Atropine Myopia Control Western Australia Clinical Trial Findings

Earlier this year, the Therapeutics Goods Administration (TGA) approved a myopia control treatment – Eikance 0.01% atropine eye drops (Aspen Australia) – for the first time in Australia.

Photophobia resulting from atropine-induced mydriasis may cause an aversion to spending time outdoors, especially during the summer months

This is undoubtedly a milestone for local myopia management. Until recently, there had been limited evidence supporting the use of 0.01% atropine eye drops for myopia control in children living in Australia (or any Western country for that matter).

WHY WE NEEDED AN AUSTRALIAN STUDY

Since the publication of the landmark atropine for the treatment of myopia (ATOM) studies in Singapore, 0.01% atropine eye drops had been a preferred myopia control approach. Yet, there is a caveat. As highlighted by Morgan and He, following the ATOM studies:

“Almost all recent studies on atropine have been carried out on children of Chinese origin… it is likely that the concentrations of atropine that are optimal in Chinese children may be too strong for use with children with light colored irises, at least in relation to the side effects. So, a good trial with children of European ancestry is a significant priority.”¹

This statement remained relevant even after the publication of the low-concentration atropine for myopia progression (LAMP) study in Hong Kong. In Phase 3 of that study, the LAMP study investigators also acknowledged that “the ATOM2 and LAMP studies were conducted on a majority of East Asian children… and [their] findings of 0.05% atropine as the optimal concentration may not be generalisable to other non-Asian children”.²

Ancestry may not be the only factor to consider. Australia’s long sunshine hours and outdoor lifestyle have been credited for its relatively low myopia prevalence, compared with parts of Europe and Asia.^3,4 Photophobia, resulting from atropine-induced mydriasis, may cause an aversion to spending time outdoors, especially during the summer months when myopia progression tends to be slower.⁵ It is thus possible that an inappropriately high concentration of atropine eye drops may be counter-productive for reducing myopia.

This was demonstrated in a German cohort of 37 European children with myopia who were naïve to atropine eye drops at baseline.6 About half of the children instilled 0.05% atropine at bedtime while the other half instilled 0.01%, and all were examined the next morning. The children who used 0.05% atropine had a relative increase in pupil size by 2.9mm, compared with only 0.8mm in those who used 0.01% concentration, while accommodative amplitude decreased by 4.2D compared to only 0.05D, respectively. Of the 19 children who used 0.05% atropine, 12 reported difficulty with near work, while none of the 18 children who used 0.01% atropine reported any reported adverse effects nor near work difficulty.

In addition to the high rates of nearwork difficulty associated with higher concentrations of atropine, potential photophobia when exposed to the bright sunlight in Australia could make children less likely to adhere to therapy.

GEOGRAPHICAL DIFFERENCES WITHIN ANCESTRY

Such environmental and lifestyle factors may explain the difference in the myopia control effect of 0.01% atropine eye drops observed between Asian children living in Australia7 and those living in Asia.^8,9 In the Western Australia (WA)-ATOM study,⁷ after one year of treatment with 0.01% atropine eye drops, we found that children of East Asian or South Asian descent only had a 0.09D (spherical equivalent) slowing of myopia progression relative to using a placebo, with almost no effect on axial length. This is about half the myopia control effect seen with 0.01% atropine use in East Asian children living in Hong Kong9 or Singapore10 (0.17 to 0.19D) and in South Asian children in India (0.22D).⁸

While the WA-ATOM study is limited by its small sample size in these ancestry groups, this data shows a potential difference in the myopia-control effect based on geographical variations. In children of European descent, the environmental effect on the efficacy of atropine eye drops will be explored as we compare the findings from European participants of the WA-ATOM study to similar studies currently being conducted in Ireland11 and the United Kingdom.¹²

THE EFFECT OF ANCESTRY AND EYE COLOUR

Despite the lack of myopia-control effects in children of East or South Asian descent with 0.01% atropine, the WA-ATOM study found that children of European, mixed Asian-European, or other non-Asian descent (e.g., Hispanic, African, Middle Eastern) still derived significant benefits from the eye drops .⁷ After the first year of treatment with 0.01% atropine, children of European descent had reduced myopia progression (in terms of both spherical equivalent change and axial elongation) by around 50%. Those of mixed Asian-European and other non-Asian descent had a slowed myopia progression by 59% in spherical equivalent and 96% in axial length, relative to a placebo. (It is worth noting that these treatment effects decreased to almost non-significant levels by the end of two years of treatment.

This is likely driven by high withdrawal rates in the placebo group who tend to have more rapid myopia progression, rather than a reduction in treatment efficacy.) The differential treatment effect size between ancestral groups had been assumed to be due to iris pigmentation, as alluded to by Morgan and He.¹ However, there is increasing evidence that the treatment and adverse effects of atropine eye drops are independent of eye colour within ancestral groups.^6,7 The reasons behind the difference in treatment response between ancestral groups remains unclear. Nonetheless, clinicians may be able to disregard eye colour when choosing an appropriate concentration of atropine eye drops but should ensure ancestry is taken into consideration.

CHOICE OF ATROPINE CONCENTRATION IN AUSTRALIAN CHILDREN

In light of the latest evidence from the WAATOM and LAMP studies, it is reasonable to prescribe higher concentrations of atropine, such as 0.05%, for children of East or South Asian descent. However, because of the aforementioned geographical variations, we should be aware that its efficacy in Australian children of Asian descent may not be as great as that observed in the LAMP study.

