas R. Association of Hypertension with All-Cause Mortality among Hospitalized Patients with COVID-19. J Clin Med. 2020 Sep 28;9(10):3136. doi: 10.3390/jcm9103136. PMID: 32998337; PMCID: PMC7650567.
  1. Yahyavi A, Hemmati N, Derakhshan P, Banivaheb B, Karimi Behnagh A, Tofighi R, TehraniYazdi A, Kabir A. Angiotensin enzyme inhibitors and angiotensin receptor blockers as protective factors in COVID-19 mortality: a retrospective cohort study. Intern Emerg Med. 2020 Oct 21:1–11. doi: 10.1007/s11739-020-02523-9. Epub ahead of print. PMID: 33085063; PMCID: PMC7576108.
  1. Kurdi A, Abutheraa N, Akil L, Godman B. A systematic review and meta-analysis of the use of renin-angiotensin system drugs and COVID-19 clinical outcomes: What is the evidence so far? Pharmacol Res Perspect. 2020 Dec;8(6):e00666. doi: 10.1002/prp2.666. PMID: 33084232; PMCID: PMC7575889.
  1. Wang Y, Chen B, Li Y, Zhang L, Wang Y, Yang S, Xiao X, Qin Q. The use of renin-angiotensin-aldosterone system (RAAS) inhibitors is associated with a lower risk of mortality in hypertensive COVID-19 patients: A systematic review and meta-analysis. J Med Virol. 2020 Oct 23. doi: 10.1002/jmv.26625. Epub ahead of print. PMID: 33095513.
  1. Xu J, Teng Y, Shang L, Gu X, Fan G, Chen Y, Tian R, Zhang S, Cao B. The Effect of Prior ACEI/ARB Treatment on COVID-19 Susceptibility and Outcome: A Systematic Review and Meta-Analysis. Clin Infect Dis. 2020 Oct 20:ciaa1592. doi: 10.1093/cid/ciaa1592. Epub ahead of print. PMID: 33079200.
Katherine Mackey, MD, MPP; Devan Kansagara, MD, MCR; Kathryn Vela, MLIS, AHIP11 January 2021
Update Alert 7: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults

Literature search update and yield

We searched MEDLINE (Ovid) weekly from October 27 to November 23, 2020 using the same search strategy as described in the original review. (1) We did not limit the search by language. This search update yielded 48 results (de-duplicated), and after an independent dual review process, we identified 14 new studies meeting our inclusion criteria (8 observational studies and 6 new systematic reviews with or without meta-analyses). (2-15) These studies are all relevant to key question (KQ) 2 regarding the association of ACEI/ARB use and COVID-19 severity and support our prior conclusion that ACEI/ARB use is not associated with a higher risk of severe COVID-19 disease. Two systematic reviews also address KQ1, adding support to our prior conclusion that ACEI/ARB use is not associated with an increased risk of SARS-CoV-2 infection. (11, 14)

Evidence Summary:

In total, 9 primary studies (8 observational, 1 RCT) have met our inclusion criteria for KQ 1 to date including studies identified in our original review, update alerts since then, and the most recent search described above. (16-24) In total, 78 primary studies (77 observational, 1 RCT) have met our inclusion criteria to date for KQ 2, excluding one retracted study.(2-9, 16, 22-90, 112) We have not identified any primary studies addressing KQ 3 regarding the benefits and harms of initiating ACEI/ARBs during COVID-19 disease (i.e. new users).

 

Key Question 1: Does the Use of ACEIs and ARBs Before Infection With SARS-CoV-2 Increase the Risk for COVID-19?

Evidence suggests that ACEI or ARB use is not associated with a higher likelihood of positive SARS-CoV-2 test results. Our confidence in this finding is high (rather than moderate as we previously concluded). New evidence since the publication of our original review includes results from a randomized controlled trial and four large database studies that included patients with a mix of disease severity. (16-19, 23) These studies consistently found that ACEI/ARB use was not associated with a higher risk of SARS-CoV-2 infection, findings which are further supported by 5 systematic reviews and/or metanalyses. (11, 14, 91-93) Because we consider these findings to be stable (meaning that future studies are likely to have the same results), we will no longer conduct literature surveillance on this KQ and will retire this KQ from our living review.

 

Key Question 2: Is Use of ACEIs and ARBs Associated With More Severe COVID-19 Illness?

Evidence suggests that use of ACEI or ARBs prior to COVID-19 disease is not associated with increased severity of COVID-19 illness. Our confidence in this finding remains high after incorporating new evidence since the publication of our original review given the consistency of results across studies,  representing adults from several geographic regions during different phases of the pandemic. Results are supported by numerous systematic reviews and/or metanalyses. (91-111)

Because we consider these findings to be stable (meaning that future studies are likely to have the same results), we will no longer conduct routine literature surveillance for this KQ. We have identified 3 in-progress trials aimed at addressing this KQ (Table 1) and will continue to monitor these trials for updates monthly and provide a brief status update quarterly. (113-115) If results would change our conclusions or strength of evidence assessment, we will provide an updated evidence synthesis.

Key Question 3: What Are the Benefits and Harms of Initiating ACEI or ARB Treatment for Patients With COVID-19?

We have identified 5 in-progress trials aimed at addressing this key question (Table 1). (116-120) We will monitor these trials for updates monthly and provide a brief status update quarterly. When results are available, we will provide an updated evidence synthesis.

 

