At the completion of this article, the reader should be able to improve the application of atropine in myopia management, including:
Understand the link between lifestyle and myopia progression, and how it informs each patient’s treatment
- Be aware of the impact of ethnicity on atropine efficacy
- Consider the treatment implications of clinically-meaningful myopia progression into adulthood.
Dr Samantha SY Lee
BSc (Optom), PhD
Centre for Ophthalmology & Visual Science (incorporating the Lions Eye Institute), University of Western Australia.
Perth, WA
Prof James Loughman
Dip Optom, FAOI, PhD
Centre for Eye Research Ireland, School of Physics, Clinical & Optometric Sciences, Technological University Dublin
Dublin, Ireland
The Western Australia Atropine for the Treatment of Myopia study remains the only randomised controlled trial in Australia that has explored the myopia control effects of 0.01% atropine versus a placebo. Lead author DR SAMANTHA LEE joins PROF JAMES LOUGHMAN to discuss how this work influences what we know about atropine and its effectiveness in different ethnicities.
Since the publication of the low-concentration for myopia progression (LAMP) study,1 it has been generally assumed that 0.05% is the optimal preferred concentration of atropine eye drops for myopia control.2 However, it is often forgotten that the recommendation to use 0.05% was based on just one study conducted on East Asian children, which may not be generalisable to the Australian or other Western or multicultural context.
For practising optometrists, this means that three important factors should be considered when choosing the concentration of atropine for myopia control: your patient’s ancestry, lifestyle and expectations.
First: ancestry
To date, the Western Australia atropine for the treatment of myopia (WA-ATOM) study3 remains the only randomised controlled trial in Australia that has explored the myopia control effects of 0.01% atropine versus a placebo. During the first 18 months of treatment, statistically-significant treatment benefits were observed in children of European descent, with approximately 40% less myopia progression and axial elongation in the 0.01% atropine group (0.44D and 0.22mm) compared to the placebo group (0.73D and 0.35mm). However, 0.01% atropine had essentially no myopia control effect in children of East Asian or South Asian descent. It should be noted that in the final six months of the study, there was an improvement in the placebo group (attributed to a higher rate of withdrawal of participants with fast myopia progression in the placebo group, which affected the results).
Similarly, the Myopia Outcome Study of Atropine in Children (MOSAIC)4 in Ireland found greater myopia control efficacy of 0.01% atropine in children of European descent, with no significant effects observed in those of non-European descent.
The MOSAIC study additionally found greater effects of 0.01% atropine in eyes with lighter irides, although their analysis may have been confounded by ethnicity. (In the WA-ATOM study, when we restricted analyses to only Europeans, no differential effect of eye colour on atropine efficacy was found).
How about in children of European descent?
Is 0.01% atropine strong enough? Would children be able to tolerate a higher concentration and yield better myopia control outcomes?
Unfortunately, the WA-ATOM study did not investigate other concentrations. Instead, we may turn to the childhood atropine for myopia progression (CHAMP) study,5 a multi-centre study in the US and Europe that compared 0.02% and 0.01% atropine to a placebo.
Interestingly, 0.01% atropine showed greater myopia control efficacy than 0.02% atropine. By the end of three years of treatment, the difference in myopia progression between the placebo and the 0.01% group was 0.24 D in spherical equivalent and 0.13 mm in axial length, compared to a small, albeit statistically significant, difference of only 0.1 D in spherical equivalent and 0.08 mm in axial length between the placebo and 0.02% groups.
The authors of the CHAMP study attributed the poor 0.02% efficacy to the 23 (or 10% of) participants in that treatment group who discontinued treatment in favour of other myopia control methods (e.g., orthokeratology or optical methods) but remained in the trial analysis. The reasons for the discontinuation of treatment in this 10% of participants are unclear. Higher concentrations of atropine eye drops for myopia control in European populations are under way, such as the second phase of MOSAIC.
Second: lifestyle
Perhaps the greatest disruption to our lifestyle in recent years was the emergence of COVID-19. Findings from several studies have undisputedly confirmed that COVID-19 restrictions led to an increase in myopia incidence and progression in children. However, its impact on the efficacy of atropine treatment had been difficult to study.
The MOSAIC study4 compared the efficacy of 0.01% atropine between the 141 children whose treatment period coincided with the full COVID-19 restrictions (from mid-March to late-July 2020) and the 63 children who were recruited after restrictions were relaxed. The investigators found 0.01% atropine had limited myopia control benefit in children who were most impacted by COVID-19 restrictions. Those least affected by COVID-19 restrictions, however, experienced the greatest treatment effect of any participant subgroup in the trial, with 40% less refractive progression and 32% less axial elongation in treated compared to untreated children.
