Recommendations of RAAS Blocker Use Amidst The Coronavirus Pandemic

  • Joshua Henrina, doctor Siloam Heart Institute; Siloam Hospitals Kebon Jeruk
  • Iwan Cahyo Santosa Putra, doctor Siloam Heart Institute; Siloam Hospitals Kebon Jeruk
  • Hoo Felicia Hadi Gunawan, doctor Siloam Heart Institute; Siloam Hospitals Kebon Jeruk
  • Irvan Cahyadi, doctor Siloam Heart Institute; Siloam Hospitals Kebon Jeruk
  • Leonardo Paskah Suciadi, doctor Siloam Heart Institute; Siloam Hospitals Kebon Jeruk
Keywords: SARS-Cov-2, COVID-19, ACEi, ARB, ACE2

Abstract

With a rapidly growing pandemic of coronavirus disease of 2019 (COVID-19), a public health emergency of international concern, the medical communities and national health systems are being tested for their preparedness. The culprit that is responsible for this viral respiratory disease, is a novel type of coronavirus, now identified as severe acute respiratory syndrome coronavirus - 2 (SARS-CoV2). At the present time, there are gaps in the knowledge regarding the safety of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for COVID-19 patients due to concern of ACE2, which is critical for viral entry and their levels are upregulated when using these (Renin Angiotensin Aldosterone System) RAAS blockers. ACE2 is a glycoprotein metalloprotease that plays an essential role in physiologic and pathological states and it is ubiquitously found in human organs. Despite sharing homology, ACE is different from ACE2, and while the former cleaves angiotensin 1 to angiotensin 2, the latter cleaves angiotensin two to angiotensin 1-7. Extrapolated from experimental animal studies, ACE2 and angiotensin 1-7 are important and protective for the lung physiology based on mice model of acute lung injury by various causes. Other evidence also demonstrates harm over benefits when stopping RAAS blockers, particularly in patients with cardiovascular disease, in which using these drugs are proven to be life-saving. In the light of the paucity of evidence derived from well-designed study, societies and colleges recommend continuing RAAS blockers until new evidence says otherwise.

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Author Biographies

Joshua Henrina, doctor, Siloam Heart Institute; Siloam Hospitals Kebon Jeruk

Research assistant

Iwan Cahyo Santosa Putra, doctor, Siloam Heart Institute; Siloam Hospitals Kebon Jeruk

Research assistant

Hoo Felicia Hadi Gunawan, doctor, Siloam Heart Institute; Siloam Hospitals Kebon Jeruk

Research Assistant

Irvan Cahyadi, doctor, Siloam Heart Institute; Siloam Hospitals Kebon Jeruk

Research Assistant

Leonardo Paskah Suciadi, doctor, Siloam Heart Institute; Siloam Hospitals Kebon Jeruk