References

  1. Mackey K, King VJ, Gurley S, Kiefer M, Liederbauer E, Vela K, Sonnen P, Kansagara D. Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults. Ann Intern Med. 2020 May 15:M20-1515. doi: 10.7326/M20-1515. Epub ahead of print. PMID: 32422062; PMCID: PMC7249560.
  1. Cheng X, Cai G, Wen X, et al. Clinical characteristics and fatal outcomes of hypertension in patients with severe COVID-19 [published online ahead of print, 2020 Nov 16]. Aging (Albany NY). 2020;12:10.18632/aging.104019. doi:10.18632/aging.104019
  1. COVID-19 RISk and Treatments (CORIST) Collaboration. RAAS inhibitors are not associated with mortality in COVID-19 patients: findings from an observational multicenter study in Italy and a meta-analysis of 19 studies. Vascul Pharmacol. 2020;135:106805. [PMID: 32992048] doi:10.1016/j.vph.2020.106805
  1. Genet B, Vidal JS, Cohen A, et al. COVID-19 In-Hospital Mortality and Use of Renin-Angiotensin System Blockers in Geriatrics Patients. J Am Med Dir Assoc. 2020;21(11):1539-1545. doi: 10.1016/j.jamda.2020.09.004. Epub 2020 Sep 9. PMID: 33138935; PMCID: PMC7480334.
  1. Kalra A, Hawkins ES, Nowacki AS, et al. Angiotensin-Converting Enzyme Inhibitors Versus Angiotensin II Receptor Blockers: A Comparison of Outcomes in Patients With COVID-19. Circ Cardiovasc Qual Outcomes. 2020 Oct;13(10):e007115. doi: 10.1161/CIRCOUTCOMES.120.007115. Epub 2020 Aug 28. PMID: 32856462; PMCID: PMC7578112.
  1. Khan KS, Reed-Embleton H, Lewis J, Bain P, Mahmud S. Angiotensin converting enzyme inhibitors do not increase the risk of poor outcomes in COVID-19 disease. A multi-centre observational study. Scott Med J. 2020 Nov;65(4):149-153. doi: 10.1177/0036933020951926. Epub 2020 Sep 1. PMID: 32873147; PMCID: PMC7468667.
  1. Lafaurie M, Martin-Blondel G, Delobel P, Charpentier S, Sommet A, Moulis G. Outcome of patients hospitalized for COVID-19 and exposure to angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in France: results of the ACE-CoV study. Fundam Clin Pharmacol. 2020 Oct 28. doi: 10.1111/fcp.12613. Epub ahead of print. PMID: 33111329.
  1. Polverino F, Stern DA, Ruocco G, et al. Comorbidities, Cardiovascular Therapies, and COVID-19 Mortality: A Nationwide, Italian Observational Study (ItaliCO). Front Cardiovasc Med. 2020 Oct 9;7:585866. doi: 10.3389/fcvm.2020.585866. PMID: 33195473; PMCID: PMC7583635.
  1. Tetlow S, Segiet-Swiecicka A, O'Sullivan R, et al. ACE inhibitors, angiotensin receptor blockers and endothelial injury in COVID-19. J Intern Med. 2020 Nov 18. doi: 10.1111/joim.13202. Epub ahead of print. PMID: 33210357.
  1. Kashour T, Bin Abdulhak AA, Tlayjeh H, Hassett LC, Noman A, Mohsen A, Al-Mallah MH, Tleyjeh IM. Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and Mortality Among COVID-19 Patients: A Systematic Review and Meta-Analysis. Am J Ther. 2020 Nov 10. doi: 10.1097/MJT.0000000000001281. Epub ahead of print. PMID: 33201001.
  1. Koshy AN, Murphy AC, Farouque O, Ramchand J, Burrell LM, Yudi MB. Renin-angiotensin system inhibition and risk of infection and mortality in COVID-19: a systematic review and meta-analysis. Intern Med J. 2020 Nov 16. doi: 10.1111/imj.15002. Epub ahead of print. PMID: 33191600.
  1. Nunes JPL. Mortality and use of angiotensin-converting enzyme inhibitors in COVID 19 disease: a systematic review. Porto Biomed J. 2020 Nov 11;5(6):e085. doi: 10.1097/j.pbj.0000000000000085. PMID: 33204892; PMCID: PMC7665268.
  1. Volpe M, Battistoni A. Systematic review of the role of renin-angiotensin system inhibitors in late studies on Covid-19: A new challenge overcome? Int J Cardiol. 2020 Dec 15;321:150-154. doi: 10.1016/j.ijcard.2020.07.041. Epub 2020 Jul 30. PMID: 32738257; PMCID: PMC7390818.
  1. Ren L, Yu S, Xu W, Overton JL, Chiamvimonvat N, Thai PN. Lack of association of antihypertensive drugs with the risk and severity of COVID-19: A meta-analysis. J Cardiol. 2020 Nov 2:S0914-5087(20)30353-1. doi: 10.1016/j.jjcc.2020.10.015. Epub ahead of print. PMID: 33168337; PMCID: PMC7605745.
  1. Ssentongo AE, Ssentongo P, Heilbrunn ES, Lekoubou A, Du P, Liao D, Oh JS, Chinchilli VM. Renin-angiotensin-aldosterone system inhibitors and the risk of mortality in patients with hypertension hospitalised for COVID-19: systematic review and meta-analysis. Open Heart. 2020 Nov;7(2):e001353. doi: 10.1136/openhrt-2020-001353. PMID: 33154144; PMCID: PMC7646321.
  1. Amat-Santos IJ , Santos-Martinez S ,  López-Otero D , et al. Ramipril in high-risk patients with COVID-19. J Am Coll Cardiol. 2020;76:268-276. [PMID: 32470515] doi:10.1016/j.jacc.2020.05.040
  1. Chodick G, Nutman A, Yiekutiel N, et al. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers are not associated with increased risk of SARS-CoV-2 infection [Letter]. J Travel Med. 2020;27. [PMID: 32406512] doi:10.1093/jtm/taaa069
  1. Dublin S , Walker R ,  Floyd JS , et al. Renin-angiotensin-aldosterone system inhibitors and COVID-19 infection or hospitalization: a cohort study. Am J Hypertens. 2020. [PMID: 33048112] doi:10.1093/ajh/hpaa168
  1. Kim J , Kim DW ,  Kim KI , et al. Korean Society of Hypertension. Compliance of antihypertensive medication and risk of coronavirus disease 2019: a cohort study using big data from the Korean National Health Insurance Service. J Korean Med Sci. 2020;35:e232. [PMID: 32597045] doi:10.3346/jkms.2020.35.e232
  1. Mancia G , Rea F ,  Ludergnani M , et al. Renin-angiotensin-aldosterone system blockers and the risk of covid-19. N Engl J Med. 2020. [PMID: 32356627] doi:10.1056/NEJMoa2006923
  1. Reynolds HR , Adhikari S ,  Pulgarin C , et al. Renin-angiotensin-aldosterone system inhibitors and risk of covid-19. N Engl J Med. 2020. [PMID: 32356628] doi:10.1056/NEJMoa2008975
  1. Mehta N , Kalra A ,  Nowacki AS , et al. Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020. [PMID: 32369097] doi:10.1001/jamacardio.2020.1855
  1. Rentsch CT, Kidwai-Khan F, Tate JP, et al. Covid-19 testing, hospital admission, and intensive care among 2,026,227 United States veterans aged 54-75 years. medRxiv. Preprint posted online 14 April 2020. doi:10.1101/2020.04.09.20059964
  1. Seo J, Son M. Update on association between exposure to renin-angiotensin-aldosterone system inhibitors and coronavirus disease 2019 in South Korea. Korean J Intern Med. 2020. [PMID: 32872736] doi:10.3904/kjim.2020.380
  1. Adrish M, Chilimuri S, Sun H, et al. The association of renin-angiotensin-aldosterone system inhibitors with outcomes among a predominantly ethnic minority patient population hospitalized with COVID-19: the Bronx experience. Cureus. 2020;12:e10217. [PMID: 32905551] doi:10.7759/cureus.10217
  1. Andrea C , Francesco M ,  Antonio N , et al. Renin-angiotensin-aldosterone system inhibitors and outcome in patients with SARS-CoV-2 pneumonia: a case series study [Letter]. Hypertension. 2020;76:e10-e12. [PMID: 32383626] doi:10.1161/HYPERTENSIONAHA.120.15312
  1. Anzola GP, Bartolaminelli C, Gregorini GA, et al. Neither ACEIs nor ARBs are associated with respiratory distress or mortality in COVID-19 results of a prospective study on a hospital-based cohort. Intern Emerg Med. 2020. [PMID: 32965603] doi:10.1007/s11739-020-02500-2
  1. Bae DJ , Tehrani DM ,  Rabadia SV , et al. Angiotensin converting enzyme inhibitor and angiotensin II receptor blocker use among outpatients diagnosed with COVID-19. Am J Cardiol. 2020;132:150-157. [PMID: 32819683] doi:10.1016/j.amjcard.2020.07.007
  1. Bean DM , Kraljevic Z ,  Searle T , et al. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are not associated with severe COVID-19 infection in a multi-site UK acute hospital trust. Eur J Heart Fail. 2020;22:967-974. [PMID: 32485082] doi:10.1002/ejhf.1924
  1. Braude P, Carter B, Short R, et al. The influence of ACE inhibitors and ARBs on hospital length of stay and survival in people with COVID-19. Int J Cardiol Heart Vasc. 2020;31:100660. doi:10.1016/j.ijcha.2020.100660
