Does 0.01% atropine have a place as a myopia control therapy?

John R. Phillips The global increase in myopia prevalence, coupled with its progressive nature and the sight-threatening complications associated with high myopia, has created a growing need for effective control interventions. While the primary aim of intervention is to minimise the final degree of myopia, the clinical use of some myopia control treatments has far outstripped the speed at which the scientific community has properly evaluated their efficacies. This is particularly true for 0.01% atropine. Among the various treatment options, 0.01% atropine has emerged as one of the most widely prescribed interventions, particularly following the Atropine for the Treatment of Myopia (ATOM) 2 study, which suggested favourable efficacy with minimal side effects. The majority of clinicians regularly prescribe this concentration, especially in Asia. However, subsequent research, including the Low Concentration of Atropine for Myopia Progression (LAMP) study and multiple meta-analyses has raised important questions about its effectiveness compared with higher concentrations and modern optical interventions. The clinical conundrum now is whether prescribing 0.01% atropine monotherapy is best practice. Does its attractive safety profile, minimal side effects and reduced rebound upon cessation still outweigh its questionable efficacy in controlling myopia progression? Emerging evidence regarding its efficacy also challenges current professional guidelines that recommend 0.01% atropine as a primary intervention. As our understanding of treatment efficacy and individual patient suitability grows, the adoption of more effective treatments should increase, allowing less effective therapies to fall from favour. Here, Jason Yam and Safal Khanal present evidence for and against the premise that 0.01% atropine has a place as a myopia control therapy. Jason C. Yam 0.01% atropine became one of the most widely used treatments for myopia control globally after the ATOM 2 trial. The 5-year results from ATOM 2 indicated that overall myopia progression and axial length (AL) elongation were lowest in the 0.01% concentration group (−1.38 ± 0.98 D; 0.75 ± 0.48 mm, respectively) compared with the 0.1% group (−1.83 ± 1.16 D; 0.85 ± 0.53 mm) and the 0.5% group (−1.98 ± 1.10 D; 0.87 ± 0.49 mm).1 In addition, atropine 0.01% resulted in minimal pupil dilation, slight loss of accommodation and no near vision loss compared with higher doses. However, when compared to a historical control from the ATOM 1 study, 0.01% atropine did not demonstrate any significant effect on AL elongation over 2 years (0.01% atropine: 0.41 ± 0.32 mm; historical control: 0.38 ± 0.38 mm), despite a notable reduction of spherical equivalent (SE) progression (0.01% atropine: −0.49 ± 0.63 D; historical control: −1.20 ± 0.69 D).2, 3 Since AL measurements provide greater precision and are less prone to errors than cycloplegic refractions,4 the surprising discrepancy—where 0.01% atropine slowed myopic SE progression but did not reduce axial elongation—raised concerns about the use of a historical control and the validity of comparing results across different patient groups. Nonetheless, many hospitals and ophthalmic clinics in the public sector and private practice have since adopted 0.01% atropine worldwide, especially in Asia and Australasia.5 Among paediatric ophthalmologists globally, nearly two-thirds regularly prescribe 0.01% atropine to mitigate myopia progression.6 To address the lack of a concurrent control group in the ATOM 2 study, the LAMP study was subsequently conducted to evaluate the efficacy of 0.05%, 0.025% and 0.01% atropine compared with a placebo control.7 The LAMP study demonstrated a clear concentration-dependent effect from 0.05% to 0.01%, with 0.05% yielding the highest treatment efficacy among these concentrations in Chinese children. Subsequently, a concentration-dependent effect was also observed in a predominantly European population, with 0.05% atropine yielding superior efficacy compared with 0.01% atropine and placebo.8-10 Several systematic reviews and meta-analyses have also suggested that 0.05% atropine is the most effective atropine concentration for myopia control among concentrations <0.1%.11-14 Additionally, 0.05% atropine demonstrated the best cost-effectiveness among 16 different treatment interventions.15 The accumulating evidence has prompted recommendations to transition from 0.01% atropine to higher, yet safe, concentrations.5, 10, 16, 17 Nevertheless, 0.01% could still have a place in myopia control therapy in the following aspects. The treatment response may vary in different ethnicities. This could possibly be attributed to their different progression rates. In the Atropine for the Treatment of Childhood Myopia in India (I-ATOM) trial, 0.01% atropine significantly reduced SE progression after 1 year (0.01% atropine: −0.16 ± 0.40 D; control: −0.35 ± 0.40 D) in Indian children.18 Although its effect on AL elongation was not statistically