Influence of angiotensin converting enzyme inhibitors/angiotensin receptor blockers on the risk of all‐cause mortality and other clinical outcomes in patients with confirmed COVID‐19: A systemic review and meta‐analysis

Abstract Since the COVID‐19 pandemic, physicians concerned about the potential adverse effects of angiotensin converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs). To explore the relationship between ACEIs/ARBs and the risk of mortality and other clinical outcomes in COVID‐19 patients, the authors conducted a systemic review and meta‐analysis. An electronic search was performed from inception to November 12, 2020 in PubMed, Medline, EMBASE, ClinicalTrials, TRIP, the Cochrane Library, CNKI, Wanfang, and CBM database. Risk of bias was assessed using the Risk Of Bias In Non‐randomized Studies of Interventions tool. The primary outcome was in‐hospital all‐cause mortality. Secondary outcomes included all‐cause mortality measured at 30‐day or longer term, mechanical ventilation, length of hospital stay, readmission, and cardiac adverse events. A total of 28 studies with 73 465 patients was included. Twenty‐two studies with 19 871 patients reported the incidence of all‐cause mortality. Results showed no association between using ACEIs/ARBs and risk of mortality crude odds ratio （OR） of 1.02, 95% CI 0.71–1.46, p = .90, I 2 = 88%, adjusted OR in 6260 patients of 0.96, 95% CI 0.77–1.18, p = .68, I 2 = 0%. While six studies with 10 030 patients reported a lower risk of mortality in ACEIs/ARBs group hazard ratio (HR) of 0.53, 95% CI 0.34–0.84, p = .007, I 2 = 68%. Similar association (for HR) was found in hypertension subgroup. There was no significant association for the secondary outcomes. Based on the available data, we concluded that ACEIs/ARBs is not associated with the risk of in‐hospital all‐cause mortality in COVID‐19 patients, but may be associated with a decreased risk of 30‐day all‐cause mortality. Patients with hypertension may benefit from using ACEIs/ARBs.


INTRODUCTION
Since the end of 2019, COVID-19 pneumonia erupted in many countries and became a pandemic, posing a great threat to human health and survival. SARS-Cov-2 can bind angiotensin converting enzyme 2 (ACE2) and allows the virus to invade cells, which may lead to activate immune response and lung injury. 1,2 ACEIs or ARBs can potentially increase ACE2 level, concern has been raised about the safety of these medications in patients with COVID-19. Although many scientific institutions have recommended that ACEIs/ARBs therapy should not be discontinued in COVID-19 patients, 3

Literature search
This systematic review was carried out in accordance with the metaanalysis of observational studies in epidemiology and preferred reporting items for systematic reviews and meta-analyses statements. An electronic search was performed from PubMed, Medline, EMBASE, ClinicalTrials, TRIP, the Cochrane Library, Chinses National Knowledge Infrastructure (CNKI), Wanfang database and Chinese BioMedical (CBM) database. Drafts of protocol was developed and reviewed.
The protocol was registered on PROSPERO on August 4, 2020 (CRD42020202402). Trials were identified through a comprehensive systematic search from inception to June 21, 2020 in PubMed, Medline, EMBASE, ClinicalTrials, TRIP, the Cochrane Library, CNKI, Wanfang and CBM database using the strategies presented in Appendix 1.
No language restrictions were applied.

Selection of studies for inclusion and review
We included studies of patients with COVID-19 confirmed by polymerase chain reaction (PCR) or genetic tests; ACEIs /ARBs use data were provided. The interventional group was ACEIs or ARBs user. The comparator was no use of ACEIs or ARBs, irrespective of combined use with other medications.
Three reviewers (NJ, XS, and YW) screened the search titles and abstracts. All potentially relevant citations were requested and inspected in detail using the full text version. Articles without full texts, duplicated publications, reports lacking data, and articles not reporting any outcomes of interest were excluded from the analysis. Disagreements were resolved by discussion with assistance from a forth reviewer (PZ).

Data extraction and management
Data from each study was extracted independently by two separate reviewers (SD and WC) using a pre-designed data extraction form.
Any disagreements were resolved by discussion with assistance from a third reviewer (SZ). We extracted all relevant characteristics of all included studies including general study characteristics, participants' information, intervention, characteristics of outcome, ACEIs/ARBsrelated risk factors with reported estimates of association and corresponding crude and adjusted estimates.