  1. Bravi F , Flacco ME ,  Carradori T , et al. Predictors of severe or lethal COVID-19, including angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, in a sample of infected Italian citizens. PLoS One. 2020;15:e0235248. [PMID: 32579597] doi:10.1371/journal.pone.0235248
  1. Chen FF , Zhong M ,  Liu Y , et al. The characteristics and outcomes of 681 severe cases with COVID-19 in China. J Crit Care. 2020;60:32-37. [PMID: 32736197] doi:10.1016/j.jcrc.2020.07.003
  1. Chen Y , Yang D ,  Cheng B , et al. Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication. Diabetes Care. 2020;43:1399-1407. [PMID: 32409498] doi:10.2337/dc20-0660
  1. Choi MH , Ahn H ,  Ryu HS , et al. Clinical characteristics and disease progression in early-stage COVID-19 patients in South Korea. J Clin Med. 2020;9. [PMID: 32585855] doi:10.3390/jcm9061959
  1. Covino M , De Matteis G ,  Burzo ML , et al; GEMELLI AGAINST COVID-19 Group. Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and prognosis of hypertensive patients hospitalized with Covid-19. Intern Med J. 2020. [PMID: 33022124] doi:10.1111/imj.15078
  1. Cui H , Wu F ,  Fan Z , et al. The effects of renin-angiotensin system inhibitors (RASI) in coronavirus disease (COVID-19) with hypertension: a retrospective, single-center trial. Med Clin (Engl Ed). 2020;155:295-298. [PMID: 33043142] doi:10.1016/j.medcle.2020.06.007
  1. Dalan R , Ang LW ,  Tan WYT , et al. The association of hypertension and diabetes pharmacotherapy with COVID-19 severity and immune signatures: an observational study. Eur Heart J Cardiovasc Pharmacother. 2020. [PMID: 32766831] doi:10.1093/ehjcvp/pvaa098
  1. De Spiegeleer A , Bronselaer A ,  Teo JT , et al. The effects of ARBs, ACEIs, and statins on clinical outcomes of COVID-19 infection among nursing home residents. J Am Med Dir Assoc. 2020;21:909-914. [PMID: 32674818] doi:10.1016/j.jamda.2020.06.018
  1. Desai A , Voza G ,  Paiardi S , et al; Humanitas COVID-19 task force. The role of anti-hypertensive treatment, comorbidities and early introduction of LMWH in the setting of COVID-19: a retrospective, observational study in Northern Italy. Int J Cardiol. 2020. [PMID: 32980434] doi:10.1016/j.ijcard.2020.09.062
  1. Felice C , Nardin C ,  Di Tanna GL , et al. Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives. Am J Hypertens. 2020. [PMID: 32511678] doi:10.1093/ajh/hpaa096
  1. Feng Y, Ling Y, Bai T, et al. COVID-19 with Different Severities: A Multicenter Study of Clinical Features. Am J Respir Crit Care Med. 2020;201(11):1380-1388. doi: 10.1164/rccm.202002-0445OC. PMID: 32275452; PMCID: PMC7258639.
  1. Feng Z , Li J ,  Yao S , et al. Clinical factors associated with progression and prolonged viral shedding in COVID-19 patients: a multicenter study. Aging Dis. 2020;11:1069-1081. [PMID: 33014523] doi:10.14336/AD.2020.0630
  1. Fosbøl EL , Butt JH ,  Østergaard L , et al. Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality. JAMA. 2020. [PMID: 32558877] doi:10.1001/jama.2020.11301
  1. Georges JL, Cochet H, Roger G, et al. Association entre l’hypertension artérielle, les traitements inhibiteurs du système rénine angiotensine et les formes graves de COVID-19. Étude prospective monocentrique française [Association of hypertension and antihypertensive agents and the severity of COVID-19 pneumonia. A monocentric French prospective study]. Ann Cardiol Angeiol (Paris). 2020;69(5):247-254. doi: 10.1016/j.ancard.2020.09.030. Epub 2020 Sep 29. PMID: 33039120; PMCID: PMC7522617.
  1. Giorgi Rossi P, Marino M, Formisano D, et al. Characteristics and outcomes of a cohort of COVID-19 patients in the Province of Reggio Emilia, Italy. PLoS One. 2020;15(8):e0238281. Published 2020 Aug 27. doi: 10.1371/journal.pone.0238281. PMID: 32853230; PMCID: PMC7451640.
  1. Golpe R , Pérez-de-Llano LA ,  Dacal D , et al. Lugo Covid-19 team. Risk of severe COVID-19 in hypertensive patients treated with renin-angiotensin-aldosterone system inhibitors. Med Clin (Barc). 2020. [PMID: 32651067] doi:10.1016/j.medcli.2020.06.013
  1. Gormez S , Ekicibasi E ,  Degirmencioglu A , et al. Association between renin-angiotensin-aldosterone system inhibitor treatment, neutrophil-lymphocyte ratio, D-dimer and clinical severity of COVID-19 in hospitalized patients: a multicenter, observational study. J Hum Hypertens. 2020. [PMID: 32839534] doi:10.1038/s41371-020-00405-3
  1. Hippisley-Cox J, Young D, Coupland C, et al. Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people. Heart. 2020;106(19):1503-1511. doi: 10.1136/heartjnl-2020-317393. Epub 2020 Jul 31. PMID: 32737124; PMCID: PMC7509391.
  1. Hu J, Zhang X, Zhang X, et al. COVID-19 is more severe in patients with hypertension; ACEI/ARB treatment does not influence clinical severity and outcome. J Infect. 2020;81(6):979-997. doi: 10.1016/j.jinf.2020.05.056. Epub 2020 May 28. PMID: 32474032; PMCID: PMC7255723.
  1. Huang W, Li T, Ling Y, et al.  [Effects of angiotensin converting enzyme inhibitor/angiotensin receptor blocker on clinical characteristics of coronavirus disease 2019 patients with hypertension]. Zhonghua Nei Ke Za Zhi. 2020 Sep 1;59(9):689-694. Chinese. doi: 10.3760/cma.j.cn112138-20200229-00155. PMID: 32838499.
  1. Huang Z , Cao J ,  Yao Y , et al. The effect of RAS blockers on the clinical characteristics of COVID-19 patients with hypertension. Ann Transl Med. 2020;8:430. [PMID: 32395474] doi:10.21037/atm.2020.03.229
  1. Iaccarino G , Grassi G ,  Borghi C , et al. SARS-RAS Investigators. Age and multimorbidity predict death among COVID-19 patients: results of the SARS-RAS study of the Italian Society of Hypertension. Hypertension. 2020;76:366-372. [PMID: 32564693] doi:10.1161/HYPERTENSIONAHA.120.15324
  1. Jung SY , Choi JC ,  You SH , et al. Association of renin-angiotensin-aldosterone system inhibitors with COVID-19-related outcomes in Korea: a nationwide population-based cohort study. Clin Infect Dis. 2020. [PMID: 32442285] doi:10.1093/cid/ciaa624
  1. Kocayigit I, Kocayigit H, Yaylaci S, et al. Impact of antihypertensive agents on clinical course and in-hospital mortality: analysis of 169 hypertensive patients hospitalized for COVID-19. Rev Assoc Med Bras (1992). 2020;66Suppl 2:71-76. [PMID: 32965360] doi:10.1590/1806-9282.66.S2.71
  1. Lam KW , Chow KW ,  Vo J , et al. Continued in-hospital ACE inhibitor and ARB use in hypertensive COVID-19 patients is associated with positive clinical outcomes. J Infect Dis. 2020. [PMID: 32702098] doi:10.1093/infdis/jiaa447
  1. Li J, Wang X, Chen J, Zhang H, Deng A. Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China. JAMA Cardiol. 2020 Jul 1;5(7):825-830. doi: 10.1001/jamacardio.2020.1624. Erratum in: JAMA Cardiol. 2020 Aug 1;5(8):968. PMID: 32324209; PMCID: PMC7180726.
  1. Liu X , Liu Y ,  Chen K , et al. Efficacy of ACEIs/ARBs versus CCBs on the progression of COVID-19 patients with hypertension in Wuhan: a hospital-based retrospective cohort study. J Med Virol. 2020. [PMID: 32687223] doi:10.1002/jmv.26315
  1. Liu Y, Huang F, Xu J, et al. Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients. medRxiv Preprint posted online 27 March 2020. doi: https://doi.org/10.1101/2020.03.20.20039586
  1. Martínez-Del Río J , Piqueras-Flores J ,  Nieto-Sandoval Martín de la Sierra P , et al. Comparative analysis between the use of renin-angiotensin system antagonists and clinical outcomes of hospitalized patients with COVID-19 respiratory infection. Med Clin (Barc). 2020. [PMID: 32782110] doi:10.1016/j.medcli.2020.07.004
  1. Matsuzawa Y , Ogawa H ,  Kimura K , et al. Renin-angiotensin system inhibitors and the severity of coronavirus disease 2019 in Kanagawa, Japan: a retrospective cohort study. Hypertens Res. 2020. [PMID: 32820236] doi:10.1038/s41440-020-00535-8
  1. Megaly M , Glogoza M . Renin-angiotensin system antagonists are associated with lower mortality in hypertensive patients with COVID-19 [Letter]. Scott Med J. 2020:36933020949219. [PMID: 32807019] doi:10.1177/0036933020949219
