According to the European Centre for Disease Prevention and Control, since 31 December 2019 to 8 May 2020 the SARS-CoV-2 pandemic led to more than 3.8 million infections and 269,068 deaths.1 There are conflicting assumptions about the possible adverse or protective effects of antihypertensive drugs acting on the renin-angiotensin-aldosterone (RAAS) system in patients with SARS-CoV-2.2-5 Given their common use, it is important to understand what evidence is available to support the various hypotheses.
Description of the two classes of drugs
RAAS plays an important role in the pathogenesis of various cardiovascular, renal and pulmonary diseases.6
ACE inhibitors interfere with RAAS by inhibiting the enzyme ACE1, preventing the formation of angiotensin II and leading to a reduction in its vasopressor, sodium reactive and cardiac effects.7
Angiotensin Receptor Blockers (ARBs) compete with angiotensin II for AT1 receptor binding, whose functional role is to mediate most of the biological effects of angiotensin II.
The indications reported for both classes of drugs are the treatment of essential hypertension and heart failure.
Role in SARS-CoV-2 infection
The understanding of the physiological role of RAAS has been enriched with the discovery of the enzyme ACE2, which catalyzes the conversion of angiotensin I to angiotensin 1-9 and angiotensin II to angiotensin 1-7.9 ACE2 has been identified as the entry receptor for SARS-CoV-2, raising doubts that drugs acting on the RAAS system may somehow worsen the infection.5 Treatment with these drugs appears to increase the expression of ACE2 in some animal and human studies, which could theoretically promote infection.10 However, many of the animal studies describing an increase in ACE2 have been conducted with high doses of ACE inhibitors or ARBs, which are difficult to transfer to humans, as noted by Sriram and colleagues.11 Other animal and human studies have found conflicting results.12 There is therefore little evidence to support an increased risk with RAAS inhibitors.
Some authors suggest, however, that the increase in the conversion enzyme ACE2 and the resulting deviation of angiotensin I to angiotensin 1-9 and 1-7, known to exert protective pulmonary and cardiac effects, could protect patients from acute lung damage from SARS-CoV-2.2,13 In addition, in vitro studies have shown that SARS-CoV-2, after input mediated by interaction with ACE2, leads to ACE2 sub-expression. Therefore, exposure to the virus could unbalance the RAAS cascade towards increased angiotensin II formation, aggravating the pulmonary and cardiovascular situation. In this circumstance, ACE inhibitors or ARBs have been proposed as useful drugs to protect against excessive increase in angiotensin II.2 Recently, according to clinical evidence that hypercoagulability conditions in COVID-19 patients aggravate the clinical course, the role of angiotensin II in the coagulative cascade has been discussed as it would exert a prothrombotic effect.14,15 According to the authors the pharmacological modulation of the RAAS system could be a promising approach for patients with COVID-19.16
Clinical evidence: benefits and risks
Observational studies conducted in patients with COVID-19 have provided potentially useful information about the risk-benefit profile of these drugs in SARS-CoV-2 infection.
A retrospective study in Chinese patients with COVID-19 showed a potential beneficial effect of RAAS inhibitors in this disease.17 Of the 3,430 patients enrolled, 1,128 (32.9%) were hypertensive and 188 (16.7%) of these were treated with ACE inhibitors or ARBs, or other antihypertensives (940, 83.3%). The risk of mortality for all causes was significantly lower in the ACE inhibitor/sartan group than in the group treated with other antihypertensives based on multivariate analysis (adjusted relative risk: 0.42, 95% confidence interval 0.19-0.92, p=0.03), also adjusted with the propensity score (adjusted relative risk: 0.30, 95% confidence interval 0.12-0.70, p=0.01). However, several limits of the study are discussed by the authors: the sample size is modest and does not allow to detect differences between ACE inhibitors and ARBs, the clinical history is not complete for all patients and the difference in the use of other antihypertensive drugs between the two groups could be due to a confusing factor.
In another study of 12,549 patients, 4,357 had a history of hypertension and 59.1% of these patients had COVID-19: there was no significant increase in test positivity for SARS-CoV-2 or risk of worsening the disease with RAAS inhibitors.18 The authors argue, however, that the assessment of drug use may not reflect actual exposure to the drugs and this may be a limitation of the study.
In another study, which evaluated data from 8,910 COVID-19 patients from 169 hospitals in Asia, Europe, and North America, there was no increase in the risk of death associated with the use of ACE inhibitors (odds ratio: 0.33, 95% confidence interval 0.20-0.54) or ARBs (odds ratio: 1.23, 95% confidence interval 0.87-1.74); because the study was not randomized and uncontrolled, confounding factors cannot be excluded.19
In addition, in a recent case-control study conducted in Lombardy, 6,272 COVID-19 patients were compared with 30,759 patients in the regional health service.20 No association with COVID-19 was demonstrated for ARBs (adjusted odds ratio: 0.95, 95% confidence interval 0.86-1.05) and ACE inhibitors (adjusted odds ratio: 0.96, 95% confidence interval 0.87-1.07).
