Update Alert 3: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults
Authors: Katherine Mackey, Devan Kansagara, Kathryn Vela
Journal: Annals of Internal Medicine (2020)

Letters26 August 2020Update Alert 3: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in AdultsFREEKatherine Mackey, MD, MPP, Devan Kansagara, MD, MCR, and Kathryn Vela, MLIS, AHIPKatherine Mackey, MD, MPPVA Portland Health Care System, Portland, Oregon (K.M., D.K., K.V.), Devan Kansagara, MD, MCRVA Portland Health Care System, Portland, Oregon (K.M., D.K., K.V.), and Kathryn Vela, MLIS, AHIPVA Portland Health Care System, Portland, Oregon (K.M., D.K., K.V.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-1068 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail An update is available for this article.We searched MEDLINE (Ovid) weekly from 7 July to 3 August 2020 using the same search strategy as described in the original review (1). We did not limit the search by language. This search update yielded 67 results (de-duplicated), and after an independent dual-review process, we identified 2 new meta-analyses and 1 reestimated meta-analysis (2–4), interim results from 1 randomized controlled trial (5), and 13 new observational studies (6–18).New EvidenceResults of 2 meta-analyses found that angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB) use was not associated with coronavirus disease 2019 (COVID-19) disease severity (2, 3). In 1 of these meta-analyses of 9 primary studies with a total of 3936 patients with hypertension, use of ACEIs or ARBs was associated with a lower mortality in COVID-19 (2). In the other meta-analysis of 15 studies of 7410 patients with hypertension, subgroup analysis found that ARB use, but not ACEI use, was associated with lower mortality (3). A third meta-analysis reestimated data from studies included in a prior review and found that exclusion of a retracted study by Mehra and colleagues did not change the prior review's finding of a lack of association with ACEI and ARB use and COVID-19 mortality (4, 19).In addition, interim findings from an ongoing randomized controlled trial (started in 2018) on the use of ramipril among patients with aortic stenosis treated with transcatheter aortic valve replacement found that the use of ramipril was not associated with the incidence or severity of COVID-19 (20). To our knowledge, this is the first study to report findings from a randomized controlled trial on the association between ACEI use and COVID-19.We also identified 13 new observational studies (6–18). One of these observational studies that was based on an analysis of insurance data in Korea addressed our first key question regarding the use of ACEIs and ARBs and COVID-19 risk, finding that increased adherence to ACEI and ARB treatment was associated with a lower incidence of COVID-19 (10). Twelve studies addressed our second key question about ACEI and ARB use and COVID-19 disease severity, and 11 of these studies found a lack of association with ACEIs or ARBs and more severe disease (6–9, 11–13, 15–18). Moreover, 3 of these 11 studies found that use of ACEIs or ARBs was associated with less severe COVID-19 illness (11, 16, 18). The exception was a French study of 149 patients hospitalized with severe COVID-19 illness (defined as an oxygen saturation of 94% or less while the patient was breathing ambient air or receiving oxygen support), 44 of whom were receiving ACEIs or ARBs (14). This study found that ACEI and ARB use was associated with a higher risk for acute kidney injury. However, this study did not examine whether ACEI or ARB use was independently associated with respiratory failure or death.Overall, inclusion of 17 studies from this search update does not change the certainty of evidence rating we reported in the original article for key questions 1 or 2. Although there is a signal toward improved outcomes among patients with COVID-19 who continue use of ACEIs or ARBs, the benefits and harms of initiating ACEIs or ARBs (that is, new users) in COVID-19 treatment remains unclear.Citation UpdateA study by Bean and colleagues that was included in our original manuscript as a preprint has now been published (20).Also of note, we attempted to register our review protocol with PROSPERO, but registration was not accepted given the stage of our review at the time. We followed standard methods and reporting guidelines for systematic reviews (21, 22). We have posted a copy of our protocol to OSF (https://osf.io/qm6h9/).References1. Mackey K, King VJ, Gurley S, et al. Risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults. A living systematic review. Ann Intern Med. 2020;173:195-203. [PMID: 32422062]. doi:10.7326/M20-1515 LinkGoogle Scholar2. Guo X, Zhu Y, Hong Y. Decreased mortality of COVID-19 with renin-angiotensin-aldosterone system inhibitors therapy in patients with hypertension: a meta-analysis [Letter]. Hypertension. 