  1. Meng J, Xiao G, Zhang J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020 Dec;9(1):757-760. doi: 10.1080/22221751.2020.1746200. PMID: 32228222; PMCID: PMC7170368.
  1. Negreira-Caamaño M, Piqueras-Flores J, Martínez-DelRio J, et al. Impact of treatment with renin-angiotensin system inhibitors on clinical outcomes in hypertensive patients hospitalized with COVID-19. High Blood Press Cardiovasc Prev. 2020. [PMID: 32949380] doi:10.1007/s40292-020-00409-7
  1. Oussalah A , Gleye S ,  Clerc Urmes I , et al. Long-term ACE inhibitor/ARB use is associated with severe renal dysfunction and acute kidney injury in patients with severe COVID-19: results from a referral center cohort in the north east of France. Clin Infect Dis. 2020. [PMID: 32623470] doi:10.1093/cid/ciaa677
  1. Palazzuoli A , Mancone M ,  De Ferrari GM , et al. Antecedent administration of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists and survival after hospitalization for COVID-19 syndrome. J Am Heart Assoc. 2020;9:e017364. [PMID: 33023356] doi:10.1161/JAHA.120.017364
  1. Pan W , Zhang J ,  Wang M , et al. Clinical features of COVID-19 in patients with essential hypertension and the impacts of renin-angiotensin-aldosterone system inhibitors on the prognosis of COVID-19 patients. Hypertension. 2020;76:732-741. [PMID: 32654555] doi:10.1161/HYPERTENSIONAHA.120.15289
  1. Parigi TL , Vespa E ,  Pugliese N. COVID-19 . ACEI/ARBs and gastrointestinal symptoms: the jury is still out on the association [Letter]. Gastroenterology. 2020. [PMID: 32682762] doi:10.1053/j.gastro.2020.06.095
  1. Peng YD, Meng K, Guan HQ, et al.  [Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV]. Zhonghua Xin Xue Guan Bing Za Zhi. 2020 Jun 24;48(6):450-455. Chinese. doi: 10.3760/cma.j.cn112148-20200220-00105. PMID: 32120458.
  1. Raisi-Estabragh Z , McCracken C ,  Ardissino M , et al. Renin-angiotensin-aldosterone system blockers are not associated with coronavirus disease 2019 (COVID-19) hospitalization: study of 1,439 UK Biobank cases. Front Cardiovasc Med. 2020;7:138. [PMID: 32766285] doi:10.3389/fcvm.2020.00138
  1. Ran J , Song Y ,  Zhuang Z , et al. Blood pressure control and adverse outcomes of COVID-19 infection in patients with concomitant hypertension in Wuhan, China. Hypertens Res. 2020. [PMID: 32855527] doi:10.1038/s41440-020-00541-w
  1. Rey JR , Caro-Codón J ,  Rosillo SO , et al. Heart failure in covid-19 patients: prevalence, incidence and prognostic implications. Eur J Heart Fail. 2020. [PMID: 32833283] doi:10.1002/ejhf.1990
  1. Reynolds HR , Adhikari S ,  Pulgarin C , et al. Renin-angiotensin-aldosterone system inhibitors and risk of covid-19. N Engl J Med. 2020. [PMID: 32356628] doi:10.1056/NEJMoa2008975
  1. Rodilla E , Saura A ,  Jiménez I , et al. Association of hypertension with all-cause mortality among hospitalized patients with COVID-19. J Clin Med. 2020;9. [PMID: 32998337] doi:10.3390/jcm9103136
  1. Sardu C , Maggi P ,  Messina V , et al. Could anti-hypertensive drug therapy affect the clinical prognosis of hypertensive patients with COVID-19 infection? Data from centers of southern Italy. J Am Heart Assoc. 2020:e016948. [PMID: 32633594] doi:10.1161/JAHA.120.016948
  1. Selçuk M , Çinar T ,  Keskin M , et al. Is the use of ACE inb/ARBs associated with higher in-hospital mortality in Covid-19 pneumonia patients? Clin Exp Hypertens. 2020;42:738-742. [PMID: 32569491] doi:10.1080/10641963.2020.1783549
  1. Senkal N , Meral R ,  Medetalibeyoglu A , et al. Association between chronic ACE inhibitor exposure and decreased odds of severe disease in patients with COVID-19. Anatol J Cardiol. 2020;24:21-29. [PMID: 32628137] doi:10.14744/AnatolJCardiol.2020.57431
  1. Shah P , Owens J ,  Franklin J , et al. Baseline use of angiotensin-converting enzyme inhibitor/AT1 blocker and outcomes in hospitalized coronavirus disease 2019 African-American patients. J Hypertens. 2020. [PMID: 32740406] doi:10.1097/HJH.0000000000002584
  1. Singh AK, Gupta R, Misra A. Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers. Diabetes Metab Syndr. 2020 Jul-Aug;14(4):283-287. doi: 10.1016/j.dsx.2020.03.016. Epub 2020 Apr 9. PMID: 32283499; PMCID: PMC7144598.
  1. Soleimani A, Kazemian S, Karbalai Saleh S, et al. Effects of angiotensin receptor blockers (ARBs) on in-hospital outcomes of patients with hypertension and confirmed or clinically suspected COVID-19. Am J Hypertens. 2020. [PMID: 32920644] doi:10.1093/ajh/hpaa149 
  1. Son M , Seo J ,  Yang S . Association between renin-angiotensin-aldosterone system inhibitors and COVID-19 infection in South Korea. Hypertension. 2020;76:742-749. [PMID: 32654557] doi:10.1161/HYPERTENSIONAHA.120.15464 
  1. Tan ND , Qiu Y ,  Xing XB , et al. Associations between angiotensin-converting enzyme inhibitors and angiotensin II receptor blocker use, gastrointestinal symptoms, and mortality among patients with COVID-19. Gastroenterology. 2020;159:1170-1172. [PMID: 32422208] doi:10.1053/j.gastro.2020.05.034
  1. Trifirò G , Massari M ,  Da Cas R , et al. ITA-COVID-19: RAAS Inhibitor Group.. Renin-angiotensin-aldosterone system inhibitors and risk of death in patients hospitalised with COVID-19: a retrospective Italian cohort study of 43,000 patients. Drug Saf. 2020. [PMID: 32852721] doi:10.1007/s40264-020-00994-5
  1. Wang Z, Zhang D, Wang S, et al. A retrospective study from 2 centers in China on the effects of continued use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in patients with hypertension and COVID-19. Med Sci Monit. 2020;26:e926651. [PMID: 32969367] doi:10.12659/MSM.926651 
  1. Xu J , Huang C ,  Fan G , et al. Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis. Front Med. 2020. [PMID: 32621202] doi:10.1007/s11684-020-0800-y
  1. Yahyavi A , Hemmati N ,  Derakhshan P , et al. Angiotensin enzyme inhibitors and angiotensin receptor blockers as protective factors in COVID-19 mortality: a retrospective cohort study. Intern Emerg Med. 2020. [PMID: 33085063] doi:10.1007/s11739-020-02523-9
  1. Yang G, Tan Z, Zhou L, et al. Effects of Angiotensin II Receptor Blockers and ACE (Angiotensin-Converting Enzyme) Inhibitors on Virus Infection, Inflammatory Status, and Clinical Outcomes in Patients With COVID-19 and Hypertension: A Single-Center Retrospective Study. Hypertension. 2020 Jul;76(1):51-58. doi: 10.1161/HYPERTENSIONAHA.120.15143. Epub 2020 Apr 29. PMID: 32348166.
  1. Yuan Y , Liu D ,  Zeng S , et al. In-hospital use of ACEI/ARB is associated with lower risk of mortality and critic illness in COVID-19 patients with hypertension [Letter]. J Infect. 2020. [PMID: 32800800] doi:10.1016/j.jinf.2020.08.014
  1. Zeng Z, Sha T, Zhang Y, et al. Hypertension in patients hospitalized with COVID-19 in Wuhan, China: a single-center retrospective observational study. medRxiv. Preprint posted online 11 April 2020. doi:10.1101/2020.04.06.20054825
  1. Zhang P, Zhu L, Cai J, et al. Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19 [published correction appears in Circ Res. 2020 Aug 28;127(6):e147. Rohit, Loomba [corrected to Loomba, Rohit]]. Circ Res. 2020;126(12):1671-1681. doi:10.1161/CIRCRESAHA.120.317134
  1. Zhou F , Liu YM ,  Xie J , et al. Comparative impacts of ACE (angiotensin-converting enzyme) inhibitors versus angiotensin II receptor blockers on the risk of COVID-19 mortality [Letter]. Hypertension. 2020;76:e15-e17. [PMID: 32493070] doi:10.1161/HYPERTENSIONAHA.120.15622
  1. Caldeira D, Alves M, Gouveia E Melo R, et al. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: systematic review and meta-analysis. Int J Cardiol Heart Vasc. 2020;31:100627. [PMID: 32875060] doi:10.1016/j.ijcha.2020.100627
  1. Usman MS , Siddiqi TJ ,  Khan MS , et al. A meta-analysis of the relationship between renin-angiotensin-aldosterone system inhibitors and COVID-19 [Letter]. Am J Cardiol. 2020;130:159-161. [PMID: 32624189] doi:10.1016/j.amjcard.2020.05.038
