Stating the facts about combination myopia management treatments
Growing evidence supports dual therapy to slow progression.
Although most studies have focused on evaluating monotherapy options, there is growing evidence suggesting that dual therapy may further slow myopic progression. (Adobe Stock/Miljan Živković)
Myopia management options and knowledge have proliferated over the past decade. This pursuit of new knowledge has been fueled by the understanding that the worldwide prevalence of myopia is increasing, and that this spike in myopia cases may increase the population’s ocular pathology burden.1,2 With this dynamic landscape and urgent need to curb the onset and progression of myopia, it is imperative that clinicians explore every avenue for improving myopic progression treatment outcomes.
Although most studies have focused on evaluating monotherapy options, there is growing evidence suggesting that dual therapy may further slow myopic progression. Thus, the purpose of this literature review is to explore the current state of knowledge related to using low-dose atropine as an adjunct therapy in patients who are also being treated with optical-based myopia management strategies.
Combination atropine and orthokeratology
Low-concentration atropine (0.01%-0.05%) has been demonstrated to be effective while having minimal adverse effects.3 Although atropine was once thought to exert its antimyopigenic effects as an antimuscarinic, its full mechanism is currently unknown.4 Orthokeratology and other optical-based, clinically proven myopia management strategies are thought to reduce myopic progression by decreasing retinal peripheral hyperopic defocus.5 Thus, one could theorize that if a patient with myopia was prescribed both atropine and orthokeratology, which may operate under different mechanisms, they may produce an additive treatment effect.
Kinoshita et al were some of the first investigators to report on this topic, with their 2-year, parallel-group, randomized trial that compared the combination of orthokeratology and atropine (n = 43) with patients who were being treated only with orthokeratology (n = 37).6,7 The authors found that the combination group had a significant slowing of axial length elongation compared with atropine alone over the duration of the study. Interestingly, Kinoshita et al found that most of the added benefit detected with the combination treatment occurred during the first 6 months of treatment.6 This result has since been corroborated by Yu et al and Tan et al.8,9
Xu et al later completed a 2-year randomized trial comparing the efficacy of standard spectacles (n = 40), standard spectacles plus atropine (n = 42), orthokeratology (n = 40), and combined atropine and orthokeratology (n = 42) treatment.10 The authors found a significant treatment difference among groups, with their pairwise comparison determining that the combined treatment was superior to atropine or orthokeratology treatment alone. Tan et al later conducted a 2-year randomized trial comparing the combination of orthokeratology plus atropine (n = 45) with orthokeratology alone (n = 44), with the authors determining a similar conclusion as the aforementioned studies.9
Lastly, Chen et al conducted a 3-year trial evaluating the effect of adding atropine in patients who were poorly responding to orthokeratology (≥ 0.30 mm of axial elongation after 1 year of treatment).11 The patients in this study were given the option to use atropine (n = 37) or not (n = 36) while continuing to wear orthokeratology after 1 year of monotherapy. After 2 years of combination treatment, Chen et al determined there were no additional benefits to adding atropine (Table).
Combination atropine and soft contact lenses
Multifocal, soft contact lenses (CLs) have also demonstrated the ability to slow myopic progression,12-14 and there is emerging data regarding their usefulness in combination with atropine. Jones et al was one of the first groups to evaluate atropine in combination with soft CLs, with the authors performing an ancillary study to the Bifocal Lenses in Nearsighted Kids (BLINK) study.13,15 The BLINK study compared monthly, center-distance soft CLs with +2.50 D or +1.50 D adds to single vision CLs of the same brand, with the authors finding that the +2.50 add CLs but not the +1.50 D add CLs were able to significantly slow myopic progression compared with single vision CLs. Jones et al’s study compared a group of 46 patients being treated with atropine and +2.50 add soft CLs to age-matched +2.50 D add and single vision CL wearers from the BLINK study. The authors found that the combination of atropine and +2.50 D add CLs did not provide an additional treatment benefit.
