Controversial Relationship Between Renin-Angiotensin System Inhibitors and Severity of COVID-19
2020; Lippincott Williams & Wilkins; Volume: 76; Issue: 2 Linguagem: Inglês
10.1161/hypertensionaha.120.15370
ISSN1524-4563
AutoresAugusto Di Castelnuovo, Raffaele De Caterina, Giovanni de Gaetano, Licia Iacoviello,
Tópico(s)COVID-19 Impact on Reproduction
ResumoHomeHypertensionVol. 76, No. 2Controversial Relationship Between Renin-Angiotensin System Inhibitors and Severity of COVID-19 Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessArticle CommentaryPDF/EPUBControversial Relationship Between Renin-Angiotensin System Inhibitors and Severity of COVID-19Announcing a Large Multicentre Case-Control Study in Italy Augusto Di Castelnuovo, Raffaele De Caterina, Giovanni de Gaetano and Licia Iacoviello Augusto Di CastelnuovoAugusto Di Castelnuovo Correspondence to Augusto Di Castelnuovo, Mediterranea Cardiocentro, Via Orazio no. 2, Napoli 80122, Italy. Email E-mail Address: [email protected] https://orcid.org/0000-0001-9767-7998 From the Mediterranea Cardiocentro, Napoli, Italy (A.D.C.) , Raffaele De CaterinaRaffaele De Caterina Cardiovascular Division, Pisa University Hospital, University of Pisa, Italy (R.D.C.) , Giovanni de GaetanoGiovanni de Gaetano Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy (G.d.G., L.I.) and Licia IacovielloLicia Iacoviello Department of Epidemiology and Prevention, IRCCS Neuromed, Pozzilli, Italy (G.d.G., L.I.) Research Centre in Epidemiology and Preventive Medicine (EPIMED), Department of Medicine and Surgery, University of Insubria, Varese, Italy (L.I.). Originally published8 May 2020https://doi.org/10.1161/HYPERTENSIONAHA.120.15370Hypertension. 2020;76:312–313Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 8, 2020: Ahead of Print Experimental evidence supports the hypothesis that the Coronavirus 2019-nCoV uses the SARS-1 coronavirus receptor ACE-2 (angiotensin-converting enzyme 2) to gain entry into target cells.1 ACE inhibitor and ARBs (angiotensin receptor blockers), widely used in patients with hypertension, heart disease, renal disease, diabetes mellitus, and the elderly, increase ACE-2 expression.2 Amplified ACE-2 expression might thus be detrimental in the presence of SARS-CoV-2 infection.3Because of the rapid diffusion of this hypothesis, patients with hypertension taking these drugs and their doctors have become increasingly concerned, and, in some cases, have even stopped or substituted the ACE inhibitor or ARB medications previously prescribed.However, it has been shown that ACE-2 expression is downregulated following SARS-1 infection, resulting in a disproportionate activation of the renin-angiotensin-aldosterone system and exacerbated progression to pneumonia.4 Therefore, the use of ACE inhibitor/ARB in patients with coronavirus 2019 (COVID-19) might have potential advantages and disadvantages.Zhang et al5 have recently reported that, among hospitalized patients with COVID-19 with hypertension, the inpatient use of ACE inhibitor/ARB was associated with a lower all-cause mortality compared with ACE inhibitor/ARB nonusers. A second study from China,6 however, suggests that ACE inhibitor/ARB is not associated with disease severity or mortality in patients with hypertension hospitalized with COVID-19 infection. These are the first, nonexhaustive scientific evidence to answer the practical question of using or not using ACE inhibitor/ARB in patients with COVID-19. The hypothesis that the use of ACE inhibitor or ARB may be helpful, neutral, or harmful in COVID-19 with hypertension or other cardiac conditions, such as heart failure or renal disease or underlying clinical conditions normally requiring or favoring the use of these drugs has to be urgently confirmed/tested in other large epidemiological studies,7,8 possibly in different geographic areas and in patients with different genetic background. Of note, the prevalence of hypertension may differ from one country to another.9National and international Societies and Agencies have recently published position statements recommending physicians