THE RELATIONSHIP BETWEEN COVID-19 SEVERITY AND THE USAGE OF ANGIOTENSIN-II RECEPTOR BLOCKERS IN HYPERTENSIVE PATIENTS

Fahmida Khanam Raha; Farah Momtaz; Md. Rubayet Siraj; Khondekar Mustaq Adnan; Saif Mukramoon Arosh; Depro Das; Md. Zahid Amin; Mohammad Shahidul Islam; Md. Nasir Uddin Ahmed; Mousumi Sanyal

doi:10.3329/brc.v9i1.63598

Authors

Fahmida Khanam Raha Department of Biochemistry and Molecular Biology, University of Dhaka, 1205, Dhaka, Bangladesh
Farah Momtaz Dr. Sirajul Islam Medical College and Hospital, 2/3, New Circular Road, Malibagh, 1217, Dhaka, Bangladesh
Md. Rubayet Siraj Central Police Hospital, 2 DIT Ave, 1000, Dhaka, Bangladesh
Khondekar Mustaq Adnan Central Police Hospital, 2 DIT Ave, 1000, Dhaka, Bangladesh
Saif Mukramoon Arosh Department of Biochemistry and Molecular Biology, University of Dhaka, 1205, Dhaka, Bangladesh
Depro Das Department of Biochemistry and Molecular Biology, University of Dhaka, 1205, Dhaka, Bangladesh
Md. Zahid Amin Central Police Hospital, 2 DIT Ave, 1000, Dhaka, Bangladesh
Mohammad Shahidul Islam Central Police Hospital, 2 DIT Ave, 1000, Dhaka, Bangladesh
Md. Nasir Uddin Ahmed Anwer Khan Modern Medical College Hospital, Dhanmondi, Dhaka-1205, Bangladesh
Mousumi Sanyal Central Police Hospital, 2 DIT Ave, 1000, Dhaka, Bangladesh

DOI:

https://doi.org/10.3329/brc.v9i1.63598

Keywords:

SARS-CoV-2, ACE2 Receptor, Hypertension, Angiotensin Receptor Blockers (ARB)

Abstract

Purpose of the study: As demonstrated by numerous epidemiological studies, the high incidence of hypertension among patients with coronavirus disease 2019 (COVID-2019) appears to be associated with an elevated risk of mortality. The angiotensin-converting enzyme (ACE) system is not expressed uniformly throughout the human population, and contemporary variations may account for part of the global disparities in infection prevalence. In addition, animal investigations have demonstrated that the ACE2 receptor is a potential infection route for the COVID-19-causing SARS-CoV-2 virus. As two-thirds of hypertension patients take ACE inhibitors/angiotensin receptor blockers, a number of concerns have been raised regarding the harmful or beneficial effects of contemporary antihypertensive medications in COVID-19. This study presents the most recent evidence for and against the impact of ACE blockade administration in the age of COVID-19 on the cohort of hypertension patients in Bangladesh (N = 300). Methods: We included in this study 300 patients who had a record of a COVID-19 test performed between July 2021 and September 2021 using RT-PCR. All the patients had a history of hypertension two years before the index date, based on the International Classification of Diseases codes (Tenth Revision, Clinical Modification, ICD-10-CM). All of them have been taking anti-hypertensive drugs for 1–2 years. We used logistic regression to estimate the odds ratio (OR) and the 95% confidence interval (CI) of COVID-19 severity in patients prescribed Angiotensin Receptor Blockers (ARB) versus those not prescribed ARB. We selected a cohort of 300 Bangladeshi patients who were covid positive and had been taking hypertensive medications for 1-5 years. Results: Among COVID-19-positive patients with hypertension, the use of ARB is associated with increased odds of hospitalization, including all patients admitted to ICU or CCU (OR = 1.008, (0.440, 2.309) and OR= 2.31, (0.024, 2.452) respectively). Participants receiving ARB have a lower odds ratio of using BiPAP, CPAP, and Ventilation (0.592, 0.010, and 0.031, respectively; p-value < 0.5) compared to the non-ARB users. Research Implications: We noticed a statistically significant association between ARB administration and mechanical ventilation in our study. Since ARB use was also related to a decreased likelihood of needing additional oxygen support, such as nasal cannula, BiPAP, and CPAP, there is sufficient evidence from other clinical factors to indicate a consistent connection between ARB use and oxygen assistance among covid-positive patients. Further research is required to determine the molecular relationship between ARB use and oxygen level in Covid-positive individuals.

