Angiotensin Receptor Blockers

Last review completed on
June 1st, 2022
Therapy Description

Hypotheses have emerged that AT1R blockers such as losartan may work to mitigate the symptoms of COVID-19 (SARS-CoV-2) infection. Competing hypotheses are that it will make the symptoms worse.


Patients who are not enrolled in a clinical trial for ACEI or ARB therapy should have their medication continued as appropriate for approved indications (hypertension, cardioprotection after myocardial infarction or heart failure, etc). No modifications should be made to ACEI/ARB therapy related to COVID-19 unless warranted by the patient’s clinical condition. 

The current recommendation from multiple medical societies is not to discontinue ACEi/ARBs in the setting of COVID-19 (see below).

Clinical Circumstances
Level of Evidence
= Supporting use article = Neutral Article  = Contradicting use article

Step 1 - In vitro SARS CoV-1/2 and MERS-CoV Step 2 - In vivo MERS-CoV
Step 3 - In vivo SARS CoV-2

List of Evidence/ Discussion

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List of major peer-reviewed studies, and type of study (preclinical, human study, etc.):

  1. Supporting Use article Liu Y, Huang F, Xu J, et al. Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients. MedRxIV. (made available prior to peer review).
  2. Supporting Use article Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005;11:875-879.
  3. Supporting Use article Zhang P, Zhu L, Cai J, et al. Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19 [published online ahead of print, 2020 Apr 17]. Circ Res. 2020;10.1161/CIRCRESAHA.120.317134.
  4. Li J, Wang X, Chen J, Zhang H, Deng A. Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China [published online ahead of print, 2020 Apr 23]. JAMA Cardiol. 2020;e201624.
  5. Supporting Use article Bean DM, Kraljevic Z, Searle T, et al. Treatment with ACE-inhibitors is associated with less severe disease with SARS-Covid-19 infection in a multi-site UK acute Hospital Trust.
  6. Tedeschi S, Giannella M, Bartoletti M, et al. Clinical impact of renin-angiotensin system inhibitors on in-hospital mortality of patients with hypertension hospitalized for COVID-19 [published online ahead of print, 2020 Apr 27]. Clin Infect Dis. 2020;ciaa492.
  7. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19 [published online ahead of print, 2020 May 1]. N Engl J Med. 2020;NEJMoa2008975.
  8. Meng J, Xiao G, Zhang J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect 2020;9:757-760.
  9. Supporting Use article M.A. Puskarich, N.W. Cummins, N.E. Ingraham, et al. A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19. EClinicalMedicine, 37 (2021), p. 100957.
  10. Supporting Use article Puskarich MA, Ingraham NE, Merck LH, et al. Efficacy of Losartan in Hospitalized Patients With COVID-19–Induced Lung Injury. JAMA Network Open. 2022; 5 (3): e222735.

Studies describing the potential mechanism of action in severe disease caused by SARS CoV-2.

  1. Liu, Y., Yang, Y., Zhang, C., Huang, F., Wang, F., Yuan, J., Wang, Z., Li, J., Li, J., Feng, C., et al. (2020). Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci 63, 364–374.
  2. Ocaranza MP, Godoy I, Jalil JE, et al. Enalapril attenuates downregulation of angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension 2006;48:572-578.
  3. Burchill LJ, Velkoska E, Dean RG, Griggs K, Patel SK, Burrell LM. Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions. Clin Sci (Lond) 2012;123:649-658.
  4. Vuille-dit-Bille RN, Camargo SM, Emmenegger L, et al. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids 2015;47:693-705.
  5. Soler MJ, Ye M, Wysocki J, William J, Lloveras J, Batlle D. Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan. Am J Physiol Renal Physiol 2009;296:F398-F405.
  6. Ishiyama Y, Gallagher PE, Averill DB, Tallant EA, Brosnihan KB, Ferrario CM. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension 2004;43:970-976.
  7. Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005; 111:2605–2610.
  8. Dijkman R, Jebbink MF, Deijs M, et al. Replication-dependent downregulation of cellular angiotensin-converting enzyme 2 protein expression by human coronavirus NL63. J Gen Virol 2012;93:1924-1929.
  9. Yang P, Gu H, Zhao Z, et al. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep 2014;4:7027-7027.
  10. Khan A, Benthin C, Zeno B, et al. A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Crit Care 2017;21:234-234.
  11. Gu H, Xie Z, Li T, et al. Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus. Sci Rep 2016;6:19840-19840.
  12. Oudit GY, Kassiri Z, Jiang C, et al. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest 2009;39:618-625.


Do angiotensin receptor blocking medications and ACE inhibitors increase ACE2 expression and increase SARS-CoV-2 virulence?