significant, there was a greater elongation in the control group (0.01% atropine: 0.22 ± 0.2 mm, control: 0.28 ± 0.28 mm).18 Additionally, the Childhood Atropine for Myopia Progression (CHAMP) study, conducted in a predominantly white population, demonstrated that at 36 months, 0.01% atropine significantly reduced the progression of the myopic SE (0.01% atropine: −1.04 D, 95% CI −1.14 to −0.94 D; placebo: −1.28 D, 95% CI −1.37 to −1.19 D), as well as elongation of AL (0.01% atropine: 0.68 mm, 95% CI 0.63–0.72 mm; placebo: 0.81 mm, 95% CI 0.76–0.85 mm), compared with the placebo.19 In the Myopia Outcome Study of Atropine in Children (MOSAIC), also involving largely white participants, the 0.01% atropine group exhibited significantly lower AL elongation (0.33 ± 0.27 mm) compared to the placebo group (0.40 ± 0.31 mm).9 Subgroup analysis revealed significant treatment effects among White participants, while no such effects were observed in non-White participants.9 Although the relative reduction in AL elongation with 0.01% atropine in regions outside East and Southeast Asia was comparable to the modest efficacy levels seen in Asian children, the change is still clinically relevant since myopia progression is faster in East Asian children than in their non-Asian counterparts.20 There is a natural growth of the eyeball and a corresponding shift in refractive state during childhood, and this process occurs more rapidly in the early years.21 Thus, when myopia develops at a younger age, the inherent eye growth combined with eye growth resulting from extrinsic factors tends to exacerbate AL elongation and SE progression,20, 22 as well as increase the risk of high myopia.23 Due to this accelerated physiological progression in younger children, myopia may continue to progress at a faster rate despite treatment with atropine, particularly with a lower concentration of 0.01%. On the other hand, in older children, where physiological eye growth may have stabilised or slowed significantly, treatment with 0.01% atropine may seem to achieve more favourable results although the efficacy of atropine is invariant across age groups.24-26 These findings suggest that atropine 0.01% could still play a role in impeding eye growth in slow progressors, who are usually older than fast progressors when considering age as a factor of progression in untreated eyes.20, 22 Li et al.25 demonstrated that myopia progression in 6-year-old children receiving 0.05% atropine was comparable to that of 8-year-olds being treated with 0.025% atropine and 10-year-olds receiving 0.01% atropine. Additionally, older children demonstrate a more acceptable tolerance towards the accommodation loss from 0.01% atropine compared with higher concentrations.25 Recent studies have shown that combining 0.01% atropine with optical methods could result in superior efficacy than monotherapy. Randomised clinical trials have consistently shown that combining 0.01% atropine with orthokeratology is more effective in slowing AL elongation than orthokeratology alone. For instance, Kinoshita et al. reported that over 2 years, combining 0.01% atropine with orthokeratology was 28% more effective in slowing axial elongation than orthokeratology alone (0.29 ± 0.20 vs. 0.40 ± 0.23 mm).27 In Hong Kong, an even greater synergistic effect of 50% reduction in axial growth (0.17 [0.03] vs. 0.34 [0.03] mm) and an average overall growth of <0.1 mm per year were observed in subjects who received combined treatment, compared to those who underwent orthokeratology monotherapy over 2 years.28 It is worth noting that the results of the trials suggest that the greatest efficacy of combining orthokeratology with 0.01% atropine was observed in low myopes and during the initial 6–12 months of treatment.27, 28 Similarly, enhanced efficacy has been found when combining 0.01% atropine with Defocus Incorporated Multiple Segments (DIMS) spectacle lenses compared with DIMS lenses or atropine monotherapy. In a retrospective analysis of the effects of combining 0.01% atropine with orthokeratology in Chinese children, SE progression slowed by 54% (−0.49 ± 0.66 vs. −1.07 ± 0.64 D) and AL elongation by 46% (0.28 ± 0.24 vs. 0.52 ± 0.22 mm) compared to single vision lenses, whereas DIMS alone yielded a 26% reduction in SE progression (−0.79 ± 0.47 vs. −1.07 ± 0.64 D) and 21% reduction in AL elongation (0.41 ± 0.22 vs. 0.52 ± 0.22 mm) over 1 year.29 Consistent findings were reported in an observational study of European children and adolescents, with the combined therapy achieving superior efficacy of 77% axial elongation control and 70% myopia progression control compared with 0.01% atropine (62% and 57%, respectively) and DIMS (57% and 57%, respectively).30 In the ATOM2 study, the cessation of 0.1% and 0.5% atropine treatment resulted in greater myopic rebounds, resulting in faster overall myopia progression compared to 0.01% atropine over 3 years.1, 31 In the 3-year results of the LAMP study, pairwise comparisons revealed that after washout, the previously treated 0.05% group had