Use of ACE inhibitors and ARBs in COVID-19 patients

ACE: Angiotensin Converting Enzyme Inhibitors; ARBs: Angiotensin II Receptor Blockers 

Version 1: 19-03-2020

Current Guidelines are quite clear, the consensus is to continue with ACE inhibitors and ARBs, see table below for details:[1]

The source of controversy is that ACE inhibitors and ARBs have been shown to cause upregulation of ACE2 in animal models.[2]

ACE2 is the cellular receptor for the SARS-CoV-2 virus.[2] Thus it is hypothesized that ACE inhibitors and ARBs may increase virulence of SARS-CoV-2 virus.[2] Clinical evidence that supports this is hypertension, diabetes, Coronary Artery Disease (CAD) and Cerebrovascular Disease are the most frequently reported comorbidities in COVID-19 studies, overall and specifically they were more highly reported in groups of patients who are non-survivors or those with a more severe clinical course.[3] It is assumed that these patients would have been on ACE inhibitors and/or ARBs but this data has not been explicitly reported.[3]

Additionally, hazard ratios (not adjusted for age) of 3.05 (95% CI of 1.6 – 5.9)[4] and 1.7 (0.92 – 3.13)[5] for hypertension and mortality have been reported. Similarly elevated hazard ratios (not adjusted for age) have been reported for CAD and diabetes as well.[4] Again, the elevated risk is hypothesized to be mediated by ACE inhibitors and/or ARB use. Calcium Channel Blockers (CCBs) have been suggested as an alternative as they do not elevate ACE2,[3] but guidelines do not recommend this yet as definitive data is lacking.

Some evidence supporting continued use comes from animal studies which show high levels of ACE2 protect against lung parenchymal damage suggesting ACE inhibitors and ARBs might actually be protective through upregulation of ACE2.[6] There is also research from mouse models of SARS-CoV-1, which also relies on ACE2 to enter the cell, that indicate a protective role for ARBs and so it is being considered as a potential therapeutic.[7]

Thus, ACE inhibitors and ARBs may be harmful, beneficial or completely neutral, at this point it is unclear, more data is needed. This is an evolving area of research, and while guidelines currently recommend continuation of ACE inhibitors and ARBs, they may change.

More details and updates can be found here:

 

http://www.nephjc.com/news/covidace2.

 

References

1.        Sparks, M. & Swapnil, H. The Coronavirus Conundrum: ACE2 and Hypertension. NephJC (2020). Available at: http://www.nephjc.com/news/covidace2.

2.        Wan, Y., Shang, J., Graham, R., Baric, R. S. & Li, F. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus. J. Virol. 94, e00127-20 (2020).

3.        Fang, L., Karakiulakis, G. & Roth, M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir. 2600, 30116 (2020).

4.        Zhou, F. et al. Articles Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan , China : a retrospective cohort study. Lancet (2020). doi:10.1016/S0140-6736(20)30566-3

5.        Wu, C. et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern. Med. (2020). doi:10.1001/jamainternmed.2020.0994

6.        Sun, M. L., Yang, J. M., Sun, Y. P. & Su, G. H. [Inhibitors of RAS Might Be a Good Choice for the Therapy of COVID-19 Pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi (2020). doi:10.3760/cma.j.issn.1001-0939.2020.0014

7.        Kuba, K. et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat. Med. 11, 875–879 (2005).

Additional Useful Links:

https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang

https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30116-8/fulltext

https://www.youtube.com/watch?v=1vZDVbqRhyM

Appendix: 

Aiche, Stephan. (2013). Inferring Proteolytic Processes from Mass Spectrometry Time Series Data. Retrieved from: https://www.researchgate.net/figure/The-renin-angiotensin-system-The-precursor-protein-Angiotensinogen-is-targeted-by-the_fig1_277716129

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