Efficacy and safety of 8 atropine concentrations for myopia control in children

Author: Ha A, Kim SJ, Shim SR, Kim YK, Jung JH.

Geographical coverage: Asia

Sector: Biomedical

Sub-sector: Treatment

Equity focus: Children.

Study population: Children (aged between 4-18) receiving atropine treatment for myopia

Review type: Effectiveness review

Quantitative synthesis method: Network meta-analysis

Qualitative synthesis method: Not applicable

Background: 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. Previous methodologies, such as limited comparisons or conventional meta-analysis using pairwise comparisons, were not able to demonstrate hierarchies among various atropine concentrations.

Objectives: 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.

Main findings:

In summary, this review determined that atropine concentrations of 1%, 0.5%, and 0.05% are the most effective according to the NMA ranking probabilities. Furthermore, the 0.05% concentration was identified as the most advantageous in terms of overall myopia progression.

A total of 16 randomised controlled trials (RCTs) met the inclusion criteria, constituting a total of 3,272 individuals. Among the 16 trials, eight different concentrations of atropine were involved: 1%, 0.5%, 0.25%, 0.1%, 0.05%, 0.025%, 0.02% and 0.01%. Low-dose atropine (0.01%) investigated in nine studies, moderate-dose atropine (0.02%e0.25%) investigated in four studies, and high-dose atropine (0.5% or 1%) investigated in eight studies, together resulting in 21 experimental groups. 13 studies reported both refraction and AXL outcomes and three reported only refraction.

Overall, most of the trials included in this analysis seemed to have a low to moderate risk of bias.

Authors assessed 30 pairwise comparisons from 16 RCTs (3,272 participants). Analysis ranked the 1%, 0.5% and 0.05% atropine concentrations as the three most beneficial for myopia control: 1% atropine (mean differences compared with control: refraction, 0.81 [95% confidence interval (CI), 0.58e1.04]; AXL, e0.35 [e0.46 to e0.25]); 0.5% atropine (mean differences compared with control: refraction, 0.70 [95% CI, 0.40e1.00]; AXL, e0.23 [e0.38 to e0.07]); 0.05% atropine (mean differences compared with control: refraction, 0.62 [95% CI, 0.17e1.07]; AXL, e0.25 [e0.44 to e0.06]). In terms of myopia control as assessed by relative risk for overall myopia progression, 0.05% ranked as the most beneficial concentration (RR, 0.39 [95% CI, 0.27e0.57]). The risk for adverse effects tended to rise as the atropine concentration increased, although this tendency was not evident for distance BCVA. No valid network formed for near BCVA.

Authors found that overall conclusions on the primary outcome did not change substantially after accounting for potential effect modifiers (studies published before 2000, with baseline mean refraction of less than e4 D, with fewer than 50 participants, or with a high risk of bias), via sensitivity analysis.

Authors note the need of further subgroup investigation to determine the relationship between ethnicity and optimal atropine dose. Given the possible effects of atropine concentration on the rebound phenomenon, future studies should focus on assessing optimal atropine dosage, not only during the trial period, but also after administration stoppage.


Inclusion criteria consisted of randomised controlled trials (RCTs) of atropine to halt or slow myopic progression. Studies were selected according to the following criteria: (1) participants younger than 18 years and had myopia; (2) atropine of any concentration used in at least one treatment arm; (3) treatment duration was at least 12 months; and (4) reporting of at least one outcome of interest, including annual rate of myopia progression.

Authors searched the Cochrane Register of Controlled Trials in the Cochrane Library, PubMed and EMBASE from inception through 14 April 2021. Authors also screened the World Health Organization International Clinical Trials Registry Platform and Clinical-Trials.gov. They hand-searched the reference lists of published articles to identify additional relevant studies, and they did not impose any language restriction in the electronic searches.

Two investigators 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 two investigators for final eligibility.

For each included trial, two individuals independently extracted data and entered them in electronic format. Means and standard deviations were extracted for continuous outcomes. If standard deviations were not provided, authors calculated them from standard errors, confidence intervals (CIs) or other measures. In the studies where the results were represented only graphically, the numerical values from graphs were extracted using Adobe Acrobat’s XI in-built measuring tool.

Two authors independently assessed the risk of bias by the revised tool used for assessment of risk of bias in randomised trials (RoB 2).

The authors compared the effects of different interventions on primary outcomes (refractive error and AXL) with adverse effects, using mean differences (MD) with 95% confidence intervals (CIs). They calculated the relative risk (RR) for the proportion of eyes showing myopia progression. Different atropine concentrations were compared according to the RR with 95% CIs. To combine direct and indirect evidence, a network meta-analysis (NMA) was performed using the R package, applying random-effects models due to the heterogeneity and relatively few studies included.

Five potential effect modifiers were identified by the authors: publication year, mean age, baseline mean refraction, sample size, and follow-up duration. The transitivity assumption was evaluated by comparing these potential effect modifiers’ distributions across studies grouped by comparison. The influence of potential effect modifiers showing dissimilarity was explored by network meta-regression and sensitivity analyses.

Applicability/external validity: Authors identify a number of limitations that may reduce applicability of review findings. Most studies were conducted in East Asia, meaning findings may not be more widely applicable. Results were not specific for children of individual ages, as mean age was used analytically. Due to the small numbers of studies considering different atropine doses, there are wide confidence intervals, offering less certainty in findings regarding ranking.

Geographic focus: Most included studies were conducted in East Asia, where children are thought to have different responses in relation to atropine. This indicates that findings cannot be applied more widely on a geographical basis.

Summary of quality assessment:

The approaches used to identify, include and critically appraise studies were highly robust, with two authors undertaking all key tasks. However, there is no evidence of any attempt being made to include unpublished material in the review. The analysis of the data, via a network meta-analysis, was highly robust; however, it is unclear how the authors dealt with unit of analysis errors that might have occurred from including trials including individuals with multiple treated eyes. We also note that the small number of studies exploring certain dosages of atropine, results in a number of the confidence intervals of estimates overlapping. For these reasons, we have medium confidence in the findings of this review.

Publication Source:

Ha A, Kim SJ, Shim SR, Kim YK, Jung JH. Efficacy and Safety of 8 Atropine Concentrations for Myopia Control in Children: A Network Meta-Analysis. Ophthalmology. 2022 Mar;129(3):322-333. doi: 10.1016/j.ophtha.2021.10.016. Epub 2021 Oct 22. PMID: 34688698