  • This speculation has been frequently cited on news outlets, social media, and even in various medical journals.20 Some studies have even suggested that angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEi) should be discontinued in patients with COVID-19. This is based upon the fact that in animal models, ACEi and ARB have been shown to increase ACE2 mRNA and protein expression in certain organs, predominantly the heart and kidneys.21,22 However, this hypothesis has several limitations, including no definitive evidence of the drugs affected lung ACE2 expression, and it does not bear out given preclinical knowledge from SARS-CoV.
Level 2: In vivo MERS CoV articles listed below Preclinical Models of SARS

Supporting Use article  Kuba et al. identified significantly mouse models of SARS treated with losartan (AT1 inhibitor) had 33% reduced lung injury (see figure 1) and significantly reduced pulmonary edema.

Figure 1 from Kube et al article
Level 4: Observational SARS CoV-2 articles listed below Observational SARS CoV-2
  • Supporting Use article  Liu et al evaluated over 500 patients aged 65+ with COVID-19 and a past medical history of hypertension. Of note, this study has not yet been peer-reviewed and should be evaluated cautiously.
    • They broke patients into 6 cohorts (ACEi, ARBs, beta blockers, calcium channel blockers, thiazide diuretics, none).
    • Univariate analysis: ARB use was associated with significantly reduced odds for the development of severe COVID-19 (OR 0.34, p = 0.025)
    • Multivariable analysis: ARB use was associated with significantly reduced odds for the development of severe COVID-19 (OR 0.25, p = 0.046)
  • Supporting Use article  In a separate analysis Liu et al also identified Angiotensin II levels in plasma from COVID-19 patients was markedly elevated and linearly associated with viral load and lung injury (See figure 2) 

Charts of results from Mouse models of SARS treated with losartan associated with 33% reduced lung injury

Figure 2

Some have hypothesized that ARBs and ACEi should be discontinued in patients with COVID-19 due to upregulation of ACE2 (the binding protein from SARS-CoV-2)

Additionally, patients on chronic angiotensin receptor blockers have increased gene expression for AT1R. Abrupt cessation may place them at increased risk for AT1R mediated inflammation.

Healthy vs COVID-19 interactions on the renin-angiotensin system

Telmisartan Discussion

This is a preliminary report of interim data and is a pre-peered review publication. This randomized, two-arm, open, multicenter trial evaluated the use of telmisartan 80mg BID plus standard care (n=40) for 14 days vs standard care alone (n=38) in adult patients who have been hospitalized with PCR-confirmed Covid-19 infection with 4 or fewer days elapsed since symptom onset.  Primary outcomes are CRP levels at day 5 and day 8. Secondary outcomes: ICU admission, occurrence of mechanical ventilation, LDH levels, hospital discharge, evaluation occurred at day 15 and 30.  

Primary outcomes of this interim analysis have shown that patients in the telmisartan group had a lower CRP serum level than patients in the control group at day 5 (Telmisartan 24.2+/- 31.4mg/L (n=32) compared with control 51.1+/- 44.8mg/L (n=28) p<0.05 and at day 8 (Telmisartan 9.0 +/- 10.0mg/L (n=13) compared with control 41.6 +/- 47.6mg/L (n=16) p<0.05. 

Secondary outcomes have shown a median discharge time of 9 days for the telmisartan group compared with 15 days in those receiving standard of care. By day 30, there were 2 out of 38 deaths in the telmisartan group compared with 4 out of 34 patients in the control group (p=0.41). No differences were observed for ICU admission, mechanical ventilation, death or composite outcome of the first occurence of ICU admission, mechanical ventilation, or death at day 15 or 30. Patients needing supplemental oxygen at day 15 was significantly higher in the control group (13 out of 14 patients) compared to the telmisartan group (2 out of 4 patients) p<0.05. LDH levels at day 5 and 8 did not reach statistical significance at day 5. 

This study shows that the ARB, telmisartan, was able to significantly reduce the inflammatory marker, CRP, in patients hospitalized with Covid-19. There was also a tendency towards a reduction in hospitalization days.

Losartan Discussion

Level 5: Random Controlled Trial SARS CoV-2 articles listed below Randomized Control Trials for Losartan:

  1. Supporting Use article  M.A. Puskarich, N.W. Cummins, N.E. Ingraham, et al. A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19. EClinicalMedicine, 37 (2021), p. 100957

    This placebo-controlled, blinded, randomized clinical trial (RCT) set out to test the efficacy of losartan in outpatients with COVID-19 across three health-systems between April and November 2020.

