Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Correlation of Macular Thickness and Visual Acuity in DME Treated by Two Doses of Intravitreal Ziv-Aflibercept Versus Bevacizumab: Analysis of a Randomized, Three-Armed Clinical Trial

Mohammad Hossein Jabbarpoor Bonyadi, MD; Ahmadreza Baghi, MD; Alireza Ramezani, MD; Mehdi Yaseri, PhD; Masoud Soheilian, MD

Abstract

BACKGROUND AND OBJECTIVE:

To report the correlation of central macular thickness (CMT) and best-corrected visual acuity (BCVA) after 1-year treatment by two doses (2.5 mg or 1.25 mg) of intravitreal ziv-aflibercept (IVZ) versus bevacizumab (IVB) in eyes with diabetic macular edema (DME).

PATIENTS AND METHODS:

In this study, the correlation of CMT and BCVA changes of the eyes enrolled in a previous clinical trial of 123 eyes were re-evaluated. The correlation of BCVA and CMT changes at each visit was evaluated in the three study arms individually. Then, the eyes in each of the arms were classified at each follow-up visit into three subgroups based on their CMT changes related to the baseline CMT: CMT decrease of 30% or more of baseline CMT, between 10% to 29% of baseline CMT, and less than 9% of baseline CMT or CMT increase.

RESULTS:

BCVA and CMT changes were correlated significantly (P < .05) in all and in half of the follow-up visits, respectively, in the eyes treated by IVZ 1.25 mg and IVB (r = 0.554 and r = 0.617 at 1 year, respectively). Nevertheless, such a significant correlation was not detected in the eyes treated by IVZ 2.5 mg in any of the follow-up visits (r = 0.202 at 1 year; P = .259). In the IVZ 2.5 mg group, BCVA improvement was observed in all subgroups with each level of CMT reductions.

CONCLUSION:

Ziv-aflibercept 2.5 mg might have a beneficial effect on DME beyond thickness reduction.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:684–690.]

Abstract

BACKGROUND AND OBJECTIVE:

To report the correlation of central macular thickness (CMT) and best-corrected visual acuity (BCVA) after 1-year treatment by two doses (2.5 mg or 1.25 mg) of intravitreal ziv-aflibercept (IVZ) versus bevacizumab (IVB) in eyes with diabetic macular edema (DME).

PATIENTS AND METHODS:

In this study, the correlation of CMT and BCVA changes of the eyes enrolled in a previous clinical trial of 123 eyes were re-evaluated. The correlation of BCVA and CMT changes at each visit was evaluated in the three study arms individually. Then, the eyes in each of the arms were classified at each follow-up visit into three subgroups based on their CMT changes related to the baseline CMT: CMT decrease of 30% or more of baseline CMT, between 10% to 29% of baseline CMT, and less than 9% of baseline CMT or CMT increase.

RESULTS:

BCVA and CMT changes were correlated significantly (P < .05) in all and in half of the follow-up visits, respectively, in the eyes treated by IVZ 1.25 mg and IVB (r = 0.554 and r = 0.617 at 1 year, respectively). Nevertheless, such a significant correlation was not detected in the eyes treated by IVZ 2.5 mg in any of the follow-up visits (r = 0.202 at 1 year; P = .259). In the IVZ 2.5 mg group, BCVA improvement was observed in all subgroups with each level of CMT reductions.

CONCLUSION:

Ziv-aflibercept 2.5 mg might have a beneficial effect on DME beyond thickness reduction.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:684–690.]

Introduction

Diabetic macular edema (DME) is one of the leading causes of significant visual loss in diabetic patients. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents have progressively demonstrated to be the first-line treatment for center-involving DME with useful clinical response.1,2 The efficacy of anti-VEGF therapy for anatomic and functional improvement in DME has been established in multiple studies.3–5

Ziv-aflibercept (IVZ) (Zaltrap; Regeneron, Tarrytown, NY), which is indicated for metastatic colorectal cancer, has recently been shown to be a cost-effective treatment of DME.4–7 Ziv-aflibercept and bevacizumab (Avastin; Genentech, South San Francisco, CA) are both anti-VEGF agents that are recombinant fusion protein and have similar mechanism. They comprise main domains from human VEGF receptors 1 and 2 fused to the Fc domain of human immunoglobulin-G1.

