What information is available regarding the risks of ACE inhibitor or ARB use during the COVID-19 pandemic?

Background

Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by the novel betacoronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1,2 The disease was first recognized in December 2019 when cases of respiratory illness were reported in Wuhan, China.3 As of May 22, 2020, over 1.5 million people in the United States have tested positive for the virus and over 94,000 have died, according to the Centers for Disease Control and Prevention.4

The clinical course of COVID-19 is varied, and the full clinical picture is not yet known.1 Presentation can range from very mild to severe or life-threatening. Common symptoms include cough, shortness of breath, fever, chills, sore throat, muscle aches, and new loss of taste or smell.5 Gastrointestinal symptoms have also been reported. Severe disease can lead to pneumonia and acute respiratory distress syndrome (ARDS), as well as acute cardiac injury, shock, acute renal failure, and death.6 Some patient populations are at increased risk for severe disease, including elderly patients, immunocompromised patients, severely obese patients, and those with serious underlying medical conditions (eg, chronic lung disease, moderate to severe asthma, serious heart conditions, diabetes, chronic kidney disease requiring dialysis, liver disease).7 There has also been concern that renin-angiotensin-aldosterone system (RAAS) inhibitors, namely angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), may increase a patient’s risk for contracting COVID-19 and/or developing severe COVID-19 disease.8,9

Role of the RAAS in COVID-19 Pathogenesis

The key link between the RAAS and COVID-19 is angiotensin converting enzyme 2 (ACE2), a membrane-bound carboxypeptidase primarily found on epithelial cells in the lungs, heart, blood vessels, kidneys, and intestines.10,11 This enzyme typically serves to counterbalance the effects of angiotensin converting enzyme (ACE1).12 In normal physiology, ACE1 catalyzes the transformation of angiotensin I to angiotensin II, which binds to type 1 angiotensin II receptors (AT1) and promotes inflammation, vasoconstriction, and thrombosis. To counter this effect, ACE2 converts angiotensin II into angiotensin (1-7), which binds to Mas receptors and, to a lesser extent, type 2 angiotensin II receptors (AT2).13,14 This binding leads to vasodilation, as well as decreased inflammation, fibrosis, and thrombosis.13 The effects of ACE2 are thought to be lung-protective, as unchecked angiotensin II activity at the AT1 receptor can lead to inflammation, increased vascular permeability, pulmonary edema, and acute lung injury, including ARDS.12,13 Data from mouse models have shown that loss of ACE2 expression and increased activation of the angiotensin II-AT1 receptor axis promotes lung injury.15

The role of ACE2 in COVID-19 pathogenesis is a complex one, because ACE2 is a key facilitator for SARS-CoV-2 cell entry as well as a potential protective factor against lung injury.13 During the initial step of the viral entry process, the S1 unit of the SARS-CoV-2 spike protein binds to ACE2 on the cell surface.13,15 Following this attachment, the spike protein is cleaved between S1 and S2 by transmembrane protease serine 2 (TMPRSS2); when this occurs, the viral S2 unit undergoes a conformational change that allows the viral and cellular membranes to fuse. Once this fusion is accomplished, the virus can enter the cell and begin replication.13 Studies with a similar SARS coronavirus (SARS-CoV) found that SARS-CoV infection leads to downregulation of ACE2 expression, leading to worsened lung injury in animal models.13,15 It is suspected that SARS-CoV-2 may cause a similar downregulation of ACE2.15

Effects of ACE Inhibitors and ARBs in COVID-19: Conflicting Hypotheses

Angiotensin converting enzyme inhibitors and ARBs are RAAS inhibitors commonly used in the treatment of hypertension, heart failure, and diabetic nephropathy.16 The ACE inhibitors act by binding directly to ACE1 and preventing the conversion of angiotensin I to angiotensin II, while ARBs act as competitive antagonists at the AT1 receptor. Unlike ACE1, ACE2 is not inhibited by ACE inhibitors, because the conformational structure of its catalytic site is different from that of ACE1.13,15 However, it is thought that ACE2 expression may be upregulated in patients treated with ACE inhibitors or ARBs, although studies in humans and animals have not consistently demonstrated this effect.15,17 The possibility has led some to hypothesize that patients taking ACE inhibitors or ARBs may have increased susceptibility to COVID-19. On the other hand, some have argued that ACE inhibitors and ARBs may have a beneficial effect in COVID-19, with different mechanisms for benefit being proposed.17 Animal studies have shown that ACE inhibitors and ARBs help stabilize cell membrane complexes between ACE2 and AT1, which may make it more difficult for SARS-CoV-2 to enter the cell. It has also been suggested that the angiotensin II inhibition produced by these agents may help prevent viral lung injury. Some pre-COVID-19 studies have found that RAAS inhibitors are associated with a lower incidence of pneumonia and improved outcomes in lower respiratory tract infections, including viral pneumonia.15

