Efficacy in Myopia Control: Does Race Matter?

Abstract

The range of available myopia control modalities is increasing rapidly.1 Likewise, the number of studies assessing these various approaches is increasing exponentially.2 Unfortunately, established and emerging therapies are typically evaluated in single-center studies with limited racial diversity. Here we evaluate the extent to which results on one race can be extrapolated to others; specifically, can results from studies on East Asian children be applied to Western children and vice versa? MYOPIA AND RACE We begin with a brief comparison of myopia in East Asians and non–East Asians that reveals two profound differences and two similarities. First, it is well established that the prevalence of myopia is higher in East Asian countries3 but is increasing around the world, with a few exceptions.4 Second, myopia progresses 30% faster in East Asian than non–East Asian children,5 but both show the same exponential slowing with age—15% per year.6 In contrast, myopia progression is strongly related to degree of axial elongation in all races, and the ratio of progression to elongation seems to be independent of race.7 Likewise, the relation between degree of myopia and the risk of eye disease seems to be the same.8 Among nine large studies of myopic maculopathy, the increased prevalence with each additional diopter of myopia is 1.57 in East Asia,9–13 1.59 in Europe and Australia,14–16 and 1.56 in Chinese Americans.17 The ratios of prevalence to diopters for retinal detachment and primary open-angle glaucoma also seem to be similar in East Asians and non–East Asians.8 EFFICACY IN MYOPIA CONTROL Progression of myopia and the success of any myopia control modality can be evaluated by measuring axial length, refractive error, or both. We previously discussed the merits of each approach18 and concluded that axial length should be the preferred measure for a number of reasons. First, axial length is more closely related to visual impairment than refractive error.19 Second, axial length measurement using optical biometry offers extraordinary repeatability20 and thus is more sensitive to change than refraction. Likewise, cycloplegia is not required for optical biometry,21 whereas it is necessary for accurate refractive error measurement. Finally, orthokeratology and atropine act on the refractive structures of the eye, confounding refractive error measurements.18 The efficacy of myopia control can be expressed in absolute terms, be it diopters or millimeters, or as a relative reduction of progression, expressed as a percentage. Implicit in the reporting of efficacy as a percentage is the assumption that it is constant with the underlying progression rate and the duration of treatment. Neither is the case. Using several statistical approaches and a range of modalities, we demonstrated that the absolute slowing of myopia progression is constant with age but diminishes with duration of treatment.18 Given the aforementioned considerations regarding the consistency of effect size across progression range and the reduction of efficacy beyond the first year of treatment, cumulative absolute reduction in elongation emerges as the preferred metric for expressing efficacy and for comparing treatments and studies.18 Expressing efficacy in absolute terms is independent of patient age and incorporates reduction of efficacy over time. The subsequent discussion thus focuses on absolute values rather than percentages. MYOPIA CONTROL AND RACE In our previous work, we used age as a proxy for propensity to progress but did not explore the possible effects of race, although, as discussed previously, progression in East Asian children is faster than in non–East Asian children. One reason for our hesitation is that myopia control therapies are typically evaluated in single-center studies with limited racial diversity. Multicenter studies of myopia control are rare,22 and evaluations involving multiple countries are even rarer, but there are two exceptions. The first was a randomized clinical trial of dual-focus soft contact lenses conducted in Canada, England, Portugal, and Singapore, of which 55% were White and 24% East Asian (presumably mostly Singaporean Chinese).23 There was no interaction between investigational site and the myopia control effect of the lenses. The second compared soft contact lenses incorporating noncoaxial ring-focus technology with dual-focus and single-vision designs at nine sites in Canada, China, and the United States.24 Of the 185 children completing the trial, 50% were Chinese and 43% were White (<10% of subjects in North America were of East Asian race). Both axial elongation and myopia progression were faster in East Asians, but there was no race-by-lens type interaction. Thus, both clinical trials failed to show that race had a significant effect on the slowing of myopia progression. Although multicountry trials are rare, there are three myopia control modalities that have been evaluated in different populations albeit in different clinical trials: progressive addition lenses, overnight orthokeratology, and 0.01% atropine. Progressive addition lenses are among the most studied myopia control devices. Fig. 1 shows the 1-year slowing of axial elongation and myopia progression from 8 randomized clinical trials of 1398 children.22,25–31 In the lower three, participant eligibility was limited to those with higher accommodative lag and esophoria,30,31 or esophoria.29 Given their apparent similarity in efficacy to the broader trials, they are not discussed separately. Two trials26,30 did not measure axial length, but the median 1-year slowing of axial elongation was 0.06 mm in trials of East Asian children25,27–29 and 0.04 and 0.07 mm in two trials of U.S. children with fewer than 10% Asian Americans.22,31 The largest 1-year slowing of axial elongation was 0.18 mm in a 2-year trial of Chinese children (inconsistent with the 0.11 D slowing)27; however, like many early studies, the authors used ultrasound, and after 2 years, the slowing was reduced to 0.11 mm. Overall, 2-year slowing of axial elongation was between 0.02 and 0.11 mm (median, 0.08 mm) in trials on East Asian children25,27–29 and 0.08 mm in a trial of U.S. children.22 One-year slowing of myopia progression was between 0.09 and 0.24 D (median, 0.16 D) in trials on East Asian Children25–29 and between 0.13 and 0.18 D (median, 0.18 D) in trials of U.S. children.22 In summary, the slowing of axial elongation and myopia progression is