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The efficacy and safety of monoclonal antibody treatments against COVID-19: A systematic review and meta-analysis of randomized clinical trials

07 Jun 2021-medRxiv (Cold Spring Harbor Laboratory Press)-

Abstract: Objectives The use of monoclonal antibody for COVID-19 showed conflicting results in prior studies and its efficacy remains unclear. We aimed to comprehensively determine the efficacy and safety profile of monoclonal antibodies in COVID-19 patients. Methods Sixteen RCTs were analyzed using RevMan 5.4 to measure the pooled estimates of risk ratios (RRs) and standardized mean differences (SMDs) with 95% CIs. Results The pooled effect of monoclonal antibodies demonstrated mortality risk reduction (RR=0.89 (95%CI 0.82-0.96), I2=13%, fixed-effect). Individually, tocilizumab reduced mortality risk in severe to critical disease (RR=0.90 (95%CI 0.83-0.97), I2=12%, fixed-effect)) and lowered mechanical ventilation requirements (RR=0.76 (95%CI 0.62-0.94), I2=42%, random-effects). Moreover, it facilitated hospital discharge (RR=1.07 (95%CI 1.00-1.14), I2=60%, random-effects). Meanwhile, bamlanivimab-etesevimab and REGN-COV2 decrease viral load ((SMD=-0.33 (95%CI -0.59 to -0.08); (SMD=-3.39 (95%CI -3.82 to -2.97)). Interestingly, monoclonal antibodies did not improve hospital discharge at day 28-30 (RR=1.05 (95%CI 0.99–1.12), I2=71%, random-effects) and they displayed similar safety profile with placebo/standard therapy (RR=1.04 (95%CI 0.76-1.43), I2=54%, random-effects). Conclusion Tocilizumab improved hospital discharge and reduced mortality as well as the need for mechanical ventilation, while bamlanivimab-etesevimab and REGN-COV2 reduced viral load in mild to moderate outpatients. In general, monoclonal antibodies are safe and should be considered in severe to critical COVID-19 patients. Registration PROSPERO (CRD42021235112)

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The efficacy and safety of monoclonal antibody treatments against COVID-19: A
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systematic review and meta-analysis of randomized clinical trials
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Ifan Ali Wafa
a
, Nando Reza Pratama
a
, David Setyo Budi
a
, Henry Sutanto
b,c
, Alfian Nur
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Rosyid
d
, Citrawati Dyah Kencono Wungu
e,f,
*
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a
Faculty of Medicine, Universitas Airlangga, Indonesia
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b
Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht
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University, The Netherlands
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c
Department of Physiology and Biophysics, State University of New York (SUNY)
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Downstate Health Sciences University, New York, USA
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d
Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas
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Airlangga, Indonesia
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e
Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas
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Airlangga, Indonesia
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f
Institute of Tropical Disease, Universitas Airlangga, Indonesia
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Word Count: 3480 words (excluding abstract and references)
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Correspondence:
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Citrawati Dyah Kencono Wungu, MD., PhD.
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Department of Physiology and Medical Biochemistry, Airlangga University
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Jalan Mayjen Prof. Dr. Moestopo No.47, Surabaya, Indonesia
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Email:
citrawati.dyah@fk.unair.ac.id
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. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

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Abstract
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Objectives: The use of monoclonal antibody for COVID-19 showed conflicting results in
36
prior studies and its efficacy remains unclear. We aimed to comprehensively
37
determine the efficacy and safety profile of monoclonal antibodies in COVID-
38
19 patients.
39
Methods: Sixteen RCTs were analyzed using RevMan 5.4 to measure the pooled
40
estimates of risk ratios (RRs) and standardized mean differences (SMDs) with
41
95% CIs.
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Results: The pooled effect of monoclonal antibodies demonstrated mortality risk
43
reduction (RR=0.89 (95%CI 0.82-0.96), I
2
=13%, fixed-effect). Individually,
44
tocilizumab reduced mortality risk in severe to critical disease (RR=0.90
45
(95%CI 0.83-0.97), I
2
=12%, fixed-effect)) and lowered mechanical ventilation
46
requirements (RR=0.76 (95%CI 0.62-0.94), I
2
=42%, random-effects).
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Moreover, it facilitated hospital discharge (RR=1.07 (95%CI 1.00-1.14),
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I
2
=60%, random-effects). Meanwhile, bamlanivimab-etesevimab and REGN-
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COV2 decrease viral load ((SMD=-0.33 (95%CI -0.59 to
50
-0.08); (SMD=-3.39 (95%CI -3.82 to -2.97)). Interestingly, monoclonal
51
antibodies did not improve hospital discharge at day 28-30 (RR=1.05 (95%CI
52
0.99–1.12), I
2
=71%, random-effects) and they displayed similar safety profile
53
with placebo/standard therapy (RR=1.04 (95%CI 0.76-1.43), I
2
=54%, random-
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effects).
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Conclusion: Tocilizumab improved hospital discharge and reduced mortality as well as the
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need for mechanical ventilation, while bamlanivimab-etesevimab and REGN-
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COV2 reduced viral load in mild to moderate outpatients. In general,
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monoclonal antibodies are safe and should be considered in severe to critical
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COVID-19 patients.
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Keywords: COVID-19; Monoclonal Antibody; Mortality; Viral load; Meta-analysis
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Registration: PROSPERO (CRD42021235112)
62
. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint

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INTRODUCTION
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Since December 2019, a novel coronavirus disease (COVID-19) firstly discovered in
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Wuhan, China has spread globally and profoundly affected various aspects of life (Li et al.,
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2020). The viral infectious disease is caused by SARS-CoV-2; an enveloped, positive-sense,
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single-stranded genomic ribonucleic acid (+ssRNA) virus from the group of Betacoronavirus
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in the family of Coronaviridae (Hu et al., 2021). In the lungs, SARS-CoV-2 binds to
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angiotensin converting enzyme type-2 (ACE-2) receptors at the membrane of pulmonary
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alveolar cells type-2 and undergoes endocytosis. Subsequently, the interaction of viral
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antigen with RIG-I-like receptors (RLRs) activates the host immune system as an effort to
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eliminate the virus from the body (Hertanto et al., 2021), predisposing to the clinical
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presentations of COVID-19 patients, ranging from asymptomatic or mild up to severe disease
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state with pneumonia and acute respiratory distress syndrome that can ultimately lead to
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death (Lai et al., 2020).
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The development of optimal and effective therapies for COVID-19 is essential to
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minimize COVID-19 morbidity and mortality (Lu, 2020; Li and De Clercq, 2020). Several
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components of the virus and host immune system have been identified as potential targets in
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COVID-19 management. A previous study reported that the SARS-CoV-2 S2 protein was
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important for viral entry and thought to be a potential target for neutralizing antibody (Walls
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et al., 2020). Moreover, the SARS-CoV-2 infection could trigger a hyperactive immune
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response, leading to cytokine release syndrome (CRS) or cytokine storm (Hertanto et al.,
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2021). Among numerous proinflammatory cytokines involved in CRS, interleukin (IL)-6 is
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one of the most critical and has been associated with a poor prognosis (Zhang et al., 2020a;
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Zhang et al., 2020b; Zhao, 2020). Therefore, the inhibition of IL-6 (e.g., by preventing the
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binding to its receptors) could prevent the occurrence of CRS and lower the severity of the
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disease. Moreover, complement C5a and white blood cells (i.e., neutrophil and monocytes)
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were detected in the bronchoalveolar lavage fluid (BALF) of COVID-19 patients, supporting
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the chemoattraction role of C5a in lungs-derived C5aR1-expressing cells; which is
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responsible for cell damage and ARDS (Carvelli et al., 2020). Of note, C5a is one of the
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major drivers for complement-mediated inflammation that rapidly responds to pathogens and
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cellular injury (Woodruff and Shukla, 2020).
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Monoclonal antibody is one of the proposed therapeutic options for COVID-19. Anti-
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SARS-CoV-2 monoclonal antibodies are among the latest investigational COVID-19
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treatments granted with emergency use authorization (EUA) from the United States Food and
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. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint

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Drug Administration (FDA). Briefly, monoclonal antibodies recognize one epitope of an
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antigen while polyclonal antibodies recognize multiple epitopes (Lipman et al., 2005). The
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variable region can be modified to target specific molecules, including the S2-protein,
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cytokines, and cytokine receptors. Among 5 Antibody isotypes—IgA (subclasses IgA1 and
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IgA2), IgE, IgD, IgM, and IgG (subclasses IgG1, IgG2, IgG3 and IgG4) —IgG is commonly
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selected for therapeutic purposes due to its strong binding affinity to an antigen and its Fc
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receptor, supported by its long serum half-life (Chames et al., 2009; Lu, 2020). As the
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consequence, the administration of neutralizing monoclonal antibody targeting SARS-CoV-2
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spike proteins allows the inhibition of virus attachment to human ACE-2 receptors, thus
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inhibits viral entry (Tian et al., 2020). To prevent complement system activation triggered
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during SARS-CoV-2 infection, a recent study proposed the use of monoclonal antibody
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against C5a (anti-C5a) (Woodruff and Shukla, 2020). Among available monoclonal
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antibodies for COVID-19, anti-IL-6 receptors and anti-SARS-CoV-2 are widely studied in
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clinical trials (Yang et al., 2020; Patel et al., 2021).
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Nonetheless, the efficacy and safety of this pharmacological agent remain
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controversial (FDA, 2020; Patel et al., 2021). Moreover, at present, the application of
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monoclonal antibody as a therapeutic agent in COVID-19 shows conflicting results in prior
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studies, demanding further investigations. Thus, this meta-analysis aims to assess the
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previously reported efficacy and safety of monoclonal antibodies on clinical and laboratory
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outcomes and its safety profile in COVID-19 patients.
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MATERIALS AND METHODS
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Search Strategy
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The PubMed (MEDLINE), ScienceDirect, Cochrane Library, Proquest and Springer
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databases were systematically searched from January 25 until February 5, 2021, without any
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limitation of publication year. We also performed manual searches, extended from February 5
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to March 5, 2021, through MedRxiv and citation searching to get evidence from unpublished
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data and retrieve potential articles without missing any additional eligible studies. The
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following keywords were used: “(COVID-19) AND ((Monoclonal Antibody) OR
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(Neutralizing Antibody) OR (Serotherapy)) AND ((Viral Load) OR (Oxygen) OR (Duration)
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OR (Mortality) OR (Inflammation))”. Additional details about the search strategy are
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available in Supplementary Materials.
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. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint

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Data Collection
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The title and abstract of the articles were screened by IAW and NRP. Duplications
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were removed using the Mendeley reference manager. We independently screened the title
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and abstract of all retrieved studies based on the following eligibility criteria: (1) participants
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confirmed at any clinical stage of COVID-19 with/without other comorbidities; (2) adult (
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years) male/female study population; (3) the study involved monoclonal antibody treatments
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of interest; (4) the study compared the intervention group with control (placebo or/and
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standard of care or combination therapy); (5) the study evaluated efficacy (i.e. mortality, need
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for mechanical ventilation, hospital discharge, virologic outcomes) or safety outcomes
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(serious adverse events); (6) study type was randomized controlled trial (RCT).
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Data Extraction and Quality Assessment
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IAW, NRP, and DSB independently extracted relevant data using the standardized
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form. The following information was extracted: first authors name and publication year,
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study design, country, sample size, age, disease severity, dosage and administration of
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monoclonal antibodies, types of comparison, and outcomes (all-cause mortality, need for
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mechanical ventilation, hospital discharge at day 28-30, change of viral load, and serious
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adverse events). Serious adverse events were defined as any untoward medical occurrence
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that are potentially related to monoclonal antibody treatment.
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The studies were classified into “low risk of bias,”some concerns,” or “high risk of
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bias” according to the Cochrane risk of bias tool for randomized trial (RoB ver.2) (Sterne et
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al., 2019). Any discrepancies were consulted with an expert and resolved by discussion until
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reaching consensus. The Grading of Recommendation Assessment, Development, and
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Evaluation (GRADE) system was used to evaluate the quality of evidence of the findings
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(Brignardello-Petersen et al., 2018; Puhan et al., 2014).
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Statistical Analysis
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Primary analyses were carried out using the Review Manager version 5.4 (The
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Cochrane Collaboration). Pooled risk ratios (RRs) for dichotomous outcomes were evaluated
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using Mantel-Haenszel method. Standardized mean differences (SMDs) of continuous
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outcomes were pooled using inverse variance. I
2
test was used to quantify heterogeneity
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between studies, with values I
2
>50% represents moderate-to-high heterogeneity. If the value
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of statistics was <50% or the p-value was >0.1, the fixed-effects model could be applied;
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otherwise, the random-effects model would be used. Begg's funnel plot and Egger’s test were
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. CC-BY-NC 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprint this version posted June 7, 2021. ; https://doi.org/10.1101/2021.06.04.21258343doi: medRxiv preprint

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