a slightly faster AL elongation—by approximately 0.04 mm—than the 0.01% group over 12 months (p = 0.04).32 These findings suggest that a tapering strategy may be beneficial during treatment cessation, although evidence is still yet to be established. The low concentration of 0.01% atropine could be particularly useful in this tapering approach. In conclusion, while 0.01% atropine has modest efficacy in myopia control, it still has a role, especially in non-Asian groups and older children, due to their slower progression rates. Furthermore, for children using optical methods, adding 0.01% atropine could yield a stronger efficacy. During the treatment cessation stage, gradually tapering to the lower concentration of 0.01% atropine could potentially reduce the rebound effect. Safal Khanal Globally, 0.01% atropine eye drops are commonly used as a myopia control therapy in children.33 The ubiquitous application of 0.01% atropine to slow childhood myopia progression is based on the premise that it offers therapeutic benefits with minimal side effects and lower rebound (acceleration of progression after stopping treatment) than higher concentrations.1, 32 As a topical therapy typically instilled once daily at bedtime, parents can easily administer 0.01% atropine to children at home without concerns for possible corneal infections associated with contact lens therapies. These advantages have led to the widespread popularity of 0.01% atropine in both research and clinical realms worldwide. Despite extensive data from several rigorous randomised controlled trials, whether 0.01% atropine has a place as a myopia control therapy continues to be contentious.5, 34-36 The primary justification for administering myopia control therapy is to limit axial eye growth to lower the risks of developing sight-threatening ocular pathologies in later life. However, a considerable body of evidence now suggests that 0.01% atropine has little to no effect on axial growth, raising the possibility that it might not reduce future myopia-related risks. The forest plot in Figure 1 shows 1-year absolute AL control treatment effects of 0.01% atropine (orange-filled circles) observed across randomised controlled trials conducted around the globe. The grey-filled circle represents the ATOM-2 study, which lacked a true placebo group but provided the initial evidence of efficacy, albeit with comparisons to a historical control from ATOM-1.2 The treatment effects of 0.01% atropine are compared with the corresponding 1-year treatment effects observed in randomised controlled trials of optical myopia control therapies (black-filled circles). A striking observation in Figure 1 is that all the 0.01% atropine studies appear in a cluster near the top half, close to the vertical neutral line, indicating minimal to no treatment effect on axial elongation. In many of these studies, the 95% confidence interval contains zero, indicating that the treatment effect was not significant. While few studies show statistically significant slowing of axial elongation with 0.01% atropine,19, 37-39 the treatment effect sizes appear small and likely not clinically or practically meaningful. Contrary to the commonly held notion that the efficacy of 0.01% atropine has been inconsistent across randomised controlled trials, the data in Figure 1 are remarkably consistent in demonstrating that 0.01% atropine offers minimal to no therapeutic benefit in terms of controlling axial eye growth. For a treatment with a small effect size, variability in statistical significance of the effect across studies should not come as a surprise. Since myopia progression is more rapid at younger ages,49 an effective therapy must be administered early to achieve optimal and maximal treatment benefits. Over the past decade, several effective myopia control therapies have been developed, some of which are presented in Figure 1. Notwithstanding the challenges of comparing efficacy across individual studies, Figure 1 illustrates that the absolute AL control treatment effect of 0.01% atropine is smaller than that of optical myopia control therapies such as dual focus, multifocal and orthokeratology lenses, as well as specialised spectacle lenses. This discrepancy in treatment efficacy is highlighted further in Figure 2, which compares the 3-year absolute AL control treatment effects for optical interventions and 0.01% atropine. Two observations stand out. First, the efficacy of 0.01% atropine in slowing axial elongation appears comparable to that of the progressive addition lens, which is regarded as a clinically ineffective therapy due to its modest (but statistically significant) effect on AL control.42 Second, the treatment effects of optical interventions are two to three times greater than that of 0.01% atropine over 3 years. This result indicates that significantly greater control of axial elongation can be achieved with optical treatments than with 0.01% atropine during a given period. By this token, it could be argued that 0.01% atropine use is a missed opportunity