Efficacy and Safety of 8 Atropine Concentrations for Myopia Control in Children

TopicComparative efficacy and safety of different concentrations of atropine for myopia control.Clinical RelevanceAtropine is known to be an effective intervention to delay myopia progression. Nonetheless, no well-supported evidence exists yet to rank the clinical outcomes of various concentrations of atropine.MethodsWe searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov on April 14, 2021. We selected studies involving atropine treatment of at least 1 year's duration for myopia control in children. We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs) and compared 8 atropine concentrations (1% to 0.01%). We ranked the atropine concentrations for the corresponding outcomes by P score (estimate of probability of being best treatment). Our primary outcomes were mean annual changes in refraction (diopters/year) and axial length (AXL; millimeters/year). We extracted data on the proportion of eyes showing myopia progression and safety outcomes (photopic and mesopic pupil diameter, accommodation amplitude, and distance and near best-corrected visual acuity [BCVA]).ResultsThirty pairwise comparisons from 16 RCTs (3272 participants) were obtained. Our NMA ranked the 1%, 0.5%, and 0.05% atropine concentrations as the 3 most beneficial for myopia control, as assessed for both primary outcomes: 1% atropine (mean differences compared with control: refraction, 0.81 [95% confidence interval (CI), 0.58–1.04]; AXL, –0.35 [–0.46 to –0.25]); 0.5% atropine (mean differences compared with control: refraction, 0.70 [95% CI, 0.40–1.00]; AXL, –0.23 [–0.38 to –0.07]); 0.05% atropine (mean differences compared with control: refraction, 0.62 [95% CI, 0.17–1.07]; AXL, –0.25 [–0.44 to –0.06]). In terms of myopia control as assessed by relative risk (RR) for overall myopia progression, 0.05% was ranked as the most beneficial concentration (RR, 0.39 [95% CI, 0.27–0.57]). The risk for adverse effects tended to rise as the atropine concentration was increased, although this tendency was not evident for distance BCVA. No valid network was formed for near BCVA.DiscussionThe ranking probability for efficacy was not proportional to dose (i.e., 0.05% atropine was comparable with that of high-dose atropine [1% and 0.5%]), although those for pupil size and accommodation amplitude were dose related. Comparative efficacy and safety of different concentrations of atropine for myopia control. Atropine is known to be an effective intervention to delay myopia progression. Nonetheless, no well-supported evidence exists yet to rank the clinical outcomes of various concentrations of atropine. We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov on April 14, 2021. We selected studies involving atropine treatment of at least 1 year's duration for myopia control in children. We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs) and compared 8 atropine concentrations (1% to 0.01%). We ranked the atropine concentrations for the corresponding outcomes by P score (estimate of probability of being best treatment). Our primary outcomes were mean annual changes in refraction (diopters/year) and axial length (AXL; millimeters/year). We extracted data on the proportion of eyes showing myopia progression and safety outcomes (photopic and mesopic pupil diameter, accommodation amplitude, and distance and near best-corrected visual acuity [BCVA]). Thirty pairwise comparisons from 16 RCTs (3272 participants) were obtained. Our NMA ranked the 1%, 0.5%, and 0.05% atropine concentrations as the 3 most beneficial for myopia control, as assessed for both primary outcomes: 1% atropine (mean differences compared with control: refraction, 0.81 [95% confidence interval (CI), 0.58–1.04]; AXL, –0.35 [–0.46 to –0.25]); 0.5% atropine (mean differences compared with control: refraction, 0.70 [95% CI, 0.40–1.00]; AXL, –0.23 [–0.38 to –0.07]); 0.05% atropine (mean differences compared with control: refraction, 0.62 [95% CI, 0.17–1.07]; AXL, –0.25 [–0.44 to –0.06]). In terms of myopia control as assessed by relative risk (RR) for overall myopia progression, 0.05% was ranked as the most beneficial concentration (RR, 0.39 [95% CI, 0.27–0.57]). The risk for adverse effects tended to rise as the atropine concentration was increased, although this tendency was not evident for distance BCVA. No valid network was formed for near BCVA. The ranking probability for efficacy was not proportional to dose (i.e., 0.05% atropine was comparable with that of high-dose atropine [1% and 0.5%]), although those for pupil size and accommodation amplitude were dose related. Myopia is the most common eye disease in children and adolescents and is most predominant in East Asia compared with other areas. It has been of increasing worldwide health concern over the past few decades, and has already reached a pandemic level.1Dolgin E. The myopia boom.Nature. 