Cardiologist, FIHA, EHFA

References

1. WHO | Pneumonia of unknown cause – China [Internet]. WHO. World Health Organization; [cited 2020 Apr 13]. Available from: http://www.who.int/csr/don/05-january-2020-pneumonia-of-unkown-cause-china/en/https://www.eshonline.org/spotlights/esh-letter-covid-19-2/
2. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet. 2020;395:565–74.
3. COVID-19 Map [Internet]. Johns Hopkins Coronavirus Resource Center. [cited 2020 Apr 13]. Available from: https://coronavirus.jhu.edu/map.html
4. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis [Internet]. 2020 [cited 2020 Apr 13];0. Available from: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30120-1/abstract
5. Coronavirus Disease (COVID-19) - events as they happen [Internet]. [cited 2020 Apr 13]. Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen
6. von Lueder TG, Krum H. RAAS Inhibitors and Cardiovascular Protection in Large Scale Trials. Cardiovasc Drugs Ther. 2013;27:171–9.
7. Ma TK, Kam KK, Yan BP, Lam Y-Y. Renin–angiotensin–aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol. 2010;160:1273–92.
8. Furuhashi M, Moniwa N, Mita T, Fuseya T, Ishimura S, Ohno K, et al. Urinary Angiotensin-Converting Enzyme 2 in Hypertensive Patients May Be Increased by Olmesartan, an Angiotensin II Receptor Blocker. Am J Hypertens. 2015;28:15–21.
9. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell [Internet]. 2020 [cited 2020 Apr 13];0. Available from: https://www.cell.com/cell/abstract/S0092-8674(20)30229-4
10. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation and Treatment Coronavirus (COVID-19). In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 [cited 2020 Apr 13]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK554776/
11. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor [Internet]. [cited 2020 Apr 15]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102627/
12. Danser AHJ, Epstein M, Batlle D. Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At Present There Is No Evidence to Abandon Renin-Angiotensin System Blockers. Hypertension [Internet]. 2020 [cited 2020 Apr 13]; Available from: https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.120.15082
13. 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;NEJMsr2005760.
14. Tikellis C, Thomas MC. Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease. Int J Pept. 2012;2012:1–8.
15. Fountain JH, Lappin SL. Physiology, Renin Angiotensin System. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 [cited 2020 Apr 14]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK470410/
16. Santos Robson Augusto. Angiotensin-(1–7). Hypertension. 2014;63:1138–47.
17. Chen L, Hao G. The role of angiotensin-converting enzyme 2 in coronaviruses/influenza viruses and cardiovascular disease. :5.
18. Touyz RM, Li H, Delles C. ACE2 the Janus-faced protein – from cardiovascular protection to severe acute respiratory syndrome-coronavirus and COVID-19. Clin Sci. 2020;134:747–50.
19. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury. Nat Med. 2005;11:875–9.
20. Tseng C-TK, Huang C, Newman P, Wang N, Narayanan K, Watts DM, et al. Severe Acute Respiratory Syndrome Coronavirus Infection of Mice Transgenic for the Human Angiotensin-Converting Enzyme 2 Virus Receptor. J Virol. 2007;81:1162–73.
21. Anavekar NS, Solomon SD. Angiotensin II receptor blockade and ventricular remodelling. J Renin Angiotensin Aldosterone Syst. 2005;6:43–8.
22. Hao G, Wang Z, Guo R, Chen Z, Wang X, Zhang L, et al. Effects of ACEI/ARB in hypertensive patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled studies. BMC Cardiovasc Disord. 2014;14:148.
23. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failureThe Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–200.
24. Yang J, Zheng Y, Gou X, Pu K, Chen Z, Guo Q, et al. Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis. Int J Infect Dis [Internet]. 2020 [cited 2020 Apr 17];0. Available from: https://www.ijidonline.com/article/S1201-9712(20)30136-3/abstract
25. Lippi G, Wong J, Henry BM. Hypertension and its severity or mortality in Coronavirus Disease 2019 (COVID-19): a pooled analysis. Pol Arch Intern Med. 2020;
26. Kuster GM, Pfister O, Burkard T, Zhou Q, Twerenbold R, Haaf P, et al. SARS-CoV2: should inhibitors of the renin–angiotensin system be withdrawn in patients with COVID-19? Eur Heart J [Internet]. [cited 2020 Apr 13]; Available from: https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa235/5810479
27. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;0:null.
28. Guo Junyi, Huang Zheng, Lin Li, Lv Jiagao. Coronavirus Disease 2019 (COVID‐19) and Cardiovascular Disease: A Viewpoint on the Potential Influence of Angiotensin‐Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome Coronavirus 2 Infection. J Am Heart Assoc. 2020;9:e016219.
29. Gilstrap Lauren G., Fonarow Gregg C., Desai Akshay S., Liang Li, Matsouaka Roland, DeVore Adam D., et al. Initiation, Continuation, or Withdrawal of Angiotensin‐Converting Enzyme Inhibitors/Angiotensin Receptor Blockers and Outcomes in Patients Hospitalized With Heart Failure With Reduced Ejection Fraction. J Am Heart Assoc. 6:e004675.
30. Piccoli GB, Anania P, Biancone L, Mezza E, Vischi M, Jeantet A, et al. Hypertensive rebound after angiotensin converting enzyme inhibitor withdrawal in diabetic patients with chronic renal failure. Nephrol Dial Transplant. 2001;16:1084–5.
31. Mudumbai SC, Takemoto S, Cason BA, Au S, Upadhyay A, Wallace AW. Thirty-day mortality risk associated with the postoperative nonresumption of angiotensin-converting enzyme inhibitors: A retrospective study of the veterans affairs healthcare system. J Hosp Med. 2014;9:289–96.
32. Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112–6.
33. Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections | Nature Communications [Internet]. [cited 2020 Apr 13]. Available from: https://www.nature.com/articles/ncomms4594
34. Gu H, Xie Z, Li T, Zhang S, Lai C, Zhu P, et al. Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus. Sci Rep. 2016;6:19840.
35. Treml B, Neu N, Kleinsasser A, Gritsch C, Finsterwalder T, Geiger R, et al. Recombinant angiotensin-converting enzyme 2 improves pulmonary blood flow and oxygenation in lipopolysaccharide-induced lung injury in piglets. Crit Care Med. 2010;38:596–601.
36. Liu J, Zhang P-S, Yu Q, Liu L, Yang Y, Guo F-M, et al. Losartan inhibits conventional dendritic cell maturation and Th1 and Th17 polarization responses: Νovel mechanisms of preventive effects on lipopolysaccharide-induced acute lung injury. Int J Mol Med. 2012;29:269–76.
37. Asperen RMW, Lutter R, Specht PA, Moll GN, Woensel JB van, Loos CM van der, et al. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1–7) or an angiotensin II receptor antagonist. J Pathol. 2011;225:618–27.
38. Klein N, Gembardt F, Supé S, Kaestle S, Nickles H, Erfinanda L, et al. Angiotensin-(1–7) Protects From Experimental Acute Lung Injury. Crit Care Med [Internet]. 2013 [cited 2020 Apr 13];41. Available from: insights.ovid.com
39. Wagenaar GTM, Laghmani EH, Fidder M, Sengers RMA, de Visser YP, de Vries L, et al. Agonists of MAS oncogene and angiotensin II type 2 receptors attenuate cardiopulmonary disease in rats with neonatal hyperoxia-induced lung injury. Am J Physiol-Lung Cell Mol Physiol. 2013;305:L341–51.
40. Zambelli V, Bellani G, Borsa R, Pozzi F, Grassi A, Scanziani M, et al. Angiotensin-(1-7) improves oxygenation, while reducing cellular infiltrate and fibrosis in experimental Acute Respiratory Distress Syndrome. Intensive Care Med Exp. 2015;3:8.
41. Yu X, Lin Q, Qin X, Ruan Z, Zhou J, Lin Z, et al. ACE2 Antagonizes VEGFa to Reduce Vascular Permeability During Acute Lung Injury. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol. 2016;38:1055–62.
42. Yang P, Gu H, Zhao Z, Wang W, Cao B, Lai C, et al. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep. 2014;4:7027.
43. Ji Y, Gao F, Sun B, Hao J, Liu Z. Angiotensin-Converting Enzyme 2 Inhibits Apoptosis of Pulmonary Endothelial Cells During Acute Lung Injury Through Suppressing SMAD2 Phosphorylation. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol. 2015;35:2203–12.
44. Unthank JL, McClintick JN, Labarrere CA, Li L, Distasi MR, Miller SJ. Molecular basis for impaired collateral artery growth in the spontaneously hypertensive rat: insight from microarray analysis. Physiol Rep. 2013;1:e0005.
45. Simões E Silva AC, Teixeira MM. ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis. Pharmacol Res. 2016;107:154–62.
46. Simões e Silva AC, Silveira KD, Ferreira AJ, Teixeira MM. ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. Br J Pharmacol. 2013;169:477–92.
47. Wang X, Khaidakov M, Ding Z, Mitra S, Lu J, Liu S, et al. Cross-talk between inflammation and angiotensin II: studies based on direct transfection of cardiomyocytes with AT1R and AT2R cDNA. Exp Biol Med Maywood NJ. 2012;237:1394–401.