A correlation between retinal thickness changes and visual acuity (VA) improvement has been reported during anti-VEGF therapy for DME in some studies with use of bevacizumab.8–9 However, such correlation has not been clearly repeated in some other studies.10–12 In a randomized, clinical trial, we recently disclosed a stronger effect of IVZ compared to intravitreal bevacizumab (IVB) during 1-year treatment period in terms of both VA improvement and macular thickness reduction in cases with center-involving DME.4–5 Looking to the data of the same trial, we herein report the possible correlation of longitudinal central macular thickness (CMT) changes with VA improvement during 1-year anti-VEGF therapy with two doses of IVZ versus IVB in DME cases.

Patients and Methods

Details of our randomized, clinical trial (registered at clinicaltrials.gov as NCT02645734) have been previously reported.4–5 The original trial adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Inclusion and exclusion criteria have been provided in detail in our previous reports.4–5 In summary, cases older than 18 years with type 1 or 2 diabetes having center-involving DME and best-corrected VA (BCVA) between 20/40 and 20/320 Snellen equivalent with no prior laser treatment within the last 3 months had been included and randomized to one of the three treatment groups: 2.5 mg (0.1 mL) IVZ (group: ziv-aflibercept 2.5 mg), 1.25 mg (0.05 mL) IVZ (group: ziv-aflibercept 1.25 mg), and 1.25 mg (0.05 mL) intravitreal bevacizumab (group: IVB). In bilateral cases, each eye was randomized separately. Each eye received assigned treatment three times every 4 weeks. After this loading dose, eyes in the IVZ groups continued to receive injections every 8 weeks, and eyes in the IVB group continued to receive injections every 4 weeks for up to 1 year. Injections were stopped if BCVA improved to 20/30 or better and/or central macular thickness (CMT) reduced to 300 μm or less. Reinjections were performed if BCVA decreased to less than 20/30 and/or CMT increased to greater than 300 μm.

For the aim of this report, the correlation of BCVA and CMT changes at each visit was evaluated in the three study arms individually. Then, the eyes in each of the three study arms were classified at each follow-up visits into three groups based on their CMT changes related to the baseline CMT: 1) CMT decrease of 30% or more of baseline CMT, 2) CMT decrease of between 10% and 29% of baseline CMT, and 3) CMT decrease of 9% or less of baseline CMT or CMT increase. The outcome measures were to detect the correlation of BCVA and CMT changes and to report the amount of BCVA changes related to the percentage of CMT reduction at every visit in each treatment arms.

Statistical Methods

To present data we used mean, standard deviation, and the range. Using separated linear mixed model, we evaluated the changes of BCVA related to the three classified CMT changes at each visit in the three study groups. In this analysis, multiple comparisons were considered by the Sidak method. Other mixed models were used to compare the CMT reduction groups in each treatment arm when considering the probable correlation of the eyes of a subject. Additionally, partial correlation coefficient used to evaluate the relation of the CMT and BCVA changes in different follow-up time. We also used locally weighted scatterplot smoothing to demonstrate this relation. All statistical analyses were performed by SPSS software (Version 24.0; IBM Corp., Armonk, NY). All tests were two-sided, and P values less than .05 were considered statistically significant.

Results

Baseline features of the eyes/patients were presented in detail in our previous report.5 Briefly, 123 eyes of 83 patients (42 eyes in the ziv-aflibercept 2.5 mg group, 42 eyes in the ziv-aflibercept 1.25 mg group, and 39 eyes in the IVB group) fulfilled all our intervention/examination sessions in the study. In 40 patients, both eyes were enrolled. Mean number of injections were 6.71, 6.67, and 11.56 in the ziv-aflibercept 2.5 mg, ziv-aflibercept 1.25 mg, and IVB groups, respectively.

Our previous report demonstrated that both BCVA improvement and CMT reduction were statistically significant at all follow-ups in the all three treatment arms (P < .001 for all treatment groups at all visits; Table1). Pairwise comparison in that report disclosed an overall better effect of ziv-aflibercept 2.5 mg compared to IVB treatment in terms of both BCVA improvement and CMT reduction. No significant difference was detected between ziv-aflibercept 2.5 mg and ziv-aflibercept 1.25 mg.

