Myopia Control With Low-Dose Atropine Eyedrops
Invited Commentary
Invited Commentary
Myopia Control With Low-Dose Atropine Eyedrops Michael X. Repka, MD, MBA
Myopia control in recent years has gone from a niche clinical care activity to the conduct of mainstream randomized treatment trials in children in many countries. This is beRelated article cause of concern about the remarkable increase in the prevalence of myopia internationally, reaching more than 80% among some East Asian university students. High myopia is typically defined as more than −6.00 diopters (D); it has been associated with significantly increased risk of myopic macular degeneration, retinal detachment, cataract, open-angle glaucoma, and blindness.1 There are 3 strategies for current myopia control being prescribed for children. The first is to reduce the population prevalence of high myopia. This population includes patients with the highest risk of myopia-associated disease and the most to gain individually from treatment. The second strategy is to reduce the ultimate correction and, more importantly, axial length of each patient with myopia. A number of studies,1,2 including a 2020 meta-analysis, 3 have found that the risks of myopiaassociated pathologies, such as myopic macular degeneration, do not only occur after a fixed cut point of myopia is reached but rather increase progressively as myopia increases from low levels of myopia. Increased risks are evident even when the patient remains in the mild and moderate ranges of myopia. Thus, there is sound medical rationale that a modest reduction in a patient’s myopic refractive error and axial elongation will reduce their risk of myopia complications. However, at this time, the reduction in rate of complications suggested from cross-sectional analyses has not been shown in randomized clinical studies of myopia, which will require decades to complete. The third strategy is to provide treatment for young children with hyperopia most at risk of developing myopia based on demographic and refractive error factors by prescribing an intervention that prevents myopia development. Current myopia control interventions include low-dose atropine eyedrops, outdoor activities, bifocal glasses, peripheral defocus contact lenses, orthokeratology, and various combinations. While each of the strategies noted above are important, these treatments are most often prescribed to children with mild to moderate myopia with slow progression and do not completely arrest or prevent its development. In this issue of JAMA Ophthalmology, the results of the first year of a 2-year clinical trial conducted in Beijing, China, among schoolchildren aged 6 to 12 years with myopia between −1.00 D and −6.00 D are presented.4 The study objective was to determine whether low-dose atropine, 0.01%, eyedrops compared with placebo eyedrops can slow the progression of myopia. Wei et al4 found a statistically significant difference in myopia progression of 0.26 D (95% CI, 0.12-0.41; P < .001) over 1 year, with the treatment group progressing a mean (SD) of jamaophthalmology.com
−0.49 (0.42) D and the placebo group progressing −0.76 (0.50) D, a 34.2% reduction. Axial elongation was reduced by 22.0%. While statistically significant, these changes were small and less than the 50% reduction hoped for. Of concern are the study’s analytic plan to not follow an intent-to-treat policy, excluding poorly compliant patients, and their relatively high rate of loss to follow-up so that only 72.3% of the randomized children were included in the analysis. Among those not included at the outcome were 10% who left the study because of a parental or patient worry about adverse effects from the eyedrops and 7% who switched to orthokeratology. This dropout rate is greater than might have been expected for an innocuous treatment. Somewhat at odds with the dropout rate, Wei et al4 reported that the atropine, 0.01%, eyedrops were well tolerated, with minimal light sensitivity and minimal impact on accommodation, similar to findings from other clinical trials.5,6 Long-term complications for low-dose atropine have not been an issue, although relatively few children have been studied systematically. Myopic progression occurs over a number of years. This study’s crossover design at 1 year eliminated the