Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic ReviewFREE
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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.
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.
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).
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).
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
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Annals of Internal Medicine
Volume 173 • Number 3 • 4 August 2020
Pages: 195 - 203
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Published online: 15 May 2020
Published in issue: 4 August 2020
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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
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
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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
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.
Disclosures:
Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-0887.
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.
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.
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
Disclosures:
Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1293.
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
Disclosures:
Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-1515.
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
Disclosures:
Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1446.
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:
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.
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:
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.