Table 2 and Figure 1 show the correlations of BCVA and CMT changes at each visit in every treatment arm separately. These data show that BCVA and CMT changes were correlated significantly in all of the follow-up visits in the ziv-aflibercept 1.25 mg group and in half of the follow-up visits in IVB groups. Nonetheless, such significant correlation was not detected in ziv-aflibercept 2.5 mg group in any of the follow-up visits.

BCVA and CMT Changes From Baseline in Each Group at Every Follow-Up Visit After Treatments

Table 1:

BCVA and CMT Changes From Baseline in Each Group at Every Follow-Up Visit After Treatments

The Correlations of Macular Thickness and BCVA Changes at Different Groups in Each Follow-Up Visit

Table 2:

The Correlations of Macular Thickness and BCVA Changes at Different Groups in Each Follow-Up Visit

Correlations of central macular thickness (CMT) and best-corrected visual acuity (BCVA) changes in three treatment arms.

Figure 1.

Correlations of central macular thickness (CMT) and best-corrected visual acuity (BCVA) changes in three treatment arms.

In another evaluation, we classified the eyes in each group at every follow-up visits into three groups based on their CMT changes related to the baseline CMT: 1) CMT decrease of 30% or more of baseline CMT, 2) CMT decrease between 10% and 29% of baseline CMT, and 3) CMT decrease 9% or less of baseline CMT or CMT increase (Table 2). Looking at the whole eyes enrolled in the study, BCVA improvements were significantly different at every visit among these three subgroups in favor of the subgroup with 30% or more CMT reduction and then the subgroup with 10% to 29% CMT reduction (Table 3). The same significant difference in BCVA improvement was detected in all follow-up visits in the ziv-aflibercept 1.25 mg group and half of the follow-up visits in the IVB group. However, in the ziv-aflibercept 2.5 mg group, none of the BCVA changes among the three subgroups reached to a significant level at any of the follow-up visits (Table 3).

BCVA and Its Changes From Initial Values of the Three Subgroups Classified According to Their Percentage of CMT Reduction Presented in Each Main Group Separately BCVA and Its Changes From Initial Values of the Three Subgroups Classified According to Their Percentage of CMT Reduction Presented in Each Main Group Separately

Table 3:

BCVA and Its Changes From Initial Values of the Three Subgroups Classified According to Their Percentage of CMT Reduction Presented in Each Main Group Separately

Discussion

In our previous report of this clinical trial, we showed a statistically significant BCVA improvement and CMT reduction up to 1 year with both 2.5-mg and 1.25-mg doses of ziv-aflibercept than with IVB in eyes with center-involved DME. In this comparative analysis on the data of the same trial, we found that visual improvement in DME was correlated with retinal thickness reduction in the eyes treated with 1.25 mg doses of IVZ and IVB. Unexpectedly, such correlation was not detected in the eyes received 2.5 mg doses of IVZ.

In the treatment of DME cases, effective roles of VEGF inhibitors have been reported in various studies in terms of both visual improvement and macular thickness reduction.13,14 Among anti-VEGF drugs, the VEGF Trap-Eye group has been more effective, and the Diabetic Retinopathy Clinical Research Network demonstrated that intravitreal aflibercept had better result than bevacizumab and ranibizumab (Lucentis; Genentech, South San Francisco, CA) in DME cases with baseline levels of vision 20/50 or less.15,16 Numerous studies have suggested that intravitreal ziv-aflibercept is safe and therefore could be a potential substitute for aflibercept considering its lower cost.4–5,17–21

Controversial correlations between VA and macular thickness in eyes treated with anti-VEGF drugs have been reported in different studies looking mostly at the primary and final values.8–12 Although positive correlation between VA improvement and CMT reduction has been reported in some studies,8,9 it has not been clearly demonstrated in some others,10–12 showing that anatomical improvement is not always associated with functional response. We also found a direct correlation between visual and thickness improvement in DME cases in all follow-up visits in ziv-aflibercept 1.25 mg and half of the follow-up visits in IVB groups. However, such correlation was not detected in ziv-aflibercept 2.5 mg group at any of the follow-up visits. Present findings show improvement in VA, which is beyond the concomitant macular thickness reduction in the eyes treated with 2.5-mg doses of ziv-aflibercept. This could be hypothesized by an assumed effect of higher concentration of ziv-aflibercept on macular perfusion, macular ischemia, and/or cell functions.

