Range of unanswered questions may be addressed by ongoing research
This article was reviewed by Donald Tran, MD
An abundance of evidence from randomised, controlled clinical trials supports the use of topical atropine to prevent myopia progression.
Study results also show that using a low dose of atropine minimises adverse effects and myopic rebound after treatment discontinuation. In addition, the findings indicate that the pharmaceutical formulation affects efficacy, said Donald Tan, MD.
Now, research in this area is continuing and is investigating not only the use of atropine for preventing myopia progression, but also whether it can prevent or delay the onset of myopia.
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Dr Tan is adjunct professor in ophthalmology, Duke - National University of Singapore Medical School, and Visiting Senior Consultant, Singapore National Eye Centre, Singapore. He previously served as Director of the Singapore Eye Research Institute (SERI) and the Singapore National Eye Centre.
Over a period of two decades, the SERI completed five randomised controlled trials on myopia progression involving approximately 1,900 children, including two studies investigating atropine [ATOM1 (Atropine for the Treatment of Myopia) and ATOM2].
Now, SERI is conducting ATOM3 that is testing atropine as intervention to prevent or delay myopia onset in children.
Discussing atropine treatment as a pharmaceutical strategy for myopia control to address the global myopia burden, Dr Tan said, “A Cochrane systematic review published in 2011 identified over 180 published interventional studies for approaches to reduce myopia progression.
Since then, more than 30 clinical trials on the use of atropine eye drops for myopia control were registered on the clinicaltrials.gov website.”
“These studies tested or are testing atropine in concentrations ranging from 1% to 0.005% in eyedrop, gel and ointment formulations and as standalone treatment or with adjunctive therapies that include orthokeratology, soft bifocal contact lenses, ketorolac, acemanisodiamine and acupuncture. Clearly, this is a fervent area of interest.”
Studies investigating topical atropine began in Asia in the 1970s. Despite the long-term history of use and evidence of its efficacy, the mechanism of action by which atropine may control myopia is unknown, Dr Tan said.
“Initially it was thought that atropine might block accommodation, but that is now known not to be true. The current concept is that it works either through a neurochemical cascade that begins with muscarinic receptors at the retina or via a non-muscarinic mechanism involving a direct effect on scleral fibroblasts mediated by inhibition of glycosoaminoglycan synthesis,” he said.
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Dr Tan is chair of the previous ATOM studies. ATOM1 was a 2-year interventional trial launched in 1999 that compared atropine 1% with placebo in children ages 6 to 12 years old with –1 to –6 D myopia.
The results showed that atropine significantly reduced myopia progression and its effect on refraction strongly correlated with a reduction in increase of axial length.
However, the treatment was associated with significant side effects, and 1 year after it was stopped, significant rebound of both axial length and spherical equivalent were observed.
To try to minimise treatment-related side effects, ATOM2 tested lower doses of atropine: 0.5%, 0.1% and 0.01%. It enrolled children aged 6–12 years with ≥–2 D of myopia.
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The trial had a 1-year washout period following 2 years of treatment, and atropine 0.01% was restarted for 2 years in any child whose myopia rebounded during the washout.
Results from ATOM2 demonstrated that both atropine-related ocular adverse events and myopic rebound decreased with decreasing dose.
The study also found that restarting atropine treatment the 0.01% formulation was able to reverse myopia progression that occurred during the washout year.
“At the end of 5 years, treatment with atropine 0.01% was associated with a 50% reduction in myopia progression,” Dr Tan said.
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Based on epidemiological evidence that a younger age of onset is associated with higher degrees of myopia measured both by higher SE and longer axial lengths, ATOM3 is designed to test whether intervention with atropine can prevent or delay the onset of myopia.
“We are doing this study in Singapore where we can confidently predict that 5-year-old children whose refraction is between +1 and –0.49 D will become myopic later in life. We call these children pre-myopes,” said Dr Tan.
ATOM3 is enrolling children aged 5–9 years whose refractive error (by cycloplegic refraction) is between +1 and –0.49 D) and who have at least one parent with myopia. They are being randomised to receive 0.01% atropine or placebo. Treatment will be continued for 2.5 years and then children will be followed during a 1-year washout period.
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Synthesising the contemporary literature
A network meta-analysis of randomised controlled studies investigating interventions for myopia control in children published in 2016 by Huang et al. found that moderate and high dose atropine markedly slowed myopia progression.
In 2017, Gong et al. published a meta-analysis that included 19 studies of atropine involving more than 3100 children.
The investigators concluded that the data showed the efficacy of atropine was dose-independent within the dose range studied, whereas the adverse effects were dose dependent, increasing with increasing dose.
Dr Tan said that the authors stated that low-dose atropine seems to herald a new therapeutic scenario that decreases the adverse effects and seems to decrease the rebound effects.
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“They even went on to suggest that pharmaceutical companies could produce 0.01% atropine commercially to aid further global research.”
In 2017, the American Academy of Ophthalmology Technology Assessment Committee issued a report on atropine for preventing myopia progression in children. The group reviewed 17 studies, of which eight were level I or II, and concluded that lower doses of atropine were slightly less effective than higher doses but were associated with less myopic rebound and fewer side effects.
“One caveat about the studies, however, is that the most robust research was carried out in Asian populations,” Dr Tan said.
Among currently ongoing studies, three are being conducted in the United States.
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The formulation effect
More recently, the Low-concentration Atropine for Myopia Progression (LAMP) study compared atropine 0.01%, 0.025% and 0.05% versus placebo in children with myopia.
Results collected after 2 years indicated that the highest concentration studied was most effective.
Dr Tan observed that the efficacy of the 0.01% concentration in ATOM2 for reducing refractive change was more similar to that seen in the LAMP group treated with atropine 0.025% while the effect of the 0.01% concentration on axial length in ATOM2 almost equaled that achieved using the 0.05% concentration in LAMP. Pupil dilatation was also almost twofold greater in the ATOM2 atropine 0.01% group than in the atropine 0.01% group in LAMP.
“It appears the effect of atropine differs in different formulation. The formulation used in LAMP was different than the ATOM formulation. Yet in ATOM-J, a study done in Japan, benefit was observed using the ATOM formulation of atropine 0.01%, but it was not as effective as the same formulation in ATOM2,” Dr Tan concluded.
“We do not know yet what the best formulation will be. More studies are needed, and certainly there are a lot ongoing.”
Read more by Cheryl Guttman KraderDonald Tan, MD
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This article is based on a presentation given by Dr. Tan at AA0 2019 in San Francisco, CA, USA. He is a consultant to pharmaceutical companies sponsoring studies of atropine treatment for myopia progression.