Steven T. Haywood MD
ACEi and ARB in COVID-19?
So far from the data coming out of Italy and China, patients with a history of hypertension have worse outcomes when they are diagnosed with COVID-19. (1, 2) Biochemists have discovered that COVID 19 uses angiotensin converting enzyme 2 (ACE2) as an entry point into cells (3, 4). Because of these two findings, some have postulated that medications that interact with the Renin Angiotensin Aldosterone System (RAAS) such as Angiotensin Converting Enzyme Inhibitors (ACEi) or an Angiotensin Receptor Blockers (ARB) may be the culprit for the worse outcomes in patients with hypertension. Here is a very simplified version of part of the RAAS.
When we add an ACEi, it makes sense that the levels of ACE 2 would increase as the levels of Angiotensin II decreased, which is the substrate for ACE 2.
However, an ARB theoretically should increase the levels of ATII therefore decreasing the levels of ACE 2 since it has more substrate to interact.
Some animal models do show an increase in the levels of ACE2 after administration of an ACEi and an ARB (5, 6, 7, 8) while others show no increase (9). In human trials, the effect of ACEi and ARB and ACE 2 is unclear. Some studies show no difference (9, 10). Other studies have shown increases in ACE 2 levels only with some RAAS medications (11, 12). None of these studies looked at patient centered outcomes. They are simply looking at the amount of an enzyme that may or may not predict the severity of the disease course.
Multiple professional organizations such as the American Heart Association and the European Society of Cardiology have made strong recommendations for patients to stay on their antihypertensives at this time based on the benefits we know they convey. There is danger in spreading word to the general public that these medications may worsen COVID-19 infections. We do not want patients to stop their treatment for chronic hypertension. At this time, we should tell our patients to continue taking any ACEi or ARB that has been prescribed to them by their primary care physician.
Zhou F et al. Clinical Course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020 Mar 11 pii: S0140-6736(20)30566-3.
Remuzzie A et al. COVID-19 and Italy: what next? Lancet 13 Mar 2020
Zhou P et al
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Ferrario C 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
Ocaranza et al. Enalapril Attenuates Downregulation of Angiotensin-Converting Enzyme 2 in the Late Phase of Ventricular Dysfunction in Myocardial Infarcted Rat. Hypertension. 2006 Oct;48(4):572-8. Epub 2006 Aug 14.
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Soler et al. Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan.Am J Physiol Renal Physiol. 2009 Feb;296(2):F398-405. Epub 2008 Nov 12.
Burrell et al. Myocardial infarction increases ACE2 expression in rat and humans.Eur Heart J. 2005 Jun;26(11):1141; author reply 1141-3. Epub 2005 Apr 15.
Ramchand et al. Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease.PLoS One. 2018 Jun 13;13(6):e0198144.
Furuhashi et al. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker.Am J Hypertens. 2015 Jan;28(1):15-21.
Vuille-dit-Bille RN, et al. Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors. Amino Acids. 2015 Apr;47(4):693-705.