Efficacy and Adverse Effects of Atropine in Childhood Myopia: A Meta-analysis

Methodological quality of the review: Medium confidence

Author: Qianwen Gong, Mirosław Janowski, Mi Luo, HongWei, Bingjie Chen, Guoyuan Yang, Longqian Liu

Region: China, Singapore, United States of America, Taiwan, Hong Kong

Sector: Myopia

Subsector: Myopia treatment with atropine in childhood

Equity focus: No

Study population: Childhood (younger than 18 years)

Type of programme: Hospital based

Review type: Other review

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Not applicable

Background: Myopia is a relatively prevalent and increasing public health concern, particularly in East Asia, where it has already reached a pandemic level. The prevalence has been reported to be 80% or higher in the young adult population in certain Asian countries or areas, such as Singapore, Hong Kong, and Taiwan and also the USA. In addition, the cost of uncorrected refractive error is a very real existing problem, affecting as many as 88 per cent of children with myopia, and thus, the implications of increasing myopia prevalence worldwide are significant. Atropine, a nonselective muscarinic antagonist, has been studied widely in recent years to prevent worsening of myopia in children. Although the exact mechanism and site of action of atropine are still unknown, different concentrations of atropine (low dose, 0.01%; moderate dose, >0.01%to<0.5%; and high dose, 0.5%to 1.0%) have been widely used topically as eye drops, with great interest in Asian areas, especially in Taiwan and Singapore. Atropine was thought to have a dose-related efficacy, but was also thought to be associated with significant adverse effects. Previous systematic reviews have assessed the efficacy of atropine, but a quantitative assessment of the adverse effects was lacking. Because race and iris colour are known factors that influence cycloplegia, the adverse effects of atropine in lightly pigmented eyes of white persons may be more severe.

Objectives: To evaluate the efficacy versus the adverse effects of various doses of atropine in the therapy for myopia in children.

Main findings: Nineteen unique studies involving 3,137 unique children were included in the analysis. The study included nine RCTs and 10 cohort studies. The quality of the included cohort studies was generally high according to the Newcastle-Ottawa Scale items. The weighted mean differences between the atropine and control groups in myopia progression were 0.50 diopters (D) per year (95% CI, 0.24-0.76 D per year P<.001) for low-dose atropine, 0.57 D per year (95% CI, 0.43-0.71 D per year P< .001) for moderate-dose atropine, and 0.62 D per year (95% CI, 0.45-0.79 D per year P< .001) for high-dose atropine (P<.001, which translated to a high effect size (Cohen d, 0.97, 1.76, and 1.94, respectively). In addition, the ES pooling revealed a large treatment effect in the outcome of interest for RCTs (ES, 2.67; 95% CI, 1.46-3.88) and cohort studies (ES, 1.30; 95% CI, 0.61-1.98). A significant heterogeneity and publication bias was found in the treatment effects for RCTs and no publication bias in cohort studies. All doses of atropine, therefore, were equally beneficial with respect to myopia progression (P=.15). High-dose atropine was associated with more adverse effects, such as the 43.1% incidence of photophobia, compared with 6.3% for low-dose atropine and 17.8% for moderate-dose atropine (χ₂²=7.05; P=.03). In addition, differences in the incidence of adverse effects between Asian and white patients were not identified (χ²₁=0.81; P=.37 for photophobia). The incidence of poor near visual acuity for low-dose atropine was 2.3% (95% CI, 0.1%-5.5%); for moderate-dose atropine,11.9% (95% CI, 7.0%-18.5%); and for high-dose atropine, 11.6% (95% CI, 0.8%-27.3%) (χ²₂=9.98; P=.007 for interaction). The incidence of allergy for moderate-dose atropine was 2.9% (95% CI, 0.1%-6.9%); for high-dose atropine, 3.9% (95% CI, 2.0%-6.2%) (χ²₁=0.24; P=.62). The incidence of other adverse effects for low-dose atropine was 4.8% (95% CI,1.0%-10.6%); for moderate-dose atropine,11% (95% CI, 6.5%-16.4%); and for high-dose atropine,11.2% (95% CI, 3.3%-21.5%) (χ²₂=3.57; P=.17 for interaction).

Methodology:

The studies were selected according to the following criteria: 1) comparative studies (such as, randomised clinical trials [RCTs], non-RCTs and cohort studies); 2) participants were younger than 18 years and had myopia; 3) atropine was used in at least one treatment arm; and (4) the study reported at least one outcome of interest, including the annual rate of myopia progression and any adverse effects.

The search was done on PubMed, Embase, and the Cochrane Central Register of Controlled Trials to yield relevant studies from their inception to 30 April 2016, using Medical Subject Headings (MeSH) and free words combined with myopia, refractive errors and atropine. We also screened ClinicalTrials.gov and the reference lists of published reviews to identify additional relevant studies. Only studies published in English were included. Two authors (Q.G. and M.L.) screened titles and abstracts to identify potentially eligible articles independently and in duplicate, and then they checked the full text to determine the final inclusions. Assessment of risk for bias of RCTs was done following the six aspects according to the Cochrane Collaboration. For observational studies, we applied the Newcastle-Ottawa Scale, which included eight items within three domains to evaluate bias in patient selection, comparability, and outcome assessments.

Data analyses were performed using Review Manager (version 5.3; Cochrane Collaboration), STATA (version 12.0; StataCorp), and SAS (version 9.4; SAS Institute, Inc) software. We calculated the weighted mean difference (WMD) and 95% CIs for different doses of atropine in refractive changes and axial elongation versus the control group, as well as the risk ratio for adverse effects between the atropine and control groups. The extent of heterogeneity was statistically quantified by Q, H, and I² statistics across studies

Applicability/external validity: The authors reported some limitations which need to be taken in account when applying the results in other settings: first, the concentration of Atropine varies a lot from one study to another, creating more heterogeneity. Second, the report on adverse effects in the included studies was not comprehensive. Third, the efficacy of atropine was reported during the duration of the trials; however, the cessation of atropine therapy has been found to lead to a rebound effect and faster progression of myopia. Four, the poor near visual acuity induced by high-dose atropine may also deter children from close work and thus slow the progression of myopia. Finally, the axial length across various doses of atropine was not evaluated.

Geographic focus: Not discussed.

Summary of quality assessment:

Medium confidence was attributed to the conclusions about the effects of this study. Although authors used appropriate methods to conduct data analysis of included studies, the literature searches were not rigorous enough to ensure that all potentially relevant studies were identified.