Statistical analysis
Meta-analysis was performed for quantitative synthesis. In cases where data was not eligible for meta-analysis, we narratively synthesized data. We summarized all dichotomous outcome data using odds ratios (ORs) or hazard ratios (HRs) and their 95% confidence intervals (CIs). We summarized all continuous outcome data using mean differences (MDs) and their 95% CIs. Heterogeneity in the study results included clinical heterogeneity, methodological heterogeneity, and statistical heterogeneity. When we suspected heterogeneity, we highlighted and fully discussed the reasons when this was possible. We visually inspected forest plots to investigate possible statistical heterogeneity; an I 2 estimate greater than or equal to 50% accompanied by a statistically significant chi-square statistic was interpreted as evidence of substantial levels of heterogeneity. If the number of studies more than 10, we conducted a funnel plot to test the reporting bias of one specific outcome. We synthesized data using a fixed-effects method for all analyses. We explored the source of heterogeneity and conducted a subgroup analysis if the source of heterogeneity was identified. We synthesized data using a random-effects model when we could not determine the source of heterogeneity. If heterogeneity was found and the source of heterogeneity was identified, a post-hoc subgroup analysis according to the particular factor was conducted. All analyses were performed in Review Manager 5.1 (The Cochrane Collaboration, Oxford, United Kingdom).

Review process and study characteristics
Two thousand seven hundred sixty two records were identified and 2654 trials were rejected after title-abstract screening. Of these, 117 full-text articles were assessed for eligibility, with 89 studies excluded  Table 1.

Risk of bias
Risk of bias assessment was shown in Appendix 2. Three studies were assessed as having serious risk of bias, and 13 studies were found to be moderate risk of bias. Twelve studies were considered as having low risk of bias.

Relationship between ACEIs/ARBs and all-cause mortality
In patients with COVID-19, a total of 23 studies with 19,938 patients reported the incidence of all-cause mortality. Meta-analysis showed no association between using ACEIs/ARBs and risk of mortality (crude

Relationship between ACEIs/ARBs and other clinical outcomes
Three studies provided long-term mortality data, but the results could not be combined. Khan  Seven studies with 4,576 patients reported the risk of ventilation and the result showed no association (crude OR of 1.29, 95% CI 0.85-1.96, p = .24, I 2 = 59%, Appendix 3, Figure 5). Among them five studies with 2,572 patients reported an adjusted OR for ventilation, still without association with ACEIs/ARBs use (adjusted OR = 1.07, 95% CI 0.74-1.54, p = .72, I 2 = 0%, Appendix 3, Figure 6). We narratively synthesized the results of duration of hospital stay, but did not show a significant difference. Only Richardson and coworker 8 reported readmission data, and again, there was not significantly different between the ACEIs group (3/168) and the ARBs group (3/245). Five studies provided the data of heart failure (HF). The HF event in Jung and coworker 9 was reported for the hypertension subgroup. Only two studies 10 If the study provided the mean age of two groups, the age was shown separately. If the study did not provide the age of two groups, only the mean age of the whole population was shown. b If the study provided the male/female number of two groups, the male/female number was shown separately. If the study did not provide the male/female number of two groups, only the male/female number of the whole population was shown.

Subgroup analysis
We preset the subgroup analysis for sex and age in the prior subgroup.
However, only few individual studies were available. Soleimani Figure 13).

Analysis of the ACEIs and ARBs use as separate subgroups is shown
in Figure 4. For the ACEIs group, four studies (one study did not pro-

F I G U R E 4
Association between ACEI or ARB use alone and in-hospital all-cause mortality. Pooled risk of in-hospital all-cause mortality was shown as crude OR (A), adjusted OR (B), and HR (C). Studies were divided into ACEI subgroup and ARB subgroup. The effect size was pooled separately Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; HR, hazard ratio; OR, odd ratio. Figure 4) compared with non-user. Three studies made head to head comparison between ACEIs and ARBs, but showed no significant association (crude OR of 1.11, 95% CI 0.75-1.64, p = .60, I 2 = 0%, Appendix 3, Figure 19).

Sensitivity analysis
Additionally, three studies 5,15,16 with serious risk of bias were excluded from the analyses of crude OR, adjusted OR for all-cause mortality, and we still did not find significant associations (crude OR of 1.13,

DISCUSSION
The inconsistent conclusions about the use of ACEIs/ARBs call for more rigorous studies to demonstrate the effect of ACEIs/ARBs in different population. Several relevant systematic reviews and metaanalysis summarized available evidence and suggested continue use of ACEIs/ARBs based on the lack of association of the treatment on the risk of mortality or severity of outcomes. By using strict paper inclusion criteria, and adjusting for confounding effect whenever possible, our systematic review provided relatively higher quality of evidence to increase the assurance of using

CONCLUSION
Based on the available data, we conclude that using ACEIs/ARBs is not associated with the risk of in-hospital all-cause mortality in COVID- 19 patients, but may be associated with a decreased risk of 30-day all-cause mortality. Patients with hypertension may benefit from using ACEIs/ARBs.

CONFLICT OF INTERESTS
There are no conflicts of interest to declare.