References

Appel, G.B. and Appel, A.S. (2004) ‘Angiotensin II receptor antagonists: Role in hypertension, cardiovascular disease, and renoprotection’, Progress in Cardiovascular Diseases, 47(2), pp. 105–115. Available at:

https://doi.org/10.1016/j.pcad.2004.04.005.

Bae, D.J. et al. (2020) ‘Angiotensin Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Use Among Outpatients Diagnosed With COVID-19.’, The American journal of cardiology, 132, pp. 150–157. Available at: https://doi.org/10.1016/j.amjcard.2020.07.007.

Baral, R., White, M. and Vassiliou, V.S. (2020) ‘Effect of Renin-Angiotensin-Aldosterone System Inhibitors in Patients with COVID-19: a Systematic Review and Meta-analysis of 28,872 Patients’, Current Atherosclerosis Reports, 22(10), p. 61. Available at: https://doi.org/10.1007/s11883-020-00880-6.

Barochiner, J. and Martínez, R. (2020) ‘Use of inhibitors of the renin‐angiotensin system in hypertensive patients and COVID‐19 severity: A systematic review and meta‐analysis’, Journal of Clinical Pharmacy and Therapeutics, 45(6), pp. 1244–1252. Available at: https://doi.org/10.1111/jcpt.13246.

Bauer, A.Z. et al. (2021) ‘Hypertension, medications, and risk of severe COVID-19: A Massachusetts community-based observational study.’, Journal of clinical hypertension (Greenwich, Conn.), 23(1), pp. 21–27. Available at: https://doi.org/10.1111/jch.14101.

Bean, D.M. et al. (2020) ‘Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are not associated with severe COVID-19 infection in a multi-site UK acute hospital trust.’, European journal of heart failure, 22(6), pp. 967–974. Available at: https://doi.org/10.1002/ejhf.1924.

Bozkurt, B., Kovacs, R. and Harrington, B. (2020) ‘Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19’, Journal of Cardiac Failure, 26(5), p. 370. Available at: https://doi.org/10.1016/j.cardfail.2020.04.013.

Bravi, F. et al. (2020) ‘Predictors of severe or lethal COVID-19, including Angiotensin Converting Enzyme inhibitors and Angiotensin II Receptor Blockers, in a sample of infected Italian citizens.’, PloS one, 15(6), p. e0235248. Available at: https://doi.org/10.1371/journal.pone.0235248.

Burchill, L.J. et al. (2012) ‘Combination renin–angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions’, Clinical Science, 123(11), pp. 649–658. Available at: https://doi.org/10.1042/CS20120162.

Burnier, M. and Brunner, H. (2000) ‘Angiotensin II receptor antagonists’, The Lancet, 355(9204), pp. 637–645. Available at: https://doi.org/10.1016/S0140-6736(99)10365-9.

Cheung, K.S., Hung, I.F.N. and Leung, W.K. (2020) ‘Association between angiotensin blockade and COVID-19 severity in Hong Kong.’, CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne, p. E635. Available at: https://doi.org/10.1503/cmaj.75865.

Choi, M.H. et al. (2020) ‘Clinical Characteristics and Disease Progression in Early-Stage COVID-19 Patients in South Korea.’, Journal of clinical medicine, 9(6). Available at: https://doi.org/10.3390/jcm9061959.

Chowdhury, M.Z.I. et al. (2020a) ‘Hypertension prevalence and its trend in Bangladesh: evidence from a systematic review and meta-analysis’, Clinical Hypertension, 26(1), p. 10. Available at: https://doi.org/10.1186/s40885-020-00143-1.

Chowdhury, M.Z.I. et al. (2020b) ‘Hypertension prevalence and its trend in Bangladesh: evidence from a systematic review and meta-analysis’, Clinical Hypertension, 26(1), p. 10. Available at: https://doi.org/10.1186/s40885-020-00143-1.

Diaz, J.H. (2020) ‘Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19’, Journal of Travel Medicine, 27(3). Available at: https://doi.org/10.1093/jtm/taaa041.

DiCiccio, T.J. and Efron, B. (1996) ‘Bootstrap confidence intervals’, Statistical Science, 11(3). Available at: https://doi.org/10.1214/ss/1032280214.

Drager, L.F. et al. (no date) ‘Is Hypertension a Real Risk Factor for Poor Prognosis in the COVID-19 Pandemic?’ Available at: https://doi.org/10.1007/s11906-020-01057-x.

Dublin, S. et al. (2021) ‘Renin-Angiotensin-Aldosterone System Inhibitors and COVID-19 Infection or Hospitalization: A Cohort Study.’, American journal of hypertension, 34(4), pp. 339–347. Available at: https://doi.org/10.1093/ajh/hpaa168.