Literature Review

Professional societies, including the American College of Cardiology, American Heart Association, Heart Failure Society of America, European Society of Cardiology, and International Society of Hypertension, have unanimously recommended continuing ACE inhibitor and ARB treatment in the context of COVID-19.18-21 These recommendations cite a lack of data demonstrating beneficial or adverse outcomes with background use of RAAS inhibitors in COVID-19. Guidelines on COVID-19 from the National Institutes of Health also recommend continuing ACE inhibitors and ARBs in patients who are currently taking them.22 Information from the American Society of Health-System Pharmacists notes that the abrupt withdrawal of RAAS inhibitors in patients with heart failure or prior myocardial infarction may cause clinical instability and lead to adverse outcomes.23

Several observational studies have been conducted to clarify the relationship between ACE inhibitor/ARB use and risk or severity of COVID-19 (Table 1).24-36 Three studies examined the relationship between ACE inhibitor/ARB therapy and the likelihood of testing positive for COVID-19.24-26 In these studies, patients taking ACE inhibitors or ARBs did not have an increased risk of testing positive compared to the general population. Other studies examined the relationship between ACE inhibitor/ARB use and outcomes in COVID-19, including risk of hospitalization, severe illness, or death.25-36 Most studies did not find any increased risk of negative outcomes associated with ACE inhibitor or ARB use; some studies found a beneficial association between ACE inhibitor/ARB use and clinical outcomes, although this potential benefit needs to be further clarified in randomized controlled trials before ACE inhibitors or ARBs are recommended for COVID-19 treatment.26-36 One study by Mehta and colleagues found an increased risk of hospital admission among patients taking ACE inhibitors and ARBs.25 However, the decision to hospitalize patients in this study was subjective and likely influenced by ACE inhibitor/ARB use or underlying disease states.25,37 Therefore, this finding should be interpreted with caution. A meta-analysis of observational data found that, among patients with COVID-19, ACE inhibitor or ARB treatment was not associated with an increased risk of severe disease or mortality.38 Additionally, ACE inhibitor/ARB exposure was not associated with an increased risk of COVID-19. A recent systematic review that included some additional preprint studies similarly concluded that ACE inhibitor or ARB use is not associated with increased COVID-19 disease severity or increased risk of positive SARS-CoV-2 test results among symptomatic patients.17 However, the authors of the review also stated that more evidence is needed to determine whether these drugs increase the risk for mild or asymptomatic infection. Several clinical trials are currently underway to assess the utility of starting or continuing ACE inhibitors and ARBs in patients with COVID-19.17,39

Table 1. Summary of published studies examining risks of ACE inhibitors and ARBs in COVID-19.24-36,38
Study design and durationSubjectsComparison GroupsResultsConclusions and limitations
Meta-analysis
Zhang X 202038

Systematic review and meta-analysis		N=12 observational studies (5 case-control and 7 cohort studies) examining the impact of ACEi/ARB use on COVID-19 incidence, severity, or mortalityACEi/ARB use vs. no ACEi/ARB useRisk of contracting COVID-19 was not significantly increased with ACEi/ARB use (OR, 0.99; 95% CI, 0.95 to 1.04; p=NS); results remained similar when ACEi use and ARB use were analyzed separately

Mortality risk was similar with ACEi/ARB exposure compared to no exposure in the overall COVID-19 patient population (OR, 0.73; 95% CI, 0.5 to 1.07; p=NS); among patients with hypertension receiving antihypertensive medication, ACEi/ARB treatment was associated with a lower risk of mortality vs other antihypertensive treatment (OR, 0.48; 95% CI, 0.29 to 0.81; p=0.006)

Risk of severe COVID-19 disease was not significantly increased with ACEi/ARB use (OR, 0.98; 95% CI, 0.87 to 1.09; p=NS)		Patients receiving ACEi/ARB treatment are not at increased risk for COVID-19 infection, severe COVID-19 disease, or mortality, and ACEi/ARB treatment should be continued in patients with COVID-19.