To report the correlation analysis more practical for clinicians, we classified the eyes in each group at every follow-up visit into three groups based on their CMT changes related to the baseline CMT. This subgroup classification demonstrated that in the cases treated by ziv-aflibercept 2.5 mg, there was an improvement in visual acuity even in the eyes with CMT decrease of 9% or less from baseline CMT, and this improvement had no significant difference with the improvement observed in the subgroups with CMT decrease of 30% or greater and between 10% and 29%.

Our limitations in this study are limited sample size, the differences in baseline VA among the groups, and using Snellen VA instead of ETDRS acuity. Considering the results of our previous reports, we can conclude that although both doses of 1.25 mg and 2.5 mg ziv-aflibercept are more effective than IVB in the treatment of center-involving DME, the 2.5 mg dose may have superiority to 1.25 mg in some particular cases with less anatomic response. The observed effect of 2.5mg intravitreal ziv-aflibercept on VA in this study is beyond the parallel ordinary macular thickness reduction and deserves more clarification in future investigations.

References

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The Correlations of Macular Thickness and BCVA Changes at Different Groups in Each Follow-Up Visit

Time (Weeks) Total Ziv-Aflibercept 2.5 mg Ziv-Aflibercept 1.25 mg Bevacizumab 1.25 mg
r P r P r P r P
4 0.242 .008 0.261 .103 0.409 .008 0.066 .689
8 0.315 .001 0.229 .149 0.445 .006 0.288 .084
12 0.315 .001 0.229 .149 0.445 .006 0.288 .084
20 0.421 < .001 0.213 .193 0.610 < .001 0.383 .018
28 0.387 < .001 0.241 .135 0.550 .001 0.317 .059
36 0.472 < .001 0.303 .092 0.578 .001 0.491 .004
44 0.472 < .001 0.303 .092 0.578 .001 0.491 .004
52 0.482 < .001 0.202 .259 0.554 .002 0.617 < .001

BCVA and Its Changes From Initial Values of the Three Subgroups Classified According to Their Percentage of CMT Reduction Presented in Each Main Group Separately

