|Year : 2022 | Volume
| Issue : 1 | Page : 21-26
Atropine in myopia – Does it reduce progression? Results of Phase 1 clinical trial in children attending a tertiary eye care center in South India
R Neena1, Ayshathu Nasheetha2, Nimmy Prakash3, Anantharaman Giridhar4
1 Pediatric Ophthalmology, Strabismus and Neuro-ophthalmology Services, Giridhar Eye Institute, Kochi, Kerala, India
2 Department of Optometry, Giridhar Eye Institute, Kochi, Kerala, India
3 Department of Biostatistics, Giridhar Eye Institute, Kochi, Kerala, India
4 Vitreo-Retina Services, Giridhar Eye Institute, Kochi, Kerala, India
|Date of Submission||25-Jul-2021|
|Date of Decision||15-Aug-2021|
|Date of Acceptance||24-Aug-2021|
|Date of Web Publication||21-Apr-2022|
Dr. R Neena
Giridhar Eye Institute, Kadavanthara, Kochi - 682 020, Kerala
Source of Support: None, Conflict of Interest: None
Aim: The aim of this study was to analyze the effectiveness of low-dose atropine (0.01%) in reducing the progression of myopia in Indian children. Materials and Methods: This was a clinical trial of Indian children with axial myopia from January 2018 to May 2019, who were prescribed low-dose atropine (0.01%) to reduce progression. Parameters studied before and after starting low-dose atropine were as follows: visual acuity for distance and near, cycloplegic refraction, ocular alignment for distance and near, near point of accommodation (NPA), near point of convergence, axial length (AXL), pupil diameter (PDM), lens thickness (LT), anterior chamber depth (ACD), adverse reaction, compliance, and dropouts. Patients were evaluated at the initiation of treatment, at 1 month, and thereafter 6 monthly with a minimum follow-up of 6 months. Any increase in spherical equivalent (SE) of myopia was taken as progression and rapid progression of myopia was considered if there was a ≥0.5 DS increase in SE of myopia within 6 months. Results: Seventy-one eyes of 36 children who opted for low-dose atropine (18 males and 18 females) and 37 eyes of 19 age-matched children (10 females and 9 males) were included in the final study and control groups, respectively. The mean age was 8.31 years (standard deviation [SD] =1.191) in the cases compared to 9.68 years (SD = 3.606) in the controls. Progression of myopia was noted in 40 eyes (56.338%) in the study group as compared to 35 eyes (94.59%) in the control group (P = 0.00). Rapid progression was noted in 23 eyes (32.39%) in the study group as compared to 23 eyes (62.16%) in the control group (P = 0.003). The mean SE of myopia increased by 0.28 D (as compared to 0.63 D increase among the controls) (P = 0.01), and the mean AXL increased by 0.14 mm (as compared to 0.25 mm among the controls) in the study group at the end of 6 months (P = 0.01). There was also a statistically significant increase in mean PDM by 0.83 mm (P = 0.01) and receding of mean NPA by 1.14 cm in cases (P = 0.03). However, these changes were clinically insignificant. No significant changes were noted in ACD, LT, NPC, and ocular alignment. No adverse reactions were reported. Conclusion: Low-dose atropine (0.01%) therapy was able to reduce the progression of myopia in the study group as compared to the controls with a good tolerance and no change in the vision-related quality of life. Long-term follow-up is, however, needed for extrapolation into the general population.
Keywords: Children, low-dose atropine, myopia
|How to cite this article:|
Neena R, Nasheetha A, Prakash N, Giridhar A. Atropine in myopia – Does it reduce progression? Results of Phase 1 clinical trial in children attending a tertiary eye care center in South India. Kerala J Ophthalmol 2022;34:21-6
|How to cite this URL:|
Neena R, Nasheetha A, Prakash N, Giridhar A. Atropine in myopia – Does it reduce progression? Results of Phase 1 clinical trial in children attending a tertiary eye care center in South India. Kerala J Ophthalmol [serial online] 2022 [cited 2022 Dec 4];34:21-6. Available from: http://www.kjophthal.com/text.asp?2022/34/1/21/343672
| Myopia: Prevalence and Global Impact|| |
Myopia is an abnormal condition breaking the emmetropization process progressing rapidly from onset at an early age and continuing until early adulthood. The most common definition of myopia is spherical equivalence −0.5 D or greater. Myopia is very common and a major cause of visual impairment in both developed and developing countries.,, The prevalence of myopia is increasing and varies by country, age, and ethnic group. In East Asia, the prevalence of myopia is very high, particularly in Japan, South Korea, Singapore, Taiwan, Hong Kong, and China. Lower rates are reported from South Asia and India.,, In India, urban children had a myopia prevalence of 4.7%, 7.0%, and 10.8% in 5-, 10-, and 15-year olds. In rural children, it was 2.8%, 4.1%, and 6.7% in 7-, 10-, and 15-year olds, respectively.,. A recent study by Saxena et al. evaluated the prevalence of myopia in Delhi. Among total of 9884 schoolchildren screened, the prevalence of myopia was 13.1% with one-fourth wearing appropriate spectacles. Myopia has become a global health problem associated with vision impairment and blinding complications and also a significant economic burden. In Singapore, the mean annual cost of myopia for a child is $148. In the US, the annual direct cost of correcting distance vision impairment due to refractive errors is between US$3.9 and US$7.2 billion.