2020;76:e13-e14. [PMID: 32458694] doi:10.1161/HYPERTENSIONAHA.120.15572 CrossrefMedlineGoogle Scholar3. Pranata R, Permana H, Huang I, et al. The use of renin angiotensin system inhibitor on mortality in patients with coronavirus disease 2019 (COVID-19): a systematic review and meta-analysis. Diabetes Metab Syndr. 2020;14:983-990. [PMID: 32615377] doi:10.1016/j.dsx.2020.06.047 CrossrefMedlineGoogle Scholar4. Alamer A, Abraham I. Mortality in COVID-19 patients treated with ACEIs/ARBs: re-estimated meta-analysis results following the Mehra et al. retraction [Letter]. Pharmacol Res. 2020;160:105053. [PMID: 32619721] doi:10.1016/j.phrs.2020.105053 CrossrefMedlineGoogle Scholar5. Amat-Santos IJ, Santos-Martinez S, López-Otero D, et al. Ramipril in high-risk patients with COVID-19. J Am Coll Cardiol. 2020;76:268-276. [PMID: 32470515] doi:10.1016/j.jacc.2020.05.040 CrossrefMedlineGoogle Scholar6. Andrea C, Francesco M, Antonio N, et al. Renin-angiotensin-aldosterone system inhibitors and outcome in patients with SARS-CoV-2 pneumonia: a case series study [Letter]. Hypertension. 2020;76:e10-e12. [PMID: 32383626] doi:10.1161/HYPERTENSIONAHA.120.15312 CrossrefMedlineGoogle Scholar7. De Spiegeleer A, Bronselaer A, Teo JT, et al. The effects of ARBs, ACEIs, and statins on clinical outcomes of COVID-19 infection among nursing home residents. J Am Med Dir Assoc. 2020;21:909-914. [PMID: 32674818] doi:10.1016/j.jamda.2020.06.018 CrossrefMedlineGoogle Scholar8. Golpe R, Pérez-de-Llano LA, Dacal D, et al. Lugo Covid-19 team. Risk of severe COVID-19 in hypertensive patients treated with renin-angiotensin-aldosterone system inhibitors. Med Clin (Barc). 2020. [PMID: 32651067] doi:10.1016/j.medcli.2020.06.013 CrossrefMedlineGoogle Scholar9. Iaccarino G, Grassi G, Borghi C, et al; SARS-RAS Investigators.. Age and multimorbidity predict death among COVID-19 patients: results of the SARS-RAS study of the Italian Society of Hypertension. Hypertension. 2020;76:366-372. [PMID: 32564693] doi:10.1161/HYPERTENSIONAHA.120.15324 CrossrefMedlineGoogle Scholar10. Kim J, Kim DW, Kim KI, et al; Korean Society of Hypertension.. Compliance of antihypertensive medication and risk of coronavirus disease 2019: a cohort study using big data from the Korean National Health Insurance Service. J Korean Med Sci. 2020;35:e232. [PMID: 32597045] doi:10.3346/jkms.2020.35.e232 CrossrefMedlineGoogle Scholar11. Lam KW, Chow KW, Vo J, et al. Continued in-hospital ACE inhibitor and ARB use in hypertensive COVID-19 patients is associated with positive clinical outcomes. J Infect Dis. 2020. [PMID: 32702098] doi:10.1093/infdis/jiaa447 CrossrefMedlineGoogle Scholar12. Liu X, Liu Y, Chen K, et al. Efficacy of ACEIs/ARBs versus CCBs on the progression of COVID-19 patients with hypertension in Wuhan: a hospital-based retrospective cohort study. J Med Virol. 2020. [PMID: 32687223] doi:10.1002/jmv.26315 CrossrefMedlineGoogle Scholar13. Parigi TL, Vespa E, Pugliese N. COVID-19. ACEI/ARBs and gastrointestinal symptoms: the jury is still out on the association [Letter]. Gastroenterology. 2020. [PMID: 32682762] doi:10.1053/j.gastro.2020.06.095 CrossrefMedlineGoogle Scholar14. Oussalah A, Gleye S, Clerc Urmes I, et al. Long-term ACE inhibitor/ARB use is associated with severe renal dysfunction and acute kidney injury in patients with severe COVID-19: results from a referral center cohort in the north east of France. Clin Infect Dis. 2020. [PMID: 32623470] doi:10.1093/cid/ciaa677 CrossrefMedlineGoogle Scholar15. Sardu C, Maggi P, Messina V, et al. Could anti-hypertensive drug therapy affect the clinical prognosis of hypertensive patients with COVID-19 infection? Data from centers of southern Italy. J Am Heart Assoc. 