Update Alert 9: 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 (2022)

LettersApril 2022Update Alert 9: 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, Kathryn Vela, MLIS, AHIPKatherine Mackey, MD, MPPVA Portland Health Care System, Portland, OregonSearch for more papers by this author, Devan Kansagara, MD, MCRVA Portland Health Care System, Portland, OregonSearch for more papers by this author, Kathryn Vela, MLIS, AHIPVA Portland Health Care System, Portland, OregonSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L21-0791 SectionsSupplemental MaterialAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail In Update Alerts 7 and 8, we summarized the state of the evidence for 2 key questions of this systematic review: whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) increase the risk for SARS-CoV-2 infection or worse outcomes (1, 2). In both cases, we have high confidence in the evidence indicating that these medications are not associated with increased risk for infection or severe disease. Because we consider these findings to be stable, we retired the key question about risk for SARS-CoV-2 infection in February 2021 and retired the key question about disease severity in June 2021.In this update alert, we summarize available evidence about our third key question: the benefits and harms of initiating an ACEI or ARB in adults with COVID-19 who were not previously receiving these medications. In Update Alert 8, we provided an overview of in-progress trials but did not identify any completed studies. In an updated literature search from 5 April to 22 November 2021 using the same search strategy as our original review (3), we identified 277 potentially relevant articles and included 4 completed trials with published results (Supplement Table 1) (4–7). We used the same methods for study selection, data extraction, quality assessment, and evidence synthesis as we described in our original review (3).Three inpatient trials evaluated ARB initiation. Specific interventions were 80 mg of telmisartan twice daily for 14 days compared with standard care, 12.5 mg of losartan twice daily for 10 days compared with standard care, and 25 mg of losartan daily for at least 14 days compared with 5 mg of amlodipine. In the trial of telmisartan, done among 158 adults in Argentina, 30-day mortality risk was lower with telmisartan than with usual care (relative risk, 0.19 [95% CI, 0.06 to 0.57]) (4). However, we have methodological concerns about this trial (rated high risk of bias) because of differences between groups at baseline as well as changes in study end points and some secondary outcomes during the study period (Supplement Table 2). The other 2 trials of losartan, one of 31 hospitalized adults with mild to moderate hypoxia done in the United States and the other of 80 hospitalized adults with hypertension in Iran, did not identify a mortality benefit (5, 6). In the U.S. study, the need for intensive care was also similar between the intervention and comparison groups (1 of 16 [6%] versus 2 of 15 [13%], respectively) (5). In addition to the inconsistency in the direction of effect across studies, all studies were small (fewer than 200 participants) and had low event rates, making results imprecise. This evidence is insufficient to determine the benefits and harms of initiating ACEIs or ARBs among adults hospitalized with COVID-19 (Supplement Table 3).We identified 1 trial done in the outpatient setting of 117 adults in the United States who tested positive for SARS-CoV-2 (7). This trial found that 25 mg of losartan twice daily for 10 days compared with placebo did not result in a lower risk for hospitalization. The absolute difference in all-cause hospitalization between groups was −3.5%, favoring the placebo (7). Although well conducted (rated low risk of bias), this trial was small, with low event rates. This evidence is insufficient to determine the effects of initiating ACEIs or ARBs among nonhospitalized adults with COVID-19 (Supplement Table 3).Given the numerous deficiencies of the existing evidence base, additional evidence is needed to determine the benefits and harms of initiating ACEIs or ARBs for COVID-19. We also note that these trials were all completed by the fall of 2020 and have unclear applicability to patients contemporaneously diagnosed with COVID-19, who may have different disease trajectories based on vaccine status, infection with different SARS-CoV-2 variants, or general improvements in COVID-19 care over time.Several clinical trials are in progress, including 3 large trials (estimated sample size >1000), and an updated list is presented in Supplement Table 4 (8–18). We will monitor these trials for updates monthly and anticipate providing a final update alert in the summer of 2022 when more results are available.References1. Mackey K, Kansagara D, Vela K. Update alert 7: risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults [Letter]. Ann Intern Med. 2021;174:W25-W29. [PMID: 33395346] doi:10.7326/L20-1446 LinkGoogle Scholar2. Mackey K, Kansagara D, Vela K. Update alert 8: risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults. Ann Intern Med. 2021;174:W54-W55. [PMID: 33900794] doi:10.7326/L21-0223 LinkGoogle Scholar3. 