Ebinger, J.E. et al. (2020) ‘Pre-existing traits associated with Covid-19 illness severity.’, PloS one, 15(7), p. e0236240. Available at: https://doi.org/10.1371/journal.pone.0236240.

Esler, M. and Esler, D. (2020) ‘Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?’, Journal of Hypertension, 38(5), pp. 781–782. Available at: https://doi.org/10.1097/HJH.0000000000002450.

European Society of Cardiology Council on Hypertension. Position statement on ACE-inhibitors and angiotensin receptor blockers (no date). Available at: https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang (Accessed: 27 October 2020).

Fang, L., Karakiulakis, G. and Roth, M. (2020a) ‘Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?’, The Lancet Respiratory Medicine, 8(4), p. e21. Available at: https://doi.org/10.1016/S2213-2600(20)30116-8.

Fang, L., Karakiulakis, G. and Roth, M. (2020b) ‘Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?’, The Lancet Respiratory Medicine, 8(4), p. e21. Available at: https://doi.org/10.1016/S2213-2600(20)30116-8.

Ferrario, C.M. et al. (2005) ‘Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.’, Circulation, 111(20), pp. 2605–10. Available at: https://doi.org/10.1161/CIRCULATIONAHA.104.510461.

Fonarow, G.C. et al. (2008) ‘Influence of Beta-Blocker Continuation or Withdrawal on Outcomes in Patients Hospitalized With Heart Failure’, Journal of the American College of Cardiology, 52(3), pp. 190–199. Available at: https://doi.org/10.1016/j.jacc.2008.03.048.

Fosbøl, E.L. et al. (2020) ‘Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality’, JAMA, 324(2), p. 168. Available at: https://doi.org/10.1001/jama.2020.11301.

Golpe, R. et al. (2020) ‘Risk of severe COVID-19 in hypertensive patients treated with renin-angiotensin-aldosterone system inhibitors.’, Medicina clinica, 155(11), pp. 488–490. Available at:

https://doi.org/10.1016/j.medcli.2020.06.013.

Grasselli, G. et al. (2020) ‘Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy.’, JAMA internal medicine, 180(10), pp. 1345–1355. Available at:

https://doi.org/10.1001/jamainternmed.2020.3539.

Gurwitz, D. (2020) ‘Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics’, Drug Development Research, 81(5), pp. 537–540. Available at:

https://doi.org/10.1002/ddr.21656.

Hakeam, H.A. et al. (2021a) ‘Association of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Blockers With Severity of COVID-19: A Multicenter, Prospective Study.’, Journal of cardiovascular pharmacology and therapeutics, 26(3), pp. 244–252. Available at: https://doi.org/10.1177/1074248420976279.

Hakeam, H.A. et al. (2021b) ‘Association of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Blockers With Severity of COVID-19: A Multicenter, Prospective Study.’, Journal of cardiovascular pharmacology and therapeutics, 26(3), pp. 244–252. Available at: https://doi.org/10.1177/1074248420976279.

Hamming, I. et al. (2004) ‘Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis’, The Journal of Pathology, 203(2), pp. 631–637. Available at: https://doi.org/10.1002/path.1570.

Heran, B.S. et al. (2008) ‘Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension’, Cochrane Database of Systematic Reviews [Preprint]. Available at:

https://doi.org/10.1002/14651858.CD003822.pub2.

Hoffmann, M. et al. (2020) ‘SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor’, Cell, 181(2), pp. 271-280.e8. Available at: https://doi.org/10.1016/j.cell.2020.02.052.

‘IBM Corp. Released 2019. IBM SPSS Statistics for Windows.’ (no date). Armonk, NY: IBM Corp.

Imai, Y. et al. (2005) ‘Angiotensin-converting enzyme 2 protects from severe acute lung failure’. Available at: https://doi.org/10.1038/nature03712.

Israili, Z. (2000) ‘Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension’, Journal of Human Hypertension, 14(S1), pp. S73–S86. Available at: https://doi.org/10.1038/sj.jhh.1000991.

Jung, S.-Y. et al. (2020) ‘Association of Renin-angiotensin-aldosterone System Inhibitors With Coronavirus Disease 2019 (COVID-19)- Related Outcomes in Korea: A Nationwide Population-based Cohort Study.’, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 71(16), pp. 2121–2128. Available at: https://doi.org/10.1093/cid/ciaa624.