Progression and high myopia
Myopia progression in East Asian children is high (−1 diopter [D] per year), and is rapid than in Western children. It is estimated that in 2050, half the global population (5 billion people) would be myopic and one-fifth of those (1 billion) would be high myopic.
High myopia is associated with sight-threatening conditions such as presenile cataracts, glaucoma, retinal detachment, myopic choroidal neovascularization, foveoschisis, staphyloma, macular atrophy, and blindness. Early onset of myopia in childhood is associated with high myopia in adult life. The ultimate goal of myopia control therapy would be to slow myopic progression during years of active eye growth so that the eventual level of myopia is lower than if the eye was allowed to grow naturally.
Atropine in myopia
Atropine eye drops have been used for myopia control for some years. The Atropine for the Treatment of Myopia 1 (ATOM 1) showed that atropine 1% eye drops slowed myopia progression significantly. In Phase 1 of the 5-year clinical trial on ATOM 2, atropine 0.01% was almost as effective in reducing myopia progression as higher concentrations. With fewer side effects and rebound after drop cessation, the low concentration of 0.01% atropine had a better treatment-to-side effect ratio. Atropine nonselectively blocks muscarinic receptors in human ciliary muscle, retina, and sclera, inhibiting thinning or stretching of sclera, and thereby eye growth. This eye growth possibly involves a series of biochemical steps and atropine inhibits one or more steps along this pathway, creating changes in feedback mechanisms. Almost all studies on efficacy of low-dose atropine have been carried out in East Asian children, and there are very little data on its effect in other ethnic populations. Therefore, we decided to evaluate the efficacy and safety of low-concentration atropine eye drops in Indian children with progressive myopia.
The aim of this study was to analyze the efficacy of low-dose atropine (0.01%) in reducing the progression of myopia in Indian children.
| Materials and Methods|| |
This was a prospective case − control study of all children between 6 and 16 years, of Indian ethnicity with documented increase of myopic refraction, who were prescribed low-dose atropine (0.01%) to reduce progression. The study was conducted at a tertiary eye care center in South India from the period of January 2018 to May 2019. The parents or guardians were given the option of choosing low dose atropine therapy after explaining about the drug usage,tests required and possible adverse reactions. Informed consent was obtained from parents or guardians, and verbal consent was obtained from all participants. The study was conducted in accordance with the Declaration of Helsinki and was approved by the appropriate institutional review board and ethics committee.
(1) Myopic refraction ≥−0.5 D, (2) documented progression of myopia ≥0.5 D in the last 6 months, (3) astigmatism <2.00 D, and (4) willingness for regular follow-up were included in this study.
(1) Coexisting ocular diseases such as cataract, glaucoma, retinal diseases, and nystagmus; (2) systemic diseases such as cardiac, endocrine, neurologic, and respiratory diseases; (3) history of ocular surgery in the past; (4) allergy to atropine; (5) previous use of atropine; and (6) use of other optical methods for myopia control such as bifocals/orthokeratology lens were excluded from this study.
Variables studied before and after starting low-dose atropine were as follows: (1) best-corrected visual acuity (BCVA) for distance and near; (2) ocular alignment for distance and near; (3) near point of accommodation (NPA); (4) near point of convergence (NPC); (5) axial length (AXL); (6) photopic pupil diameter (PDM); (7) lens thickness (LT); (8) anterior chamber depth (ACD); (9) spherical equivalent (SE) of myopia from cycloplegic refraction; and (10) adverse reactions, compliance, and dropouts.