All studies were observational, and confounders may not have been appropriately taken into account in all studies. ACEi/ARB exposure was determined through medical record review, and therefore may not represent actual drug consumption. Most patients were hospitalized.
Observational Studies
Mancia 202024

Population-based case-control study conducted in Italy		N=37,031 patients aged 40 years or olderPatients with confirmed COVID-19 (n=6272)

Controls without confirmed COVID-19 (n=30,759)		ACEi treatment was not associated with an increased risk of COVID-19 (OR, 0.96; 95% CI, 0.87 to 1.07)

ARB treatment was not associated with an increased risk of COVID-19 (OR, 0.95; 95% CI, 0.86 to 1.05)

Results were similar regardless of disease severity		ACEi/ARB treatment is not independently associated with an increased risk of contracting COVID-19.

Data are observational, and residual confounding may be possible.
Mehta 202025

Retrospective cohort study utilizing registry data from a single health system in the United States		N=18,472 patients tested for COVID-19ACEi use at the time of COVID-19 testing (n=1322)

ARB use at the time of COVID-19 testing (n=982)

No ACEi/ARB use at the time of COVID-19 testing (n=16,168)		Positive test results were not increased among patients taking ACEi vs no ACEi (OR, 0.89; 95% CI, 0.72 to 1.10), ARB vs no ARB (OR, 1.09; 95% CI, 0.87 to 1.37), or ACEi/ARB vs no ACEi/ARB (OR, 0.97; 95% CI, 0.81 to 1.15)

Compared to COVID-positive patients not taking ACEi, patients taking ACEi were more likely to be hospitalized (OR, 1.84; 95% CI, 1.22 to 2.79) and more likely to require ICU admission (OR, 1.77; 95% CI, 1.07 to 2.92)

Compared to COVID-positive patients not taking ARB, patients taking ARB were more likely to be hospitalized (OR, 1.61; 95% CI, 1.04 to 2.50)		ACEi/ARB therapy was not associated with an increased risk of testing positive for COVID-19; further studies are required to examine the impact of ACEi/ARB therapy on clinical outcomes in patients who test positive for COVID-19.

Event rates were low in ACEi and ARB users, as this study was conducted early in the course of the pandemic. The decision to hospitalize patients was subjective and may have been influenced by ACEi/ARB use or underlying disease states. Risk of bias due to confounding is high for hospitalization and ICU admission outcomes and these should be interpreted with caution.
Reynolds 202026

Retrospective observational study at a single health system in the United States

N=12,594 patients with COVID-19 test resultsPositive COVID-19 test result (n=5894)

Negative COVID-19 test result (n=6700)		Positive test results were not more frequent among patients taking ACEi/ARB compared to the general study population (58.1% vs 57.7%; difference, 0.5; 95% CI, -2.6 to 3.6)

Among patients who tested positive, ACEi/ARB therapy was not associated with an increased incidence of severe disease (24.8% vs 24.9%; difference, -0.1; 95% CI, -3.7 to 3.5)

Results were consistent when ACEi and ARB drug classes were analyzed individually

Results were consistent when only patients with hypertension were analyzed		RAAS inhibitor treatment was not associated with an increased risk of testing positive for COVID-19, and among those who tested positive, RAAS inhibitors were not associated with an increased risk for severe disease.

Data are observational, and residual confounding may be possible.
de Abajo 202027

Observational case-population study conducted in Spain		N=12,529 adultsAdults admitted to the hospital for confirmed COVID-19 (n=1139)

Population controls (n=11,390)		Patients currently using RAAS inhibitors were not more likely to require admission to the hospital than patients using other antihypertensive drugs (OR, 0.94; 95% CI, 0.77 to 1.15); these results were consistent when ACEi and ARB drug classes were analyzed individually

In diabetic patients taking RAAS inhibitors, the risk of hospitalization for COVID-19 was decreased compared to diabetic patients taking other antihypertensives (OR, 0.53; 95% CI, 0.34 to 0.80)		Outpatient use of RAAS inhibitors was not associated with an increased risk for hospitalization due to COVID-19.