Time (Weeks) Total Ziv-Aflibercept 2.5 mg Ziv-Aflibercept 1.25 mg Bevacizumab 1.25 mg
CMT Change From Baseline (%) P CMT Change From Baseline (%) P CMT Change From Baseline (%) P CMT Change From Baseline (%) P
≥ 30 10–29 ≤9 or Increase ≥ 30 10–29 ≤9 or Increase ≥ 30 10–29 ≤9 or Increase ≥ 30 10–29 ≤9 or Increase
4 BCVA (logMAR) 0.44±0.2 0.46±0.3 0.42±0.2 .848 0.30 ± 0.3 0.38±0.2 0.35±0.3 .739 0.42±0.1 0.36±0.2 0.42±0.2 .811 0.61±0.2 0.58±0.3 0.53±0.2 .682
BCVA change (logMAR) −0.35±0.2 −0.16±0.2 −0.15±0.2 .005 −0.43±0.2 −0.15±0.3 −0.13±0.2 .017 −0.42±0.2 −0.20±0.2 −0.18±0.2 .034 −0.18±0.2 −0.14±0.2 −0.12±0.2 .893
8 BCVA (logMAR) 0.38±0.2 0.35±0.2 0.4±0.2 .709 0.27±0.2 0.35±0.2 0.32±0.1 .619 0.38±0.1 0.32±0.2 0.32± 0.2 .618 0.51±0.3 0.40±0.2 0.54±0.2 .355
BCVA change (logMAR) −0.39±0.2 −0.3±0.2 −0.16±0.2 .003 −0.31±0.2 −0.22±0.2 −0.14±0.2 .362 −0.51±0.2 −0.35±0.2 −0.2±0.2 .019 −0.38±0.3 −0.36±0.2 −0.14±0.2 .114
12 BCVA (logMAR) 0.32±0.2 0.29±0.2 0.36±0.2 .479 0.24±0.2 0.32±0.2 0.30±0.1 .484 0.34±0.1 0.24±0.1 0.28±0.2 .422 0.4±0.2 0.32±0.2 0.49±0.2 .360
BCVA change (logMAR) −0.39±0.2 −0.3±0.2 −0.16±0.2 .003 −0.31±0.2 −0.22±0.2 −0.14±0.2 .362 −0.51±0.2 −0.35±0.2 −0.2±0.2 .019 −0.38±0.3 −0.36±0.2 −0.14±0.2 .114
20 BCVA (logMAR) 0.32±0.2 0.37±0.2 0.37±0.2 .594 0.28±0.2 0.35±0.2 0.24±0.1 .420 0.31±0.1 0.35±0.2 0.32±0.1 .885 0.37±0.2 0.42±0.3 0.52±0.2 .388
BCVA change (logMAR) −0.42±0.3 −0.24±0.2 −0.13±0.3 < .001 −0.31±0.2 −0.15±0.2 −0.28±0.2 .130 −0.58±0.3 −0.29±0.2 −0.08±0.3 .001 −0.4±0.3 −0.30±0.2 −0.07±0.3 .028
28 BCVA (logMAR) 0.34±0.2 0.38±0.2 0.38±0.2 .740 0.27±0.2 0.29±0.2 0.26±0.2 .805 0.33±0.1 0.35±0.1 0.37±0.2 .962 0.44±0.2 0.49±0.2 0.53±0.3 .824
BCVA change (logMAR) −0.37±0.2 −0.23±0.2 −0.14±0.3 .005 −0.31±0.2 −0.2±0.2 −0.29±0.2 .504 −0.54±0.3 −0.26±0.2 −0.06±0.3 .006 −0.3±0.3 −0.24±0.2 −0.08± 0.3 .264
36 BCVA (logMAR) 0.32±0.2 0.32±0.2 0.40±0.3 .364 0.22±0.1 0.31±0.2 0.19±0.0 .232 0.32±0.1 0.28±0.2 0.36±0.3 .920 0.43±0.2 0.38±0.2 0.62±0.2 .021
BCVA change (logMAR) −0.44±0.3 −0.21±0.2 −0.18±0.2 < .001 −0.32±0.2 −0.19±0.1 −0.32±0.2 .349 −0.57±0.3 −0.27±0.2 −0.15±0.2 .002 −0.45±0.3 −0.16±0.2 −0.08±0.2 .006
44 BCVA (logMAR) 0.29±0.2 0.31±0.2 0.40±0.3 .185 0.20±0.1 0.31±0.2 0.2±0.1 .238 0.32±0.1 0.28±0.2 0.37±0.3 .818 0.36±0.2 0.36±0.2 0.62±0.2 .001
BCVA change (logMAR) −0.44±0.3 −0.21±0.2 −0.18±0.2 < .001 −0.32±0.2 −0.19±0.1 −0.32±0.2 .349 −0.57±0.3 −0.27±0.2 −0.15±0.2 .002 −0.45±0.3 −0.16±0.2 −0.08±0.2 .006
52 BCVA (logMAR) 0.26±0.2 0.25±0.2 0.47±0.3 .007 0.16±0.1 0.28±0.2 0.2±0.0 .323 0.29±0.1 0.24±0.2 0.36±0.2 .459 0.35±0.3 0.25±0.1 0.75±0.3 .006
BCVA change (logMAR) −0.44±0.2 −0.32±0.2 −0.08±0.3 < .001 −0.34±0.2 −0.33±0.3 −0.31±0.2 .872 −0.54±0.3 −0.33±0.2 −0.08±0.3 .023 −0.45±0.3 −0.28±0.2 0.09±0.2 .001

BCVA and CMT Changes From Baseline in Each Group at Every Follow-Up Visit After Treatments

Time (Months) BCVA CMT

Total Ziv 2.5 mg Ziv 1.25 mg IVB Total Ziv 2.5 mg Ziv 1.25 mg IVB

0 Value 0.62 ± 0.33 0.53 ± 0.32 0.64 ± 0.31 0.7 ± 0.35 387 ± 118 367 ± 115 383 ± 114 412 ± 124

4 Value 0.44 ± 0.29 0.35 ± 0.29 0.41 ± 0.25 0.56 ± 0.3 320 ± 88 311 ± 98 315 ± 83 336 ± 82
Change −0.18 ± 0.25 −0.18 ± 0.25 −0.23 ± 0.25 −0.14 ± 0.25 −66 ± 93 −56 ± 102 −68 ± 91 −75 ± 87
Change % −25 ± 45 −29 ± 51 −33 ± 33 −12 ± 49 −14 ± 17 −13 ± 18 −15 ± 18 −16 ± 15
P within < .001 < .001 < .001 < .001 < .001 < .001

