ACE-I/ARB use and severity of disease

Clinical Question

What impact do ACE-I and ARBs have on SARS-CoV2 infection and severity of disease?

Key Findings

  • There is insufficient data to determine the effects of ACEIs/ARBs on COVID-19 disease severity and outcomes.
  • Since there is a well-known mortality benefit for ACE-I and ARBs in patients with cardiovascular disease, it is recommended to continue ACE-I and ARBs in all patients who are currently taking them until more is known.

Summary of Information

As previously known in the case of SARS, SARS-CoV2 has been shown to utilize ACE2 as a receptor for viral cell entry.[1] We know from prior studies in healthy animals that ACE-I and ARB use increases ACE2 expression and activity.[2] It has also been shown that patients taking the ARB olmesartan have been found to have increased secretion of ACE2 in urine.[3] Given that ACE2 plays a role in SARS-CoV2 infection, and many patients in the general population take ACE-I and ARBs, the question of how ACE-I or ARB use impacts SARS-CoV2 infection has become important to answer.

The need to answer this question of ACE-I/ARBs in SARS-CoV2 is underscored by the finding that in an analysis looking at 1099 patients with Covid-19 from Wuhan, patients with diabetes, hypertension, and CVD (the patients most likely to have prescriptions for chronic ACE-I and ARBs) were highly represented and were roughly three or four times more likely to reach the primary combined endpoint of use of mechanical ventilation, admission to ICU or death compared to patients without these comorbidities.[4] Unfortunately data on ACE-I or ARB use was not published in this analysis nor can causation be inferred from this retrospective study. Another retrospective cohort study of 112 patients with cardiovascular disease (defined as HTN, CHF and CAD) found that there was no difference in severity of disease or mortality among Covid-19 patients with and without ACE-I and ARB use.[5]

Currently given the lack of solid data, there has been much debate arguing for or against the use of ACE-I and ARBs in SARS-CoV2 infected patients. The rationale suggesting against the use of ACEIs/ARBs is based on the hypothesis that because treatment with ACE-I and ARBs upregulates ACE2, these patients could be at risk for increased viral entry and replication of SARS-CoV2.[2][3][6]

Alternatively, it has been proposed that ACE-I/ARBs may have a protective role. The ACE/Ang II pathway has been shown to have a causative role in lung failure in previous mice models of acid-induced lung injury.[7] A recent study of 12 cases of Covid-19 in Shenzhen, China positively correlated Ang II levels with COVID-19 viral load and severity of lung injury.[8] This leads to the rationale that perhaps ACEIs/AT1R inhibitors could inhibit the ACE/Ang II pathway to offer some protective benefit against lung injury.

The ACE2/Ang (1-7) pathway is thought to have a divergent effect from the ACE/Ang II pathway. Imai et al showed that ACE2 activity was protective against lung injury in mice models, in contrast to ACE/Ang II.[6] Sun, Yang, Sun et al hypothesize that COVID-19 binding ACE2 exhausts the ACE2/Ang (1-7) pathway. It should be noted that only their abstract is available in English[9] and their rationale may have been extrapolated from previous studies showing SARS-CoV downregulating ACE2 activity.[10] Theoretically, downregulation of the protective ACE2/Ang (1-7) pathway could lead to an imbalance of the ACE/Ang II pathway, leading to deleterious effects on lung function. Phadke and Saunik have also tentatively hypothesized that ACE-I and ARBs could block SARS-CoV2 from gaining viral entry via ACE2.[11]

While there are many theories, there is insufficient data to determine the effects of ACEIs/ARBs on COVID-19 disease severity and outcomes. The HFSA/ACC/AHA put out a joint official statement on 3/17/2020 recommending the continued use of ACE-I/ARBs t patients with cardiovascular disease to provide optimal cardiovascular care given the dearth of data for or against ACE-I and ARB use in COVID-19.[12] Kuster et al also argue continued given the well-known mortality benefit for ACE-I and ARBs in patients with cardiovascular disease. Thus they recommend continuing to prescribe ACE-I and ARBs in these patients until more is known.[13]

Early studies examining the relationship between COVID-19 severity and ACEI/ARB use includes a retrospective study out of China including 476 patients in three cities.[14] Patients were stratified into “moderate”, “severe”, and “critical” groups based on the 5th edition of the guidelines of the Diagnosis and Treatment of COVID-19 issued by the National Health Commission of China. There were more patients taking ACEI/ARB in the moderate compared with severe and critical groups. However, the authors acknowledge that this is a preliminary conclusion and more studies are required to examine the relationship between ACEI/ARB use and COVID-19 severity.

