A Meta-analysis of the Relationship Between Renin-Angiotensin-Aldosterone System Inhibitors and COVID-19

Abstract

The angiotensin converting enzyme (ACE) 2 is a cell surface protein used for entry into type II pneumocytes and other tissues by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the infective agent of COVID-19.1Vaduganathan M Vardeny O Michel T McMurray JJ Pfeffer MA Solomon SD Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1405) Google Scholar It has been demonstrated that ACE2 is upregulated on tissues by renin-angiotensin-aldosterone system (RAAS) inhibitors. This raised concerns that RAAS inhibitors may increase susceptibility and worsen prognosis in COVID-19. In contrast, ACE2 facilitates degradation of angiotensin II and has an anti-inflammatory function and may actually protect the lungs and other tissues from injury.1Vaduganathan M Vardeny O Michel T McMurray JJ Pfeffer MA Solomon SD Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1405) Google Scholar Thus, the effect of RAAS inhibitors on susceptibility and prognosis of COVID-19 continues to be the subject of much debate.1Vaduganathan M Vardeny O Michel T McMurray JJ Pfeffer MA Solomon SD Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1405) Google Scholar Individual observational studies in the area have yielded equivocal results; hence, we sought to conduct a meta-analysis of all available data to provide greater insight. For this study, PubMed and Scopus were searched in May 2020 using the following keywords and their MeSH terms: “COVID-19,” “hypertension,” “ACE inhibitors (ACEIs),” and “Angiotensin receptor blockers (ARBs).” Studies were included if they:1Vaduganathan M Vardeny O Michel T McMurray JJ Pfeffer MA Solomon SD Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19.N Engl J Med. 2020; 382: 1653-1659Crossref PubMed Scopus (1405) Google Scholar they reported the risk of testing positive for COVID-19 and/or the risk of mortality in COVID-positive patients; and2Mancia G Rea F Ludergnani M Apolone G Corrao G Renin–angiotensin–aldosterone system blockers and the risk of Covid-19.N Engl J Med. 2020; 382: 2431-2440Crossref PubMed Scopus (759) Google Scholar compared hypertensive patients prescribed RAAS inhibitors to those not using these drugs. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) from each study were pooled using a random-effects model. A p-value <0.05 was considered significant. Our initial search yielded 950 potential studies. After exclusions, eight studies2Mancia G Rea F Ludergnani M Apolone G Corrao G Renin–angiotensin–aldosterone system blockers and the risk of Covid-19.N Engl J Med. 2020; 382: 2431-2440Crossref PubMed Scopus (759) Google Scholar, 3Mehta N Kalra A Nowacki AS Anjewierden S Han Z Bhat P Carmona-Rubio AE Jacob M Procop GW Harrington S Milinovich A Svensson LG Jehi L Young JB Chung MK Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; (Published online on May 05, 2020)Crossref Scopus (279) Google Scholar, 4Meng J Xiao G Zhang J He X Ou M Bi J et al.Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension.Emerg Microbes Infect. 2020; 9: 757-760Crossref PubMed Scopus (425) Google Scholar, 5Peng YD Meng K Guan HQ Leng L Zhu RR Wang BY et al.[Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV].Zhonghua Xin Xue Guan Bing Za Zhi. 2020; 48: E004PubMed Google Scholar, 6Reynolds HR Adhikari S Pulgarin C Troxel AB Iturrate E Johnson SB et al.Renin–angiotensin–aldosterone system inhibitors and risk of Covid-19.N Engl J Med. 2020; 382: 2441-2448Crossref PubMed Scopus (760) Google Scholar, 7Richardson S Hirsch JS Narasimhan M Crawford JM McGinn T Davidson KW et al.Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City Area.JAMA. 2020; Crossref PubMed Scopus (5344) Google Scholar, 8Yang G Tan Z Zhou L Yang M Peng L Liu J et al.Effects of ARBs and ACEIs on virus infection, inflammatory status and clinical outcomes in COVID-19 patients with hypertension: a single center retrospective study.Hypertens (Dallas, Tex: 1979). 2020; 76: 51-58Crossref PubMed Scopus (188) Google Scholar, 9Zhang P Zhu L Cai J Lei F Qin JJ Xie J Liu YM Zhao YC Huang X Lin L Xia M Chen MM Cheng X Zhang X Guo D Peng Y Ji YX Chen Y Chen J She ZG Wang Y Xu Q Tan R Wang H Lin J Luo P Fu S Cai H Ye P Xiao B Mao W Liu L Yan Y Liu M Chen M Zhang XJ Wang X Touyz RM Xia J Zhang BH Huang X Yuan Y Rohit L Liu PP Li H 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; 126: 1671-1681Crossref PubMed Scopus (754) Google Scholar with a total of 62,706 patients (n = 20,316 ACEI/ARB users and n = 42,390 nonusers) remained for analysis. Study and baseline characteristics are provided in Table 1. Pooled analysis revealed no significant association between the likelihood of testing positive for COVID-19 