    Patients were randomized 1:1 to receive either losartan 25 mg orally twice daily (N=58) versus placebo (N=59) for 10 days (dose was reduced to once daily for eGFR<30ml/min.) The primary objective was to test if losartan treatment decreased hospitalization during the 15 days following enrollment. Secondary outcomes sought to determine if losartan improves self-reported dyspnea, functional status, or fever. Secondary outcomes included COVID-19 related emergency department or clinic presentations, ventilator free days, and death.

    Of the 117 patients enrolled in the trial, only 4 patients (3.4%) met the primary outcome of all-cause hospitalization at or before day 15, lower than the expected rate of 11% (15% in the control vs. 7% hypothesized in the treatment group), all occurring before August 15, 2020. The authors did not observe a statistically significant difference in the primary outcome between the arms, with 3 events in the losartan arm (5.2%; 95% CI 1.1, 14.4%) versus 1 in the placebo arm (1.7%; 95% CI 0.0, 9.1%), corresponding to an absolute difference of -3.5% (95% CI -13.2, 4.8%; p = 0.320) favoring placebo. Secondary outcomes showed no difference in hospitalizations. Only 1 patient in each arm was admitted to the ICU and zero died.

    Due to the low primary efficacy event rate, decreased rate of enrollment due to decreased local COVID-19 positivity rates, and the low enrollment of participants due to the development of new treatments and pending availability of vaccines, the trial was terminated early by the investigators prior to treatment allocation unblinding. While underpowered and not statistically significant, it should be noted that in terms of both hospital admission and any healthcare encounter, placebo outperformed losartan, and a risk of harm cannot be ruled out. Surrogate indicators of lung injury (dyspnea and functional status) and inflammation (temperature) do not support significant impact on these mechanisms of action. It is unlikely losartan affects a clinically significant reduction in hospitalization of low-risk outpatients with COVID-19.

  2. Supporting Use article Puskarich MA, Ingraham NE, Merck LH, et al. Efficacy of Losartan in Hospitalized Patients With COVID-19–Induced Lung Injury. JAMA Network Open. 2022; 5 (3): e222735

    This prospective, blinded, and placebo-controlled randomized clinical trial of hospitalized patients with COVID-19 was conducted at 13 hospitals in the United States from April 2020 to February 2021. Hospitalized patients with PCR positive COVID-19 and a SOFA score of at least 1 were eligible for participation. Patients receiving RAAS inhibitors prior to admission, had a history of adverse reactions to ACEI or ARBs, history of kidney or liver disease, were pregnant or breastfeeding, or had a serum potassium level >5 meq/L were excluded from the study.

    This trial compared losartan 50mg PO BID vs placebo for 10 days or until hospital discharge. The primary outcome was the worst measured PaO2:FiO2 ratio on day 7. Secondary outcomes included: 7-point ordinal COVID-19 severity score, time to discharge, oxygen, ventilation, or vasopressors free days, and 28-day mortality. In addition to the clinical outcomes studied, pharmacokinetic and RAAS component measurements were collected for Angiotensin II (AII), angiotensin 1-7, and angiotensin-converting enzymes 1 and 2 in a subset of participants.

    205 patients were enrolled. 101 patients were randomized to receive losartan and included in the intent to treat analysis. 104 were randomized to receive placebo and included in the intent to treat analysis. The primary outcome: Pao2: Fio2 ratio did not differ between the groups. (median [IQR], 297 [196-366] vs 297 [130-366]). When reviewing the secondary outcomes the authors observed no difference in time to hospital discharge or in-hospital mortality. By day 28, 11 participants (10.6%) in the intervention group died vs 9 participants (8.9%) in the placebo group (11 participants in each group by day 90). There were no differences in oxygen or  mechanical ventilation free days in the first 10 days following randomization, and the ordinal outcome did not differ between treatment groups. More patients in the losartan group required vasopressors (20 vs 11) contributing to more vasopressor free days in the placebo arm. There was not a statistically different number of adverse events between the two groups, although a numerically higher number of cardiovascular SAEs were noted in the losartan group. Acute kidney injury was more common in the interventionl group (20 patients [19.4%] vs 9 patients [8.8%]; P = .04). There was no viral load difference observed between the treatment groups. When evaluating the pharmacokinetic data, there was no losartan or carboxylosartan in any placebo treated participant, while losartan and carboxylosartan pharmacokinetics were consistent with expected values in those treated with losartan.

    Despite a moderate to severely ill cohort, well-matched baseline Pao2:Fio2 ratios, and pharmacologically relevant steady state concentrations, the authors found no evidence that treatment with losartan improved lung injury or clinical outcomes, nor significantly affected major circulating RAAS components.

Society Recommendations

List of Recommendations from Various Societies

List of Societies and Various recommendations regarding ACE/ARB use