investigators’ ability to detect multiyear evidence of effectiveness. It will not be possible to know if this first-year positive control effect has permanently affected the refractive error trajectory of their patients. In addition, we will not know in this population whether continuing the eyedrops for additional treatment years can have additional control effect for a number of years, thus significantly decreasing the eventual myopic refractive error. Many studies of myopia control are treating for a minimum of 2 to 3 years before concluding that there is a benefit,5,6 with Atropine for the Treatment of Myopia 1 (ATOM1) investigators treating for 5 years in patients whose myopia was still progressing.5 Additionally, while this crossover design decision likely helped recruitment, it means the authors will be uncertain about the occurrence of any rebound of myopia progression after stopping treatment. The magnitude of control with atropine, 0.01%, eyedrops in this study appears similar to that reported with the same dose after 1 year from the Low-Concentration Atropine for Myopia Progression (LAMP) study7 but not as favorable as the magnitude found in the ATOM2 trial.8 The best concentration of low-dose atropine eyedrops remains to be determined, but this study suggests to me that a stronger formulation should be considered for a more substantial effect. School-aged myopic progression has been greatest in East Asian individuals so there should be a greater opportunity to show a myopia control benefit in terms of refractive error progression in this population compared with Western populations who have lesser rates of higher myopia. While a 34% decrease in progression of myopia, as seen in the study by Wei et al,4 was respectable, this percentage decline might be considered insufficient in North America and Europe, where over(Reprinted) JAMA Ophthalmology Published online October 1, 2020
© 2020 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a University of Canberra User on 10/03/2020
E1
Invited Commentary
Myopia Control With Low-Dose Atropine Eyedrops
all myopia rates and severity are lower. Results from clinical trials of low-dose atropine treatment in Europe and North America are not expected for at least 2 years. If a family is interested in myopia control with daily lowdose atropine eyedrops, the parents and their child should be counseled to expect the treatment to require a minimum of 2
ARTICLE INFORMATION Author Affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Corresponding Author: Michael X. Repka, MD, MBA, Wilmer Eye Institute, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21289-9028 ([email protected]). Published Online: October 1, 2020. doi:10.1001/jamaophthalmol.2020.3830 Conflict of Interest Disclosures: Dr Repka is protocol chairman for an ongoing myopia control study of low-dose atropine in the US sponsored by the National Eye Institute being conducted by the Pediatric Eye Disease Investigator Group. REFERENCES 1. Flitcroft DI. The complex interactions of retinal, optical and environmental factors in myopia
E2
years, with a treatment time of 3 or 4 years more likely to achieve a meaningful reduction in myopia. At present in the US, the use of low-dose atropine is prescribed off-label and needs to be compounded by a pharmacy and the costs are out of pocket for the family, making the decision to use this medication more complicated.
aetiology. Prog Retin Eye Res. 2012;31(6):622-660. doi:10.1016/j.preteyeres.2012.06.004
Ophthalmology. 2016;123(2):391-399. doi:10.1016/j. ophtha.2015.07.004
2. Vongphanit J, Mitchell P, Wang JJ. Prevalence and progression of myopic retinopathy in an older population. Ophthalmology. 2002;109(4):704-711. doi:10.1016/S0161-6420(01)01024-7
6. 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
3. Haarman AEG, Enthoven CA, Tideman JWL, Tedja MS, Verhoeven VJM, Klaver CCW. The complications of myopia: a review and meta-analysis. Invest Ophthalmol Vis Sci. 2020;61 (4):49. doi:10.1167/iovs.61.4.49 4. Wei S, Li S-M, An W, et al. Safety and efficacy of low-dose atropine eyedrops for the treatment of myopia progression in Chinese children: a randomized clinical trial. JAMA Ophthalmol. Published online October 1, 2020. doi:10.1001/ jamaophthalmol.2020.3820 5. 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.
