key: cord-258230-s4ty52kb authors: Grover, Abhinav; Oberoi, Mansi title: A systematic review and meta-analysis to evaluate the clinical outcomes in COVID-19 patients on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers date: 2020-06-15 journal: Eur Heart J Cardiovasc Pharmacother DOI: 10.1093/ehjcvp/pvaa064 sha: doc_id: 258230 cord_uid: s4ty52kb INTRODUCTION: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) share their target receptor site with the SARS-CoV-2 virus, that may cause ACE2 receptor up-regulation which raised concerns regarding ACEI and ARB use in COVID-19 patients. However, many medical professional societies recommended their continued use given the paucity of clinical evidence, but there is a need for an updated systematic review and meta-analysis of the latest clinical studies. METHODS AND RESULTS: A search was conducted on PubMed, Google Scholar, EMBASE, and various preprint servers for studies comparing clinical outcomes and mortality in COVID-19 patients on ACEIs and/or ARBs, and a meta-analysis was performed. A total of 16 studies were included for the review and meta-analysis. There were conflicting findings reported in the rates of severity and mortality in several studies. In a pooled analysis of four studies, there was a statistically non-significant association of ACEI/ARB use with lower odds of developing severe disease vs. non-users [odds ratio (OR) = 0.81, 95% confidence interval (CI): 0.41–1.58, I(2)=50.52, P-value = 0.53). In a pooled analysis of six studies, there was a statistically non-significant association of ACEI/ARB use with lower odds of mortality as compared with non-users (OR = 0.86, 95% CI = 0.53–1.41, I(2) = 79.12, P-value = 0.55). CONCLUSION: It is concluded that ACEIs and ARBs should be continued in COVID-19 patients, reinforcing the recommendations made by several medical societies. Additionally, the individual patient factors such as ACE2 polymorphisms which might confer higher risk of adverse outcomes need to be evaluated further. Severe acute respiratory syndrome coronavirus 2 (SARS-COV2) causes coronavirus disease (COVID-19), a potentially fatal disease that is of immense global public health concern. The initial cases were reported in December 2019 in Wuhan, China. 1 Since then, there have been 3 041 764 confirmed COVID-19 patients in the world as of 27 April 2020, with a total of 211 167 deaths. The USA has the greatest number (988 189) of confirmed cases, with a total of 56 259 deaths. Most cases were diagnosed in New York (291 996), with a total of 22 668 deaths. 2 Several studies, including a recent meta-analysis, have reported that co-existing conditions, including hypertension, cardiac diseases, cerebrovascular diseases, and diabetes, were common among patients with COVID-19 who had severe illness, were admitted to the intensive care unit (ICU), received mechanical ventilation, or died than among patients who had mild illness. 3, 4 Notably, of the most frequent comorbidities reported in these studies of patients with COVID-19, hypertension in particular is often treated with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). 5 This could theoretically result in an up-regulation of ACE2, which is an active binding target for SARS-CoV-2 virus, 6 in the epithelial cells of the lung, intestine, kidney, and blood vessels. Although this raised concerns regarding the use of these drugs in COVID-19 patients, several animal studies presented conflicting findings regarding increased ACE2 expression due to ACEIs and ARBs, and previous human studies suggested that administration of an ACEI/ARB does not increase ACE2 expression. 7 In light of these findings and a paucity of clinical outcome studies, many professional cardiovascular and hypertension societies including the European Society of Cardiology, Italian Society of Pharmacology, International Society of Hypertension (ISH), European Society of Hypertension, Joint American Heart Association/American College of Cardiology/ American Heart Failure Association, and others recommended the continued use of ACEIs/ARBs in COVID-19 patients. [8] [9] [10] [11] [12] However, since the conception of these recommendations, several clinical studies have been conducted which evaluated the association of ACEIs and ARBs with clinical severity and mortality outcomes in COVID-19 patients. Therefore, the medical literature was systematically reviewed, and a meta-analysis was performed of the current clinical studies evaluating the safety and efficacy of ACEs and ARBs in COVID-19 patients. A literature search was conducted on the PubMed/MEDLINE database using keywords, i.e. 