Inhibitors of the Renin–Angiotensin–Aldosterone System and Covid-19
John A. Jarcho, M.D., Julie R. Ingelfinger, M.D., Mary Beth Hamel, M.D., M.P.H., Ralph B. D’Agostino, Sr., Ph.D., and David P. Harrington, Ph.D.
SARS-CoV-2, the coronavirus that causes Covid-19, enters human cells by binding of its viral spike protein to the membrane-bound form of the monocarboxypeptidase angiotensin-converting enzyme 2 (ACE2).1 From the viewpoint of human physiology, ACE2 plays an important regulatory role in the renin–angiotensin–aldosterone system (RAAS), metabolizing angiotensin II (a potent vasoconstrictor) to generate angiotensin-(1–7) (a vasodilator).2 Studies in animals have suggested that angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) may up-regulate ACE2 expression,3 thus increasing the availability of target molecules for SARS-CoV-2.
These considerations have led to speculation that ACE inhibitors and ARBs might be harmful in patients with Covid-19.4,5 Although this is only a hypothesis, the argument has aroused potential concerns. Case series have indicated that hypertension, diabetes, and coronary artery disease — conditions for which clinicians often prescribe RAAS inhibitors — are more common in patients with severe Covid-19 than in those with milder illness.6 Coverage of the hypothesis by the press and some websites has emphasized the theoretical risk with statements such as, “People with high blood pressure and diabetes could be at higher risk of severe or fatal coronavirus symptoms because of how their medicines work, scientists say,”7 and, “[Reports suggest that] you are four times as likely to die from Covid-19 if you are taking one of these drugs, prior to contracting the virus.”8
In this rapidly evolving setting, clinicians are weighing the alleged harm of continuing these medications in patients for whom ACE inhibitors and ARBs have known benefit against the harm to their cardiovascular and kidney health associated with discontinuing them. Three articles now published in the Journal provide data about whether ACE inhibitors and ARBs are indeed harmful in the context of the Covid-19 epidemic. All are observational studies with the looming possibility of confounding, but each has unique strengths, and their message is consistent — none of the three studies showed evidence of harm with continued use of ACE inhibitors and ARBs.
Mehra et al.9 conducted a database study involving patients who had been hospitalized in 11 countries on three continents. The study included 8910 patients who had received a diagnosis of Covid-19, who had been admitted to the hospital between December 20, 2019, and March 15, 2020, and who had either died in the hospital or survived to hospital discharge. In multivariate logistic-regression analysis, an age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk of in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk of in-hospital death. A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or ARB would be indicated) also did not show harm.
Mancia et al.10 conducted a case–control study involving patients with confirmed Covid-19 in the Lombardy region of Italy, which has been severely affected by the pandemic. In this analysis, 6272 people with confirmed SARS-CoV-2 infection that had been diagnosed between February 21 and March 11, 2020, were compared with 30,759 controls who were matched according to age, sex, and municipality of residence. In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection. An additional analysis comparing patients with severe or fatal infections with matched controls also did not show an association between these drugs and severe Covid-19.
Reynolds et al.11 conducted a study based on data from the electronic health records of 12,594 patients in the New York University (NYU) Langone Health system who were tested for Covid-19 between March 1 and April 15, 2020. A total of 5894 patients had a positive test, among whom 1002 had severe illness (defined as admission to the intensive care unit, mechanical ventilation, or death). Propensity-score matching was performed among all tested patients and among patients with hypertension (to assess whether the likelihood of a positive test result was associated with each of several antihypertensive drug classes), as well as among Covid-19–positive patients and all such patients with hypertension (to assess whether the likelihood of severe illness among those with a positive test was associated with the same drug classes). The investigators’ Bayesian analysis showed no positive association for any of the analyzed drug classes, including ACE inhibitors and ARBs, for either a positive test result or severe illness.
Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe Covid-19 among those infected, or the risk of in-hospital death among those with a positive test. Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs is unlikely to be harmful in patients with Covid-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion.12-15
We note that Mehra et al. found that use of either ACE inhibitors or statins may be associated with a lower risk of in-hospital death than nonuse, but neither of the other two studies estimated a lower risk of Covid-19 or the likelihood of a positive test among patients treated with these agents. The unexpected result in the study by Mehra et al. may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with Covid-19.
Professional scientific societies and experts have spoken with one voice in advising that patients should not discontinue ACE inhibitor or ARB therapy out of a concern that they are at increased risk for infection, severe illness, or death during the Covid-19 pandemic.16-18 The data from these three studies support those recommendations. Ultimately, one or more randomized trials will be needed to answer definitively the question of whether ACE inhibitors or ARBs pose a harm to patients with Covid-19.
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.
- Varagic J, Ahmad S, Nagata S, Ferrario CM. ACE2: angiotensin II/angiotensin-(1-7) balance in cardiac and renal injury. Curr Hypertens Rep 2014;16:420-420.
- Soler MJ, Barrios C, Oliva R, Batlle D. Pharmacologic modulation of ACE2 expression. Curr Hypertens Rep 2008;10:410-414.
- Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020;8(4):e21-e21.
- Esler M, Esler D. Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic? J Hypertens 2020;38:781-782.
- Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-1720.
- Blanchard S. Medicines taken by 6.6 million people with high blood pressure and diabetes could raise the risk of deadly coronavirus symptoms, scientists claim. Daily Mail. March 13, 2020
- Kendrick M. Perhaps 4X more likely to die of COVID-19 if take ACE inhibitors (reduce blood pressure). VitaminDWiki. March 22, 2020
- Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621.
- Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin–angiotensin–aldosterone system blockers and the risk of Covid-19. N Engl J Med 2020;382:2431-2440.