and patients to continue treatment with their usual antihypertensive therapy, until convincing evidence will be available supporting either hypothesis.10–12We have, therefore, launched a large multicentre case-control study in Italy. This study is presently ongoing. Hospitalized individuals with confirmed COVID-19 pulmonary symptoms are enrolled. Data extracted from clinical records at one-time point report the highest degree of severity of COVID-19 occurring during hospitalization. Patients are thus classified as suffering no complications, or experiencing either mild pneumonia, or severe pneumonia, or acute respiratory distress syndrome, or death. Classification of disease severity follows the World Health Organization criteria. Cases are COVID-19 patients with severe pneumonia or acute respiratory distress syndrome or death. Controls are those patients healed with only mild pneumonia as the worst in-hospital diagnosis. Main variables of interest are the exposure to either ACE inhibitor or ARB and possible reasons for their use. Individuals stopping ACE inhibitor/ARB use during hospitalization will be considered separately. The association between use of ACE inhibitor or ARB and severity of COVID-19 will be assessed by multivariable logistic regression analysis, stratified by recruitment center. Data on potential confounders, obtained by medical records, include age, sex, history of myocardial infarction, diabetes mellitus, heart failure, hypertension, cancer, respiratory or kidney diseases, severe inflammation, coagulation abnormalities, and use of other drugs. Secondary analyses will test the association of specific type of ACE inhibitor/ARB with COVID-19 severity outcomes.At the moment, 32 hospital centers from 14 Italian regions have agreed to participate, and data from more than 1000 patients have already been entered into a centralized electronic database. The project has been registered in URL: https://www.clinicaltrials.gov (Unique identifier: NCT04318418) and has been approved by the coordinating center's Ethics Committee and by the institutional Ethics Committees of all participating hospitals.We expect to recruit about 2000 patients in the forthcoming weeks. Although the proportion of cases and controls might not be exactly predicted, we expect to collect a sufficient number of cases and controls to test if the use of ACE inhibitor/ARB is independently (positively or negatively) associated with COVID-19 severity, with adequate statistical power.Sources of FundingNone.DisclosuresNone.FootnotesCorrespondence to Augusto Di Castelnuovo, Mediterranea Cardiocentro, Via Orazio no. 2, Napoli 80122, Italy. Email dicastel@ngi.itReferences1. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, 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.CrossrefMedlineGoogle Scholar2. Esler M, Esler D. Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic?J Hypertens. 2020; 38:781–782. doi: 10.1097/HJH.0000000000002450.CrossrefMedlineGoogle Scholar3. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?Lancet Respir Med2020; 8(4):e21. doi: 10.1016/S2213-2600(20)30116-8CrossrefMedlineGoogle Scholar4. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.Nat Med. 2005; 11:875–879. doi: 10.1038/nm1267CrossrefMedlineGoogle Scholar5. Zhang P., Zhu L., Cai J., Lei F., Qin J. J., Xie J., Liu Y. M., Zhao Y. C., Huang X., Lin Let 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 [published online ahead of print, 2020 Apr 17].Circ Res. 2020;10.1161/CIRCRESAHA.120.317134. doi:10.1161/CIRCRESAHA.120.317134LinkGoogle Scholar6. 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 [published online ahead of print, 2020 Apr 23].JAMA Cardiol. 2020;e201624. doi:10.1001/jamacardio.2020.1624CrossrefGoogle Scholar7. 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; 382:1653–1659. doi: 10.1056/NEJMsr2005760CrossrefMedlineGoogle Scholar8. 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. 