'ACE inhibitors AND COVID' and 'ARB AND COVID'. We applied search filters to include humans and English language studies published up to 1 May 2020. Additional papers of possible interest were identified by examining references of pertinent review articles and searching Google Scholar and preprint servers such as MedRxiv and BioRxiv. We included studies which evaluated clinical severity and mortality outcomes for patients with COVID-19 on an ACEI, an ARB, or both. We excluded those studies which were in vitro or conducted in animal models, as well as those human studies which evaluated only ACE expression levels ( Figure 1 ). Information on the demographics, comorbidities, and pharmacotherapy with ACEIs, ARBs, and other drugs, clinical severity outcomes, and mortality was extracted. The meta-analysis for severity and mortality was conducted for four and six peer-reviewed studies, respectively, using the comprehensive metaanalysis (CMA) software version 3 (Biostat Inc., Englewood, NJ, USA). The studies were assessed for methodological quality based on the Newcastle-Ottawa Scale (NOS). 13 The NOS has eight criteria and generates scores ranging from 0 (high risk of bias) to 9 (low risk of bias). Studies with NOS scores of >7 were regarded as high quality. Heterogeneity was assessed using the Higgin's I 2 test, and the choice of fixed or random effects model was made based on the calculated heterogeneity. The publication bias was reported by using funnel plots. We reported the findings based on both a fixed and random effects model derived from the heterogeneity of the studies. A total of 276 articles were found in the search. Based on the screening of titles of the articles, 178 were excluded as they did not meet the inclusion criteria. Further, abstracts of 98 articles were read and, subsequently, the full text of 41 articles were reviewed. Of these, 16 articles were shortlisted which compared the clinical and/or mortality outcomes of COVID-19 patients on an ACEI or ARB with nonusers. [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] Finally, these 16 studies were included for review and, out of these, six and four studies were included in the meta-analysis of mortality and severity outcomes in COVID-19 patients on an ACEI/ ARB, respectively ( Table 1) . 14, 20, [22] [23] [24] 27 (Table 2) Table 2) . In a pooled analysis of four peer-reviewed studies, there was a statistically non-significant association of an ACEI/ARB with lower odds of developing severe disease vs. non-users (OR = 0.81, 95% CI 0.41-1.58, I 2 = 50.52, P-value = 0.53) (Figures 2 and 3) . Similarly, Reynolds et al. found a slightly lower rate of severe outcomes which included admission to the ICU, the use of non-invasive or invasive mechanical ventilation, or death in patients on an ACEI/ARB (24.8%) vs. no ACEI/ARB (24.9%) 14, 15, [17] [18] [19] 21, 22, [25] [26] [27] [28] [29] ( Table 2) . On the contrary, Guo Table 2) . In a pooled analysis of six peer-reviewed studies, there was a statistically non-significant association of ACEIs/ARBs with lower odds of mortality as compared with non-users (OR = 0.86, 95% CI = 0.53-1.41, I 2 = 79.12, P-value = 0.55) (Figures 4 and 5) The sensitivity of the pooled results of clinical severity and mortality outcomes to the removal of each study is reported in Supplementary material online, Figures S1-S4. Despite the worldwide implementation of public health measures such as social distancing, contact tracing, and mass testing to aid in the control of COVID-19, the global cases have risen to >3 million, and >200 000 patients had lost their lives by 27 April 2020, 2,31 which further requires attention. Several studies have reported increased rates of COVID-19-associated mortality in patients with significant comorbidities such as hypertension, cardiovascular disease, chronic kidney disease, or heart failure. 3, 4 Although ACEIs and ARBs are commonly prescribed to treat some of these comorbidities, the fact that the ACE2 receptor is the main binding site for entry of SARS-CoV-2 caused concerns regarding the use of ACEIs and ARBs in such patients. 