Antihypertensive drugs and risk of COVID-19?
Authors: Christopher J Tignanelli, Nicholas E Ingraham, Matthew A Sparks, Ronald Reilkoff, Tamara Bezdicek, Bradley Benson, Timothy Schacker, Jeffrey G Chipman, Michael A Puskarich
Journal: The Lancet Respiratory Medicine (2020)

Lei Fang and colleagues1Fang L Karakiulakis G Roth M Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.Lancet Respir Med. 2020; (published online March 11.)https://doi.org/10.1016/S2213-2600(20)30116-8Summary Full Text Full Text PDF Scopus (2084) Google Scholar suggest that clinicians should consider withholding angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) because of a potential increased risk of worse clinical outcomes in patients with coronavirus disease 2019 (COVID-19), and they suggest calcium channel blockers as an alternative. The hypothesis behind this suggestion is that the entry point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the ACE2 receptor and that ACEIs and ARBs have the potential to upregulate ACE2. However, data for this mechanism are largely from animal studies of heart tissue. Human data have not consistently shown increased ACE2 levels.2Ramchand J Patel SK Srivastava PM Farouque O Burrell LM 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; 13e0198144Crossref PubMed Scopus (140) Google Scholar, 3Walters TE Kalman JM Patel SK Mearns M Velkoska E Burrell LM 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; 19: 1280-1287PubMed Google Scholar This premature hypothesis has generated confusion across various media channels and in the medical community. Some medical centres have suggested withholding renin–angiotensin system (RAS) inhibitors, despite calls from international societies (eg, the European Society of Cardiology, Hypertension Canada, The Canadian Cardiovascular Society, UK Renal Association, and the International Society of Hypertension) urging against such action. Fang and colleagues based their hypothesis on unadjusted observational data and proposed that patients with hypertension are at increased risk of mortality from COVID-19, attributable to ACE2 as the binding protein for SARS-CoV-2. Although unadjusted observational data suggest that patients with hypertension are at increased risk of mortality, no data are available for the blood pressure regimen of patients with more severe or fatal COVID-19.4Wang D Hu B Hu C et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.JAMA. 2020; 323: 1061-1069Crossref PubMed Scopus (16201) Google Scholar It is equally plausible that patients with hypertension have an overactive RAS, placing them at increased risk for pulmonary complications from COVID-19 in view of the counter-regulatory role of ACE2 on activated RAS. It is also important to distinguish between use of ACEIs and ARBs, because these drugs could have differential effects on RAS components. Similar to severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2 binds with the ACE2 receptor for intracellular invasion, and the mechanism for acute lung injury during infection has been postulated to be mediated through activation of RAS.5Li W Moore MJ Vasilieva N et al.Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.Nature. 2003; 426: 450-454Crossref PubMed Scopus (4540) Google Scholar In several studies, RAS blockade has been proposed as a potential treatment for COVID-19 (figure).6Gurwitz D Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.Drug Dev Res. 2020; (published online March 4.)DOI:10.1002/ddr.21656Crossref PubMed Scopus (610) Google Scholar Angiotensin 2 (AT2) primarily activates the type 1 angiotensin 2 receptor (AT1R), which potentially mediates pulmonary inflammation, fibrosis, and oedema.7Kuba K Imai Y Rao S Jiang C Penninger JM Lessons from SARS: control of acute lung failure by the SARS receptor ACE2.J Mol Med. 2006; 84: 814-820Crossref PubMed Scopus (117) Google Scholar ACE2 activation results in low amounts of AT2 and increased production of the anti-inflammatory heptapeptide angiotensin(1-7). Impaired ACE2 activity results in excessive amounts of AT2, allowing for unopposed activation of AT1R and subsequent development of acute respiratory distress syndrome (ARDS).5Li W Moore MJ Vasilieva N et al.Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.Nature. 