Unpublished findings from the WA-ATOM study told a similar story. Instead of lockdowns, WA imposed a lockout, which in turn allowed residents of the state to maintain a COVID-free lifestyle for most part of the pandemic. Nonetheless, there was a one-month period early in the pandemic when children were rarely seen in schools, playgrounds and beaches,6 followed by another month where social gatherings were limited and playgrounds were closed.7 In participants using 0.01% atropine eye drops, we similarly found faster axial elongation by 0.056 mm/year, during the COVID lockdown compared to the non-lockdown periods. On the other hand, the rate of axial elongation in those on the placebo eye drops was similar during lockdown and non-lockdown. These findings collectively suggest that low-concentration atropine treatment outcomes may be influenced through behavioural modification.
Third, and perhaps most importantly: patient expectations
It may be hard to predict a patient’s tolerance and response to atropine eye drops. As optometrists would notice from other areas of clinical practice, ocular response to different treatments can be variable, including intraocular pressure-lowering therapy, topical steroids and the various myopia control methods.
As summarised in Table 1, various trials comparing 0.01% atropine to a placebo have reported highly varied findings, although this is not particularly surprising given the methodological and other differences between trials.
For example, both the WA-ATOM3 and the Pediatric Eye Disease Investigator Group (PEDIG)8 studies have similar trial inclusion criteria for participants, similar age, and half of each trial cohort comprise children of European descent. Yet, the WA-ATOM study found a moderate effect of 0.01% atropine while the PEDIG study found no effect. However, to date, the PEDIG study stands as the only trial to not show a positive effect of 0.01% atropine.
Weirder still, the US- and Europe-based CHAMP study5, published merely one month before the US-based PEDIG study – both in the same journal – found that 0.01% atropine controls both spherical equivalent and axial length, and that it performed better than the 0.02% concentration. Although about 10% of the children who were treated with 0.02% discontinued the eye drops in favour of other privately-sought myopia control, they were still included in the analysis.
While starting a patient at a higher concentration of atropine may improve the chances of a positive response to treatment, it also increases the risk of intolerance and thus poor adherence to treatment. Conversely, a lower concentration may have limited myopia-control efficacy, resulting in patients losing confidence in the treatment altogether. Thus, it is important to manage the expectations of patients prior to initiating treatment.
Optometrists could choose a starting concentration on the basis of balancing the needs for myopia control versus the risk of intolerance to the chosen concentration. Higher concentrations might be more suitable in higher risk patients, whereas a more conservative approach might be taken in lower risk eyes (e.g. older children, lower myopes, pre-myopes).
Where necessary, the dose should be modified as quickly as possible to optimise both tolerability/adherence and efficacy. Clinical decisions should be based on the individual risk profile of patients in the chair and adapted based on their response to the prescribed regimen.
Myopia control: a long-term commitment or possibly don’t bother
In addition to discussing the starting concentration, patients should be informed about the long-term relationship they should maintain with their atropine eye drops.
Atropine eye drops, and very likely most, if not all, forms of myopia control treatment, is associated with the infamous ‘rebound’ myopia progression after cessation of treatment.9,10 Younger age and higher concentrations of atropine are associated with greater rebound effects, as confirmed by the LAMP study.1 However, for how long should treatment continue?
The ATOM2 study11 in Singapore, which investigated a two-year treatment regime of atropine with concentrations of 0.5%, 0.1% or 0.01%, found 67%, 59%and 24% of participants, respectively, had a rebound myopia progression by 0.50 D or more in the following 12 months. Importantly, the children with progressing myopia post-atropine treatment were on average approximately 1.4 years younger than those with relatively stable myopia (11.1 vs 12.5 years at the time of stopping atropine).
The ATOM2 investigators then re-started those children with progressive myopia on 0.01% atropine for another two years – totalling five years of trial. When the participants were re-examined 10 years later – 15 years after the beginning of the five-year trial – final refractive errors did not significantly differ between the 0.5%, 0.1% and 0.01% groups.12 This was despite most of the participants in the 0.5% and 0.1% group undergoing treatment for an additional two years with 0.01% atropine (total four years of treatment).
In the first two years of the WA-ATOM study,3 we found a moderate effect of 0.01% atropine on myopia control, relative to a placebo. However, in the following year when children discontinued eye drop use, there was a rebound in myopia progression in the children who had used 0.01% atropine, such that overall myopia progression over the three years were similar between the treatment and placebo groups (Figure 1).13
These findings from the long-term observational study of the ATOM and the WA-ATOM study suggest that low-concentration atropine therapy (and possibly all forms of myopia control) is a long-term – more than a few years – commitment. They demonstrate that treatment should not be terminated based on any arbitrary criterion such as age or clinical trial termination. Instead, treatment decisions on when and how to end treatment should be personalised to every individual patient, otherwise any benefits of treatment would be negated by premature cessation. The MOSAIC trial in Ireland is also currently investigating the impact of sudden versus gradual (tapered) 0.01% atropine treatment cessation and will report on this at the upcoming Association for Research in Vision and Ophthalmology conference in May 2024.