  1. Zhang X , Yu J ,  Pan LY , et al. ACEI/ARB use and risk of infection or severity or mortality of COVID-19: a systematic review and meta-analysis. Pharmacol Res. 2020;158:104927. [PMID: 32422341] doi:10.1016/j.phrs.2020.104927
  1. Alamer A , Abraham I . Mortality in COVID-19 patients treated with ACEIs/ARBs: re-estimated meta-analysis results following the Mehra et al. retraction [Letter]. Pharmacol Res. 2020;160:105053. [PMID: 32619721] doi:10.1016/j.phrs.2020.105053
  1. Baral R , White M ,  Vassiliou VS . Effect of renin-angiotensin-aldosterone system inhibitors in patients with COVID-19: a systematic review and meta-analysis of 28,872 patients. Curr Atheroscler Rep. 2020;22:61. [PMID: 32830286] doi:10.1007/s11883-020-00880-6 
  1. Barochiner J , Martínez R . Use of inhibitors of the renin-angiotensin system in hypertensive patients and COVID-19 severity: a systematic review and meta-analysis. J Clin Pharm Ther. 2020. [PMID: 32767823] doi:10.1111/jcpt.13246
  1. Chan CK, Huang YS, Liao HW, et al; National Taiwan University Hospital Study Group of ARF, the Taiwan Primary Aldosteronism Investigators and the Taiwan Consortium for Acute Kidney Injury and Renal Diseases. Renin-angiotensin-aldosterone system inhibitors and risks of severe acute respiratory syndrome coronavirus 2 infection: a systematic review and meta-analysis. Hypertension. 2020;76:1563-1571. [PMID: 32869673] doi:10.1161/HYPERTENSIONAHA.120.15989
  1. Flacco ME , Acuti Martellucci C ,  Bravi F , et al. Treatment with ACE inhibitors or ARBs and risk of severe/lethal COVID-19: a meta-analysis. Heart. 2020. [PMID: 32611676] doi:10.1136/heartjnl-2020-317336
  1. Greco A, Buccheri S, D'Arrigo P, et al. Outcomes of renin-angiotensin-aldosterone system blockers in patients with COVID-19: a systematic review and meta-analysis [Letter]. Eur Heart J Cardiovasc Pharmacother. 2020;6:335-337. [PMID: 32671399] doi:10.1093/ehjcvp/pvaa074
  1. Grover A , Oberoi M . A systematic review and meta-analysis to evaluate the clinical outcomes in COVID-19 patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Eur Heart J Cardiovasc Pharmacother. 2020. [PMID: 32542337] doi:10.1093/ehjcvp/pvaa064
  1. Guo X , Zhu Y ,  Hong Y . Decreased mortality of COVID-19 with renin-angiotensin-aldosterone system inhibitors therapy in patients with hypertension: a meta-analysis [Letter]. Hypertension. 2020;76:e13-e14. [PMID: 32458694] doi:10.1161/HYPERTENSIONAHA.120.15572
  1. Hasan SS, Kow CS, Hadi MA, Zaidi STR, Merchant HA. Mortality and Disease Severity Among COVID-19 Patients Receiving Renin-Angiotensin System Inhibitors: A Systematic Review and Meta-analysis. Am J Cardiovasc Drugs. 2020 Sep 12:1–20. doi: 10.1007/s40256-020-00439-5. Epub ahead of print. PMID: 32918209; PMCID: PMC7486167.
  1. Kurdi A, Abutheraa N, Akil L, Godman B. A systematic review and meta-analysis of the use of renin-angiotensin system drugs and COVID-19 clinical outcomes: What is the evidence so far? Pharmacol Res Perspect. 2020 Dec;8(6):e00666. doi: 10.1002/prp2.666. PMID: 33084232; PMCID: PMC7575889.
  1. Liu X, Long C, Xiong Q, et al. Association of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with risk of COVID-19, inflammation level, severity, and death in patients with COVID-19: a rapid systematic review and meta-analysis. Clin Cardiol. 2020. [PMID: 32757246] doi:10.1002/clc.23421
  1. Lo KB, Bhargav R, Salacup G, Pelayo J, Albano J, McCullough PA, Rangaswami J. Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers and outcomes in patients with COVID-19: a systematic review and meta-analysis. Expert Rev Cardiovasc Ther. 2020 Oct 5:1-12. doi: 10.1080/14779072.2020.1826308. Epub ahead of print. PMID: 32945216.
  1. Patoulias D, Katsimardou A, Stavropoulos K, Imprialos K, Kalogirou MS, Doumas M. Renin-Angiotensin System Inhibitors and COVID-19: a Systematic Review and Meta-Analysis. Evidence for Significant Geographical Disparities. Curr Hypertens Rep. 2020 Sep 10;22(11):90. doi: 10.1007/s11906-020-01101-w. PMID: 32910274; PMCID: PMC7481766.
  1. Pirola CJ , Sookoian S . Estimation of renin-angiotensin-aldosterone-system (RAAS)-inhibitor effect on COVID-19 outcome: a meta-analysis. J Infect. 2020. [PMID: 32474043] doi:10.1016/j.jinf.2020.05.052 
  1. Pranata R, Permana H, Huang I, et al. The use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. Diabetes Metab Syndr. 2020;14:983-990. [PMID: 32615377] doi:10.1016/j.dsx.2020.06.047
  1. Salah HM , Calcaterra G ,  Mehta JL . Renin-angiotensin system blockade and mortality in patients with hypertension and COVID-19 infection. J Cardiovasc Pharmacol Ther. 2020:1074248420947628. [PMID: 32748634] doi:10.1177/1074248420947628
  1. Wang Y, Chen B, Li Y, Zhang L, Wang Y, Yang S, Xiao X, Qin Q. The use of renin-angiotensin-aldosterone system (RAAS) inhibitors is associated with a lower risk of mortality in hypertensive COVID-19 patients: A systematic review and meta-analysis. J Med Virol. 2020 Oct 23. doi: 10.1002/jmv.26625. Epub ahead of print. PMID: 33095513. 
  1. Xu J, Teng Y, Shang L, Gu X, Fan G, Chen Y, Tian R, Zhang S, Cao B. The Effect of Prior ACEI/ARB Treatment on COVID-19 Susceptibility and Outcome: A Systematic Review and Meta-Analysis. Clin Infect Dis. 2020 Oct 20:ciaa1592. doi: 10.1093/cid/ciaa1592. Epub ahead of print. PMID: 33079200.
  1. Mehra MR, Desai SS, Kuy S, et al. Retraction: cardiovascular disease, drug therapy, and mortality in covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621 [Letter]. N Engl J Med. 2020. [PMID: 32501665] doi:10.1056/NEJMc2021225
  1. S. National Library of Medicine. Coronavirus (COVID-19) ACEi/ARB Investigation (CORONACION). ClinicalTrials.gov Identifier: NCT04330300 [updated 30 June 2020]. Accessed at https://www.clinicaltrials.gov/ct2/show/NCT04330300 on 15 December 2020.
  1. S. National Library of Medicine. The Randomized Elimination or Prolongation of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Coronavirus Disease 2019. ClinicalTrials.gov Identifier: NCT04338009 [updated 24 April 2020]. Accessed at https://www.clinicaltrials.gov/ct2/show/NCT04338009 on 15 December 2020.
  1. S. National Library of Medicine. Suspension of Angiotensin Receptor Blockers and Angiotensin-converting Enzyme Inhibitors and Adverse Outcomes in Hospitalized Patients with Coronavirus Infection (COVID-19). A Randomized Trial. ClinicalTrials.gov Identifier: NCT04364893 [updated 2 July 2020]. Accessed at https://www.clinicaltrials.gov/ct2/show/NCT04364893 on 15 December 2020.
  1. S. National Library of Medicine. Efficacy of Captopril in Covid-19 Patients With Severe Acute Respiratory Syndrome (SARS) CoV-2 Pneumonia (CAPTOCOVID). ClinicalTrials.gov Identifier: NCT04355429 [updated 28 April 2020]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04355429 on 15 December 2020.
  1. S. National Library of Medicine. Angiotensin Converting Enzyme Inhibitors in Treatment of Covid 19. ClinicalTrials.gov Identifier: NCT04345406 [updated 14 April 2020]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04345406 on 15 December 2020.
  1. S. National Library of Medicine. Losartan for Patients With COVID-19 Not Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04311177 2020 [updated 16 November]. Accessed at https://clinicaltrials.gov/ct2/show/results/NCT04311177 on 15 December 2020.
  1. S. National Library of Medicine. Losartan for Patients With COVID-19 Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04312009 2020 [updated 4 December 2020]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04312009 on 15 December 2020.
  1. S. National Library of Medicine. Losartan for Patients With COVID-19 Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04335786 2020 [updated 9 June 2020]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04335786 on 15 December 2020.