Khera, R. et al. (2020) ‘Association of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers with the Risk of Hospitalization and Death in Hypertensive Patients with Coronavirus Disease-19.’, medRxiv : the preprint server for health sciences [Preprint]. Available at: https://doi.org/10.1101/2020.05.17.20104943.

Kuba, K. et al. (2005) ‘A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.’, Nature medicine, 11(8), pp. 875–9. Available at: https://doi.org/10.1038/nm1267.

Lafaurie, M. et al. (2021) ‘Outcome of patients hospitalized for COVID-19 and exposure to angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in France: results of the ACE-CoV study.’, Fundamental & clinical pharmacology, 35(1), pp. 194–203. Available at: https://doi.org/10.1111/fcp.12613.

Lam, K.W. et al. (2020) ‘Continued In-Hospital Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Use in Hypertensive COVID-19 Patients Is Associated With Positive Clinical Outcome.’, The Journal of infectious diseases, 222(8), pp. 1256–1264. Available at: https://doi.org/10.1093/infdis/jiaa447.

Lee, I.T. et al. (2020) ‘ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs.’, Nature communications, 11(1), p. 5453. Available at: https://doi.org/10.1038/s41467-020-19145-6.

Lee, S.J. et al. (2021) ‘Possible Benefit of Angiotensin II Receptor Blockers in COVID-19 Patients: A Case Series’, Journal of the Renin-Angiotensin-Aldosterone System, 2021, pp. 1–6. Available at: https://doi.org/10.1155/2021/9951540.

Li, J. et al. (2020) ‘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 cardiology, 5(7), pp. 825–830. Available at: https://doi.org/10.1001/jamacardio.2020.1624.

Li, W. et al. (2003) ‘Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus’, Nature, 426(6965), pp. 450–454. Available at: https://doi.org/10.1038/nature02145.

Li, X.C., Zhang, J. and Zhuo, J.L. (2017) ‘The vasoprotective axes of the renin-angiotensin system: Physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases.’, Pharmacological research, 125(Pt A), pp. 21–38. Available at: https://doi.org/10.1016/j.phrs.2017.06.005.

Liu, X. et al. (2020) ‘Association of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with risk of COVID ‐19, inflammation level, severity, and death in patients with COVID ‐19: A rapid systematic review and meta‐analysis’, Clinical Cardiology, p. clc.23421. Available at: https://doi.org/10.1002/clc.23421.

Lopes, R.D. et al. (2021) ‘Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial.’, JAMA, 325(3), pp. 254–264. Available at: https://doi.org/10.1001/jama.2020.25864.

López-Otero, D. et al. (2021) ‘Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on COVID-19 in a western population. CARDIOVID registry.’, Revista espanola de cardiologia (English ed.), 74(2), pp. 175–182. Available at: https://doi.org/10.1016/j.rec.2020.05.018.

Mcinnes, I.B. and Mcmurray, J.J. v (2020) ‘Naveed Sattar , MD’, 142, pp. 4–6. Available at: https://doi.org/10.1161/CIRCULATIONAHA.120.047659.

Mehta, N. et al. (2020) ‘Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19).’, JAMA cardiology, 5(9), pp. 1020–1026. Available at: https://doi.org/10.1001/jamacardio.2020.1855.

Million, M. et al. (2020) ‘Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France.’, Travel medicine and infectious disease, 35, p. 101738. Available at: https://doi.org/10.1016/j.tmaid.2020.101738.

Organization, W.H. (2020) World Health Organization. Clinical management of COVID-19. Available at: WHO/2019-nCoV/clinical/2020.5.

Pan, W. et al. (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, 76(3), pp. 732–741. Available at: https://doi.org/10.1161/HYPERTENSIONAHA.120.15289.

Patel, A.B. and Verma, A. (2020) ‘COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence?’, JAMA, 323(18), pp. 1769–1770. Available at: https://doi.org/10.1001/jama.2020.4812.

Pinto-Sietsma, S.-J. et al. (2020) ‘Antihypertensive drugs in COVID-19 infection.’, European heart journal. Cardiovascular pharmacotherapy, pp. 415–416. Available at: https://doi.org/10.1093/ehjcvp/pvaa058.

Platt, R.W., Hanley, J.A. and Yang, H. (2000) ‘Bootstrap confidence intervals for the sensitivity of a quantitative diagnostic test.’, Statistics in medicine, 19(3), pp. 313–22. Available at: https://doi.org/10.1002/(sici)1097-0258(20000215)19:3<313::aid-sim370>3.0.co;2-k.