2015; 519: 276Crossref PubMed Scopus (425) Google Scholar,2Morgan I.G. French A.N. Ashby R.S. et al.The epidemics of myopia: aetiology and prevention.Prog Retin Eye Res. 2018; 62: 134-149Crossref PubMed Scopus (366) Google Scholar Myopia is predicted to affect 4.8 billion people in the world by 2050, which means that in 30 years, 50% of the world's population will be myopic.3Holden B.A. Fricke T.R. 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Myopia also impacts children's overall quality of life, specifically in terms of academic performance, physical activity, social interaction, and future job choices.5Zhao C. Cai C. Ding Q. Dai H. Efficacy and safety of atropine to control myopia progression: a systematic review and meta-analysis.BMC Ophthalmol. 2020; 20: 1-8Crossref PubMed Scopus (10) Google Scholar Therefore, a treatment to retard or even stop myopia progression effectively in children is coveted by researchers, clinicians, and medical practitioners. Several approaches have been used to slow down progression of myopia, such as increased outdoor activity, reduced near work, peripheral defocusing lenses, and orthokeratology contact lenses.6Walline J.J. Myopia control: a review.Eye Contact Lens. 2016; 42: 3-8Crossref PubMed Scopus (82) Google Scholar Atropine, a nonselective muscarinic antagonist, has been studied widely in recent years as an option for myopia control.7Huang J. Wen D. Wang Q. et al.Efficacy comparison of 16 interventions for myopia control in children: a network meta-analysis.Ophthalmology. 2016; 123: 697-708Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar Reports have indicated that 1.0% atropine can halt myopia progression, but this treatment was associated with vision-related adverse effects as well.8Lixia L. Weizhong L. Yunru L. et al.Treatment outcomes of myopic anisometropia with 1% atropine: a pilot study.Optom Vis Sci. 2013; 90: 1486-1492Crossref PubMed Scopus (23) Google Scholar,9Yi S. Huang Y. Yu S.-Z. et al.Therapeutic effect of atropine 1% in children with low myopia.J AAPOS. 2015; 19: 426-429Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar In one recent study, 0.01% atropine was determined to be effective and to have fewer adverse vision-related effects.10Chia A. Lu Q.-S. Tan D. Five-year clinical trial on atropine for the treatment of myopia 2: myopia control with atropine 0.01% eyedrops.Ophthalmology. 2016; 123: 391-399Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar To date, much uncertainty remains, as do dosing and safety concerns, regarding the clinical use of atropine. Previous methodologies, such as limited comparisons or conventional meta-analysis using pairwise comparisons, were not able to demonstrate hierarchies among various atropine concentrations.5Zhao C. Cai C. Ding Q. Dai H. Efficacy and safety of atropine to control myopia progression: a systematic review and meta-analysis.BMC Ophthalmol. 2020; 20: 1-8Crossref PubMed Scopus (10) Google Scholar,11Gong Q. Janowski M. Luo M. et al.Efficacy and adverse effects of atropine in childhood myopia: a meta-analysis.JAMA Ophthalmol. 2017; 135: 624-630Crossref PubMed Scopus (116) Google Scholar Direct and indirect comparison of different doses is essential to enable clinicians and parents to choose the optimal treatment for myopia control. Network meta-analysis (NMA), an extension of traditional meta-analysis, provides an inclusive estimate of the efficacy or safety of multiple experimental trials not previously compared directly with adequate precision, or at all.12Lumley T. Network meta-analysis for indirect treatment comparisons.Stat Med. 2002; 21: 2313-2324Crossref PubMed Scopus (817) Google Scholar,13Greco T. Biondi-Zoccai G. Saleh O. et al.The attractiveness of network meta-analysis: a comprehensive systematic and narrative review.Heart Lung Vessel. 