 

Disclosures:

Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1446.

Katherine Mackey MD MPP, Devan Kansagara MD MCR, Kathryn Vela MLIS AHIP29 April 2021
Update Alert 8 of Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review

In Update Alert 7, we summarized the state of the evidence for the key questions of this systematic review: whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) increase the risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or worse outcomes and whether these medications are effective in treatment of coronavirus disease 2019 (COVID-19).(1)  Given our high confidence in evidence indicating that use of ACEI/ARBs does not increase the risk of SARS-CoV-2 infection, we retired this key question from our living review. In this Update Alert we provide a summary of results from two clinical trials addressing the question of whether continuing ACEI/ARBs in COVID-19 is associated with worse outcomes. We also provide an update on completed and in-progress clinical trials on the effectiveness of ACEI/ARBs in treatment of COVID-19 and results of our literature surveillance from November 23, 2020 to April 4, 2021 using the same search strategy as described in the original review.(2)

Key Question 2: Is Use of ACEIs and ARBs Associated With More Severe COVID-19 Illness?

Because of high confidence based on 78 studies (77 observational studies, 1 RCT) in the finding that ACEI/ARB use is not associated with COVID-19 severity, we ended our routine literature surveillance for this key question but planned to report on the findings of three in-progress clinic trials. Results are now available for two trials that compared COVID-19 disease severity and mortality in adults who continued or discontinued ACEI/ARBs once COVID-19 was diagnosed; the third trial was suspended due to challenges with funding and low incidence of COVID-19 at the study site.(3-5)

In the REPLACE COVID trial, a randomized, open-label multi-center trial of 152 adults, continuation of ACE/ARBs did not result in more severe disease as measured by a composite outcome incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction.(6) Similarly, the BRACE-CORONA trial conducted in Brazil of 659 adults with mild to moderate COVID-19 found no significant difference in days alive and out of the hospital in the ACE/ARB continuation group compared to the discontinuation group.(7) These findings support our conclusion that use of ACEI or ARBs prior to COVID-19 disease is not associated with increased severity of COVID-19 illness. Because we consider these findings to be stable (meaning that future studies are likely to have the same results), we will retire this key question from our living review.

Key Question 3: What Are the Benefits and Harms of Initiating ACEI or ARB Treatment for Patients With COVID-19?