2020:e016948. [PMID: 32633594] doi:10.1161/JAHA.120.016948 CrossrefMedlineGoogle Scholar16. Senkal N, Meral R, Medetalibeyoglu A, et al. Association between chronic ACE inhibitor exposure and decreased odds of severe disease in patients with COVID-19. Anatol J Cardiol. 2020;24:21-29. [PMID: 32628137] doi:10.14744/AnatolJCardiol.2020.57431 CrossrefMedlineGoogle Scholar17. Xu J, Huang C, Fan G, et al. Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis. Front Med. 2020. [PMID: 32621202] doi:10.1007/s11684-020-0800-y CrossrefMedlineGoogle Scholar18. Zhou F, Liu YM, Xie J, et al. Comparative impacts of ACE (angiotensin-converting enzyme) inhibitors versus angiotensin II receptor blockers on the risk of COVID-19 mortality [Letter]. Hypertension. 2020;76:e15-e17. [PMID: 32493070] doi:10.1161/HYPERTENSIONAHA.120.15622 CrossrefMedlineGoogle Scholar19. Zhang X, Yu J, Pan LY, et al. ACEI/ARB use and risk of infection or severity or mortality of COVID-19: a systematic review and meta-analysis. Pharmacol Res. 2020;158:104927. [PMID: 32422341] doi:10.1016/j.phrs.2020.104927 CrossrefMedlineGoogle Scholar20. Bean DM, Kraljevic Z, Searle T, et al. 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. Eur J Heart Fail. 2020;22:967-974. [PMID: 32485082] doi:10.1002/ejhf.1924 CrossrefMedlineGoogle Scholar21. Moher D, Liberati A, Tetzlaff J, et al; PRISMA Group.. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264-9, W64. [PMID: 19622511] LinkGoogle Scholar22. U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(14)-EHC063-EF. Accessed at https://effectivehealthcare.ahrq.gov/products/cer-methods-guide/overview on 11 May 2020. Google Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Katherine Mackey, MD, MPP; Devan Kansagara, MD, MCR; Kathryn Vela, MLIS, AHIPAffiliations: VA Portland Health Care System, Portland, Oregon (K.M., D.K., K.V.)Disclaimer: The views expressed in this article are those of the authors and do not necessarily represent the views of the U.S. Department of Veterans Affairs or the U.S. government.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-1068.Corresponding Author: Devan Kansagara, MD, MCR, VA Portland Health Care System, 3710 Southwest U.S. Veterans Hospital Road, Mail Code: R&D 71, Portland, OR 97239; e-mail, kansagar@ohsu.edu.This article was published at Annals.org on 26 August 2020. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoRisks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults Katherine Mackey , Valerie J. King , Susan Gurley , Michael Kiefer , Erik Liederbauer , Kathryn Vela , Payten Sonnen , and Devan Kansagara Update Alert: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults Devan Kansagara , Katherine Mackey , and Kathryn Vela Update Alert 2: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults Katherine Mackey , Devan Kansagara , and Kathryn Vela Update Alert 4: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults Katherine Mackey , Devan Kansagara , and Kathryn Vela Update Alert 5: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults Katherine Mackey , Devan Kansagara , and Kathryn Vela Update Alert 6: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults Katherine Mackey , Devan Kansagara , and Kathryn Vela Update Alert 7: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults Katherine Mackey , Devan Kansagara , and Kathryn Vela Update Alert 8: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults Katherine Mackey , Devan Kansagara , and Kathryn Vela Update Alert 9: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults Katherine Mackey , Devan Kansagara , Kathryn Vela Update Alert 10: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults Katherine Mackey , Devan Kansagara , Kathryn Vela Metrics Cited byThe impact of the cardiovascular risk factors on short-term in-hospital outcome of patients with COVID-19Past, present and future of living systematic review: a bibliometrics analysisOutpatient Management of COVID-19 6 October 2020Volume 173, Issue 7Page: 130-131KeywordsAngiotensin converting enzyme inhibitorAngiotensin receptor blockerCOVID-19HypertensionMortalityObservational studiesOxygenRespiratory failureStenosisSystematic reviews ePublished: 26 August 2020 Issue Published: 6 October 2020 PDF downloadLoading ...