Another study out of China includes a retrospective study including 1128 patients with hypertension diagnosed with COVID-19 (188 patients taking ACEI/ARBs, 940 not taking ACEI/ARBs) at nine hospitals.[15] ACEI/ARB use was associated with lower-risk of all-cause mortality due to COVID-19 compared with non-ACEI/ARB use. However, the authors acknowledge that it is possible that unmeasured confounding factors may be present and instead, suggest that in-hospital use of ACEI/ARB was not associated with increased mortality in COVID-19. They also acknowledge that additional studies are required to examine the relationship between ACEI/ARB use and COVID-19 severity. It is also noted that exclusion criteria included a number of significant comorbidities.

Similarly, another recent retrospective study from China reported that patients with COVID-19 and essential hypertension taking ACE-I/ARBs (n=43) were less likely to develop critical disease (9.3% vs. 22.9%; p = 0.061) and had a lower mortality (4.7% vs. 13.3%; p = 0.283) than those patients with essential hypertension not taking an ACE-I/ARB (n=83). These investigators also reported lower levels of CRP and procalcitonin in the patients receiving an ACE-I/ARB compared to those who did not, suggesting a possible anti-inflammatory mechanism in COVID-19.[16]

Currently, many clinical trials have begun recruitment (as of 4/22/2020) looking at the effect of ACE-I/ARBs on COVID-19. There are two trials investigating losartan in outpatient and inpatient COVID-19 positive patients (NCT04311177 and NCT04312009, respectively). Another clinical trial is recruiting COVID-19 patients with primary hypertension who are already taking ACEi/ARB, aiming to randomize them to an alternative BP medication or continue with the ACEi/ARB that they have already been prescribed (NCT04330300). Similarly, a randomized clinical trial is investigating the impact of continuation vs. discontinuation of ACE-I/ARBs in hospitalized COVID-19 patients (NCT04338009). A clinical trial, since withdrawn, proposed to explore the therapeutic use of soluble recombinant ACE2, based on the rationale that recombinant ACE2 may be able to competitively inhibit COVID-19 binding (NCT04287686).

Author Information

Authors: Daniel Wang MS4 and Ritika Prasad MS4, UC San Diego School of Medicine
Completed date: March 23, 2020
Last updated on: April 22, 2020

Reviewed by: Gary Smithson MD
Reviewed on: April 14, 2020

This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego. For more information about the project, please visit http://earth2-covid.ucsd.edu

References

  1. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-280.e8.  [PMID:32142651]
  2. 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(20):2605-10.  [PMID:15897343]
  3. Furuhashi M, Moniwa N, Mita T, et al. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens. 2015;28(1):15-21.  [PMID:24842388]
  4. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020.  [PMID:32109013]
  5. Peng YD, Meng K, Guan HQ, et al. [Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV]. Zhonghua Xin Xue Guan Bing Za Zhi. 2020;48(0):E004.  [PMID:32120458]
  6. Diaz JH. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Travel Med. 2020.  [PMID:32186711]
  7. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112-6.  [PMID:16001071]
  8. Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364-374.  [PMID:32048163]
  9. Sun ML, Yang JM, Sun YP, et al. [Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(0):E014.  [PMID:32061198]
  10. 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(8):875-9.  [PMID:16007097]
  11. Phadke MA, Saunik S. Use of angiotensin receptor blockers such as Telmisartan, Losartsan in nCoV Wuhan Corona Virus infections – Novel mode of treatment. April 2020. https://www.bmj.com/content/368/bmj.m406/rr-2. Accessed April 16, 2020.
  12. HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19. Published March 17, 2020. Accessed April 22, 2020.
  13. Kuster GM, Pfister O, Burkard T, et al. SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Eur Heart J. 2020.  [PMID:32196087]
  14. Feng Y, Ling Y, Bai T, et al. COVID-19 with Different Severity: A Multi-center Study of Clinical Features. Am J Respir Crit Care Med. 2020.  [PMID:32275452]
  15. 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. Circ Res. 2020.  [PMID:32302265]
  16. Yang G, Tan Z, Zhou L, et al. Angiotensin II Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors Usage is Associated with Improved Inflammatory Status and Clinical Outcomes in COVID-19 Patients With Hypertension. medRxiv. April 2020. doi:10.1101/2020.03.31.20038935
Last updated: April 30, 2020