5, 32 Several evidence-based consensus and position statements were formulated by various cardiovascular and hypertension societies which recommended continued use of ACEIs and ARBs in COVID-19 patients, citing the lack of any contrary clinical evidence. [8] [9] [10] [11] [12] Since then, however, several clinical studies have evaluated the association of ACEIs and ARBs in COVID-19 patients and comorbidities. It is imperative to accurately predict clinical outcomes of COVID-19 patients, especially those with comorbidities and taking an ACEI or ARB, to decide whether to continue or switch to another medication. However, there were conflicting findings reported in several studies, as Meng (Figures 2 and 3) . ACEI and ARB use in COVID-19 patients mortality outcomes, strengthening their conclusions regarding safety of ACEI/ARB use; however, a large sample size study conducted in New York in >1000 COVID-19 patients by Richardson et al. raised concerns of worse mortality outcomes with ACEI/ARB use and cannot be overlooked. 15, 21 In a pooled analysis of six peer-reviewed studies, there was a statistically non-significant association of ACEI/ ARB use with lower odds of mortality as compared with non-users (OR = 0.86, 95% CI = 0.53-1.41, I 2 = 79.12, P-value = 0.55) (Figures 4 and 5) . Several hypotheses have been put forward explaining the positive and negative aspects of ACEI/ARB administration in COVID-19 patients. Positive effects include ACE2 receptor blockade, disabling viral entry into the heart and lungs, and an overall decrease in inflammation secondary to ACEIs/ARBs, suggesting that the use of an ACEI might be protective against respiratory complications. Negative effects include a possible retrograde feedback mechanism, by which ACE2 receptors are up-regulated, which may lead to severe pneumonia, increasing the risk of severe outcomes and mortality. 33 Individuals with ACE2 polymorphisms have an increased genetic predisposition for an increased risk of SARS-CoV-2 infection and may have harmful effects of ACEIs/ARBs. 34 This aspect is worth considering and needs to be evaluated in future studies. To the best of our knowledge, this systematic review is a comprehensive exploration and analysis of existing literature in this topic to date. Our review has limitations in its rigour due to the scarce existing data and diverse study types available. The rapidly emerging knowledge base of COVID-19 presents the possibility that a few studies (particularly unpublished/under peer review) remain uncaptured. However, we have tried our best to mitigate this by allowing broad search terms and by including many databases and repositories. We have also tried to comprehensively review and analyse the existing data. Considering the inconsistent clinical studies and conflicting hypotheses, it is essential to evaluate the clinical outcomes in COVID-19 patients on ACEIs/ARBs in future large studies, particularly randomized controlled trials, and additionally evaluate the association of clinical outcomes with ACE2 polymorphisms. Based on this, there are ongoing trials studying the effect of losartan (an ARB) in patients with COVID-19 in outpatient and inpatient settings (NCT04311177 and NCT04312009). 35, 36 Conclusion It is concluded that ACEIs and ARBs should be continued in COVID-19 patients, reinforcing the recommendations made by several medical societies. Additionally, the individual patient factors such as ACE2 polymorphisms which might confer higher risk of adverse outcomes need to be evaluated further. A.G.: conception and design, data acquisition and analysis, drafting the manuscript, and final approval of the manuscript. M.O.: data acquisition, drafting and final approval of the manuscript. Supplementary material is available at European Heart Journal -Cardiovascular Pharmacotherapy online. 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SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor Outcomes in patients with COVID-19 infection taking ACEI/ARB Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Losartan for Patients With COVID-19 Not Requiring Hospitalization -Full Text View -ClinicalTrials Losartan for Patients With COVID-19 Requiring Hospitalization -Full Text View -ClinicalTrials Data availability statement: The data underlying this article are available in the article and in its online Supplementary material.