 

We identified published results of one study in our search, a single arm, open-label trial on the safety of losartan initiation among 34 adults at the University of Kansas Hospital finding that losartan use in the intervention group was associated with a lower incidence of adverse events (defined as any untoward medical occurrence in a subject during the study) compared to external, non-randomized controls.(8) This study was not designed to evaluate losartan effectiveness in COVID-19 treatment. We previously identified five planned or in-progress clinical trials evaluating ACE/ARBs initiation in COVID-19 treatment (Table 1). Three of these trials remain in-progress.(9-11) Two are complete but results are not published yet.(11-12) We will monitor these trials for updates monthly and provide a brief status update in the fall of 2021. When results are available, we will provide an updated evidence synthesis.

 

References:

  1. Mackey K, Kansagara D, Vela K. Update Alert 7: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults. Ann Intern Med. 2021 Feb;174(2):W25-W29. doi: 10.7326/L20-1446. Epub 2021 Jan 5. PMID: 33395346; PMCID: PMC7791405.
  2. Mackey K, King VJ, Gurley S, Kiefer M, Liederbauer E, Vela K, Sonnen P, Kansagara D. Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults. Ann Intern Med. 2020 May 15:M20-1515. doi: 10.7326/M20-1515. Epub ahead of print. PMID: 32422062; PMCID: PMC7249560.
  3. U.S. National Library of Medicine. The Randomized Elimination or Prolongation of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Coronavirus Disease 2019. ClinicalTrials.gov Identifier: NCT04338009 [updated 24 April 2020]. Accessed at https://www.clinicaltrials.gov/ct2/show/NCT04338009 on 8 April 2021.
  4. U.S. National Library of Medicine. Suspension of Angiotensin Receptor Blockers and Angiotensin-converting Enzyme Inhibitors and Adverse Outcomes in Hospitalized Patients with Coronavirus Infection (COVID-19). A Randomized Trial. ClinicalTrials.gov Identifier: NCT04364893 [updated 2 July 2020]. Accessed at https://www.clinicaltrials.gov/ct2/show/NCT04364893 on 8 April 2021.
  5. U.S. National Library of Medicine. Coronavirus (COVID-19) ACEi/ARB Investigation (CORONACION). ClinicalTrials.gov Identifier: NCT04330300 [updated 30 June 2020]. Accessed at https://www.clinicaltrials.gov/ct2/show/NCT04330300 on 8 April 2021.
  6. Cohen, J. B., et al. (2021). "Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial." The Lancet Respiratory Medicine 9(3): 275-284.
  7. Lopes, R. D., et al. (2021). "Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial." JAMA 325(3): 254-264.
  8. Bengtson CD, Montgomery RN, Nazir U, Satterwhite L, Kim MD, Bahr NC, Castro M, Baumlin N, Salathe M. An Open Label Trial to Assess Safety of Losartan for Treating Worsening Respiratory Illness in COVID-19. Front Med (Lausanne). 2021 Feb 17;8:630209. doi: 10.3389/fmed.2021.630209. PMID: 33681257; PMCID: PMC7926174.
  9. Efficacy of Captopril Nebulization in Covid-19 Patients Suffering of SARS CoV-2 Pneumonia. A Randomized Phase II Study [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04355429 on 8 April 2021.
  10. Randomized Trial of ACEIs in Treatment of COVID-19 [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04345406 on 8 April 2021.
  11. PRAETORIAN-COVID: A Double-blind, Placebo-controlled Randomized Clinical Trial With Valsartan for PRevention of Acute rEspiraTORy dIstress Syndrome in hospitAlized patieNts With SARS-COV-2 (COVID-19) Infection Disease [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04335786 on 8 April 2021.
  12. Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04312009 on 8 April 2021.

13. Losartan for Patients With COVID-19 Not Requiring Hospitalization [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/results/NCT04311177 on 8 April 2

Disclosures:

Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1446.

Katherine Mackey MD MPP, Devan Kansagara MD MCR, Kathryn Vela MLIS AHIP9 February 2022
Update Alert 9 of Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review

In Update Alerts 7-8, we summarized the state of the evidence for two key questions of this systematic review: whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) increase the risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or worse outcomes. (1-2) In both cases, we have high confidence in evidence indicating that these medications are not associated with increased risk of infection or severe disease. Because we consider these findings to be stable, we retired the key question regarding risk of SARS-CoV-2 infection in February 2021 and retired the key question regarding disease severity in June 2021.

 

In this Update Alert, we summarize available evidence regarding our third key question: the benefits and harms of initiating an ACEI or ARB among adults with COVID-19 who were not previously taking these medications. In Update Alert 8, we provided an overview of in-progress trials but did not identify any completed studies. In an updated literature search from April 5, 2021 to November 22, 2021 using the same search strategy as our original review, we identified 277 potentially relevant articles and included four completed trials with published results (Supplement Table 1). (4-7) We used the same methods for study selection, data extraction, quality assessment, and evidence synthesis as we described in our original review. (3)

 

Three inpatient trials evaluated ARB initiation. Specific interventions were telmisartan 80mg twice daily for 14 days compared to standard care, losartan 12.5mg twice daily for 10 days compared to standard care, and losartan 25mg daily for at least 14 days compared to amlodipine 5mg. In the trial of telmisartan, conducted among 158 adults in Argentina, 30-day mortality risk was lower with telmisartan compared to usual care (RR = 0.19; 95% CI [0.06, 0.57]). (4) However, we have methodological concerns regarding this trial (rated high risk of bias) due to differences between groups at baseline as well as changes in study endpoints and some secondary outcomes during the study period (Supplement Table 2). The other two trials of losartan, one of 31 hospitalized adults with mild-moderate hypoxia conducted in the US and the other of 80 hospitalized adults with hypertension in Iran, did not identify a mortality benefit. (5-6) In the US study, need for intensive care was also similar between intervention and comparison groups (1/16 [6%] compared to 2/15 [13%], respectively). (5) In addition to the inconsistency in the direction of effect across studies, all studies were small (fewer than 200 participants) and had low event rates, making results imprecise. This evidence is insufficient to determine the benefits and harms of initiating ACEI/ARBs among adults hospitalized with COVID-19 (Supplement Table 3).

 

We identified one trial conducted in the outpatient setting of 117 adults in the US who tested positive for SARS-CoV-2. (7). This trial found that losartan 25mg twice daily for 10 days compared to placebo did not result in a lower risk of hospitalization. The absolute difference in all-cause hospitalization between groups was -3.5% favoring the placebo. (7) While well-conducted (rated low risk of bias), this trial was small with low event rates. This evidence is insufficient to determine the impacts of initiating ACEI/ARBs among non-hospitalized adults with COVID-19 (Supplement Table 3).

 

Given the numerous deficiencies of the existing evidence base, additional evidence is needed to determine the benefits and harms of initiating ACEI/ARBs in COVID-19. We also note that these trials were all completed by the fall of 2020 and have unclear applicability to patients contemporaneously diagnosed with COVID-19, who may have different disease trajectories based on vaccine status, infection with different SARS-CoV-2 variants, or general improvements in COVID-19 care over time.

 

Several clinical trials are in-progress, including three large trials (estimated sample size >1000), and an updated list is presented in Supplement Table 4. (8-18) We will monitor these trials for updates monthly and anticipate providing a final Update Alert in the summer of 2022 when more results are available.