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 Scholar4. Duarte M, Pelorosso F, Nicolosi LN, et al. Telmisartan for treatment of Covid-19 patients: an open multicenter randomized clinical trial. EClinicalMedicine. 2021;37:100962. [PMID: 34189447] doi:10.1016/j.eclinm.2021.100962 CrossrefMedlineGoogle Scholar5. Geriak M, Haddad F, Kullar R, et al. Randomized prospective open label study shows no impact on clinical outcome of adding losartan to hospitalized COVID-19 patients with mild hypoxemia. Infect Dis Ther. 2021;10:1323-1330. [PMID: 33977506] doi:10.1007/s40121-021-00453-3 CrossrefMedlineGoogle Scholar6. Nouri-Vaskeh M, Kalami N, Zand R, et al. Comparison of losartan and amlodipine effects on the outcomes of patient with COVID-19 and primary hypertension: a randomised clinical trial. Int J Clin Pract. 2021;75:e14124. [PMID: 33650197] doi:10.1111/ijcp.14124 CrossrefMedlineGoogle Scholar7. Puskarich MA, Cummins NW, Ingraham NE, et al. A multi-center phase II randomized clinical trial of losartan on symptomatic outpatients with COVID-19. EClinicalMedicine. 2021;37:100957. [PMID: 34195577] doi:10.1016/j.eclinm.2021.100957 CrossrefMedlineGoogle Scholar8. Randomized Controlled Trial of Losartan for Patients With COVID-19 Requiring Hospitalization [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04312009 on 24 November 2021. Google Scholar9. Efficacy of Captopril Nebulization in Covid-19 Patients Suffering of SARS CoV-2 Pneumonia. A Randomized Phase II Study [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04355429 on 24 November 2021. Google Scholar10. Effectiveness and Safety of Telmisartan in Acute Respiratory Failure Due to COVID-19 [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04510662 on 24 November 2021. Google Scholar11. A Randomized, Double-blind, Placebo-Controlled Trial to Evaluate the Efficacy of Ramipril to Prevent ICU Admission, Need for Mechanical Ventilation or Death in Persons With COVID-19 [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04366050 on 24 November 2021. Google Scholar12. Host Response Mediators in Coronavirus (COVID-19) Infection - Is There a Protective Effect of Losartan on Outcomes of Coronavirus Infection? [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04606563 on 24 November 2021. Google Scholar13. Randomized, Double-Blind, Placebo-Controlled Pilot Clinical Trial of the Safety and Efficacy of Telmisartan for the Mitigation of Pulmonary and Cardiac Complications in COVID-19 Patients [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04360551 on 24 November 2021. Google Scholar14. Comparison Of Therapeutics for Hospitalized Patients Infected With SARS-CoV-2 In a Pragmatic aDaptive randoMizED Clinical Trial During the COVID-19 Pandemic (COVID MED Trial) [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04328012 on 24 November 2021. Google Scholar15. Controlled evaLuation of Angiotensin Receptor Blockers for COVID-19 respIraTorY Disease [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04394117 on 24 November 2021. Google Scholar16. Evaluation of the Potential Benefit of Renin-angiotensin System Inhibitors (RASi, ACEi/ARB) in High-risk Patients With COVID-19. The COVID-RASi Trial [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04591210 on 24 November 2021. Google Scholar17. Randomized, Double-Blind, Placebo-Controlled Pilot Clinical Trial of the Safety and Efficacy of Telmisartan for the Treatment of COVID-19 in Hospitalized Patients [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04715763 on 24 November 2021. Google Scholar18. Randomized Trial of ACEIs in Treatment of COVID-19 [clinical trial]. Accessed at https://clinicaltrials.gov/ct2/show/NCT04345406 on 24 November 2021. Google Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: VA Portland Health Care System, Portland, OregonDisclaimer: 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=L21-0791.Corresponding Author: Katherine Mackey, MD, MPP, VA Portland Health Care System, 3710 SW US Veterans Hospital Road, Portland, OR 97239; e-mail, Katherine.[email protected]gov.This article was published at Annals.org on 8 February 2022. 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 3: 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 10: 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 Metrics Cited byUpdate Alert 10: Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in AdultsKatherine Mackey, MD, MPP, Devan Kansagara, MD, MCR, Kathryn Vela, MLIS, AHIP April 2022Volume 175, Issue 4Page: W47-W48 ePublished: 8 February 2022 Issue Published: April 2022 PDF downloadLoading ...