What are the dose-dependent effects of atropine?

Paper title: Varying Dose of Atropine in Slowing Myopia Progression in Children Over Different Follow-Up Periods by Meta-Analysis

Authors: Gan, Jiahe (1,2), Li, Shi-Ming (1,2), Wu, Shanshan (3), Cao, Kai (1,2), Ma, Dandan (1,2), He, Xi (1,2), Hua, Ziyu (1,2), Kang, Meng-Tian (1,2), Wei, Shifei (1,2), Bai, Weiling (1,2), Wang, Ningli (1,2)

1. Beijing Tongren Eye Center, Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

2. Beijing Ophthalmology and Visual Science Key Laboratory, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
3. Department of Epidemiology and Health Statistics, Peking University School of Public Health, Beijing, China.

Date: Jan 2022

Reference: Gan J, Li SM, Wu S, Cao K, Ma D, He X, Hua Z, Kang MT, Wei S, Bai W, Wang N. Varying Dose of Atropine in Slowing Myopia Progression in Children Over Different Follow-Up Periods by Meta-Analysis. Front Med (Lausanne). 2022 Jan 13; 8:756398

[Link to open access paper]

Atropine is a popular treatment choice for managing myopia progression, despite being ‘off-label’ in some countries. It has been the subject of several clinical trials and meta-analyses in order to establish ideal dosing strategies, expected rebound effects, continued treatment effects and side-effect management. Previous studies have shown higher doses of atropine give increased risk of side effects alongside a dose-dependent effect of less myopia progression and axial elongation. Moderate to lower atropine concentrations have been more readily applied in practice due to fewer side effects.

This meta-analysis evaluated overall safety and efficacy of atropine in slowing myopia progression and assessed if treatment effects are reliant on dose or treatment period. The authors selected 12 randomised controlled trials (RCTs) and 15 cohort studies for analysis. All had used atropine in at least one treatment group and a placebo or non-treatment group as the control and had reported myopia progression and side effects. The studies featured over 5000 children aged 5-15yrs with follow-up periods between 12 and 144 months. Most were conducted in Asian countries with 7 from Europe, India and the U.S.

Efficacy and safety outcomes were assessed as mean annual changes in refraction per year measured in mm and dioptres and by reported adverse effects. Data on pupil and accommodation changes was also gathered. For sub-group analysis, atropine doses were categorised as either low (0.01%), moderate (>0.01-0.5%) or high (0.5-1.0%).

The found that:

• All concentrations of atropine were found to give higher odds ratio (OR) relative to the control drop for side effects incidence. High dose atropine had the highest OR for inducing photophobia, blurred near vision and allergic responses, followed by moderate and low doses.
• All concentrations of atropine showed higher odds ratio (OR) of slowing myopia progression compared to the control drop. The combined OR was 3.50, 7.67 and 6.98 for the low, moderate and high doses respectively. Mean differences in myopia progression between treatment and control groups were 0.35, 0.67D and 0.73D for low, moderate and high doses, respectively.
• For a number of fast progressing children (>1.0D per year), high-dose atropine gave the lowest OR for rapid myopia progression (OR 0.10), followed by moderate (OR 0.16) and low dose concentrations (OR 0.29).
• The OR for rapid myopia progression in slower progressing children was 6.98 for high-dose atropine, 7.67 for moderate and 3.50 for low-dose atropine.

After extracting studies with extreme results from the study, atropine was shown to provide a dose-dependent effect on refractive and axial length changes. However, although high dose atropine gave less progression and axial elongation in the first year of treatment, lower dose atropine showed greater efficacy for less progression (-0.23D) and axial elongation (0.09mm) in a second treatment year compared to high dose atropine (0.14D and -0.15mm, respectively).

Compared to moderate to high concentrations, low dose atropine was found to provide efficacy beyond one-year of use while maintaining minimal side effects. This points to lower dose atropine being more acceptable than higher for use in controlling myopia progression in children

The risk of myopia progression was seen to be lower with high-dose atropine for fast progressing children and with low doses for slower progressing children. If the rate of myopia progression varies between fast and slow progressors, the dose used to control myopia progression could be adjusted for the individual’s progression rate and treatment time.

However, higher dose atropine was also shown to have a dose-dependent effect for side effect such as photophobia. Therefore, the benefits and side effects need to be considered carefully by both parents and practitioners.

Limitations to this study include high heterogeneity due to finding greater effects for myopia slowing for Asian children, from grouping different concentrations due to incomplete data on some concentrations, combining results of RCTs and cohort studies and from varying follow-up periods. It may also suffer from publication bias from insufficient cohort sizes and a lack of reporting on negative results such as side effects.

Further studies could investigate long-term efficacy of varying atropine dosage for different ethnicities, how to minimise adverse effects while maintaining efficacy and how factors such as age, ethnicity, initial degree of myopia and speed of progression may impact the dose used.

More research is also needed to understand the underlying mechanism behind dose-dependent benefits and side effects of atropine and if the reduced efficacy seen with high doses over longer periods is due to naturally slower axial length growth with increasing age.

Title: Varying Dose of Atropine in Slowing Myopia Progression in Children Over Different Follow-Up Periods by Meta-Analysis

Authors: Gan, Jiahe; Li, Shi-Ming; Wu, Shanshan; Cao, Kai; Ma, Dandan; He, Xi; Hua, Ziyu; Kang, Meng-Tian; Wei, Shifei; Bai, Weiling; Wang, Ningli

Purpose: To evaluate the efficacy and safety of atropine for slowing myopia progression and to investigate whether the treatment effect remains constant with continuing treatment

Methods: Studies were retrieved from MEDLINE, EMBASE, and the Cochrane Library from their inception to May 2021, and the language was limited to English. Randomized controlled trials (RCTs) and cohort studies involving atropine in at least one intervention and placebo/non-atropine treatment in another as the control were included and subgroup analysis based on low dose (0.01%), moderate dose (0.01%-<0.5%), and high dose (0.5-1.0%) were conducted. The Cochrane Collaboration and Newcastle-Ottawa Scale were used to evaluate the quality of RCTs and cohort studies, respectively. 

Results: Twelve RCTs and fifteen cohort studies involving 5,069 children aged 5 to 15 years were included. The weighted mean differences in myopia progression between the atropine and control groups were 0.73 diopters (D), 0.67 D, and 0.35 D per year for high-dose, moderate-dose, and low-dose atropine, respectively (χ² = 13.76; P = 0.001, I ² = 85.5%). After removing studies that provided extreme findings, atropine demonstrated a significant dose-dependent effect on both refractive change and axial elongation, with higher dosages of atropine resulting in less myopia progression (r = 0.85; P = 0.004) and less axial elongation (r = -0.94; P = 0.005). Low-dose atropine showed less myopia progression (-0.23 D; P = 0.005) and less axial elongation (0.09 mm, P < 0.001) in the second year than in the first year, whereas in high-dose atropine more axial elongation (-0.15 mm, P = 0.003) was observed. The higher dose of atropine was associated with a higher incidence of adverse effects, such as photophobia with an odds ratio (OR) of 163.57, compared with an OR of 6.04 for low-dose atropine and 8.63 for moderate-dose atropine (P = 0.03). 

Conclusions: Both the efficacy and adverse effects of atropine are dose-dependent in slowing myopia progression in children. The efficacy of high-dose atropine was reduced after the first year of treatment, whereas low-dose atropine had better efficacy in a longer follow-up period.

[Link to open access paper]