In children of European, mixed Asian- European, or other non-Asian descent, 0.01% atropine seems to have a significant myopia-control effect and may be suitable. Nonetheless, as demonstrated by the LAMP study, patient age is an important factor in the efficacy of these. Younger children may still require higher concentrations of atropine eye drops . In patients using higher concentrations, clinicians should closely monitor for adverse effects, especially photophobia and near work difficulties, as these may decrease adherence to treatment and thus efficacy.

MYOPIA-CONTROL IS EXPENSIVE; THE ALTERNATIVE IS WORSE

It is not just the potential adverse effects of atropine eye drops that may deter treatment adherence. Some practitioners may have encountered carers of children with myopia who were reluctant to commence or continue myopia control because of the financial cost. At the time of writing, low-concentration atropine eye drops, including the Eikance 0.01% and off-labelled treatment, cost about AU$40–50 a month. This adds up to at least $960 over two years, which is similar to a two-year treatment with orthokeratology, although it varies greatly between practices. Private health insurance is likely to cover only a small portion of the cost, if any. These treatment costs are in addition to consultation fees, carers’ time taken off work for their children’s eye care appointments, and spectacle costs. Thus, active myopia control incurs significant out-of-pocket costs for families.

Yet, consider a ‘let it rip’ scenario, where no active myopia control is undertaken, allowing the eye to elongate at least until one’s mid- 20s. Fricke et al.¹³ estimated that the lifetime cost of this scenario is about AU$11,459, compared to AU$11,217 when treated with anti-myopia spectacles that have been proven to be effective. These are slightly cheaper than the estimated AU$13,017 lifetime cost of myopia with low-concentration atropine therapy during childhood. (While the estimated lifetime cost of myopia control with orthokeratology contact lenses is about AU$14,687.) The authors reported that the costs of not implementing myopia control are likely to have been underestimated, as they do not account for the other financial strains of high myopia, such as auxiliary costs of potential vision impairment. Obvious psychosocial benefits, such as better quality of life in individuals with low myopia but good vision relative to one with high myopia complications, are also not measurable.

We expect the cost of myopia control to reduce soon as the rate of manufacturing atropine eye drops (of various concentrations) or other approaches increase. This will likely make myopia control with low-concentration atropine eye drops more affordable than anti-myopia spectacles or not implementing myopia control. Until then, even if a patient rejects one form of myopia control because of its side effect profile, exploring an alternative effective myopia control approach remains worthwhile, even financially, for our patients.

Dr Samantha Lee is a postdoctoral research fellow at the University of Western Australia and the Lions Eye Institute’s Genetics and Epidemiology group and is co-leading the WA Atropine for the Treatment of Myopia Study. She is also involved with several international projects aimed at understanding how genes and environment interact to influence an individual’s risk of myopia and glaucoma.

Prof David Mackey is one of the top international researchers on ocular genetics and leads the Lions Eye Institute’s Genetics and Epidemiology research group. In 2019, he was made an Officer in the General Division of the Order of Australia (AO) for “distinguished service to medicine, and to medical education, in the field of ophthalmology, as a clinician-scientist and academic”.

References 

1. Morgan IG, He M. An important step forward in myopia prevention: low-dose atropine. Ophthalmology. 2016;123(2):232-233. 
2. Yam JC et al. Three-Year Clinical Trial of Low- Concentration Atropine for Myopia Progression Study: Continued Versus Washout: Phase 3 Report. Ophthalmology. 2021. 
3. French AN et al. Comparison of refraction and ocular biometry in European Caucasian children living in Northern Ireland and Sydney, Australia. Invest Ophthalmol Vis Sci. 2012;53(7):4021-4031. 
4. Read SA et al. Patterns of Daily Outdoor Light Exposure in Australian and Singaporean Children. Translational Vision Science & Technology. 2018;7(3):8. 
5. Cui D et al. Effect of day length on eye growth, myopia progression, and change of corneal power in myopic children. Ophthalmology. 2013;120(5):1074-1079. 
6. Joachimsen L et al. Side effects of topical atropine 0.05% compared to 0.01% for myopia control in German school children: a pilot study. Int Ophthalmol. 2021;41(6):2001- 2008. 
7. Lee SS et al. Low-concentration atropine eye drops for myopia control in a multi-racial cohort of Australian children: a randomised clinical trial. Clin Exp Ophthalmol. 2022. 
8. Saxena R et al. Atropine for treatment of childhood myopia in India (I-ATOM): multicentric randomized trial. Ophthalmology. 2021. 
9. Yam JC et al. Low-Concentration Atropine for Myopia Progression (LAMP) Study: A Randomized, Double-Blinded, Placebo-Controlled Trial of 0.05%, 0.025%, and 0.01% Atropine Eye Drops in Myopia Control. Ophthalmology. 2019;126(1):113-124. 
10. Chia A et al. Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (Atropine for the Treatment of Myopia 2). Ophthalmology. 2012;119(2):347-354. 11. McCrann S et al. Myopia Outcome Study of Atropine in Children (MOSAIC): an investigator-led, double-masked, placebo-controlled, randomised clinical trial protocol. HRB Open Research. 2019;2(15). 12. Azuara-Blanco A et al. Low-dose (0.01%) atropine eye-drops to reduce progression of myopia in children: a multicentre placebo-controlled randomised trial in the UK (CHAMP-UK) study protocol. The British Journal of Ophthalmology. 2019. 13. Fricke TR et al. Establishing a method to estimate the effect of antimyopia management options on lifetime cost of myopia. The British Journal of Ophthalmology. 2022.