2020: 75(6):1382–1385. doi: 10.1161/HYPERTENSIONAHA.120.15082LinkGoogle Scholar9. Costanzo S, de Gaetano G, Iacoviello L. Put pressure worldwide on blood pressure control.J Thorac Dis. 2016; 8:E1610–E1613. doi: 10.21037/jtd.2016.12.43CrossrefMedlineGoogle Scholar10. Agenzia Italiana del Farmaco (AIFA), Precisazioni AIFA su Malattia da coronavirus Covid-19 ed utilizzo di ACE-INIBITORI E SARTANI, Italy.Available at: https://www.aifa.gov.it/web/guest/-/precisazioni-aifa-su-malattia-da-coronavirus-covid-19-ed-utilizzo-di-ace-inibitori-e-sartani. Accessed May 20, 2020Google Scholar11. European Society of Cardiology (ESC). Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers.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 May 20, 2020.Google Scholar12. European Medicine Agency. EMA advises continued use of medicines for hypertension, heart or kidney disease during COVID-19 pandemic.Available at: https://www.ema.europa.eu/en/news/ema-advises-continued-use-medicines-hypertension-heart-kidney-disease-during-covid-19-pandemic. Accessed May 20, 2020.Google Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited ByDominiczak A and Meyer T (2021) Hypertension Update: A Reflection of the Past Decade, Hypertension, 78:6, (1670-1673), Online publication date: 1-Dec-2021. Di Castelnuovo A, Costanzo S, Antinori A, Berselli N, Blandi L, Bonaccio M, Cauda R, Guaraldi G, Menicanti L, Mennuni M, Parruti G, Patti G, Santilli F, Signorelli C, Vergori A, Abete P, Ageno W, Agodi A, Agostoni P, Aiello L, Al Moghazi S, Arboretti R, Astuto M, Aucella F, Barbieri G, Bartoloni A, Bonfanti P, Cacciatore F, Caiano L, Carrozzi L, Cascio A, Ciccullo A, Cingolani A, Cipollone F, Colomba C, Colombo C, Crosta F, Danzi G, D'Ardes D, de Gaetano Donati K, Di Gennaro F, Di Tano G, D'Offizi G, Fantoni M, Fusco F, Gentile I, Gianfagna F, Grandone E, Graziani E, Grisafi L, Guarnieri G, Larizza G, Leone A, Maccagni G, Madaro F, Maitan S, Mancarella S, Mapelli M, Maragna R, Marcucci R, Maresca G, Marongiu S, Marotta C, Marra L, Mastroianni F, Mazzitelli M, Mengozzi A, Menichetti F, Meschiari M, Milic J, Minutolo F, Molena B, Montineri A, Mussini C, Musso M, Niola D, Odone A, Olivieri M, Palimodde A, Parisi R, Pasi E, Pesavento R, Petri F, Pinchera B, Poletti V, Ravaglia C, Rognoni A, Rossato M, Rossi M, Sangiovanni V, Sanrocco C, Scorzolini L, Sgariglia R, Simeone P, Taddei E, Torti C, Vettor R, Vianello A, Vinceti M, Virano A, Vocciante L, De Caterina R and Iacoviello L (2021) Heparin in COVID-19 Patients Is Associated with Reduced In-Hospital Mortality: The Multicenter Italian CORIST Study, Thrombosis and Haemostasis, 10.1055/a-1347-6070, 121:08, (1054-1065), Online publication date: 1-Aug-2021. Di Castelnuovo A, Costanzo S, Antinori A, Berselli N, Blandi L, Bonaccio M, Bruno R, Cauda R, Gialluisi A, Guaraldi G, Menicanti L, Mennuni M, My I, Parruti A, Patti G, Perlini S, Santilli F, Signorelli C, Stefanini G, Vergori A, Ageno W, Aiello L, Agostoni P, Al Moghazi S, Arboretti R, Aucella F, Barbieri G, Barchitta M, Bartoloni A, Bologna C, Bonfanti P, Caiano L, Carrozzi L, Cascio A, Castiglione G, Chiarito M, Ciccullo A, Cingolani A, Cipollone F, Colomba C, Colombo C, Crosta F, Dalena G, Dal Pra C, Danzi G, D'Ardes D, de Gaetano Donati K, Di Gennaro F, Di Tano G, D'Offizi G, Filippini T, Maria Fusco F, Gaudiosi C, Gentile I, Gini G, Grandone E, Guarnieri G, Lamanna G, Larizza G, Leone A, Lio V, Losito A, Maccagni G, Maitan S, Mancarella S, Manuele R, Mapelli M, Maragna R, Marra L, Maresca G, Marotta C, Mastroianni F, Mazzitelli M, Mengozzi A, Menichetti F, Milic J, Minutolo F, Molena B, Mussinelli R, Mussini C, Musso M, Odone A, Olivieri M, Pasi E, Perroni A, Petri F, Pinchera B, Pivato C, Poletti V, Ravaglia C, Rossato M, Rossi M, Sabena A, Salinaro F, Sangiovanni V, Sanrocco C, Scorzolini L, Sgariglia R, Simeone P, Spinicci M, Trecarichi E, Veronesi G, Vettor R, Vianello A, Vinceti M, Visconti E, Vocciante L, De Caterina R and Iacoviello L (2021) Lopinavir/Ritonavir and Darunavir/Cobicistat in Hospitalized COVID-19 Patients: Findings From the Multicenter Italian CORIST Study, Frontiers in Medicine, 10.3389/fmed.2021.639970, 8 Sui Y, Li J, Venzon D and Berzofsky J (2021) SARS-CoV-2 Spike Protein Suppresses ACE2 and Type I