- Reynolds HR, Adhikari S, Pulgarin C, et al. Renin–angiotensin–aldosterone system inhibitors and risk of Covid-19. N Engl J Med 2020;382:2441-2448.
- Meng J, Xiao G, Zhang J, et al. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect 2020;9:757-760.
- 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 2020April17 (Epub ahead of print).
- Li J, Wang X, Chen J, Zhang H, Deng A. Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) infection in Wuhan, China. JAMA Cardiol 2020April23 (Epub ahead of print).
- Bean DM, Kraljevic Z, Searle T, et al. Treatment with ACE-inhibitors is associated with less severe disease with SARS-Covid-19 infection in a multi-site UK acute hospital trust. May 12, 2020
- American College of Cardiology. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. March 17, 2020
- European Society of Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. March 13, 2020
- Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19. N Engl J Med 2020
- António Tralhão, Luís Ferreira Moita, Pedro Póvoa. (2020) Potential benefit of angiotensin II in COVID-19 patients: beyond reasonable doubt?. Critical Care
- Wagner Gouvea dos Santos. (2020) Natural history of COVID-19 and current knowledge on treatment therapeutic options. Biomedicine & Pharmacotherapy
- Ying Huang, Changming Xie, Xiaoke Chen, Qianhui Hong, Hui Huang. (2020) Would ACEIs/ARBs be beneficial for COVID-19 patients without hypertension?. Pharmacological Research
- Jeffrey K. Aronson, Daniel Auker‐Howlett, Virginia Ghiara, Michael P. Kelly, Jon Williamson. (2020) The use of mechanistic reasoning in assessing coronavirus interventions. Journal of Evaluation in Clinical Practice
- Wei Pan, Jishou Zhang, Menglong Wang, Jing Ye, Yao Xu, Bo Shen, Hua He, Zhen Wang, Di Ye, Mengmeng Zhao, Zhen Luo, Mingxiao Liu, Pingan Zhang, Jian Gu, Menglin Liu, Dan Li, Jianfang Liu, Jun Wan. (2020) Clinical Features of COVID-19 in Patients With Essential Hypertension and the Impacts of Renin-angiotensin-aldosterone System Inhibitors on the Prognosis of COVID-19 Patients. Hypertension
- O. M. Drapkina, L. E. Vasilyeva. (2020) Debatable points of using angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists in patients with COVID-19. Cardiovascular Therapy and Prevention
- Nicholas Moore, Bruce Carleton, Patrick Blin, Pauline Bosco-Levy, Cecile Droz. (2020) Does Ibuprofen Worsen COVID-19?. Drug Safety
- Aristidis Tsatsakis, Demetrious Petrakis, Taxiarchis Konstantinos Nikolouzakis, Anca Oana Docea, Daniela Calina, Marco Vinceti, Marina Goumenou, Ronald N. Kostoff, Charalampos Mamoulakis, Michael Aschner, Antonio F. Hernández. (2020) COVID-19, an opportunity to reevaluate the correlation between long-term effects of anthropogenic pollutants on viral epidemic/pandemic events and prevalence. Food and Chemical Toxicology
- Hadeel A. Alsufyani, James R. Docherty. (2020) The renin angiotensin aldosterone system and COVID-19. Saudi Pharmaceutical Journal.
- L. A. Magee, A. Khalil, P. von Dadelszen. (2020) Pregnancy hypertension diagnosis and care in COVID‐19 era and beyond. Ultrasound in Obstetrics & Gynecology
- Alfonso Fasano, Emanuele Cereda, Michela Barichella, Erica Cassani, Valentina Ferri, Anna Lena Zecchinelli, Gianni Pezzoli. (2020) COVID ‐19 in Parkinson’s Disease Patients Living in Lombardy, Italy. Movement Disorders
- Jishou Zhang, Menglong Wang, Wen Ding, Jun Wan. (2020) The interaction of RAAS inhibitors with COVID-19: Current progress, perspective and future. Life Sciences
- Dhrubajyoti Bandyopadhyay, Tauseef Akhtar, Adrija Hajra, Manasvi Gupta, Avash Das, Sandipan Chakraborty, Ipsita Pal, Neelkumar Patel, Birendra Amgai, Raktim K. Ghosh, Gregg C. Fonarow, Carl J. Lavie, Srihari S. Naidu. (2020) COVID-19 Pandemic: Cardiovascular Complications and Future Implications. American Journal of Cardiovascular Drugs
- Beth Woodward, Muhammed Kermali. (2020) COVID‐19: The heart of the issue. Journal of Cardiac Surgery.
- Gülistan Bahat. (2020) COVID-19 and the Renin Angiotensin System: Implications for the Older Adults. The journal of nutrition, health & aging
- Mohamad Syafeeq Faeez Md Noh. (2020) COVID-19 and Cerebral Hemorrhage: Proposed Mechanisms. Journal of Neuroradiology
- Daniel S. Cormican, Daniel Winter, Stephen McHugh, Abraham Sonny, Jerome Crowley, Raymond Yu, Frank Barrack, Iván J Núñez Gil, Harish Ramakrishna. (2020) SARS-CoV2 Cardiovascular Complications: Implications for Cardiothoracic Anesthesiology. Journal of Cardiothoracic and Vascular Anesthesia
- (2020) Risk of Covid-19 with renin-angiotensin-aldosterone system medications. Reactions Weekly
- Donato Gemmati, Barbara Bramanti, Maria Luisa Serino, Paola Secchiero, Giorgio Zauli, Veronica Tisato. (2020) COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males?. International Journal of Molecular Sciences
- (2020) OUP accepted manuscript. European Heart Journal - Cardiovascular Pharmacotherapy.