and the use of ACEIs (OR 0.96 [0.88 to 1.04]; p = 0.29; I2 = 0%) (Figure 1) or ARBs (OR 0.99 [0.91 to 1.08]; p = 0.90; I2 = 5%) (Figure 1). Similarly, no significant difference was observed in mortality rate among hypertensive patients prescribed RAAS inhibitors compared with hypertensive patients not prescribed these medications (OR 0.74 [0.34 to 1.58]; p = 0.43; I2 = 65%) (Figure 1).Table 1Baseline and study characteristicsStudyDesignCountryTotal patientsCOVID-19 positive (%)RAAS inhibitor group (Total, ACEi, ARB)Non-RAAS inhibitor group (Total, non-ACEI, non-ARB)AgeMale (%)AdjustmentStudies reporting mortalityMeng et al.Cross-sectionalChina42-17, -, -25, -, -64.5 (55.80 - 69.00)57.1-Richardson et al.RetrospectiveUSA2411--, 140, 1942077, -, -63 (52 - 75)60.3-Yang et al.RetrospectiveChina126-43, -, -83, -, -66 (61 - 73)49.2-Yudong et al.RetrospectiveChina112-22, -, -90, -, -62--Zhang et al.RetrospectiveChina1128-188, -, -940, -, --ACEIARB - 53.2-Studies reporting risk of testing positive for COVID-19Mancia et al.Case-controlItaly37,03116.915,375, 8071, 730421,656, -, -68 ± 1363Multivariable adjustment for severity, sex, municipality, age at diagnosis, a number of treatment-related covariates and markers of patient clinical statusMehta et al.Cross-sectionalUSA184729.42285, 1322, 98216187, 17150, 17490ACEI - 63, ARB -64ACEI - 49, ARB - 59Propensity matched for age, sex, diabetes, coronary artery disease, hypertension, chronic obstructive pulmonary disease and heart failureReynolds et al.Cross-sectionalUSA338446.81692, 954, 10571692, 954, 1057ACEI - 64.7, ARB - 66ACEI - 56, ARB - 50Propensity matched for age; sex; race; ethnic group; body-mass index; smoking history; history of hypertension, myocardial infarction, heart failure, diabetes, chronic kidney disease, and obstructive lung disease (e.g., asthma and obstructive pulmonary diseases); and other classes of medication.RAAS inhibitor = Renin-angiotensin-aldosterone system inhibitor; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker. Open table in a new tab RAAS inhibitor = Renin-angiotensin-aldosterone system inhibitor; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker. The results of the current meta-analysis suggest that neither ACEI nor ARB use is significantly associated with the odds of testing positive with COVID-19. This result can be considered robust, as it was derived from 3 large-scale studies2Mancia G Rea F Ludergnani M Apolone G Corrao G Renin–angiotensin–aldosterone system blockers and the risk of Covid-19.N Engl J Med. 2020; 382: 2431-2440Crossref PubMed Scopus (759) Google Scholar,3Mehta N Kalra A Nowacki AS Anjewierden S Han Z Bhat P Carmona-Rubio AE Jacob M Procop GW Harrington S Milinovich A Svensson LG Jehi L Young JB Chung MK Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19).JAMA Cardiol. 2020; (Published online on May 05, 2020)Crossref Scopus (279) Google Scholar,6Reynolds HR Adhikari S Pulgarin C Troxel AB Iturrate E Johnson SB et al.Renin–angiotensin–aldosterone system inhibitors and risk of Covid-19.N Engl J Med. 2020; 382: 2441-2448Crossref PubMed Scopus (760) Google Scholar which adjusted for multiple potential confounding factors, including age, sex and co-morbidities. Our findings also show no significant association between RAAS inhibitor use and mortality in COVID-19 patients; however, this result must be viewed with caution as – due to the lack of data – we were unable to analyze ACEI users and ARB users separately, and adjusted data was reported by only one study. In this context, specific aspects of our analysis are notable. COVID-19 patients using RAAS inhibitors are older and have a higher burden of comorbidities, and this may have confounded our results. Adjustment for these factors could potentially shift the results in favor of RAAS inhibitors. Thus, our results support the consensus by multiple specialty societies, which recommend continued usage of RAAS inhibitors in COVID-19 patients and among the general public who have been prescribed these medications. Javed Butler: is a consultant for Abbott, Amgen, Applied Therapeutics, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squib, CVRx, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Relypsa, Vifor. Stephen J Greene: has received a Heart Failure Society of America/ Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis; has received research support from Amgen, Bristol-Myers Squibb and Novartis; has served on advisory boards for Amgen and Cytokinetics; and serves as a consultant for Amgen and Merck. Richard A Krasuski: is a consultant and receives research funding from Actelion Pharmaceuticals. He is also an investigator for Edwards Lifesciences and is an unpaid member of the scientific advisory board for Ventripoint.