Efficacy and adverse effects of atropine for myopia control in children: a meta-analysis of randomised controlled trials

Authors: Chen CW, Yao JY.

Geographical coverage: China, India, Hong Kong, Singapore and Taiwan

Sector: Biomedical

Sub-sector: Treatment

Equity focus: Participants younger than 18 years

Study population: General population

Review type: Other review

Quantitative synthesis method: Systematic review and meta-analysis

Qualitative synthesis method: Not applicable

Background: Myopia, known as nearsightedness, is widely recognised as an urgent public health issue causing significant visual loss for a range of ocular comorbidities, including cataract, retinal detachment and glaucoma. Atropine (low dose, 0.01%; moderate dose, 0.01% to 0.5%; and high dose, 1%) has been used to control myopia progression for many years. The exact mechanism of how atropine retards is still unclear, in that it may alter corneal curvature, vitreous chamber depth, lens thickness (LT) and anterior chamber depth (ACD).

Objectives: To explore the rebound effects and safety of atropine on accommodation amplitude in slowing myopia progression.

Main findings:

Authors included a total of 17 randomised controlled trials (RCTs) consisting of 2,995 participants comprising 1,584 and 1,371 in the intervention and control groups, respectively. Low-dose atropine (0.01%) was reviewed in eight studies, moderate-dose atropine (0.01% to 0.5%) in four studies, and high-dose atropine (1%) in five studies, together resulting in 21 interventional groups in 17 studies. Five studies were conducted in China, three studies each were conducted in Singapore, Taiwan, Hong Kong, and one study each was conducted in Spain, Japan and India.

In terms of quality of the RCTs, the trial seems to have a moderate risk of bias, with most trials reporting adequate random sequence generation, allocation concealment, and blinding of outcome assessment.

The authors observed high heterogeneity in the data related to spherical equivalent changes and myopia progression. A subgroup analysis revealed significant progression for low and moderate doses compared to the control group, with no statistical difference found in the high dose. The overall effect was 0.38D per year. Significant heterogeneity was also found among studies assessing axial elongation. Subgroup analysis showed significantly less axial elongation for all doses compared to the control group. Atropine was found to significantly improve myopia progression.

A subgroup analysis of rebound effects showed a higher annual rate of myopia progression in short periods of cessation. High-dose atropine was favored. Accommodation amplitude significantly reduced, with no statistical difference identified in the low-dose atropine group. A significant difference was found in pupil size between photopic and mesopic size.

No statistical significance was reported in low-dose atropine related to changes on BCVA, but significance was shown in the high-dose group. No significant difference was found between the atropine and control groups in changes in ACD, near vision, LT, IOP, and T-BUT.

The authors reported potential publication bias in the review.

Methodology:

Authors included only RCTs based on the following criteria: 1) participants were younger than 18 years with myopia; (2) atropine was used for at least one treatment arm; and (3) the study reported at least one outcome of interest, including the mean myopia progression (D per year), axial elongation, pupil size, accommodation amplitude, and any adverse effects. The exclusion criteria were as follows: (1) secondary articles such as review articles; (2) original data could not be extracted and obtained after contacting the author.

Authors searched PubMed, EMBASE, Ovid, and the Cochrane Library for RCTs in any languages to yield relevant studies from their inception to 30 March  2021. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov was also searched to retrieve additional ongoing trials. Two reviewers independently screened data of included studies. Authors extracted the following information from each trial: (1) study characteristics (author, year of publication, country, intervention and control group, and follow-up duration); (2) patient characteristics (the number of cases and age and baseline refraction). Risk of bias was assessed using the Cochrane Collaboration tool.

Authors conducted a meta-analysis on the changes in different concentrations of atropine versus control conditions based on RCTs. The authors calculated mean difference and 95% confidence intervals. They also assessed heterogeneity using the I² statistic. Authors considered performing a sensitive and subgroup analyses to further investigate heterogeneity.

Applicability/external validity:

Authors note that this study confirms that atropine is effective in slowing childhood myopic progression.

Geographic focus:

Authors included RCTs from high, middle and low income countries and did not describe how applicable the results may be to low and middle income settings.  

Summary of quality assessment:

This review is grounded on well-defined inclusion criteria and suitable statistical analyses. In instances of high heterogeneity, the authors employed subgroup analysis and conducted a sensitivity analysis to assess the degree of heterogeneity. However, notable limitations were observed. The searches were confined to electronic databases, and it remains unclear if the authors limited the search to articles written only in English. Moreover, it is uncertain whether the authors used a rigorous method when screening studies for inclusion and extracting data from the included studies. For these reasons we have low confidence in the findings f this review.