In routine clinical practice, optometrists are increasingly noticing that myopia can continue to progress into adulthood. The Raine Study found that one in three people in their 20s continue to have myopia progression, and one in seven people who had no myopia at 20-years-old would go on to develop myopia eight years later.14 There is evidence that some myopes may be susceptible to clinically meaningful refractive progression and axial elongation into adulthood.15 This means that there is a long timeframe, from childhood up to the third or even fourth decade of life, during which myopia can worsen. Consequently, it’s possible that myopia control should continue into adulthood.
Modern medicine has provided the luxury of one-time fixes or short-term treatment – cataract surgery, antibiotics treatment for infections, laser refractive surgeries, or simply taking a paracetamol tablet for relieving headaches. Because of this, it’s important to remind patients and parents that myopia control is likely to be a long-term commitment. Without adhering to this long-term commitment, the benefits of any short-term treatment may be negated.
More reading
Managing your practice’s myopia integration
What is the ideal concentration of atropine for myopia control?
Don’t forget about myopia progression in adults
References
1.Yam JC, Zhang XJ, Zhang Y, et al. Three-Year Clinical Trial of Low-Concentration Atropine for Myopia Progression Study: Continued Versus Washout: Phase 3 Report. Ophthalmology. 2021.
2. Khanal S, Phillips JR. Which low-dose atropine for myopia control? Clinical & Experimental Optometry. 2020; 103 (2): 230-232.
3. Lee SS, Lingham G, Blaszkowska M, et al. Low-concentration atropine eyedrops for myopia control in a multi-racial cohort of Australian children: a randomised clinical trial. Clin Exp Ophthalmol. 2022.
4. Loughman J, Kobia-Acquah E, Lingham G, et al. Myopia outcome study of atropine in children: Two-year result of daily 0.01% atropine in a European population. Acta ophthalmologica. 2023.
5. Zadnik K, Schulman E, Flitcroft I, et al. Efficacy and Safety of 0.01% and 0.02% Atropine for the Treatment of Pediatric Myopia Progression Over 3 Years: A Randomized Clinical Trial. JAMA Ophthalmol. 2023.
6. McNeill H. A timeline of WA’s COVID-19 response: Was our success luck, good management, or a bit of both? WA Today 2020.
7. Department of Health Western Australia. Phase 3 of COVID-19 roadmap to commence from Saturday, June 6. In: Health Do, ed. Perth2020.
8. Repka MX, Weise KK, Chandler DL, et al. Low-Dose 0.01% Atropine Eye Drops vs Placebo for Myopia Control: A Randomized Clinical Trial. JAMA Ophthalmol. 2023; 141 (8): 756-765.
9. Sánchez–Tena MÁ, Ballesteros–Sánchez A, Martinez–Perez C, Alvarez–Peregrina C, De–Hita–Cantalejo C, Sánchez–González MC, et al. Assessing the rebound phenomenon in different myopia control treatments: A systematic review. Ophthalmic and Physiological Optics. 2024 Jan 9;44(2):270–9.
10. Brennan NA, Toubouti YM, Cheng X, Bullimore MA. Efficacy in myopia control. Progress in Retinal and Eye Research. 2021 Jul;83:100923. doi:10.1016/j.preteyeres.2020.100923
11. Chia A, Lu QS, Tan D. Five-Year Clinical Trial on Atropine for the Treatment of Myopia 2: Myopia Control with Atropine 0.01% Eyedrops. Ophthalmology. 2016; 123 (2): 391-399.
12. Li Y, Yip M, Ning Y, et al. Topical Atropine for Childhood Myopia Control: The Atropine Treatment Long-Term Assessment Study. JAMA Ophthalmol. 2023.
13. Lee SS, Nilagiri VK, Lingham G, et al. Myopia progression following 0.01% atropine cessation in Australian children: findings from the WA-ATOM study. Clin Exp Ophthalmol. 2024; [Accepted for publication on 31 Jan 2024 and in press].
14. Lee SS, Lingham G, Sanfilippo PG, et al. Incidence and Progression of Myopia in Early Adulthood. JAMA Ophthalmol. 2022; 140 (2): 162-169.
15. Bullimore MA, Lee SS-Y, Schmid KL, Rozema JJ, Leveziel N, Mallen EA, et al. IMI—onset and progression of myopia in young adults. Investigative Opthalmology & Visual Science. 2023 May 1; 64 (6): 2. doi:10.1167/iovs.64.6.2
