key: cord-0857946-lboa7rtn authors: Barochiner, J.; Martinez, R. title: Use of inhibitors of the renin angiotensin system and COVID-19 prognosis: a systematic review and meta-analysis date: 2020-05-26 journal: nan DOI: 10.1101/2020.05.19.20106799 sha: 104423a83fe50425f87d6e1478bd5cfa656e7247 doc_id: 857946 cord_uid: lboa7rtn Background: controversy has arisen in the scientific community on whether the use of renin angiotensin system (RAS) inhibitors in the context of COVID-19 would be of benefit or harmful. A meta-analysis of eligible studies comparing the occurrence of severe and fatal COVID-19 in infected patients who were under treatment with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) vs no treatment or other antihypertensives was conducted. Methods: PubMed, Google Scholar, the Cochrane Library, MedRxiv and BioRxiv were searched for relevant studies. Fixed-effect models or random-effect models were used depending on the heterogeneity between estimates. Results: a total of fifteen studies with 21,614 patients were included. The use of RAS inhibitors was associated with a non-significant 20% decreased risk of the composite outcome (death, admission to intensive care unit, mechanical ventilation requirement or progression to severe or critical pneumonia): RR 0.81 (95%CI: 0.63-1.04), p=0.10, I2=82%. In a subgroup analysis that included hypertensive subjects only, ACEI/ARB were associated with a 27% significant decrease in the risk of the composite outcome (RR 0.73 (95%CI: 0.56-0.96), p=0.02, I2=65%). Conclusion: the results of this pooled analysis suggest that the use of ACEI/ARB does not worsen the prognosis, and could even be protective in hypertensive subjects. Patients should continue these drugs during their COVID-19 illness. December 2019 and caused by the betacoronavirus SARS-CoV-2, was declared a pandemic by the World Health Organization in March 2020, affecting more than 3,400,000 people and causing more than 240,000 deaths. [1] Interestingly, COVID-19 seems to manifest as a more severe disease in people with cardiovascular comorbidities, such as hypertension, [2, 3] although is not yet very clear whether this association is independent from advanced age. [4] Myocardial injury has been proposed as the link between the inflammatory pathogenesis during the progress of the disease and the poorer prognosis. [5, 6] It has been postulated that the virus could damage myocardial cells through several mechanisms including direct damage and systemic inflammatory responses. [6] Subjects with preexisting cardiovascular diseases might be more susceptible to COVID-19-induced heart injury. Sars-Cov-2 gains entrance to cells through the angiotensin-converting enzyme 2 (ACE2),[7] a carboxypeptidase that converts angiotensin II into angiotensin-(1-7) and counterbalances the renin-angiotensin-aldosterone system, exerting protective effects in the cardiovascular system. Given that there are limited reports that ACE inhibitors affect the expression of ACE2 in the heart and the kidney,[8] there has been a growing concern about angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) increasing patient susceptibility to viral host cell entry and propagation.[9,10] Of note, many patients with cardiovascular comorbidities are treated with these drug classes. On the other hand, it is hypothesized that SARS-CoV-2, like SARS-CoV, not only gains initial entry through ACE2 but also subsequently All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05. 19.20106799 doi: medRxiv preprint downregulates ACE2 expression, [11] and deregulated ACE2 may theoretically mediate acute lung injury. [12] In fact, some experts have advocated for the use of ACEI and ARB to prevent organ injury and there are currently eleven registered clinical trials that will evaluate the potential benefit of ARB or ACEI in either hospitalized or not hospitalized COVID-19 infected patients. To date, there is insufficient clinical or scientific evidence to recommend the discontinuation or maintenance of ACEI/ARB treatment in face of COVID-19. Therefore, in this article, we conducted a systematic literature search to determine a possible association between the use of ACEI/ARB and the progression of COVID-19 to severe forms or death. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement[13] was followed for the conduct and reporting of this systematic review (PRISMA checklist provided as supplementary material). To identify publications regarding the clinical outcomes of COVID-19 in infected patients under treatment or not under treatment with ACEI/ARB, an extensive search of the literature was conducted in Medline (through PubMed interface), Cochrane Library, Google Scholar and the preprint servers for the health sciences MedRxiv and BioRxiv, from December 2019 to May, 2 nd 2020. In addition, we manually searched from the reference lists of all relevant retrieved All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. PaO2/FiO2 ratio <300, and/or lung infiltrates >50% of the lung field within 24-48 hours whereas critical pneumonia was defined as respiratory failure, septic shock, and/or multiple organ dysfunction/failure and critical pneumonia as respiratory failure, septic shock, and/or multiple organ dysfunction/failure. Data were collected by two independent reviewers (RM and JB) and entered into a predesigned data extraction form. Differences between the two reviewers regarding study eligibility were resolved by consensus. Study and population characteristics were extracted from each included study. Regarding study characteristics, the name of the first author, the date of publication, the study type, the number of centers and countries contributing to All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106799 doi: medRxiv preprint the research as well as possible funding were extracted. Also, total population, mean age, percentage of male participants, number of patients taking ACEI and/or ARB, number of patients taking other antihypertensives or no treatment, type and dose of antihypertensive drug, number of patients experiencing the primary outcome in each treatment group as well as details for possible matched characteristics were recorded. Finally, the presence of comorbidities such as hypertension, diabetes, cardio and cerebrovascular disease were also extracted. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies. [15] In this scale, a 'star system' is used, in which a study is judged on three aspects: selection of the study groups; comparability of the groups; and ascertainment of either the exposure or outcome of interest for case-control or cohort studies, respectively. A study can be awarded a maximum of one star for each numbered item within the selection and exposure categories. A maximum of two stars can be given for comparability. In this systematic review, studies with scores above 6 were considered as high quality, 3-6 as moderate and those with scores below than 3 as low quality. [16] Pooled analysis was performed to estimate the risk ratio (RR) and 95% confidence interval (95% CI) comparing the occurrence of the composite outcome in COVID-19 infected patients under treatment with ACEI/ARB vs no treatment or treatment other than ACEI/ARB. All analyses were conducted using RevMan software version 5.3. Fixed-effect models or random-effect All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106799 doi: medRxiv preprint 8 models were used depending on the heterogeneity between estimates. We used the I 2 statistics to assess the magnitude of heterogeneity. The fixed effect model was used if I 2 <50% and the random effect model was used if I 2 ≥50%. Publication bias was examined by the use of a funnel plot of each study's effect size against the precision (1/SE). We planned to conduct three subgroup analyses: a) including only high quality studies; b) including only peer-reviewed published studies; c) including only hypertensive subjects. Our comprehensive search initially identified 798 articles. The flowchart diagram in Figure 1 shows our literature search, study selection, and the number of studies included. After removing duplicates, reviews, letters, guidelines or consensus, and studies not addressing the research question, 24 full-text articles were assessed for eligibility. Among them, 17 studies that satisfied the eligibility criteria were included in this systematic review. After unsuccessfully trying to contact the authors, we had to exclude two of these studies from the quantitative analysis because the data of interest were not extractable. Therefore, 15 studies were finally included in the meta-analysis, totaling 21,614 COVID-19 patients. Among them, 6477 were taking ACEI or ARB and 15,137 were under other or no treatment. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All of the selected studies were published in 2020 and were all of observational nature. [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] In nine studies, the outcome that matched our research question was death; [20, 23, [25] [26] [27] [28] [31] [32] [33] in two studies, severe pneumonia; [19, 21] in one study, critical or severe pneumonia; [18] points (between 7 and 9), indicating high quality studies, except for one study that scored 6 points (moderate quality). In a qualitative synthesis, one study showed a higher risk of the outcome with the use of ACEI/ARB,[29] three studies showed a lower risk, [18, 28, 31 ] and thirteen studies found no association. [17, [19] [20] [21] [22] [23] [24] [25] [26] [27] 30 ,32,33] Among the 17 studies included in the systematic review, we had to exclude two studies [24,33] from the meta-analysis because the data of interest were not extractable. The results of our pooled analysis for the identified studies are presented in Figure 2 . The use of ACEI or ARB was found to decrease the risk of the composite outcome (death, admission to ICU, mechanical ventilation All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In our subgroup analyses, no significant differences were found when excluding the study with a NOS score below 7 or when excluding preprints. Of note, in the subgroup analysis that included only hypertensive subjects, the use of ACEI/ARB was found to significantly reduce the risk of the composite outcome: Finally, the funnel plot indicated some degree of publication bias, with a lack of small studies showing increased risk of ACEI/ARB use ( Figure S1 ). In this meta-analysis we found that the use of ACEI/ARB was not associated with an increased risk of death, admission to intensive care unit (ICU), mechanical ventilation requirement or progression to severe or critical pneumonia in COVID-19 infected patients. In fact, we observed a tendency (although non-significant) towards a protective effect. Controversy has arisen in the scientific community regarding the use of RAS inhibitors in the context of COVID-19: some experts hypothesized that these drugs might increase susceptibility to the virus by increasing the expression of ACE2, the SARS-CoV2 receptor for host cell entry.