Angiotensin Receptor Blockers

Last Review Performed on: May 3rd, 2020

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.

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.

Preclinical Models of SARS

COVID-19

  • Liu et al (reference 2a, above) 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 Of note, this study has not yet been peer-reviewed and should be evaluated cautiously.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)

  • In a separate analysis Liu et al (reference 3a, above) 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 below)

Mouse models of SARS treated with Losartan associated with 33% reduced lung injury.

Kuba et al, Nature Medicine, 2005

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

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).

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.

Current clinical trials underway

  1. ACE Inhibitors, Angiotensin II Type-I Receptor Blockers and Severity of COVID-19

    1. Not yet recruiting, Italy

  2. Coronavirus ACEi/ARB Investigation (CORONACION)

    1. Recruiting, Ireland

  3. Hypertension in Patients Hospitalized With COVID-19

    1. Completed, China

  4. ACE Inhibitors or ARBs Discontinuation in Context of SARS-CoV-2 Pandemia

    1. Recruiting, France

  5. Renin-Angiotensin System Inhibitors and COVID-19

    1. Recruiting, Italy

  6. Comparison Of Therapeutics for Hospitalized Patients Infected With SARS-CoV-2 In a Pragmatic aDaptive randoMizED Clinical Trial During the COVID-19 Pandemic (COVID MED Trial)

    1. Recruiting, New York, USA

  7. Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19

    1. Not yet recruiting

  8. Losartan for Patients With COVID-19 Requiring Hospitalization

    1. Recruiting, University of Minnesota

  9. Losartan for Patients With COVID-19 Not Requiring Hospitalization

    1. Recruiting, University of Minnesota

  10. The Fleming [FMTVDM] Directed CoVid-19 Treatment Protocol (FMTVDM)

    1. Enrolling by invitation, California

  11. Study of Open Label Losartan in COVID-19

    1. Recruiting, Kansas

  12. Long-term Use of Drugs That Could Prevent the Risk of Serious COVID-19 Infections or Make it Worse (TRAPSAH)

    1. Not yet recruiting, France

  13. Coronavirus Response - Active Support for Hospitalised Covid-19 Patients (CRASH-19)

    1. Not yet recruiting, Nigeria

  14. Do Angiotensin Receptor Blockers Mitigate Progression to Acute Respiratory Distress Syndrome With SARS-CoV-2 Infection

    1. Recruiting, California

  15. Telmisartan for Treatment of COVID-19 Patients

    1. Recruiting, Argentina

Major studies

    1. Liu Y, Huang F, Xu J, et al. Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients. MedRxIV. (made available prior to peer review) https://www.medrxiv.org/content/10.1101/2020.03.20.20039586v1.

    2. 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.

Studies describing the potential mechanism of action in severe disease causing 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. https://doi.org/10.1007/s11427-020-1643-8

  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.