7. 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;126(1):113-124. doi:10.1016/j.ophtha.2018.05.029 8. Chia A, Chua W-H, Cheung Y-B, et al. Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (Atropine for the Treatment of Myopia 2). Ophthalmology. 2012;119(2):347-354. doi:10.1016/j.ophtha.2011. 07.031
JAMA Ophthalmology Published online October 1, 2020 (Reprinted)
© 2020 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a University of Canberra User on 10/03/2020
jamaophthalmology.com
Invited Commentary
Invited Commentary
Myopia Control With Low-Dose Atropine Eyedrops Michael X. Repka, MD, MBA
Myopia control in recent years has gone from a niche clinical care activity to the conduct of mainstream randomized treatment trials in children in many countries. This is beRelated article cause of concern about the remarkable increase in the prevalence of myopia internationally, reaching more than 80% among some East Asian university students. High myopia is typically defined as more than −6.00 diopters (D); it has been associated with significantly increased risk of myopic macular degeneration, retinal detachment, cataract, open-angle glaucoma, and blindness.1 There are 3 strategies for current myopia control being prescribed for children. The first is to reduce the population prevalence of high myopia. This population includes patients with the highest risk of myopia-associated disease and the most to gain individually from treatment. The second strategy is to reduce the ultimate correction and, more importantly, axial length of each patient with myopia. A number of studies,1,2 including a 2020 meta-analysis, 3 have found that the risks of myopiaassociated pathologies, such as myopic macular degeneration, do not only occur after a fixed cut point of myopia is reached but rather increase progressively as myopia increases from low levels of myopia. Increased risks are evident even when the patient remains in the mild and moderate ranges of myopia. Thus, there is sound medical rationale that a modest reduction in a patient’s myopic refractive error and axial elongation will reduce their risk of myopia complications. However, at this time, the reduction in rate of complications suggested from cross-sectional analyses has not been shown in randomized clinical studies of myopia, which will require decades to complete. The third strategy is to provide treatment for young children with hyperopia most at risk of developing myopia based on demographic and refractive error factors by prescribing an intervention that prevents myopia development. Current myopia control interventions include low-dose atropine eyedrops, outdoor activities, bifocal glasses, peripheral defocus contact lenses, orthokeratology, and various combinations. While each of the strategies noted above are important, these treatments are most often prescribed to children with mild to moderate myopia with slow progression and do not completely arrest or prevent its development. In this issue of JAMA Ophthalmology, the results of the first year of a 2-year clinical trial conducted in Beijing, China, among schoolchildren aged 6 to 12 years with myopia between −1.00 D and −6.00 D are presented.4 The study objective was to determine whether low-dose atropine, 0.01%, eyedrops compared with placebo eyedrops can slow the progression of myopia. Wei et al4 found a statistically significant difference in myopia progression of 0.26 D (95% CI, 0.12-0.41; P < .001) over 1 year, with the treatment group progressing a mean (SD) of jamaophthalmology.com
−0.49 (0.42) D and the placebo group progressing −0.76 (0.50) D, a 34.2% reduction. Axial elongation was reduced by 22.0%. While statistically significant, these changes were small and less than the 50% reduction hoped for. Of concern are the study’s analytic plan to not follow an intent-to-treat policy, excluding poorly compliant patients, and their relatively high rate of loss to follow-up so that only 72.3% of the randomized children were included in the analysis. Among those not included at the outcome were 10% who left the study because of a parental or patient worry about adverse effects from the eyedrops and 7% who switched to orthokeratology. This dropout rate is greater than might have been expected for an innocuous treatment. Somewhat at odds with the dropout rate, Wei et al4 reported that the atropine, 0.01%, eyedrops were well tolerated, with minimal light sensitivity and minimal impact on accommodation, similar to findings from other clinical trials.5,6 Long-term complications for low-dose atropine have not been an issue, although relatively few children have been studied systematically. Myopic progression occurs over a number of years. This study’s crossover design at 1 year eliminated the investigators’ ability to detect multiyear evidence of effectiveness. It will not be