Interferon Expression in Primary Cells From Macaque Lung Bronchoalveolar Lavage, Frontiers in Immunology, 10.3389/fimmu.2021.658428, 12 Boari G, Chiarini G, Bonetti S, Malerba P, Bianco G, Faustini C, Braglia-Orlandini F, Turini D, Guarinoni V, Saottini M, Viola S, Ferrari-Toninelli G, Pasini G, Mascadri C, Bonzi B, Desenzani P, Tusi C, Zanotti E, Nardin M and Rizzoni D (2020) Prognostic factors and predictors of outcome in patients with COVID-19 and related pneumonia: a retrospective cohort study, Bioscience Reports, 10.1042/BSR20203455, 40:12, Online publication date: 23-Dec-2020. Di Castelnuovo A, Costanzo S, Antinori A, Berselli N, Blandi L, Bonaccio M, Cauda R, Gialluisi A, Guaraldi G, Menicanti L, Mennuni M, Mussinelli R, My I, Parruti G, Patti G, Perlini S, Santilli F, Signorelli C, Stefanini G, Vergori A, Abete P, Ageno W, Agostoni P, Aiello L, Al Moghazi S, Arboretti R, Aucella F, Barbieri G, Barchitta M, Bartoloni A, Bonfanti P, Cacciatore F, Caiano L, Carrozzi L, Cascio A, Castiglione G, Cianfrone S, Ciccullo A, Cingolani A, Cipollone F, Colomba C, Colombo C, Cozzi O, Crisetti A, Crosta F, Danzi G, D'Ardes D, de Gaetano Donati K, Di Gennaro F, Di Tano G, D'Offizi G, Fusco F, Gentile I, Graziani E, Guarnieri G, Larizza G, Leone A, Lio V, Lucia M, Maccagni G, Madaro F, Maitan S, Mancarella S, Manuele R, Mapelli M, Maragna R, Marcucci R, Maresca G, Marongiu S, Marotta C, Marra L, Mastroianni F, Mazzitelli M, Mengozzi A, Menichetti F, Meschiari M, Milic J, Minutolo F, Molena B, Mussini C, Musso M, Odone A, Olivieri M, Palimodde A, Pasi E, Pesavento R, Petri F, Pinchera B, Pivato C, Poletti V, Ravaglia C, Rossato M, Rossi M, Sabena A, Salinaro F, Sangiovanni V, Sanrocco C, Scoppettuolo G, Scorzolini L, Sgariglia R, Simeone P, Trecarichi E, Vettor R, Vianello A, Vinceti M, Virano A, Vocciante L, De Caterina R and Iacoviello L (2020) RAAS inhibitors are not associated with mortality in COVID-19 patients: Findings from an observational multicenter study in Italy and a meta-analysis of 19 studies, Vascular Pharmacology, 10.1016/j.vph.2020.106805, 135, (106805), Online publication date: 1-Dec-2020. Castelnuovo A, Costanzo S, Antinori A, Berselli N, Blandi L, Bruno R, Cauda R, Guaraldi G, Menicanti L, My I, Parruti G, Patti G, Perlini S, Santilli F, Signorelli C, Spinoni E, Stefanini G, Vergori A, Ageno W, Agodi A, Aiello L, Agostoni P, Moghazi S, Astuto M, Aucella F, Barbieri G, Bartoloni A, Bonaccio M, Bonfanti P, Cacciatore F, Caiano L, Cannata F, Carrozzi L, Cascio A, Ciccullo A, Cingolani A, Cipollone F, Colomba C, Crosta F, Pra C, Danzi G, D'Ardes D, Donati K, Giacomo P, Gennaro F, Di Tano G, D'Offizi G, Filippini T, Fusco F, Gentile I, Gialluisi A, Gini G, Grandone E, Grisafi L, Guarnieri G, Lamonica S, Landi F, Leone A, Maccagni G, Maccarella S, Madaro A, Mapelli M, Maragna R, Marra L, Maresca G, Marotta C, Mastroianni F, Mazzitelli M, Mengozzi A, Menichetti F, Meschiari M, Minutolo F, Montineri A, Mussinelli R, Mussini C, Musso M, Odone A, Olivieri M, Pasi E, Petri F, Pinchera B, Pivato C, Poletti V, Ravaglia C, Rinaldi M, Rognoni A, Rossato M, Rossi I, Rossi M, Sabena A, Salinaro F, Sangiovanni V, Sanrocco C, Scorzolini L, Sgariglia R, Simeone P, Spinicci M, Trecarichi E, Venezia A, Veronesi G, Vettor R, Vianello A, Vinceti M, Vocciante L, De Caterina R and Iacoviello L (2020) Use of hydroxychloroquine in hospitalised COVID-19 patients is associated with reduced mortality: Findings from the observational multicentre Italian CORIST study, European Journal of Internal Medicine, 10.1016/j.ejim.2020.08.019, 82, (38-47), Online publication date: 1-Dec-2020. Lévy B and Fauvel J (2020) Renin-angiotensin system blockers and severe acute respiratory syndrome coronavirus 2, Archives of Cardiovascular Diseases, 10.1016/j.acvd.2020.07.001, 113:8-9, (572-578), Online publication date: 1-Aug-2020. August 2020Vol 76, Issue 2 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.120.15370PMID: 32383624 Originally publishedMay 8, 2020 PDF download Advertisement SubjectsACE/Angiotensin Receptors/Renin Angiotensin SystemEpidemiology
Referência(s)