Related: New and emerging myopia management: Low dose atropine
Erdinest et al has since implemented a 3-year retrospective review that compared patients who were treated with a daily disposable CL plus atropine (n = 26), atropine (n = 29), or with single vision spectacles (n = 30). Patients who were receiving atropine were treated for 2 years with the drop, then tapered off the drop for 6 months and followed for an additional 6 months. Erdinest et al determined there was no significant benefit to the combination treatment compared with atropine treatment alone.
Combination atropine and spectacles
Although different spectacle designs have been evaluated as a means for slowing the progression of myopia for many years, these early investigations have failed to find a clinically meaningful effect.16 Nevertheless, more recent designs that promote the reduction of peripheral retinal hyperopic defocus across the full peripheral retina have shown to significantly reduce myopic progression.17 Nucci et al were among the first investigators to tackle this topic, with the authors completing a 1-year unmasked study that compared patients treated with Defocus Incorporated Multiple Segments (DIMS) spectacles (n = 30), atropine (n = 53), DIMS plus atropine (n = 31), and single vision spectacles (control; n = 32). The authors determined that all 3 treatments provided a significant reduction in myopic progression. The combination group also obtained a significantly better treatment effect than monotherapy for refractive error but not for axial length.18
Related: New and emerging myopia management: Spectacles
Likewise, Huang et al completed a retrospective study that compared the treatment effect between patients treated with DIMS plus atropine (n = 40), DIMS (n = 49), or single vision spectacles (control; n = 47). The authors found a significant difference between the treatment groups and the control group, as well as a greater treatment effect with the combination group than with the monotherapy group.19 Between-study differences could be attributed to Huang et al enrolling Asian patients and Nucci et al enrolling European patients.
Conclusion
Although the literature is still emerging, most studies suggest that 0.01% atropine in combination with optical interventions provides an additional treatment benefit; however, this additional reduction in ocular growth may be limited to the first 6 months of treatment. More work is needed to understand whether slightly higher concentrations of low-dose atropine (0.05%/0.025 vs 0.01%) will provide a better treatment effect when in combination with optical interventions, and to understand whether subsets of patients may have a better result.
References
1. Holden BA, Fricke TR, Wilson DA, et al. Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050. Ophthalmology. 2016;123(5):1036-1042. doi:10.1016/j.ophtha.2016.01.006
2. Flitcroft DI. The complex interactions of retinal, optical and environmental factors in myopia aetiology. Prog Retin Eye Res. 2012;31(6):622-660. doi:10.1016/j.preteyeres.2012.06.004
3. Yam JC, Li FF, Zhang X, et al. Two-year clinical trial of the low-concentration atropine for myopia progression (LAMP) study: phase 2 report. Ophthalmology. 2020;127(7):910-919. doi:10.1016/j.ophtha.2019.12.011
4. Zhao Q, Hao Q. Clinical efficacy of 0.01% atropine in retarding the progression of myopia in children. Int Ophthalmol. 2021;41(3):1011-1017. doi:10.1007/s10792-020-01658-0
5. Smith EL 3rd, Hung LF, Huang J. Relative peripheral hyperopic defocus alters central refractive development in infant monkeys. Vision Res. 2009;49(19):2386-2392. doi:10.1016/j.visres.2009.07.011
