Is 0.01% atropine an effective and safe treatment for myopic children? a systemic review and meta-analysis

Authors: Tsai HR, Chen TL, Wang JH, Huang HK, Chiu CJ.

Geographical coverage: Asia and Europe

Sector: Biomedical

Sub-sector: Treatment

Equity focus: Study focuses exclusively on children. Considers impact of treatment for different ethnic groups.

Study population: Children aged under 18 with myopia.

Review type: Effectiveness review

Quantitative synthesis method: Systematic review and meta-analysis

Qualitative synthesis method: Not applicable

Background: The efficacy of atropine to prevent myopia progression in children has been studied widely. Different concentrations of atropine (0.01% to 1%) have been shown to inhibit myopic progression. High dose atropine has been subject to significant adverse effects, while studies have shown that low dose atropine, especially 0.01%, may slow SER progression with minimal side effects, although results have been inconsistent regarding the effect in inhibiting axial elongation.

Objectives: To increase the statistical power and elucidate the conflicting results of 0.01% atropine in childhood myopia and to conduct analysis of known confounding factors such as different ethnicity, baseline age, and baseline myopia status to identify the ideal recipients for 0.01% atropine in myopia control.

Main findings:

Overall findings of this study showed that 0.01% atropine had a favourable efficacy and adequate safety for managing childhood myopia over a one-year period, with the children who received it showing significantly less progression in axial length and refraction. 0.01% atropine has a better treatment effect in children with lower refractive error and older age and seems more effective in non-Asian patients.

Five randomised controlled trials (RCTs) from 2019 to 2021 and three retrospective studies from 2015 to 2019 were included in the final meta-analysis. In total, 1,178 participants (0.01% atropine group, 600; control group, 578) were included. All RCTs were conducted in Asian countries (Hong Kong, India, Japan and China), while the retrospective studies enrolled European or multi-ethnic participants and were performed in Italy or the United States. Among included studies, one RCT and one retrospective study had follow-up data for two years, while others provided one-year follow-up data.

Most domain-level judgements in the enrolled RCTs indicated a low risk of bias. The assessment revealed a moderate overall risk of bias in three non-RCTs.

The results demonstrate that 0.01% atropine significantly retarded SER progression compared with the controls (weighted mean difference [WMD], 0.28 dioptre (D) per year; 95% confidence interval (CI) = 0.17, 0.38; p <0.01), and axial elongation (WMD, -0.06 mm; 95% CI = -0.09, −0.03; p <0.01) during the one-year period. Patients receiving 0.01% atropine showed no significant changes in accommodative amplitude (WMD, -0.45 D; 95% CI = -1.80, 0.90; p = 0.51) but showed dilated photopic pupil diameter (WMD, 0.35 mm; 95% CI = 0.02, 0.68; p = 0.04) and mesopic pupil diameter (WMD, 0.20 mm; 95% CI = 0.08, 0.32; p <0.01). In the subgroup analysis of SER progression, myopic children with lower baseline refraction (>-3 D) and older age (>10-year-old) obtained better responses. The European and multi-ethnicity groups showed greater effect than the Asian groups.

Authors acknowledged several limitations: most included studies had short-term follow-up periods (one year in six studies and two years in two studies), meaning the long-term efficacy and safety profiles of 0.01% atropine eye drops cannot be obtained from this study. The benefit-risk ratio between 0.01% atropine and other low dose atropine (such as 0.05% and 0.025%) cannot be directly compared in this study. However, currently, there was only one trial that compared those doses of atropine directly. A meta-regression to assess the association between baseline characteristics and myopia progression after 0.01% atropine treatment was not conducted, since the power may be insufficient to identify the potential effect.

Authors note the need of further studies to elucidate the long-term efficacy and safety of 0.01% atropine eye drops and their applicability in different ethnic groups.

Methodology:

Studies were included in the systematic review if: (1) they were randomised control trials (RCTs), cohort studies, or case-control studies; (2) they compared a group treated with 0.01% atropine for myopia control with a control group; (3) the participants with a diagnosis of myopia were younger than 18 years; (4) at least one efficacy or safety outcome relevant to the review was reported in the studies, including the change in SER, AL, accommodative amplitude, and pupil size; and (5) the mean follow-up period was at least one year. Review articles, case reports, case series, and animal or laboratory studies were excluded.

Studies describing the efficacy of 0.01% atropine in myopia control before June 2021 were identified from the PubMed, EMBASE and Cochrane Library databases. No language restrictions were applied. The reference sections of the retrieved articles were assesed to identify other relevant studies. Relevant studies were retrieved from the ClinicalTrials.gov registry and the International Clinical Trials Registry Platform.

Two authors independently extracted data of included studies and the methodological quality of the non-randomised studies was assessed using risk of bias in non-randomised studies-of interventions, and that of the RCTs was evaluated using the Cochrane Collaboration’s risk-of-bias assessment tool.

The effect size of each study was presented as WMD with 95% CIs for continuous outcome measures (SER, AL, accommodative amplitude, mesopic pupil size and photopic pupil size). When standard deviation data was not applicable, standard deviations authors calculated with formulas described in the Cochrane Handbook for Systematic Reviews of Interventions. The pooled estimates and their CIs were calculated using the DerSimonian and Laird random-effects model, considering the heterogeneity of the study populations. The statistical heterogeneity among studies was tested using I² statistics and was considered significant when the I² statistic was ≥50%. A leave-one-out sensitivity analysis was performed to evaluate each study’s influence on the overall effect by removing studies sequentially. Authors performed a subgroup analysis according to the study design, study population, mean age and mean baseline refraction to explore the potential heterogeneity.

Applicability/external validity: Authors note that impact of 0.01% atropine cannot be directly compared with other doses, or for longer than a one-year period.

Geographic focus: Included RCTs were all conducted in Asia, however the review considers how impact of treatment varies by ethnicity, but not by country.

Summary of quality assessment:

There were a number of weaknesses in the approaches to identify, include and appraise studies. There is no evidence that unpublished material was considered for inclusion, or that more than one author undertook the searching process. While the analysis of data was reasonably robust, separate analysis was not undertaken based on study quality and there is no evidence of consideration of unit of analysis errors, despite many of the included studies being RCTs. For these reasons, we have low confidence in the results of this study.