Atropine & Myopia Progression
The increasing prevalence of myopia and high myopia has significant economic and social impacts. Δ We face an epidemic of myopia as its global prevalence continues to rise at an alarming rate.
Most myopia is associated with excessive elongation of the eye that stretches the retina and choroid and increases the risk of ocular pathologies, including retinal detachment and myopic maculopathy.
Myopia control in recent years has gone from a niche clinical care activity to the conduct of mainstream randomized treatment trials in children in many countries.
This is because of concern about the remarkable increase in the prevalence of myopia internationally Currently, multiple methods are used to control the progression of myopia, including low-dose atropine eye drops, orthokeratology (OK) lens, peripheral defocus contact lenses, increased outdoor activity and sunlight exposure time.
High myopia is typically defined as more than −6.00 diopters (D); it has been associated with significantly increased risk of myopic macular degeneration, retinal detachment, cataract, open-angle glaucoma, and blindness.
There are 3 strategies for current myopia control being prescribed for children. The first is to reduce the population prevalence of high myopia. This population includes patients with the highest risk of myopia-associated disease and the most to gain individually from treatment.
The second strategy is to reduce the ultimate correction and, more importantly, axial length of each patient with myopia. A number of studies, including a 2020 meta-analysis, have found that the risks of myopia-associated pathologies, such as myopic macular degeneration, do not only occur after a fixed cut point of myopia is reached but rather increase progressively as myopia increases from low levels of myopia.
Increased risks are evident even when the patient remains in the mild and moderate ranges of myopia.
The Use of Orthokeratology (OK) Lens
Currently, OK lens use is the most common approach to slowing down myopia progression especially in mainland China Δ. OK lens wear temporarily reduces the degree of myopia and controls the speed of myopia progression.
However, some myopic children do not fully benefit from this approach because of individual differences in the response to OK lens, decreased visual quality, the limited range of refractive correction available and the strict compliance expectations for successful OK lens wear.
At present, another effective method to control myopia progression in children is atropine eye drop administration. Atropine has a dose-related effect on myopia progression with greater effect and more obvious side effects, including photophobia, poor near vision and rebound effects after cessation, seen with higher doses.
ΔAll these risks appear to be substantially mitigated by the administration of low atropine Δ concentrations.Δ Many studies have shown that moderate and low concentrations of atropine (eg, 0.01%, 0.025%, 0.05%, 0.1%) could control the progression of myopia in children with reasonable efficacy, minimal side effects, convenient use and slight rebound effects after discontinuation.
However, there are differences in the efficacy and side effects (reduction in amplitude of accommodation pupil dilation and symptoms such as photophobia and near blur vision) with different concentrations of low-dose atropine.
The Latest Research
An abundance of evidence from randomized, controlled clinical trials supports the use of topical atropine to prevent myopia progression. Study results also show that using a low dose of atropine minimizes 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.
Dr. Tan is adjunct professor in ophthalmology, Duke-National University of Singapore Medical School, and Visiting Senior Consultant, Singapore National Eye Centre, Singapore.
Over a period of two decades, the SERI completed five randomized controlled trials on myopia progression involving about 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.”
“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,” he said.
Brief History
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,” he said. 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.
Dr. Tan is chair of the previous ATOM studies. ATOM1 was a two-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 minimize 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. The trial had a one-year washout period following two years of treatment, and atropine 0.01% was restarted for two 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 five years, treatment with atropine 0.01% was associated with a 50% reduction in myopia progression,” Dr. Tan said. 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.
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 randomized 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. A network meta-analysis of randomized 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 metaanalysis 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.
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. Among currently ongoing studies, three are being conducted in the United States.
The Formulation Effect
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 two 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. “We do not know yet what the best formulation will be,” Dr. Tan concluded. “More studies are needed, and certainly there are a lot ongoing.”