6. Kinoshita N, Konno Y, Hamada N, et al. Efficacy of combined orthokeratology and 0.01% atropine solution for slowing axial elongation in children with myopia: a 2-year randomised trial. Sci Rep. 2020;10(1):12750. doi:10.1038/s41598-020-69710-8
7. Kinoshita N, Konno Y, Hamada N, Kanda Y, Shimmura-Tomita M, Kakehashi A. Additive effects of orthokeratology and atropine 0.01% ophthalmic solution in slowing axial elongation in children with myopia: first year results. Jpn J Ophthalmol. 2018;62(5):544-553. doi:10.1007/s10384-018-0608-3
8. Yu S, Du L, Ji N, et al. Combination of orthokeratology lens with 0.01% atropine in slowing axial elongation in children with myopia: a randomized double-blinded clinical trial. BMC Ophthalmol. 2022;22(1):438. doi:10.1186/s12886-022-02635-0
9. Tan Q, Ng AL, Cheng GP, Woo VC, Cho P. Combined 0.01% atropine with orthokeratology in childhood myopia control (AOK) study: a 2-year randomized clinical trial. Cont Lens Anterior Eye. 2023;46(1):101723. doi:10.1016/j.clae.2022.101723
10. Xu S, Li Z, Zhao W, et al. Effect of atropine, orthokeratology and combined treatments for myopia control: a 2-year stratified randomised clinical trial. Br J Ophthalmol. 2022;bjophthalmol-2022-321272. doi:10.1136/bjo-2022-321272
11. Chen Z, Zhou J, Xue F, Qu X, Zhou X. Two-year add-on effect of using low concentration atropine in poor responders of orthokeratology in myopic children. Br J Ophthalmol. 2022;106(8):1069-1072. doi:10.1136/bjophthalmol-2020-317980
12. Walline JJ, Greiner KL, McVey ME, Jones-Jordan LA. Multifocal contact lens myopia control. Optom Vis Sci. 2013;90(11):1207-1214. doi:10.1097/OPX.0000000000000036
13. Walline JJ, Walker MK, Mutti DO, et al. Effect of high add power, medium add power, or single-vision contact lenses on myopia progression in children: the BLINK randomized clinical trial. JAMA. 2020;324(6):571-580. doi:10.1001/jama.2020.10834
14. Chamberlain P, Peixoto-de-Matos SC, Logan NS, Ngo C, Jones D, Young G. A 3-year randomized clinical trial of MiSight lenses for myopia control. Optom Vis Sci. 2019;96(8):556-567. doi:10.1097/OPX.0000000000001410
15. Jones JH, Mutti DO, Jones-Jordan LA, Walline JJ. Effect of combining 0.01% atropine with soft multifocal contact lenses on myopia progression in children. Optom Vis Sci. 2022;99(5):434-442. doi:10.1097/OPX.0000000000001884
16. Gwiazda J, Hyman L, Hussein M, et al. A randomized clinical trial of progressive addition lenses versus single vision lenses on the progression of myopia in children. Investig Ophthalmol Vis Sci. 2003;44(4):1492-1500. doi:10.1167/iovs.02-0816
17. Lam CS, Tang WC, Lee PH, et al. Myopia control effect of defocus incorporated multiple segments (DIMS) spectacle lens in Chinese children: results of a 3-year follow-up study. Br J Ophthalmol. 2022;106(8):1110-1114. doi:10.1136/bjophthalmol-2020-317664
18. Nucci P, Lembo A, Schiavetti I, Shah R, Edgar DF, Evans BJW. A comparison of myopia control in European children and adolescents with defocus incorporated multiple segments (DIMS) spectacles, atropine, and combined DIMS/atropine. PLoS One. 2023;18(2):e0281816. doi:10.1371/journal.pone.0281816
19. Huang Z, Chen XF, He T, Tang Y, Du CX. Synergistic effects of defocus-incorporated multiple segments and atropine in slowing the progression of myopia. Sci Rep. 2022;12(1):22311. doi:10.1038/s41598-022-25599-z
20. Hao Q, Zhao Q. Changes in subfoveal choroidal thickness in myopic children with 0.01% atropine, orthokeratology, or their combination. Int Ophthalmol. 2021;41(9):2963-2971. doi:10.1007/s10792-021-01855-5
21. Erdinest N, London N, Lavy I, et al. Low-concentration atropine monotherapy vs. combined with MiSight 1 day contact lenses for myopia management. Vision (Basel). 2022;6(4):73. doi:10.3390/vision6040073