12 Value 0.32 ± 0.23 0.28 ± 0.22 0.28 ± 0.18 0.4 ± 0.28 283 ± 82 260 ± 71 281 ± 70 311 ± 98
Change −0.3 ± 0.28 −0.25 ± 0.26 −0.36 ± 0.27 −0.3 ± 0.31 −102 ± 126 −108 ± 108 −99 ± 141 −99 ± 130
Change % −40 ± 59 −31 ± 86 −49 ± 35 −41 ± 37 −22 ± 25 −26 ± 19 −20 ± 28 −20 ± 27
P within < .001 < .001 < .001 < .001 < .001 < .001

22 Value 0.36 ± 0.24 0.3 ± 0.21 0.35 ± 0.2 0.43 ± 0.28 285 ± 68 265 ± 65 280 ± 52 310 ± 79
Change −0.27 ± 0.31 −0.23 ± 0.25 −0.3 ± 0.35 −0.27 ± 0.32 −103 ± 120 −107 ± 115 −103 ± 130 −99 ± 117
Change % −27 ± 81 −29 ± 74 −20 ± 113 −32 ± 43 −22 ± 23 −24 ± 19 −21 ± 24 −20 ± 25
P within < .001 < .001 < .001 < .001 < .001 < .001

32 Value 0.37 ± 0.25 0.28 ± 0.21 0.35 ± 0.22 0.48 ± 0.28 280 ± 74 255 ± 65 282 ± 55 305 ± 91
Change −0.25 ± 0.31 −0.25 ± 0.27 −0.27 ± 0.36 −0.22 ± 0.3 −107 ± 123 −115 ± 120 −99 ± 134 −105 ± 116
Change % −23 ± 85 −32 ± 75 −14 ± 120 −23 ± 44 −23 ± 23 −26 ± 20 −20 ± 24 −22 ± 25
P within < .001 < .001 < .001 < .001 < .001 < .001

42 Value 0.33 ± 0.25 0.24 ± 0.17 0.32 ± 0.22 0.43 ± 0.29 279 ± 79 251 ± 66 272 ± 57 315 ± 95
Change −0.29 ± 0.29 −0.27 ± 0.23 −0.35 ± 0.31 −0.25 ± 0.32 −110 ± 135 −120 ± 129 −119 ± 139 −92 ± 139
Change % −42 ± 38 −49 ± 36 −46 ± 42 −33 ± 35 −23 ± 26 −27 ± 22 −24 ± 24 −18 ± 31
P within < .001 < .001 < .001 < .001 < .001 < .001

52 Value 0.3 ± 0.27 0.2 ± 0.16 0.28 ± 0.21 0.43 ± 0.36 265 ± 74 242 ± 63 261 ± 57 295 ± 90
Change −0.33 ± 0.32 −0.33 ± 0.26 −0.38 ± 0.34 −0.26 ± 0.35 −123 ± 133 −125 ± 125 −131 ± 141 −113 ± 139
Change % −48 ± 52 −56 ± 40 −48 ± 65 −39 ± 49 −26 ± 25 −29 ± 21 −27 ± 24 −22 ± 30
P within < .001 < .001 < .001 < .001 < .001 < .001
Authors

From the Ophthalmic Research Center, Labbafinejad Medical Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran (MHJB, AB, AR, MY, MS); Negah Eye Hospital, Tehran, Iran (AR, MS); and Torfe Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran (AR).

Supported and funded by the Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Iran.

The authors report no relevant financial disclosures.

Address correspondence to Masoud Soheilian, MD, Labbafinejad Medical Center, Pasdaran Ave., Boostan 9 St., Tehran 16666, Iran; email: masoud_soheilian@yahoo.com.

Received: October 01, 2018
Accepted: March 25, 2019

10.3928/23258160-20191031-03

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