Patients were evaluated at the initiation of treatment, at 1 month, and thereafter every 6 months with the above parameters. The minimum follow-up was of 6 months. BCVA for distance was measured in logarithm of the minimum angle of resolution (logMAR), with Early Treatment Diabetic Retinopathy Study chart. Near visual acuity was tested using spectacle correction with a reduced logMAR chart placed at 33 cm. Ocular alignment for distance and near was evaluated with cover/uncover tests over spectacle correction. The NPA and NPC were measured using a Royal Air Force (RAF) rule with spectacle correction in place. AXL, PDM, LT, and ACD were measured using A Scan Biometer (LENSTAR LS 900-HAAG STREIT USA) before cycloplegic refraction. Cycloplegic refraction was done with CTC drops (1 drop of cyclopentolate 1%, 1 drop of tropicamide 1%, and 1 drop of cyclopentolate 1% instilled 10 min apart) and performed 30 min after the last drop, using an autorefractor (Topcon KR-800). SE of each eye was calculated as spherical power plus half of the cylinder power. Participants were prescribed glasses and asked to instill atropine 0.01% eye drops (MYOPIN-Appasamy Associates or MYATRO-Entod Pharmaceuticals Ltd) every day at bedtime and report any adverse reactions at 1 month of usage and thereafter every 6 months. Compliance was assessed as good if the parents reported instilling low-dose atropine drops at bedtime at least 5 days a week and poor if they defaulted more than 2 days a week.
The parents and the children were verbally asked for any difficulty in daily activities indoors at school and outdoors at each visit. The primary outcome was progression of myopia, defined as change in SE over Phase 1 (6 months). An increase in SE of myopia was taken as progression. Rapid progression of myopia was considered if there was a ≥0.5 DS increase in SE of myopia within 6 months. All the study variables were compared with those of age-matched normals which formed the control group. Statistical analysis was performed using Minitab 19 version and SPSS (2007) for Windows, Version 16.0. (Chicago, IL, USA). 16.0 version, and P values were calculated using Z-test, Wilcoxon signed-rank test, paired t-test, two-sample t-test, and Mann–Whitney U-test.
| Results|| |
Out of the 62 children who were enrolled for the low-dose atropine therapy, only 71 eyes of 36 children (18 males and 18 females) were included in the study group as the rest were lost for follow-up or excluded due to poor compliance to the drops. Similarly, fifty children who chose not to use low-dose atropine were enrolled as the control group, but only 37 eyes of 19 children were included in the final control group. The mean age was 8.31 years (standard deviation [SD] =1.191) in the cases compared to 9.68 years (SD = 3.606) in the controls. The mean SE of myopia in the study group was −5.38 D initially as compared to −5.35 D in the control group and increased by 0.28 D to −5.66 D in the study group as compared to 0.63 D increase (−5.98 D) among the controls (P = 0.01) at the end of 6 months [Figure 1]. Progression of myopia was noted in 40 eyes (56.338%) in the study group as compared to 35 eyes (94.59%) in the control group (P = 0.00) [Table 1]. Rapid progression was noted in 23 eyes (32.39%) in the study group as compared to 23 eyes (62.16%) in the control group (P < 0.0001) and this was statistically significant (P = 0.003) [Table 2]. The mean AXL increased by 0.14 mm in the study group as compared to 0.25 mm among the controls (P = 0.01) at the end of 6 months [Figure 2]. There was also a statistically significant increase in mean PDM by 0.83 mm (P = 0.01) [Figure 3] and receding of mean NPA by 1.14 cm in the study group (P = 0.03) [Figure 4], however, there was no change or loss in distance or near BCVA and these changes were clinically insignificant. No significant changes were noted in ACD, LT, NPC, distance and near BCVA, and ocular alignment in the study and control groups. No adverse reactions were reported.
|Figure 1: Mean spherical equivalent across two groups. #Mann–Whitney U-test used to find the P value, **Statistically significant|
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|Figure 2: Mean axial length across two groups. @Two-sample t-test, #Mann–Whitney U-test used to find the P value, **Statistically significant|
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|Figure 3: Mean near point of accommodation across two groups. #Mann–Whitney U-test used to find the P value, **Statistically significant|
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|Figure 4: Mean pupil diameter across two groups. @Two-sample t-test, #Mann–Whitney U-test used to find the P value, **Statistically significant|
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| Discussion|| |
In this clinical trial of low-dose atropine in 71 eyes of 36 children, there were statistically significant changes from baseline in SE of myopia, AXL, PDM, and NPA in cases at the end of 6 months. Despite low-dose atropine therapy, myopia progressed in 56.338% of eyes and rapid progression happened in 32.39% of eyes in the study group, however, this increase was much lower than age-matched controls, in whom 94.59% progressed and rapid progression occurred in 62.16% of eyes. AXL elongation also was much more among controls than in the study group. Low-dose atropine was well tolerated by all children despite pupil dilatation and accommodation loss. The vision-related quality of life was not affected. BVCA for distance and near was well preserved and no adverse reactions were reported at the end of 6 months.