possible to know if this first-year positive control effect has permanently affected the refractive error trajectory of their patients. In addition, we will not know in this population whether continuing the eyedrops for additional treatment years can have additional control effect for a number of years, thus significantly decreasing the eventual myopic refractive error. Many studies of myopia control are treating for a minimum of 2 to 3 years before concluding that there is a benefit,5,6 with Atropine for the Treatment of Myopia 1 (ATOM1) investigators treating for 5 years in patients whose myopia was still progressing.5 Additionally, while this crossover design decision likely helped recruitment, it means the authors will be uncertain about the occurrence of any rebound of myopia progression after stopping treatment. The magnitude of control with atropine, 0.01%, eyedrops in this study appears similar to that reported with the same dose after 1 year from the Low-Concentration Atropine for Myopia Progression (LAMP) study7 but not as favorable as the magnitude found in the ATOM2 trial.8 The best concentration of low-dose atropine eyedrops remains to be determined, but this study suggests to me that a stronger formulation should be considered for a more substantial effect. School-aged myopic progression has been greatest in East Asian individuals so there should be a greater opportunity to show a myopia control benefit in terms of refractive error progression in this population compared with Western populations who have lesser rates of higher myopia. While a 34% decrease in progression of myopia, as seen in the study by Wei et al,4 was respectable, this percentage decline might be considered insufficient in North America and Europe, where over(Reprinted) JAMA Ophthalmology Published online October 1, 2020
© 2020 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a University of Canberra User on 10/03/2020
E1
Invited Commentary
Myopia Control With Low-Dose Atropine Eyedrops
all myopia rates and severity are lower. Results from clinical trials of low-dose atropine treatment in Europe and North America are not expected for at least 2 years. If a family is interested in myopia control with daily lowdose atropine eyedrops, the parents and their child should be counseled to expect the treatment to require a minimum of 2
ARTICLE INFORMATION Author Affiliation: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Corresponding Author: Michael X. Repka, MD, MBA, Wilmer Eye Institute, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21289-9028 ([email protected]). Published Online: October 1, 2020. doi:10.1001/jamaophthalmol.2020.3830 Conflict of Interest Disclosures: Dr Repka is protocol chairman for an ongoing myopia control study of low-dose atropine in the US sponsored by the National Eye Institute being conducted by the Pediatric Eye Disease Investigator Group. REFERENCES 1. Flitcroft DI. The complex interactions of retinal, optical and environmental factors in myopia
E2
years, with a treatment time of 3 or 4 years more likely to achieve a meaningful reduction in myopia. At present in the US, the use of low-dose atropine is prescribed off-label and needs to be compounded by a pharmacy and the costs are out of pocket for the family, making the decision to use this medication more complicated.
aetiology. Prog Retin Eye Res. 2012;31(6):622-660. doi:10.1016/j.preteyeres.2012.06.004
Ophthalmology. 2016;123(2):391-399. doi:10.1016/j. ophtha.2015.07.004
2. Vongphanit J, Mitchell P, Wang JJ. Prevalence and progression of myopic retinopathy in an older population. Ophthalmology. 2002;109(4):704-711. doi:10.1016/S0161-6420(01)01024-7
6. 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
3. Haarman AEG, Enthoven CA, Tideman JWL, Tedja MS, Verhoeven VJM, Klaver CCW. The complications of myopia: a review and meta-analysis. Invest Ophthalmol Vis Sci. 2020;61 (4):49. doi:10.1167/iovs.61.4.49 4. Wei S, Li S-M, An W, et al. Safety and efficacy of low-dose atropine eyedrops for the treatment of myopia progression in Chinese children: a randomized clinical trial. JAMA Ophthalmol. Published online October 1, 2020. doi:10.1001/ jamaophthalmol.2020.3820 5. 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.
7. 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;126(1):113-124. doi:10.1016/j.ophtha.2018.05.029 8. Chia A, Chua W-H, Cheung Y-B, et al. Atropine for the treatment of childhood myopia: safety and efficacy of 0.5%, 0.1%, and 0.01% doses (Atropine for the Treatment of Myopia 2). Ophthalmology. 2012;119(2):347-354. doi:10.1016/j.ophtha.2011. 07.031
JAMA Ophthalmology Published online October 1, 2020 (Reprinted)
© 2020 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ by a University of Canberra User on 10/03/2020
jamaophthalmology.com
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