References:

 

  1. Mackey K, Kansagara D, Vela K. Update Alert 7: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults. Ann Intern Med. 2021 Feb;174(2):W25-W29. doi: 10.7326/L20-1446. Epub 2021 Jan 5. PMID: 33395346; PMCID: PMC7791405.
  2. Mackey K, Kansagara D, Vela K. Update Alert 8: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults. Ann Intern Med. 2021 Jun;174(6):W54-W55. doi: 10.7326/L21-0223. Epub 2021 Apr 27. PMID: 33900794; PMCID: PMC8082523.
  3. Mackey K, King VJ, Gurley S, Kiefer M, Liederbauer E, Vela K, Sonnen P, Kansagara D. Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults. Ann Intern Med. 2020 May 15:M20-1515. doi: 10.7326/M20-1515. Epub ahead of print. PMID: 32422062; PMCID: PMC7249560.
  4. Duarte, M., et al. (2021). "Telmisartan for treatment of Covid-19 patients: An open multicenter randomized clinical trial." EClinicalMedicine 37: 100962.
  5. Geriak, M., et al. (2021). "Randomized Prospective Open Label Study Shows No Impact on Clinical Outcome of Adding Losartan to Hospitalized COVID-19 Patients with Mild Hypoxemia." Infectious Diseases & Therapy 11: 11.
  6. Nouri-Vaskeh M, Kalami N, Zand R, Soroureddin Z, Varshochi M, Ansarin K, Rezaee H, Taghizadieh A, Sadeghi A, Ahangari Maleki M, Esmailnajad A, Saleh P, Haghdoost M, Maleki M, Sharifi A. Comparison of losartan and amlodipine effects on the outcomes of patient with COVID-19 and primary hypertension: A randomised clinical trial. Int J Clin Pract. 2021 Jun;75(6):e14124. doi: 10.1111/ijcp.14124. Epub 2021 Mar 13. PMID: 33650197; PMCID: PMC7995089.
  7. Puskarich, M. A., et al. (2021). "A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19." EClinicalMedicine 37: 100957.
  8. Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04312009 on 24 November 2021.
  9. Efficacy of Captopril Nebulization in Covid-19 Patients Suffering of SARS CoV-2 Pneumonia. A Randomized Phase II Study (CAPTOCOVID) [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04355429 on on 24 November 2021.
  10. Telmisartan in Respiratory Failure Due to COVID-19 (STAR-COVID) [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04510662 on 24 November 2021.
  11. Ramipril for the Treatment of COVID-19 (RAMIC) [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04366050 on 24 November 2021.
  12. Host Response Mediators in Coronavirus (COVID-19) Infection - Is There a Protective Effect of Losartan on Outcomes of Coronavirus Infection? (ARBs CORONA II) [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04606563 on 24 November 2021.
  13. Pilot Clinical Trial of the Safety and Efficacy of Telmisartan for the Mitigation of Pulmonary and Cardiac Complications in COVID-19 Patients [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04360551 on 24 November 2021.
  14. COVID MED Trial - Comparison of Therapeutics for Hospitalized Patients Infected With COVID-19 (COVIDMED) [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04328012 on 24 November 2021.
  15. CLARITY Controlled evaLuation of Angiotensin Receptor blockers for COVID-19 respIraTorY disease [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04394117 on 24 November 2021.
  16. Evaluation of the Potential Benefit of Renin-angiotensin System Inhibitors (RASi, ACEi/ARB) in High-risk Patients With COVID-19 (COVID-RASi) [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04591210 on 24 November 2021.
  17. INvestigating TELmisartin Study (INTEL) [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04715763 on 24 November 2021.

Angiotensin Converting Enzyme Inhibitors in Treatment of Covid 19 [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04345406 on 2

Disclosures:

Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L21-0791.

Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 173Number 34 August 2020
Pages: 195 - 203

History

Published online: 15 May 2020
Published in issue: 4 August 2020

Keywords

Authors

Affiliations

Katherine Mackey, MD, MPP
VA Portland Health Care System, Portland, Oregon (K.M., K.V., P.S., D.K.)
Valerie J. King, MD, MPH
Oregon Health & Science University, Portland, Oregon (V.J.K., S.G., M.K., E.L.)
Susan Gurley, MD, PhD
Oregon Health & Science University, Portland, Oregon (V.J.K., S.G., M.K., E.L.)
Michael Kiefer, MD
Oregon Health & Science University, Portland, Oregon (V.J.K., S.G., M.K., E.L.)
Erik Liederbauer, MD
Oregon Health & Science University, Portland, Oregon (V.J.K., S.G., M.K., E.L.)
Kathryn Vela, MLIS, AHIP
VA Portland Health Care System, Portland, Oregon (K.M., K.V., P.S., D.K.)
Payten Sonnen, BS
VA Portland Health Care System, Portland, Oregon (K.M., K.V., P.S., D.K.)
Devan Kansagara, MD, MCR
VA Portland Health Care System, Portland, Oregon (K.M., K.V., P.S., D.K.)
Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the views of the U.S. Department of Veterans Affairs or the U.S. government.
Acknowledgment: The authors thank Julia Haskin, MA, for her graphic design of Figure 1.
Reproducible Research Statement: Study protocol and data set: Available from Dr. Kansagara (e-mail, [email protected]). Statistical code: Not applicable.
Corresponding Author: Devan Kansagara, MD, MCR, VA Portland Health Care System, 3710 Southwest U.S. Veterans Hospital Road, Mail Code: R&D 71, Portland, OR 97239; e-mail, [email protected].
Current Author Addresses: Drs. Mackey and Kansagara, Ms. Vela, and Ms. Sonnen: VA Portland Health Care System, 3710 Southwest U.S. Veterans Hospital Road, Mail Code: R&D 71, Portland, OR 97239.
Dr. King: The Center for Evidence-based Policy, Oregon Health & Science University, 3030 South Moody Avenue, Portland, OR 97201.
Drs. Gurley, Kiefer, and Liederbauer: Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239.
Author Contributions: Conception and design: K. Mackey, S. Gurley, D. Kansagara.
Analysis and interpretation of the data: K. Mackey, V.J. King, M. Kiefer, E. Liederbauer, D. Kansagara.
Drafting of the article: K. Mackey, S. Gurley, P. Sonnen, D. Kansagara.
Critical revision for important intellectual content: K. Mackey, V.J. King, D. Kansagara.
Final approval of the article: K. Mackey, V.J. King, S. Gurley, M. Kiefer, E. Liederbauer, K. Vela, P. Sonnen, D. Kansagara.
Statistical expertise: E. Liederbauer.
Administrative, technical, or logistic support: P. Sonnen.
Collection and assembly of data: K. Mackey, V.J. King, M. Kiefer, E. Liederbauer, K. Vela, D. Kansagara.
This article was published at Annals.org on 15 May 2020.

Metrics & Citations

Metrics

Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. For an editable text file, please select Medlars format which will download as a .txt file. Simply select your manager software from the list below and click Download.

For more information or tips please see 'Downloading to a citation manager' in the Help menu.

Format





Download article citation data for:
Katherine Mackey, Valerie J. King, Susan Gurley, et al. Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review. Ann Intern Med.2020;173:195-203. [Epub 15 May 2020]. doi:10.7326/M20-1515

View More

Get Access

Login Options:
Purchase

You will be redirected to acponline.org to sign-in to Annals to complete your purchase.

Create your Free Account

You will be redirected to acponline.org to create an account that will provide access to Annals.

View options

PDF/ePub

View PDF/ePub

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media