Case and control data were derived from different sources. Data are observational, and residual confounding may be possible.
Mehra 202028

Observational study utilizing registry data from the Surgical Outcomes Collaborative (169 hospitals in 11 Asian, European, and North American countries)		N=8910 hospitalized patients with COVID-19 who had final hospitalization outcome data reported in the registrySurvived to hospital discharge (n=8395)

Died in hospital (n=515)		ACEi use at the time of hospitalization was more common among survivors than non-survivors (9.0% vs 3.1%; difference, 5.9; 95% CI, 4.3 to 7.5)

ARB use at the time of hospitalization was not significantly different between survivors and non-survivors (6.2% vs 7.4%; difference, -1.2; 95% CI, -3.5 to 1.1)

ACEi use was associated with an increased chance of survival to hospital discharge (OR, 0.33; 95% CI, 0.20 to 0.54); ARB use was not associated with increased chance of survival (OR, 1.23; 95% CI, 0.87 to 1.74)		Neither ACEi nor ARB therapy was associated with a negative impact on survival to hospital discharge.

Data are observational, and residual confounding may be possible.
Zhang P 202029

Retrospective, multicenter observational study conducted in China		N=1128 hospitalized adults with hypertension diagnosed with COVID-19ACEi/ARB use during hospitalization (n=188)

No ACEi/ARB use during hospitalization (n=940)		Risk of 28-day all-cause mortality was lower among patients receiving ACEi/ARB (HR, 0.42; 95% CI, 0.19 to 0.92; p=0.03); results were consistent in the propensity score-matched analysis (HR, 0.37; 95% CI, 0.15 to 0.89; p=0.03)

Risk of septic shock was also lower among patients who received ACEi/ARB (HR, 0.36; 95% CI, 0.16 to 0.84; p=0.01); this was consistent in the propensity score-matched analysis (HR, 0.32; 95% CI, 0.13 to 0.80; p=0.01)		In-hospital use of ACEi or ARB therapy was associated with a lower risk of 28-day all-cause mortality compared to ACEi/ARB non-use.

Pre-hospital use of ACEi/ARB therapy was not recorded. The number of patients receiving ACEi/ARB therapy was relatively small. Data are observational, and residual confounding may be possible.
Feng 202030

Retrospective, multicenter observational study conducted in China		N=476 hospitalized patients with COVID-19Moderate COVID-19 (n=352)

Severe COVID-19 (n=54)

Critical COVID-19 (n=70)		Most patients who were receiving ACEi/ARB therapy (87.9%) were in the moderate severity group; 6.1% of patients receiving ACEi/ARB therapy had severe disease, and 6.1% were considered critical (p=0.004 for moderate vs severe and critical groups)Most patients taking ACEi/ARB in this study had moderate disease; further study is required to determine the impact of ACEi/ARB use in COVID-19.

Only 33 patients in the study were receiving ACEi/ARB therapy. Data are observational, and confounding is possible. It is not clear how ACEi/ARB use was determined. No analysis to address the potential impact of confounding variables was reported.
Li 202031

Retrospective, single-center observational study conducted in China		N=362 hospitalized patients with hypertension and COVID-19ACEi/ARB use at time of admission and continued use during hospitalization (n=115)

No ACEi/ARB use (n=247)		Use of ACEi or ARB was not significantly more likely among patients with severe illness vs patients with non-severe illness (9.2% vs 10.1%; p=NS and 24.9% vs 21.2%; p=NS for ACEi and ARB respectively); this remained true when patients receiving ACEi or ARB were analyzed as a single composite group (32.9% vs 30.7% in severe illness and non-severe illness respectively; p=NS)

Use of ACEi or ARB was not significantly more likely among non-survivors vs survivors (9.1% vs 9.8%; p=NS and 19.5% vs 23.9%; p=NS for ACEi and ARB respectively); this remained true when patients receiving ACEi or ARB were analyzed as a single composite group (27.3% vs 33.0% in non-survivors and survivors respectively; p=NS)		ACEi/ARB use was not significantly different among patients with severe illness vs patients with non-severe illness, or among non-survivors vs survivors.