2015; 7: 133PubMed Google Scholar Network meta-analysis concerns both direct and indirect treatment effects identifiable within an entire pool of evidence. This makes it possible to build up treatment hierarchies on the basis of valid statistical inference methods.14Greco T. Landoni G. Biondi-Zoccai G. et al.A Bayesian network meta-analysis for binary outcome: how to do it.Stat Methods Med Res. 2016; 25: 1757-1773Crossref PubMed Scopus (48) Google Scholar Therefore, we conducted the present study to draw more decisive conclusions regarding the ranking of various atropine concentrations for treatment efficacy and safety using NMA to enable integration of multiple direct and indirect comparisons uniquely. The protocol of this systematic review was registered prospectively at The International Prospective Register of Systematic Reviews (PROSPERO) (Identifier, CRD42021248957). All research adhered to the tenets of the Declaration of Helsinki. Individual patient-level consent was not required. The reporting of this NMA is based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2015 NMA Checklist.15Hutton B. Salanti G. Caldwell D.M. et al.The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.Ann Intern Med. 2015; 162: 777-784Crossref PubMed Scopus (2822) Google Scholar We included randomized controlled trials (RCTs) of atropine to halt or slow myopic progression. The studies were selected according to the following criteria: (1) participants were younger than 18 years and had myopia, (2) atropine of any concentration was used in at least 1 treatment arm, (3) treatment duration was at least 12 months, and (4) reporting of at least 1 outcome of interest, including annual rate of myopia progression. We systematically searched the Cochrane Register of Controlled Trials in The Cochrane Library, PubMed, and EMBASE from inception through April 14, 2021. Our search strategies were developed with assistance from an academic librarian with expertise in systematic review and based on established terminology using the extensive MESH and EMBASE search terms when available. The keywords included were myopia, refractive errors, and atropine. We also screened the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. We hand-searched the reference lists9Yi S. Huang Y. Yu S.-Z. et al.Therapeutic effect of atropine 1% in children with low myopia.J AAPOS. 2015; 19: 426-429Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar,11Gong Q. Janowski M. Luo M. et al.Efficacy and adverse effects of atropine in childhood myopia: a meta-analysis.JAMA Ophthalmol. 2017; 135: 624-630Crossref PubMed Scopus (116) Google Scholar,16Shih Y.F. Hsiao C.K. 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Chang J. et al.Pharmacotherapeutic candidates for myopia: a review.Biomed Pharmacother. 2021; 133: 111092Crossref PubMed Scopus (6) Google Scholar of published articles to identify additional relevant studies. We did not impose any language restriction in the electronic searches. The full search strategies are described in Appendix 1 (available at www.aaojournal.org). To identify relevant reports, retrieved articles were exported to Endnote version X9 (Thomson Reuters), wherein duplicates were found and removed. Two investigators (A.H. and Y.K.K.) independently assessed the titles and abstracts for potential eligibility, and the full-text articles were retrieved for those that seemed relevant. These articles were then assessed independently by the 2 investigators for final eligibility. Non–English-language reports were assessed by a single individual (A.H. and S.R.S.) who was a native or fluent speaker of the language. We resolved discrepancies in the eligibility classification of the full-text articles through discussion and consensus or, if needed, adjudication by a third investigator (J.H.J.). When more than 1 report used data from the same study, we included only the latest report to avoid duplicate counting of the data. For each included trial, 2 individuals (A.H. and Y.K.K.) independently extracted data and entered them in electronic format into Microsoft Access 2016 (Microsoft Corporation). An algorithm checked for conflicting data entries. Differences were discussed, and a third reviewer (J.H.J.) was contacted if consensus was not reached. Trial characteristics of interest included: (1) study identification (name of first author, year of publication), (2) country of study, (3) number of participants, (4) race or ethnicity of study population, (5) ages and sexes of participants, (6) intervention and control, (7) length of follow-up, (8) baseline