48. Zhang P, Zhu L, Cai J, Lei F, Qin J-J, Xie 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. 2020;CIRCRESAHA.120.317134.
49. Ferrario Carlos M., Jessup Jewell, Chappell Mark C., Averill David B., Brosnihan K. Bridget, Tallant E. Ann, et al. Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2. Circulation. 2005;111:2605–10.
50. Du R-H, Liang L-R, Yang C-Q, Wang W, Cao T-Z, Li M, et al. Predictors of Mortality for Patients with COVID-19 Pneumonia Caused by SARS-CoV-2: A Prospective Cohort Study. Eur Respir J [Internet]. 2020 [cited 2020 Apr 14]; Available from: https://erj.ersjournals.com/content/early/2020/04/01/13993003.00524-2020
51. REKOMENDASI RAAS ANTAGONIS PADA COVID-19 - News & Event | Perhimpunan Dokter Spesialis Kardiovaskuler Indonesia (PERKI) [Internet]. [cited 2020 Apr 13]. Available from: http://www.inaheart.org/news_and_events/news/2020/3/26/rekomendasi_raas_antagonis_pada_covid-19
52. 20200329 ADS Letter re COVID-19 and Diabetes HPs 29032020_Update .pdf [Internet]. [cited 2020 Apr 19]. Available from: https://diabetessociety.com.au/downloads/20200329%20ADS%20Letter%20re%20COVID-19%20and%20Diabetes%20HPs%2029032020_Update%20.pdf
53. Secretariat Y. Statement on COVID-19 and Blood Pressure Medication [Internet]. HBPRCA | High Blood Pressure Research Council of Australia. 2020 [cited 2020 Apr 19]. Available from: https://www.hbprca.com.au/statement-on-covid-19/
54. COVID-19 Information – American Society of Pediatric Nephrology (ASPN) [Internet]. [cited 2020 Apr 19]. Available from: https://www.aspneph.org/covid-19-information/
55. COVID-19: An ACP Physician’s Guide + Resources (Last Updated April 17, 2020 at 4 PM) - Treatment: Pharmacotherapy [Internet]. [cited 2020 Apr 19]. Available from: https://assets.acponline.org/coronavirus/scormcontent/?&_ga=2.24115962.1176416039.1587301912-1499942903.1587301912#/lessons/Mql0jIISmbXLiv0N6vF-nByg_ATABT_p
56. HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19 [Internet]. American College of Cardiology. [cited 2020 Apr 19]. Available from: http%3a%2f%2fwww.acc.org%2flatest-in-cardiology%2farticles%2f2020%2f03%2f17%2f08%2f59%2fhfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19
57. The Renal Association, UK position statement on COVID-19 and ACE Inhibitor/Angiotensin Receptor Blocker use - The Renal Association [Internet]. [cited 2020 Apr 19]. Available from: https://renal.org/covid-19/ra-resources-renal-professionals/renal-association-uk-position-statement-covid-19-ace-inhibitorangiotensin-receptor-blocker-use/
58. A statement from the International Society of Hypertension on COVID-19 | The International Society of Hypertension [Internet]. [cited 2020 Apr 19]. Available from: https://ish-world.com/news/a/A-statement-from-the-International-Society-of-Hypertension-on-COVID-19/
59. CCS_CHFS_Update_COVID__CV_medications_Mar20.pdf [Internet]. [cited 2020 Apr 19]. Available from: http://www.ccs.ca/images/Images_2020/CCS_CHFS_Update_COVID__CV_medications_Mar20.pdf
60. Khan N. Hypertension Canada’s Statement on: Hypertension, ACE-Inhibitors and Angiotensin Receptor Blockers and COVID-19 [Internet]. 2020 [cited 2020 Apr 15]. Available from: https://hypertension.ca/wp-content/uploads/2020/03/2020-30-15-Hypertension-Canada-Statement-on-COVID-19-ACEi-ARB.pdf
61. COVID-19: Comunicado Urgente | Manejo de pacientes hipertensos | [Internet]. Seh-lelha - Sociedad Española de Hipertensión Liga Española para la Lucha contra la Hipertensión Arterial. 2020 [cited 2020 Apr 19]. Available from: https://www.seh-lelha.org/covid-19/
62. Cohen J. NephJC statement on SARS-CoV-2 virus, COVID-19, and ACEi/ARB treatment. :4.
63. Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers [Internet]. [cited 2020 Apr 19]. Available from: https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang, https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang
64. ESH LETTER COVID-19 | European Society of Hypertension [Internet]. [cited 2020 Apr 19]. Available from: https://www.eshonline.org/spotlights/esh-letter-covid-19-2/
Published
2020-05-20
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How to Cite
Henrina, J., Putra, I., Gunawan, H. F., Cahyadi, I., & Suciadi, L. (2020). Recommendations of RAAS Blocker Use Amidst The Coronavirus Pandemic. Indonesian Journal of Cardiology, 1(1). https://doi.org/10.30701/ijc.1007
Section
Review Article