[9,10] On the other hand, scientific societies recommend not to discontinue RAS inhibitors because of All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 26, 2020. Recent evidence has consistently shown that hypertension and other cardiovascular morbidities are more frequent in COVID-19 infected patients who carry the worst prognosis. [2, 3, 43] Of note, most of these studies did not make adjustments for important co-variates such as age, although more recent studies are starting to show that this association holds even after such adjustments. [44, 45] As many subjects with cardiovascular morbidities are under treatment with ACEI/ARB, it has been speculated that the use of these drugs could be the underlying cause of the relation between these morbidities and a poorer COVID-19 prognosis. If this was the case, we would have found a greater risk of severe forms of COVID-19 in subjects under treatment with All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106799 doi: medRxiv preprint 12 ACEI/ARB, but we have not. In fact, the evidence presented in this metaanalysis supports the idea that ACEI/ARB should not be discontinued when treating COVID-19 patients with cardiovascular morbidities. On the other hand, RAS inhibitors have established benefits in protecting the cardiovascular system. [46, 47] Their discontinuation may increase the chance of decompensation in high-risk patients as the benefits that are specific to these drugs may not be offset by other antihypertensive agents. For instance, it has been shown that withdrawal of ACEI/ARB during heart failure hospitalization is associated with higher rates of postdischarge mortality. [48] Besides, antihypertensive medication changes would require frequent dose adjustment and management of adverse effects, increasing the need for patients to visit their doctors and, therefore, the exposure to COVID-19 and risk of infection. Clearly, more research is needed to elucidate the multifacetic role of the RAS in connection with SARS-CoV-2 infection. The evidence regarding the use of RAS inhibitors in patients with COVID-19 infection is still emerging. Currently, in patients who previously used ACEI/ARB, the use of these drugs may not need to be discontinued in order to prevent COVID-19 complications. Finally, our findings must be interpreted in the context of the meta-analysis limitations. First, we could not make a distinction between the effects of ACEI and ARB separately, since most studies evaluated the two drug classes together. Second, all the studies included in the meta-analysis were observational and some were preprints. We could not find any randomized clinical trials that already showed results addressing our research question. On the other hand, in planning future trials, randomizing subjects to discontinue drugs with proven benefits would probably raise ethical concerns. Third, most of All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106799 doi: medRxiv preprint 13 the included observational studies were retrospective cohorts and potential selection bias of patients is an indisputable concern. Fourth, residual confounders may be present in these observational studies and, even when measured, many studies did not make adjustments for such potential confounders. It must be noted, however, that not adjusting for age and cardiovascular morbidities would shift the results towards a higher risk since these variables are positively associated with the use of ACEI/ARB and with COVID-19 poorer outcomes. In conclusion, large prospective studies are required to confirm our finding and to explore the mechanisms for a possible protective role of RAS inhibitors in the context of COVID-19. In the meantime, these early results suggest that patients on ACEI/ARB should continue their treatment during COVID-19 illness, supporting current recommendations from multiple scientific societies. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 26, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 26, 2020. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106799 doi: medRxiv preprint Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia inWuhan, China Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Coronavirus Disease 2019 (COVID-19): Do Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers Have a Biphasic Effect? Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan Clinical features of patients infected with 2019 novel coronavirus in Wuhan The impact of diagnostic criteria for gestational diabetes on its prevalence: a systematic review and meta-analysis Treatment with ACE-inhibitors is associated with less severe disease with SARS-Covid-19 infection in a multi-site UK acute Hospital COVID-19 with Different Severity: A Multi-center Study of Clinical Features The Use of Adjuvant Therapy in Preventing Progression to Severe Pneumonia in Patients with Coronavirus Disease 2019: A Multicenter Data Analysis Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19) Anti-hypertensive Angiotensin II receptor blockers associated to mitigation of disease severity in elderly COVID-19 patients FSAACCAHAstatement-addresses-concerns-re-using-RAASantagonists-in-COVID Role of the renin-angiotensin-aldosterone system and proinflammatory mediators in cardiovascular disease Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Short-Term Mortality After Sepsis: A Population-Based Cohort Study No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted Impact of angiotensin-converting enzyme inhibitors and statins on viral pneumonia China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China Coronavirus disease 2019 in elderly patients: Characteristics and prognostic factors based on 4-week follow-up China Medical Treatment Expert Group for Covid-19. Comorbidity and its impact on 1590 patients with Covid-19 in China: A Nationwide Analysis Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19 Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At Present There Is No Evidence to Abandon Renin-Angiotensin System Blockers Initiation, Continuation, or Withdrawal of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers and Outcomes in Patients Hospitalized With Heart Failure With Reduced Ejection Fraction No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All studies were conducted in 2020.ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; CV, cardiovascular;NOS, Newcastle-Ottawa Scale; PC, prospective cohort; RC, retrospective cohort.All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106799 doi: medRxiv preprint All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Fig. 3 Sensitivity analysis including studies on hypertensive subjects only All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint this version posted May 26, 2020. . https://doi.org/10.1101/2020.05.19.20106799 doi: medRxiv preprint