and annual mean change in refraction, (9) baseline and annual mean change in axial length (AXL), (10) proportion of eyes showing overall or rapid myopic progression, and (11) adverse outcomes (i.e., photopic and mesopic pupil diameters, change in accommodation amplitude, and distance and near best-corrected visual acuity [BCVA]). For studies reporting more than 2 atropine concentrations that could be subjected independently to the present NMA, data were extracted from all of the atropine-treated arms. In the cases of studies involving interventions other than atropine, we included only the data from the atropine-treated arms. We specified tropicamide as a control at the outset, because a previous study by Shih et al29Shih Y.-F. Chen C.-H. Chou A.-C. et al.Effects of different concentrations of atropine on controlling myopia in myopic children.J Ocul Pharmacol Ther. 1999; 15: 85-90Crossref PubMed Scopus (197) Google Scholar found that 0.5% tropicamide showed a similar effect to a placebo on myopia progression.7Huang J. Wen D. Wang Q. et al.Efficacy comparison of 16 interventions for myopia control in children: a network meta-analysis.Ophthalmology. 2016; 123: 697-708Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar Likewise, single-vision spectacle lenses or multifocal progressive lenses were prespecified as a control along with a placebo.16Shih Y.F. Hsiao C.K. Chen C.J. et al.An intervention trial on efficacy of atropine and multi-focal glasses in controlling myopic progression.Acta Ophthalmol. 2001; 79: 233-236Crossref Scopus (162) Google Scholar We extracted means and standard deviations for continuous outcomes. If standard deviations were not provided, we calculated them from standard errors, confidence intervals (CIs), or other measures.30Lipsey M.W. Wilson D.B. Practical Meta-analysis. SAGE Publications, Inc., Thousand Oaks, CA2001Google Scholar, 31Higgins J.P. Deeks J.J. Selecting studies and collecting data.in: Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons, Hoboken, NJ2008: 151-185Crossref Scopus (1123) Google Scholar, 32Higgins J. Deeks J.J. Altman D.G. Special topics in statistics.in: Cochrane Handbook for Systematic Reviews of Interventions. John Wiley & Sons, Hoboken, NJ2008: 272-275Crossref Scopus (865) Google Scholar In the studies where the results were represented only graphically, the numerical values from graphs were extracted using Adobe Acrobat's XI inbuilt measuring tool (Adobe Systems Incorporated).33Silva V. Carvalho A. Grande A. et al.Can data extraction from figures perform a meta-analysis.In: Abstracts of the 20th Cochrane Colloquium; 2012 30 Sep-3 Oct; Auckland, New Zealand. John Wiley & Sons. 2012; Google Scholar,34Durg S. Dhadde S.B. Vandal R. et al.Withania somnifera (Ashwagandha) in neurobehavioural disorders induced by brain oxidative stress in rodents: a systematic review and meta-analysis.J Pharm Pharmacol. 2015; 67: 879-899Crossref PubMed Scopus (63) Google Scholar We assessed the risk of bias by the revised tool used for assessment of risk of bias in randomized trials (RoB 2).35Sterne J.A.C. Savović J. Page M.J. et al.RoB 2: a revised tool for assessing risk of bias in randomised trials.BMJ. 2019; 366: 14898Google Scholar This tool evaluated 5 bias domains, including randomization processes, adherence to assigned interventions, missing outcome data, bias of measurement, and bias of reported results. Each domain was graded as follows: low risk of bias, some concerns, or high risk of bias. Two investigators (A.H. and J.H.J.) independently assessed the risk of bias, and discrepancies were resolved through discussion. We used mean annual change in refraction (in diopters/year) and mean annual change in AXL (in millimeters/year) as the primary outcomes. For all of the comparisons, the stated values represent the differences in primary outcomes between the first and second interventions. In terms of refractive error, a positive mean difference (MD) therefore indicates that the first intervention was better (less myopia progression). In terms of AXL, a negative MD indicates that the first intervention was better (less axial elongation). Secondary outcomes were proportion of eyes showing overall myopia progression, proportion of eyes showing rapid myopia progression, photopic and mesopic pupil diameter (in millimeters), change in accommodation (in amplitude/year), and distance and near BCVA (in logarithm of the minimum angle of resolution). We