similar in East Asian and non–East Asian children, with the treatment efficacy low in both groups. Of course, low treatment efficacy makes assessment of the impact of any covariate, including race, more challenging.FIGURE 1: One-year slowing of axial elongation and myopia progression in randomized clinical trials of progressive addition lens. Closed bars are for East Asian children,25–29 and open bars are for U.S. children.22,30,31What about myopia control therapies with greater efficacy? Overnight orthokeratology for myopia control has been evaluated extensively,32–41 with numerous meta-analyses showing a 2-year slowing of axial elongation of around 0.25 mm. There have been relatively few randomized clinical trials of overnight orthokeratology,35,41,42 presumably in part due to the inability to mask participants to their allocation. The remaining early and long-term studies33,34,36–40 used concurrent or historical controls32,33,42 and are included here to allow for a more robust comparison. Fig. 2 shows the slowing of axial elongation from 10 studies of 652 children. The Danish clinical trial of Jakobsen and Moller41 reported 18-month efficacy. To project to 24 months, we assumed that the reduction in elongation between 12 and 18 months was duplicated during the 18- to 24-month period, giving an adjusted estimate of 0.29 mm. Two-year slowing of axial elongation was between 0.22 and 0.36 mm (median, 0.26 mm) in studies of East Asian children32,34–36,38,39 and between 0.20 and 0.32 mm (median, 0.25 mm) in trials of European37,40,41 and U.S. children.33 In summary, the clinically meaningful slowing of axial elongation with overnight orthokeratology is similar in East Asian and non–East Asian children.FIGURE 2: Two-year slowing of axial elongation studies of overnight orthokeratology. Closed bars are for East Asian children,32,34–36,38,39 and open bars are for European37,40,41 and U.S. children.33Although 1% atropine has been prescribed by some clinicians to slow myopia progression for decades, the notion of 0.01% atropine as a treatment is relatively new. In recent years, results of several clinical trials have been published43–48 with more expected soon. Fig. 3 shows the 1-year slowing of axial elongation and myopia progression from 6 clinical trials of 1265 children. Data beyond 1 year are only available for half of these studies.46,48,49 One-year slowing of axial elongation was between 0.04 and 0.09 mm in East Asian children43–46 and 0.06 and 0.08 mm in Indian47 and Australian children,48 respectively. Likewise, slowing of myopia progression was between 0.08 and 0.26 D in East Asian children43–46 and 0.19 and 0.23 D in Indian47 and Australian children,48 respectively. The Australian trial classified participants as 49% European, 18% East Asian, 22% South Asian, and 12% of other or mixed ancestry.48 Although differences among these groups were observed in a post hoc analysis, the “study was not powered to detect the difference between racial groups.” In summary, the slowing of axial elongation and myopia progression is similar in East Asian and non–East Asian children, with the treatment efficacy modest in all populations. Again, identifying differences is hampered by low efficacy.FIGURE 3: One-year slowing of axial elongation and myopia progression in randomized clinical trials of 0.01% atropine. Closed bars are for East Asian children,43–46 and open bars are for Indian47 and Australian children.48FURTHER CONSIDERATIONS Our evaluation failed to find evidence of a difference between East Asians and non–East Asians in terms of myopia control treatment effect. We acknowledge that our observations are not derived from rigorous clinical study designs and that “absence of evidence is not evidence of absence.”50 None of the individual examples are statistically robust for the purpose of detecting differences and should thus be considered inconclusive rather than negative. Nonetheless, the consistency across two multicountry clinical trials and three sets of between-trial comparisons provides some level of support for the proposition that no difference exists. Although the aforementioned results suggest that efficacy is consistent across race, two clinical trials of 2% pirenzepine ophthalmic gel, a selective muscarinic antagonist, provide a further interesting example.51,52 In a U.S. clinical trial of 145 children (73% White, 12% Hispanic, 7% African American, 4% Asian, and 4% other), the 1-year slowing of axial elongation was 0.04 mm, and the slowing of myopia progression was 0.27 D.52 In a corresponding trial of children of predominantly of Chinese extraction in Singapore, Hong Kong, and Thailand, the 1-year slowing of axial elongation was 0.13 mm, and the slowing of myopia progression was 0.37 D.51 Thus, the dioptric efficacy is similar, with a potential discrepancy in the ultrasound-based axial efficacy. Also, there have been multiple single-center clinical trials of other multifocal soft contact lenses in China, the United States, and Europe, but the variation in lens designs makes comparisons untenable. Likewise, emerging spectacle technologies53,54 and low-level red-light therapy55,56 have only been evaluated in Chinese children. The apparent lack of difference in treatment response between East Asian and Western children may be unsurprising. Although prevalence of myopia is known to vary between these groups, there is little evidence of a genetic basis for this divergence. The outstanding way in which the societies vary is by educational intensity and is therefore of a cultural nature.57 A prime example of this effect can be seen in the difference in myopia prevalence in Chinese children in Singapore and Australia.58 The absence of distinct biological differences between races in terms of susceptibility to myopia may explain the observed similarity of response to myopia control treatment. We conclude that, on the basis of available evidence, the efficacy of individual myopia control treatments is largely independent of race. More generally, in terms of slowing of axial elongation, treatment efficacy is independent of progression rate.18 It does not matter whether the child is progressing faster because they are younger rather than older or because they are East Asian rather than of European descent; the benefit of any myopia control modality seems to be the same. Mark A. Bullimore, MCOptom, PhDCollege of Optometry, University of HoustonHouston, Texas[email protected]Noel A. Brennan, MScOptom, PhDJohnson & Johnson VisionJacksonville, Florida