This was a small study conducted at a single center in China, and no adjustments were reported to account for confounding variables despite differences in baseline characteristics.
Tedeschi 202032

Multicenter cohort study conducted in Italy		N=311 hospitalized patients with hypertension and confirmed COVID-19Chronic RAAS inhibitor use vs. no RAAS inhibitor useChronic RAAS inhibitor use was not independently associated with in-hospital mortality (HR, 0.97; 95% CI, 0.68 to 1.39; p=NS)In patients with hypertension, RAAS inhibitor use did not impact in-hospital mortality due to COVID-19.

This study had a relatively small sample size, although the mortality rate in the study population was high (42%).
Yang 202033

Retrospective, single-center observational study conducted in China		N=126 hospitalized COVID-19 patients with pre-existing hypertensionACEi/ARB use (n=43)

No ACEi/ARB use (n=83)		Proportion of patients with critical illness was numerically lower in the ACEi/ARB user group, although differences were not statistically significant (9.3% vs 22.9%; p=NS)

Mortality was numerically lower in the ACEi/ARB user group, although differences were not statistically significant (4.7% vs 13.3%; p=NS)		ACEi/ARB therapy may be used in patients with COVID-19 and pre-existing hypertension.

This was a small study conducted at a single center in China. Data are observational, and residual confounding may be possible.
Tan 202034

Retrospective, single-center observational study conducted in China		N=100 hospitalized patients with COVID-19 and hypertensionACEi/ARB use (n=31)

No ACEi/ARB use (n=69)		Patients receiving ACEi/ARB treatment were less likely to experience GI symptoms (38.7% vs 58%; p=0.031) or show abnormalities in liver function markers (22.6% vs 42%; p=0.043)

All-cause mortality was lower among patients receiving ACEi/ARB (0% vs 15.9%; p<0.01)		ACEi/ARB use during the COVID-19 disease course was associated with a lower risk of GI symptoms, liver abnormalities, and mortality in hospitalized COVID-19 patients.

This was a small study conducted at a single center in China, and no adjustments were reported to account for confounding variables despite differences in baseline characteristics.
Huang 202035

Observational single-center registry study conducted in China		N=50 hospitalized patients with hypertension and COVID-19RAAS inhibitor treatment prior to admission and during hospitalization (n=20)

No RAAS inhibitor treatment (n=30)		In-hospital mortality was not significantly different between groups; no deaths occurred in the RAAS inhibitor user group and 3 deaths occurred in the non-user group (p=NS)

Time from disease onset to hospital discharge was not significantly different between RAAS inhibitor users (mean, 40.7 days) and non-users (mean, 45.38 days; p=NS)		There were no obvious differences in COVID-19 disease course between RAAS inhibitor users and non-users.

This was a very small study from a single center in China, and no statistical adjustments were made to account for confounding variables despite differences in baseline characteristics. Medications and hypertension history were self-reported by patients.
Meng 202036

Retrospective, single-center observational study conducted in China		N=42 hospitalized patients with COVID-19 and hypertensionACEi/ARB therapy (n=17)

Other antihypertensive drug therapy (n=25)		Severe COVID-19 disease was numerically less common among patients receiving ACEi/ARB (23.5% vs 48%; p=NS)

No patients receiving ACEi/ARB therapy died, and 1 patient receiving other antihypertensive therapy died		In hospitalized patients with hypertension and COVID-19, antihypertensive therapy with ACEi/ARB may be associated with improved outcomes vs antihypertensive therapy with other agents; however, the sample size of this study was too small to find a significant difference between groups.

This was a very small study from a single center in China, and no statistical adjustments were made to account for confounding variables.
Abbreviations: ACEi=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blocker; CI=confidence interval; COVID-19=coronavirus disease 2019; GI=gastrointestinal; HR=hazard ratio; ICU=intensive care unit; NS=not significant; OR=odds ratio; RAAS=renin-angiotensin-aldosterone system.

Conclusion

Despite initial theoretical concerns, the available evidence from observational studies does not suggest that ACE inhibitors or ARBs are harmful in the context of COVID-19. Therefore, patients receiving these drugs for chronic conditions should continue to take them as prescribed during the COVID-19 pandemic. More studies are required to determine if ACE inhibitors and/or ARBs have a beneficial effect in patients with COVID-19. The evidence on this issue will continue to evolve as randomized controlled trials are conducted and the results of these trials are presented.

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Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

June 2020

The information presented is current as of May 13, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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