also extracted data on side effects such as frequencies of photophobia or allergic conjunctivitis. We compared the effects of competing interventions on the primary outcomes (i.e., refractive error and AXL) and adverse effects according to the MD with 95% CIs. In terms of the proportion of eyes showing myopia progression, relative risk (RR) was calculated, specifically by dividing the progression proportion in the atropine group by that in the control group. The effects of different atropine concentrations were compared according to the RR with 95% CIs. Network meta-analysis is a technique for simultaneous comparison of 3 or more interventions in a single analysis by combining direct with indirect evidence across an entire network of studies.36Chaimani A. Caldwell D.M. Li T. et al.Undertaking network meta-analyses. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons, Inc, Hoboken, NJ2019: 285-320Google Scholar Indirect comparisons, which are those that are not made directly within studies, can be estimated by mathematical combinations of the available direct intervention effect estimates.36Chaimani A. Caldwell D.M. Li T. et al.Undertaking network meta-analyses. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons, Inc, Hoboken, NJ2019: 285-320Google Scholar To combine direct and indirect evidence in the present study, an NMA was performed using the R package netmeta (R Foundation for Statistical Computing, Vienna, Austria), which implements a frequentist method based on a graph-theoretical approach according to the electrical network theory.37Rücker G. Network meta-analysis, electrical networks and graph theory.Res Synth Methods. 2012; 3: 312-324Crossref PubMed Google Scholar The netmeta function accounts for within-study correlation by reweighting (based on back-calculation of variances using the Laplacian matrix and its pseudoinverse) all of the comparisons of each multiarm study.38Schwarzer G. Carpenter J.R. Rücker G. et al.Network Meta-Analysis.Meta-Analysis with R. Springer, 2015: 187-216Crossref Google Scholar We chose to apply random-effects models rather than fixed-effects models because the studies we included were heterogeneous and relatively few.39Borenstein M. Hedges L.V. Higgins J.P. Rothstein H.R. Introduction to Meta-analysis. John Wiley & Sons, Hoboken, NJ2021Crossref Google Scholar Transitivity is the key assumption underlying NMA's valid estimation of effects for indirect comparisons.40Cipriani A. Higgins J.P. Geddes J.R. Salanti G. Conceptual and technical challenges in network meta-analysis.Ann Intern Med. 2013; 159: 130-137Crossref PubMed Scopus (597) Google Scholar Transitivity assumes that distributions of effect modifiers (covariates that are associated with intervention effects) are balanced across comparisons in the network.41Salanti G. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool.Res Synth Methods. 2012; 3: 80-97Crossref PubMed Google Scholar Given the lack of any evidence for robust effect modifiers in trials on atropine's effects on childhood myopia progression, we used both clinical and methodologic experience to identify the 5 potential effect modifiers that follow: (1) publication year, (2) mean age, (3) baseline mean refraction, (4) sample size, and (5) follow-up duration. The transitivity-assumption plausibility was evaluated by comparison of these potential effect modifiers' distributions across studies grouped by comparison.42Spitzer M. Wildenhain J. Rappsilber J. Tyers M. BoxPlotR: a web tool for generation of box plots.Nat Methods. 2014; 11: 121-122Crossref PubMed Scopus (430) Google Scholar Two independent investigators (A.H., and J.H.J.) visually assessed the potential effect modifiers' distributions over the individual atropine concentrations and determined, by consensus, whether considerable dissimilarity existed that threatened the transitivity assumption (Appendix 2, available at www.aaojournal.org). Then, we explored the influence of potential effect modifiers showing dissimilarity by network meta-regression and sensitivity analyses. Heterogeneity, which influences the extent to which generalizable conclusions can be drawn, manifests as variability among study designs, analytical methods, participants, outcomes, or interventions.36Chaimani A. Caldwell D.M. Li T. et al.Undertaking network meta-analyses. Cochrane handbook for systematic reviews of interventions. 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