2003; 426: 450-454Crossref PubMed Scopus (4540) Google Scholar, 8Kuba 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: 875-879Crossref PubMed Scopus (2650) Google Scholar Fang and colleagues postulate that patients with SARS-CoV-2 treated with ARBs and ACEIs are at a higher risk for severe COVID-19 infection because of a potential upregulation of ACE2. However, preclinical models of SARS-CoV infection do not support this hypothesis. In 2005, Kuba and colleagues8Kuba 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: 875-879Crossref PubMed Scopus (2650) Google Scholar found that mice treated with losartan after acid aspiration-induced acute lung injury (with addition of SARS-CoV spike protein) had significantly diminished lung injury and pulmonary oedema compared with mice treated with placebo.8Kuba 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: 875-879Crossref PubMed Scopus (2650) Google Scholar Furthermore, recombinant human ACE2 infusions or losartan both prevented severe lung injury and pulmonary oedema in ACE2-knockout mice.9Imai Y Kuba K Rao S et al.Angiotensin-converting enzyme 2 protects from severe acute lung failure.Nature. 2005; 436: 112-116Crossref PubMed Scopus (2010) Google Scholar Administration of recombinant human ACE2 improved lung injury in patients with SARS-CoV infection and in acid aspiration and sepsis-induced models of ARDS.8Kuba 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: 875-879Crossref PubMed Scopus (2650) Google Scholar, 9Imai Y Kuba K Rao S et al.Angiotensin-converting enzyme 2 protects from severe acute lung failure.Nature. 2005; 436: 112-116Crossref PubMed Scopus (2010) Google Scholar This premise supports the initiation of randomised controlled trials assessing recombinant human ACE2 infusions and losartan in patients with COVID-19. Severe ARDS secondary to impaired ACE2 activity has been identified in other viral pneumonias (eg, H5N1 and H7N9 influenza).10Zou Z Yan Y Shu Y et al.Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections.Nat Commun. 2014; 53594Crossref PubMed Scopus (319) Google Scholar Treatment of mice after infection with H5N1 influenza with losartan versus placebo was associated with reduced pulmonary oedema, pulmonary neutrophil infiltration, and significantly improved survival.10Zou Z Yan Y Shu Y et al.Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections.Nat Commun. 2014; 53594Crossref PubMed Scopus (319) Google Scholar Although controversy exists about the role of RAS inhibition in COVID-19, no evidence is available to support routine discontinuation of ACEIs or ARBs. Preclinical evidence suggests that RAS blockade might attenuate progression of COVID-19. We argue that clinical equipoise exists and, before the medical community makes recommendations for patients to withhold potentially life-saving drugs, there is a critical and urgent need for multicentre trials to test this hypothesis in patients with COVID-19. Related links•The latest guidance from WHO on ibuprofen and COVID-19 (dated: 19.03.2020)•Statement from Prof Michael Roth on how to interpret the original letter •The latest guidance from WHO on ibuprofen and COVID-19 (dated: 19.03.2020)•Statement from Prof Michael Roth on how to interpret the original letter We declare no competing interests. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?The most distinctive comorbidities of 32 non-survivors from a group of 52 intensive care unit patients with novel coronavirus disease 2019 (COVID-19) in the study by Xiaobo Yang and colleagues1 were cerebrovascular diseases (22%) and diabetes (22%). Another study2 included 1099 patients with confirmed COVID-19, of whom 173 had severe disease with comorbidities of hypertension (23·7%), diabetes mellitus (16·2%), coronary heart diseases (5·8%), and cerebrovascular disease (2·3%). In a third study,3 of 140 patients who were admitted to hospital with COVID-19, 30% had hypertension and 12% had diabetes. Full-Text PDF Antihypertensive drugs and risk of COVID-19?Lei Fang and colleagues1 extrapolated results from a molecular study of coronaviruses, which showed that this group of viruses uses angiotensin-converting enzyme 2 (ACE2) to target cells on the epithelium of the lungs, intestine, kidneys, and blood vessels.2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), would probably share these properties. Full-Text PDF Antihypertensive drugs and risk of COVID-19?Lei Fang and colleagues1 postulate that because severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor to facilitate host cell entry,2,3 disease severity and mortality of coronavirus disease 2019 (COVID-19) might be increased in patients taking angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) during the COVID-19 pandemic, because the ACE2 receptor might be upregulated with use of ACEIs and ARBs. Full-Text PDF Antihypertensive drugs and risk of COVID-19? – Authors' replyWe thank Joshua Brown, Kevin Lo and colleagues, and Christopher Tignanelli and colleagues for their responses to our Correspondence1, and we welcome the opportunity to reply. Full-Text PDF