Several studies have shown that atropine eye drops are effective in slowing myopia progression in young children. In a randomized controlled trial involving 400 children aged 6–12 years, ATOM 1, it was found that over a 2-year period, atropine 1% eye drops slowed myopia progression to −0.28+-0.92 compared with −1.20+−0.69 D in the placebo group, with a 77% reduction in myopia progression with no axial elongation. However, the associated blurred near vision, photophobia, and risk of increased ultraviolet exposure deter parents from widely adopting the treatment. In the ATOM 2 trial, 0.5%, 0.1%, and 0.01% atropine slowed myopia progression to −0.3+−0.60 D, −0.38+−0.60 D, and −0.49+−0.63 D, respectively, over 2 years. Overall, myopia progression and change in axial elongation at the end of 5 years were lowest in the 0.01% group (−1.38+−0.98 D and 0.75+−0.48 mm, respectively). Atropine 0.01% also caused minimal pupil dilation (0.8 mm), minimal loss of accommodation (2–3 D), and no near visual loss compared with higher doses. We too got statistically significant less progression of myopia (−0.28+−0.47 D) in the study group as compared to controls (−0.63+−0.6 D) and less AXL elongation in cases (0.14+−0.129 mm) as compared to controls (0.25+−0.22 mm). The mean increase in photopic PDM was 0.82+−1.357 mm and the mean loss of accommodation was 1.89 D in the study group, which were comparable to ATOM 2. ATOM 2 was limited by the lack of a control group, but we had an age-matched control group. In another randomized, double-blinded, placebo-controlled trial of 0.05%, 0.025%, and 0.01% atropine eye drops in myopia control, called the Low-Concentration Atropine for Myopia Progression (LAMP 1) study, the mean SE change was −0.59+−0.61 D and −0.81+−0.53 D in the 0.01% atropine groups and placebo groups, respectively (P < 0.001), after 1 year, with a respective mean increase in AL of 0.36+−0.29 mm and 0.41+−0.22 mm (P < 0.001), which were comparable to our results [Table 3]. The accommodation amplitude loss was 0.26+−3.04 D in 0.01% atropine and 0.32+−2.91 D in placebo in LAMP study and was lower than ATOM 2 and our study. The photopic pupil sizes increased, respectively, by 0.49+−0.80 mm in the 0.01% atropine group and 0.13+−1.07 mm in the placebo group (P < 0.001) and again were lower than ATOM 2 and our study. Visual acuity and vision-related quality of life were not affected in each group. Kothari and Rathod studied the efficacy of 1% atropine eye drops for myopia in Indian eyes and found that baseline rate of progression was reduced from −0.6 D/year to −0.2 D/year after 1% atropine therapy although progressive addition photo Gray lenses had to be prescribed to avoid photophobia. The only published study in the Indian population with 0.01% atropine, the recent I-ATOM study, noted a significant reduction of 54% reduction in mean SE progression with 0.01% atropine. Ours is probably the only other case − control trial to provide good evidence of efficacy and safety of low-concentration atropine in retarding myopia progression in Indian eyes.
The fact that, despite good compliance in our study, 56.338% of study eyes progressed with 32.39% showing rapid progression raises some relevant questions:
(1) Is 0.01% ideal for all ages and ethnicities? (2) Is the effect different in differently pigmented eyes and in different races? (3) How to manage the rapid progressors? (4) Can we stop after the peak effect is got in the 2nd year as per ATOM studies? (5) Should we abruptly stop or taper the drops?
There are very few studies on the use of low dose atropine use in Indian eyes and almost all studies published are from East Asia. Only few studies have analysed the changes in axial length,pupil size,accomodation,convergence,lens thickness,ocular alignment along with the change in spherical equivalent of myopia in low dsoe atropine users; which in turn help us in understanding the vision related quality of life with low dose atropine use. The drawbacks of our study are the possibility of selection and reporting bias due to the nonmasked, nonrandomized nature of the trial, small sample size, and shorter duration. The mean age in our study group was 8.306 years as compared to 9.68 in the control group, and this age difference may be clinically significant in the context of myopia and may have affected the evaluation. We hope to get more cases, longer follow-up, and solutions to unanswered questions as the study progresses to Phase II (1 year).
| Conclusion|| |
Low-dose atropine (0.01%) therapy was able to reduce the progression of myopia in the study group as compared to the controls with a good tolerance and no change in the vision-related quality of life. Long-term follow-up is, however, needed for extrapolation into the general population.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]