to intervene with a more effective treatment. Some recommend initiating treatment with 0.01% atropine followed by gradual stepwise titration to higher concentrations based on the rate of myopia progression.50 However, instituting an ineffective treatment like 0.01% atropine at an age when progression is typically fastest delays the use of more effective treatments and lessens the potential myopia control benefits. Others assert that 0.01% atropine might benefit older children as the treatment response to lower concentrations is poor at younger ages.25 Yet, this argument fails to consider age as a potential effect mediator: The poor treatment response may be due to the natural history of faster progression at younger ages.51 Regardless, a more effective therapy should always remain a priority to ensure maximum treatment benefits for children with myopia. In clinical care, practitioners are faced with the challenge of deciding whether to recommend a therapy, as aggregate efficacy results from clinical trials may not always translate to practice. A common efficacy metric used in evidence-based medicine to gauge the potential clinical impact of therapies is the number needed to treat (NNT), which indicates the absolute benefit of a treatment to an individual patient.52 Defined as the number of cases needing treatment to produce one beneficial outcome, NNT is calculated as the reciprocal of the absolute risk reduction by subtracting the control event rate from the treatment event rate.53 Restated, NNT is simply the reciprocal of the difference between the proportion of events in the treatment and control groups. An NNT of one would indicate perfect treatment efficacy, implying that every treated individual achieves the intended treatment benefit. Table 1 presents the absolute risk reduction and NNT, calculated for 0.01% atropine and dual-focus contact lenses to achieve one beneficial outcome of <0.50 D myopia progression over 3 years. These calculations used responder analysis data from the published reports of randomised clinical trials.19, 45 What should be considered an appropriate NNT value for effective therapy is debatable and likely depends on multiple factors, including baseline risk, population, cost–benefit estimates and adverse events.54 Nevertheless, Table 1 shows that the NNT of 0.01% atropine to achieve one beneficial outcome of <0.50 D myopia progression over 3 years is nearly five times higher than that of dual-focus lenses, suggesting that the potential clinical benefit of 0.01% atropine treatment is substantially lower compared with treatment with dual-focus lenses. Parents and children seeking care for school-age myopia expect that the administration of a myopia control therapy will yield significant therapeutic benefits, slowing progression to reduce both the final amount of myopia and future myopia-related risks. However, 0.01% atropine is unlikely to meet these expectations due to its ineffectiveness in slowing axial eye growth, as described in the earlier sections. Instead, using 0.01% atropine may set unrealistic expectations for parents and children regarding its potential benefits for myopia control. Given 0.01% atropine's poor AL control, children receiving treatment will continue to show significant progression, resulting in a perceived sense of treatment failure. Since effective myopia control requires a long-term treatment commitment throughout childhood, an ineffective treatment like 0.01% atropine could impose a significant financial burden for rather minimal benefits. Additionally, the use of 0.01% atropine still requires children to wear a refractive correction for clear vision and provides no tangible benefit as would other therapeutic agents like anti-allergy drops.55 The absence of meaningful treatment benefits of 0.01% atropine, combined with the practical challenges associated with its use, could lead to frustration and dissatisfaction in parents and children, potentially reducing enthusiasm to pursue treatment over the long term. Results from randomised controlled trials have provided consistent and compelling evidence that 0.01% atropine has little to no effect in slowing axial elongation of the eye. Administering a treatment with limited efficacy, like 0.01% atropine, not only delays the implementation of more effective treatments, but also sets unrealistic expectations for parents and children. Based on currently available evidence, the clinical utility of 0.01% atropine as a myopia control therapy appears underwhelming and unjustified if the primary objective is to slow axial eye growth to reduce myopia-related risks in later life. John R. Phillips: writing – original draft (equal); writing – review and editing (equal). Jason C. Yam: writing – original draft (equal); writing – review and editing (equal). Safal Khanal: writing – original draft (equal); visualization (lead); writing – review and editing (equal). John R. Phillips: Inventor on patents related to contact lenses for myopia control. The other authors declare no conflicts of interest.