key: cord-0948406-z22a5yzo
authors: Mackey, Katherine; King, Valerie J.; Gurley, Susan; Kiefer, Michael; Liederbauer, Erik; Vela, Kathryn; Sonnen, Payten; Kansagara, Devan
title: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review
date: 2020-05-15
journal: Ann Intern Med
DOI: 10.7326/m20-1515
sha: 877c491d9b3ac5d0fc7fb2bbb8d3921437511188
doc_id: 948406
cord_uid: z22a5yzo

BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) in COVID-19 disease 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)

C oncerns 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 the disease 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 reninangiotensin 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) .

Angiotensin-converting enzyme 2 is distinct and not directly related to the clinical use of ACEIs or ARBs, or to their mechanisms of action. Angiotensinconverting enzyme inhibitors target angiotensinconverting 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 (AT 1 ), which mediates most of the vasopressor effects of angiotensin II (11) . Angiotensinreceptor blockers work by binding to AT 1 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 AT 1 receptor antagonism with ARBs may promote and stabilize cell membrane complexes between ACE2 and AT 1 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? What are the benefits and harms of initiating these drugs as treatment for patients with COVID-19?

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).

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, available at Annals.org, for search strategy and terms.) We also identified additional citations through hand-searching of reference lists. Angiotensin (1-7)

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; AT 1 = type 1 angiotensin receptor; RAS = renin-angiotensin system; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Risks and Impact of ACEIs or ARBs in Adults With SARS-CoV-2 Infection

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.

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) .

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) .

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.

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

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) .

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, Ϫ0.5 [CI, Ϫ2.6 to 3.6]) (37) .

A community-based case-control study from the Lombardy region of Italy included all patients older than 40 years with diagnosed COVID-19 (33 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.

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 

Risks and Impact of ACEIs or ARBs in Adults With SARS-CoV-2 Infection 

Risks and Impact of ACEIs or ARBs in Adults With SARS-CoV-2 Infection REVIEW Annals.org Annals of Internal Medicine 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) . 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 in-crease 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 hyper- tension 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.

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 

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) (44) (45) (46) (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 Risks and Impact of ACEIs or ARBs in Adults With SARS-CoV-2 Infection REVIEW Annals.org Annals of Internal Medicine 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.

Preventing a covid-19 pandemic

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

JNC 8: relaxing the standards

Cardiovascular disease and risk management: standards of medical care in diabetes-2020. Diabetes Care

Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus

Novel ACE2-Fc chimeric fusion provides long-lasting hypertension control and organ protection in mouse models of systemic renin angiotensin system activation. Kidney Int

Detection of soluble angiotensin-converting enzyme 2 in heart failure: insights into the endogenous counter-regulatory pathway of the renin-angiotensinaldosterone system

Brain angiotensinconverting enzyme type 2 shedding contributes to the development of neurogenic hypertension

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy?

Classical reninangiotensin system in kidney physiology

Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics

Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19

The Coronavirus Conundrum: ACE2 and Hypertension. Accessed at www.nephjc.com/news/covidace2 on 25

Differential effect of low dose thiazides on the renin angiotensin system in genetically hypertensive and normotensive rats

Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov

Exploring diseases/traits and blood proteins causally related to expression of ACE2, the putative receptor of 2019-nCov: A Mendelian randomization analysis

The ACE2 gene: its potential as a functional candidate for cardiovascular disease

Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism

Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury

Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Accessed at www.effective healthcare.ahrq

Global research on coronavirus disease (COVID-19) Accessed at www

Accessed at www.ohri.ca/programs/clinical _epidemiology/nosgen

Grading the strength of a body of evidence when assessing health care interventions: an EPC update

RoB 2: a revised tool for assessing risk of bias in randomised trials

Treatment with ACE-inhibitors is associated with less severe disease with SARS-Covid-19 infection in a multi-site UK acute Hospital Trust

COVID-19 with different severity: a multi-center study of clinical features

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

Anti-hypertensive angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients

Renin-angiotensinaldosterone system blockers and the risk of covid-19

Cardiovascular disease, drug therapy, and mortality in covid-19

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

Covid-19 testing, hospital admission, and intensive care among 2,026,227 United States veterans aged 54-75 years

Renin-angiotensinaldosterone system inhibitors and risk of covid-19

Characteristics and outcomes of a cohort of SARS-CoV-2 patients in the province of Reggio Emilia

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

Hypertension in patients hospitalized with COVID-19 in Wuhan, China: a single-center retrospective observational study

Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19

COVID-19) ACEi/ ARB Investigation (CORONACION). ClinicalTrials.gov Identifier: NCT04330300

Efficacy of Captopril in Covid-19 Patients With Severe Acute Respiratory Syndrome (SARS) CoV-2 Pneumonia (CAPTOCOVID)

Angiotensin Converting Enzyme Inhibitors in Treatment of Covid 19

Losartan for Patients With COVID-19 Not Requiring Hospitalization

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

Initiation, continuation, or withdrawal of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and outcomes in patients hospitalized with heart failure with reduced ejection fraction

Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial

Sonnen: VA Portland Health Care System

Veterans Hospital Road, Mail Code: R&D 71

The Center for Evidence-based Policy

Critical revision for important intellectual content