Finally, given the role of cardiovascular disease among comorbidities in COVID-19 patients,21 discontinuation of antihypertensives may increase the frequency of negative outcomes in these patients.22
Since there is no clinical evidence in the literature that ACE inhibitors and ARBs can worsen SARS-CoV-2 infections, stopping treatment with these drugs or switching to other antihypertensives are not recommended by any of the national and international scientific societies and regulatory agencies. On the contrary, recommendations and guidelines published to date by the Italian Medicines Agency (AIFA),23 European Medicines Agency (EMA),24 European Society of Cardiology,25 Italian Society of Pharmacology,26 Heart Failure Society of America, American College of Cardiology and American Heart Association,27 International Society of Hypertension,28 and European Society of Hypertensionn29 agree that treatment with RAAS inhibitors should be continued in hypertensive patients with COVID-19 unless clinically contraindicated.30
In conclusion, current evidence does not support the discontinuation of drug treatment with ACE inhibitors and ARBs or the switch to other antihypertensives; treatment should therefore be continued, as pointed out by various scientific societies and regulatory agencies.
Gabriele Puglisi, Salvatore Crisafulli, Gianluca Trifirò, Janet Sultana
Department of Biomedical, Dental and Morphological and Functional Imaging Sciences, University of Messina
- Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 2020;DOI:10.1002/ddr.21656 CDI
- Zheng Y, Ma Y, et al. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020;17:259-60. CDI
- Watkins J. Preventing a COVID-19 pandemic. BMJ 2020;368:m810. CDI
- Fang L, Karakiulakis G, et al. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020;DOI:10.1016/S2213-2600(20)30116-8 CDI
- Kobori H, Nangaku M, et al. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 2007;59:251-87. CDI
- Atlas S. The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J Manag Care Pharm 2007;13(8 Suppl B):9-20. CDI
- Katzung B, Trevor A. Farmacologia generale e clinica, X edizione italiana, Piccin, pp. 821-822, ISBN 9788829928477.
- Donoghue M, Hsieh F, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000;87:E1–E9.
- Ferrario C, Jessup J, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin converting enzyme 2. Circulation 2005;111:2605-10. CDI
- Sriram K, Insel P. Risks of ACE inhibitor and ARB usage in COVID-19: evaluating the evidence. Clin Pharmacol Ther 2020;DOI:10.1002/cpt.1863. CDI
- Vaduganathan M, Vardeny O, et al. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med.2020;382:1653-9. CDI
- Sarzani R, Giulietti F, et al. Severe acute respiratory syndrome coronavirus 2 infection, angiotensin-converting enzyme 2 and treatment with angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers. Eur J Prev Cardiol 2020;DOI:10.1177/2047487320918421. CDI
- Tang N, Li D, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-7. CDI
- Verdecchia P, Reboldi G, et al. ACE-inibitori, sartani e sindrome respiratoria acuta da coronavirus 2. G Ital Cardiol 2020;21:321-7. CDI
- Verdecchia P, Cavallini C, et al. The pivotal link between ACE2 deficiency and SARS-CoV-2 infection. Eur J Intern Med 2020;DOI:10.1016/j.ejim.2020.04.037 CDI
- Zhang P, Zhu L, 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 2020;DOI:10.1161/CIRCRESAHA.120.317134. CDI
- Reynolds H, Adhikari S, et al. Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19. N Engl J Med 2020;DOI:10.1056/NEJMoa2008975. CDI
- Mehra M, Desai S, et al. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med 2020;DOI:10.1056/NEJMoa2007621. CDI
- Mancia G, Rea F, et al. Renin-angiotensin-aldosterone system blockers and the risk of Covid-19. N Engl J Med 2020;DOI:10.1056/NEJMoa2006923. CDI
- Wang D, Hu B, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;DOI:10.1001/jama.2020. CDI
- Trifirò G, Crisafulli S, et al. Should patients receiving ACE inhibitors or angiotensin receptor blockers be switched to other antihypertensive drugs to prevent or improve prognosis of novel coronavirus disease 2019 (COVID-19)? Drug Saf 2020;DOI:10.1007/s40264-020-00935-2. CDI
- Bavishi C, Maddox T, et al. Coronavirus disease 2019 (COVID-19) infection and renin angiotensin system blockers. JAMA Cardiol 2020;DOI:10.1001/jamacardio.2020.1282 CDI