consensus statement ARB and ACE

• Dr. Matt Dawes, Cardiovascular Physician/Clinical Pharmacologist, Auckland DHB and Sr lecturer, University of Auckland
• A/Prof James Fisher, Department of Physiology, University of Auckland
• Prof Julian Paton, Director, Manaaki Mānawa – The Heart Research Centre, and Department of Physiology, University of Auckland
• Dr. Kannaiyan Rabindranath, Consultant Nephrologist, Waikato DHB
• Dr. Sharen Supershad, Consultant Nephrologist, Northland DHB
• Dr. Hari Talreja, Consultant Nephrologist, Counties Manukau DHB
• Dr. Jasmine Tan, Consultant Nephrologist, Waitematā DHB
• Dr. Sajed Valappil, Consultant Nephrologist, Waitematā DHB
• Dr. Walter van der Merwe, Consultant Hypertension Specialist, The Hypertension Clinic, Auckland
• Ms. Veronica van der Merwe, Nurse specialist, The Hypertension Clinic, Auckland
• Ms. Lisa Wong, Research Operations Manager, Manaaki Mānawa – The Heart Research Centre

The consensus has also been supported by Professor Rob Doughty (Heart Foundation Chair, ADHB, University of Auckland).

There has been an unprecedented interest generated in the medical fraternity and on social media around the interaction of Coronavirus (SARS-CoV2) and ACE inhibitors (ACEi) and angiotensin receptor blockers (ARB), and whether these medications increase the risk of COVID-19.

This was triggered by correspondences published in well-known medical journals, Lancet Respiratory Medicine and BMJ.^1,2  They observe that the COVID-19 patients with comorbidities such as hypertension, diabetes, cardiovascular disease had more severe disease. The authors hypothesized that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19. They suggest that ACEi and ARB can increase ACE2 enzyme, which is a receptor used by the virus to gain entry into the host cells. Therefore, these drugs could potentially increase the risk of severe infection.

We reviewed the evidence supporting this theory, and would like to make the following observations:

1. The studies from China report higher prevalence of hypertension in those who developed severe COVID-19 disease.^3,4  However, a conclusion cannot be drawn that hypertension results in severe infection as these are analyses were unadjusted for confounders such as age, and there was no reported data on ACEi and ARB use in these studies.
2. The authors suggest that ACEi and ARB upregulate ACE2 enzyme that enhances infectivity of the SARS CoV2 virus based on a few animal studies.⁵  However, other animal and human studies did not find any association of circulating ACE2 levels with the use of ACEi or ARBs.^6,7Therefore, it is questionable whether these drugs increase ACE2 concentration in lungs and kidneys to allow severe viral infection.
3. To the contrary, there is some evidence that ACEi might actually confer some protection in viral pneumonias.⁸ Based on similar hypothesis, there are on-going trials studying the effect of Losartan (ARB) in patients with COVID-19 in outpatient and inpatient settings.^9,10

Therefore, based on the currently available evidence, we DO NOT advise patients on ACEi or ARB to change therapy. These commonly used medications confer benefits in patients with cardiovascular disease and diabetes, and should not be changed unless clinically indicated. The current evidence on COVID-19 and hypertension/ ACEi or ARB in humans is inadequately adjusted and prone to bias, and therefore remains inconclusive.

Our recommendation is consistent with the viewpoint of numerous societies from around the world including the European Society of Cardiology, the International Society for Hypertension, European Renal Association and European Dialysis and Transplant Association.

References:

1. Fang L, Karakiulakis G, Roth M. (2020). Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?  Lancet Respir Med. 2020 Mar 11;  doi: 10.1016/S2213-2600(20)30116-8. [Epub ahead of print]
2. Sommerstein R. Re: Preventing a covid-19 pandemic: ACE inhibitors as a potential risk factor for fatal Covid-19. BMJ 2020;368:m810
3. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020; published  online Feb 24. https://doi.org/10.1016/S2213-2600(20)30079-5.
4. Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; published online Feb 28. DOI:10.1056/NEJMoa2002032.
5. 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 May 24;111(20):2605-10. Epub 2005 May 16.
6. Burrell L, Risvanis J, Kubota E, et al. Myocardial infarction increases ACE2 expression in rat and humans, European Heart Journal, Volume 26, Issue 4, February 2005, Pages 369–375, https://doi.org/10.1093/eurheartj/ehi114
7. Walters TE, Kalman JM, Patel SK et al. Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling. Europace. 2017 Aug 1;19(8):1280-1287. doi: 10.1093/europace/euw246.
8. Henry C, Zaizafoun M, Stock E et al. Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia. Proc (Bayl Univ Med Cent). 2018 Oct 26;31(4):419-423. doi: 10.1080/08998280.2018.1499293.
9. Randomized Controlled Trial of Losartan for Patients With COVID-19 Not Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04311177
10. Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization. ClinicalTrials.gov Identifier: NCT04312009.