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It was only a matter of time before eyecare providers began implementing combination myopia management therapies for their patients who had progressive myopia. After all, eyecare providers are eager to change the paradigm and landscape when it comes to the frightening projections with regards to the myopia epidemic.¹

Combination myopia management therapies involve combining two individual myopia control treatments. For example, orthokeratology can be combined with topical low-dose atropine. As one can imagine, atropine can be combined with just about any optical myopia treatments, such as soft contact lens modalities and specially designed spectacles to provide a multitude of combination therapy options that suit the child's lifestyle and needs. We know from previous studies^2,3 that orthokeratology or low-dose atropine alone can stand their ground when it comes to efficacy in controlling progressive myopia, but does the marriage of their combination serve to give even more treatment efficacy?

Though the eagerness to implement aggressive strategies for progressive myopia is in good faith, practitioners need to have a thorough understanding of the available data on combination therapies before implementing these treatments in clinic. After all, additive treatments require more resources, time, and financial commitments from both providers as well as patients and their families. When reviewing the available data, it is important to pay careful attention to not only the efficacy of the combination treatments compared to monotherapy alone, but to also keep an attentive eye (no pun intended) on the limitations and considerations when it comes to prescribing combination therapies for myopia management.

A good place to start increasing our understanding of combination therapies for progressive myopia management is to begin by reviewing studies evaluating combination therapies against monotherapy. Let’s start by reviewing these three clinical trials:

Study #1: Efficacy of combined orthokeratology and 0.01% atropine solution for slowing axial elongation in children with myopia: a 2-year randomized trial.⁴  This randomized control trial was conducted in Japan during the course of two years. Ultimately, 73 children aged 8 to 12 years old, who had refractive errors between –1D through –6D of myopia, were randomly assigned to one of two groups: orthokeratology monotherapy or combination therapy of 0.01% atropine with orthokeratology.

The primary outcome of the study concluded that combination therapy was more effective in slowing axial length compared to monotherapy of orthokeratology alone during a two-year period in these Japanese children. Upon closer inspection of the outcomes, it is interesting to note that combination therapy seemed to be effective only for lower amounts of myopia (1D to 3D), and not significant for greater than 3D myopia. Additionally, though the study was conducted for two years, there was a stronger combined effect during the first 12 months of the study.

Study #2: Combined 0.01% atropine with orthokeratology in childhood myopia control (AOK) study: a 2-year randomized clinical trial.⁵  This randomized control trial, conducted in China during the course of two years, evaluated 96 children aged 6 to 11 years who had refractive error from –1D through –4D. The study compared children undergoing monotherapy (orthokeratology) with combination therapy (adding 0.01% atropine to orthokeratology).

Combination therapy proved to be more effective in controlling axial length compared to orthokeratology monotherapy alone but only for the first six-month interval. A point of differentiation between study #1 is that this study indicated that an additive effect was still observed in subgroups of children who had low baseline myopia (–1.00D to –3.00D) and those who had greater than –3.00D of myopia during a course of two years. Further, although axial length measurements showed slowing of myopia progression, spherical equivalent refraction did not demonstrate the same differences in myopia progression. As a precaution, variation in individual characteristics of all enrolled children and factors—such as environmental differences, the amount of time subjects spent in near work or engaging in outdoor activities, and genetic factors (e.g., the number of myopic parents, ethnic considerations, and others)—should be considered when making a direct comparison of these two studies.

The investigators also measured pupil sizes and noted that larger pupils were found in the combination group. This group also demonstrated more myopia control effect; the same effect was not for the monotherapy orthokeratology group. The impact of pupil sizes was evaluated in another study with orthokeratology treatment, in which the authors concluded larger pupil sizes facilitated the effect of orthokeratology in slowing axial length.⁶

Study #3: Two-year add-on effect of using low concentration atropine in poor responders of orthokeratology in myopic children.⁷  This study attempted to answer the question of whether combination therapy could benefit the group that arguably needs the most help: the “fast progressors.” This interesting study reviewed Chinese children whose axial length continued to progress despite a successful orthokeratology fitting after one year. Subjects were retrospectively reviewed and identified as “fast progressors” if they demonstrated an axial length growth greater than 0.3mm. Once identified, this group of 73 children, all under 12 years of age at the time of orthokeratology initiation, were placed in one of two groups: OKA (combination group, orthokeratology and 0.01% atropine) and OK (orthokeratology monotherapy alone) for the next two years.

Surprisingly, there was no difference in the mean axial length changes between the OKA group compared to the OK group. Also, similar to studies #1 and #3, this study demonstrated that myopia control efficacy decreases over time in the combined treatment group.

Therapy Options Going Forward

Naturally, after reviewing the pivotal studies above, more questions emerge. One major question is whether the combined effect of low-dose atropine and orthokeratology is sustainable long-term. Considering many practitioners would like to utilize this additional approach for their patients who are poor responders of orthokeratology monotherapy, can they justify adding low-dose atropine as an additive therapy? Is the addition of low-dose atropine truly beneficial compared to orthokeratology monotherapy alone?

Though there is a plethora of information available on combination therapies, we still need more data before many of these questions can be answered. First, we need longer-term data. Second, we need a better understanding of the mechanisms at play. If we use combined therapy, we could target multiple pathways that could ultimately prove to be more beneficial.

When considering clinical implications of additional therapy, the environmental influences should not take a back seat. Additive therapy should not be used in lieu of focusing on lifestyle modifications. For example, patients should continually be encouraged to monitor the quality and amount of time spent doing near work or engaging in outdoor activities.

1. Dolgin E. The myopia boom. Nature. 2015 Mar 19;519:276-278.

2. Yam JC, Jiang Y, Tang SM, 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 Jan;126:113-124.

3. Cho P, Cheung SW. Retardation of myopia in Orthokeratology (ROMIO) study: a 2-year randomized clinical trial. Invest Ophthalmol Vis Sci. 2012 Oct 11;53:7077-7085.

4. 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 Jul 29;10:12750.

5. 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 Feb;46:101723.

6. Chen Z, Niu L, Xue F, et al. Impact of pupil diameter on axial growth in orthokeratology. Optom Vis Sci. 2012 Nov;89:1636-1640.

7. 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 Aug;106:1069-1072.