Reynolds, H.R. et al. (2020) ‘Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19.’, The New England journal of medicine, 382(25), pp. 2441–2448. Available at: https://doi.org/10.1056/NEJMoa2008975.

Rothlin, R.P. et al. (2020) ‘Telmisartan as tentative angiotensin receptor blocker therapeutic for COVID ‐19’, Drug Development Research, 81(7), pp. 768–770. Available at: https://doi.org/10.1002/ddr.21679.

Saavedra, J.M. (2020) ‘Angiotensin receptor blockers and COVID-19’, Pharmacological Research, 156, p. 104832. Available at: https://doi.org/10.1016/j.phrs.2020.104832.

Şenkal, N. et al. (2020) ‘Association between chronic ACE inhibitor exposure and decreased odds of severe disease in patients with COVID-19.’, Anatolian journal of cardiology, 24(1), pp. 21–29. Available at: https://doi.org/10.14744/AnatolJCardiol.2020.57431.

Soler, M.J. et al. (2008) ‘Pharmacologic Modulation of ACE2 Expression’.

Son, M., Seo, J. and Yang, S. (2020) ‘Association Between Renin-Angiotensin-Aldosterone System Inhibitors and COVID-19 Infection in South Korea.’, Hypertension (Dallas, Tex. : 1979), 76(3), pp. 742–749. Available at: https://doi.org/10.1161/HYPERTENSIONAHA.120.15464.

Vaduganathan, M., Vardeny, O., Michel, T., McMurray, J.J.V., et al. (2020a) ‘Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19’, New England Journal of Medicine, 382(17), pp. 1653–1659. Available at: https://doi.org/10.1056/NEJMsr2005760.

Vaduganathan, M., Vardeny, O., Michel, T., McMurray, J.J.V., et al. (2020b) ‘Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19’, New England Journal of Medicine, 382(17), pp. 1653–1659. Available at: https://doi.org/10.1056/NEJMsr2005760.

Vaduganathan, M., Vardeny, O., Michel, T., McMurray, J.J. v, et al. (2020) ‘Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19.’, The New England journal of medicine, 382(17), pp. 1653–1659. Available at: https://doi.org/10.1056/NEJMsr2005760.

Wan, Y. et al. (2020) ‘Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus.’, Journal of virology, 94(7). Available at:

https://doi.org/10.1128/JVI.00127-20.

Wang, Yixuan et al. (2021) ‘The use of renin-angiotensin-aldosterone system (RAAS) inhibitors is associated with a lower risk of mortality in hypertensive COVID-19 patients: A systematic review and meta-analysis.’, Journal of medical virology, 93(3), pp. 1370–1377. Available at: https://doi.org/10.1002/jmv.26625.

Weir, M. (1999) ‘The renin-angiotensin-aldosterone system: a specific target for hypertension management’, American Journal of Hypertension, 12(4), pp. 205–213. Available at: https://doi.org/10.1016/S0895-7061(99)00103-X.

Xu, J. et al. (2021) ‘The Effect of Prior Angiotensin-Converting Enzyme Inhibitor and Angiotensin Receptor Blocker Treatment on Coronavirus Disease 2019 (COVID-19) Susceptibility and Outcome: A Systematic Review and Meta-analysis’, Clinical Infectious Diseases, 72(11), pp. e901–e913. Available at: https://doi.org/10.1093/cid/ciaa1592.

Yan, H. et al. (2020) ‘Role of Drugs Affecting the Renin-Angiotensin-Aldosterone System on Susceptibility and Severity of COVID-19: A Large Case-Control Study from Zheijang Province, China’, medRxiv, p. 2020.04.24.20077875. Available at: https://doi.org/10.1101/2020.04.24.20077875.

Zhang, X. et al. (2020) ‘ACEI/ARB use and risk of infection or severity or mortality of COVID-19: A systematic review and meta-analysis’, Pharmacological Research, 158, p. 104927. Available at:

https://doi.org/10.1016/j.phrs.2020.104927.

Zhong, J.-C. et al. (2011) ‘Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression’, Regulatory Peptides, 166(1–3), pp. 90–97. Available at:

https://doi.org/10.1016/j.regpep.2010.09.005.

Zhou, F. et al. (2020) ‘Comparative Impacts of ACE (Angiotensin-Converting Enzyme) Inhibitors Versus Angiotensin II Receptor Blockers on the Risk of COVID-19 Mortality.’, Hypertension (Dallas, Tex. : 1979). United States, pp. e15–e17. Available at: https://doi.org/10.1161/HYPERTENSIONAHA.120.15622.