Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Comparison of Ranibizumab and Bevacizumab for Macular Edema Secondary to Retinal Vein Occlusions in Routine Clinical Practice

Mehnaz Khan, MS, MD; Karen M. Wai, BA; Fabiana Q. Silva, MD; Sunil Srivastava, MD; Justis P. Ehlers, MD; Aleksandra Rachitskaya, MD; Amy Babiuch, MD; Ryan Deasy, MD; Peter K. Kaiser, MD; Andrew P. Schachat, MD; Alex Yuan, MD, PhD; Rishi P. Singh, MD

Abstract

BACKGROUND AND OBJECTIVE:

To determine outcomes of intravitreal ranibizumab (IVR) (Lucentis; Genentech, South San Francisco, CA) versus bevacizumab (IVB) (Avastin; Genentech, South San Francisco, CA) for treatment of macular edema (ME) secondary to retinal vein occlusion (RVO) in routine clinical practice.

PATIENTS AND METHODS:

A retrospective study identified treatment-naïve patients with ME secondary to RVO where treatment with either IVB or IVR was initiated. Retreatment criteria were based on ophthalmic examination and/or spectral-domain optical coherence tomography findings.

RESULTS:

Central RVO/hemi-RVO cohort: At 12 months, change in visual acuity (VA) (IVR: +12.9 letters, IVB +6.9 letters; P = .53), central subfield thickness (CST) (IVR: −144.1 μm, IVB: −153.9 μm; P = .88), and number of injections (IVR: 5.40 injections, IVB: 5.64 injections; P = .70) were not different between groups. Branch RVO cohort: At 12-month follow-up, no differences in change in VA (IVR: +15.2 letters, IVB: +10.6 letters; P = .46), CST (IVR: −23.1 μm, IVB: −91.4 μm; P = .16), or number of injections (IVR: 5.93 injections, IVB: 5.13 injections; P = .15) were noted.

CONCLUSION:

There is no notable difference in outcome between IVR and IVB when treating ME from RVO in routine clinical practice.

[Ophthalmic Surg Lasers Imaging Retina. 2017;48:465–472.]

Abstract

BACKGROUND AND OBJECTIVE:

To determine outcomes of intravitreal ranibizumab (IVR) (Lucentis; Genentech, South San Francisco, CA) versus bevacizumab (IVB) (Avastin; Genentech, South San Francisco, CA) for treatment of macular edema (ME) secondary to retinal vein occlusion (RVO) in routine clinical practice.

PATIENTS AND METHODS:

A retrospective study identified treatment-naïve patients with ME secondary to RVO where treatment with either IVB or IVR was initiated. Retreatment criteria were based on ophthalmic examination and/or spectral-domain optical coherence tomography findings.

RESULTS:

Central RVO/hemi-RVO cohort: At 12 months, change in visual acuity (VA) (IVR: +12.9 letters, IVB +6.9 letters; P = .53), central subfield thickness (CST) (IVR: −144.1 μm, IVB: −153.9 μm; P = .88), and number of injections (IVR: 5.40 injections, IVB: 5.64 injections; P = .70) were not different between groups. Branch RVO cohort: At 12-month follow-up, no differences in change in VA (IVR: +15.2 letters, IVB: +10.6 letters; P = .46), CST (IVR: −23.1 μm, IVB: −91.4 μm; P = .16), or number of injections (IVR: 5.93 injections, IVB: 5.13 injections; P = .15) were noted.

CONCLUSION:

There is no notable difference in outcome between IVR and IVB when treating ME from RVO in routine clinical practice.

[Ophthalmic Surg Lasers Imaging Retina. 2017;48:465–472.]

Introduction

Visual morbidity from retinal vein occlusion (RVO) is largely a result of the subsequent macular edema (ME).1 Pathophysiologic studies have shown markedly elevated vitreous levels of vascular endothelial growth factor (VEGF) in patients with RVO.2 Additionally, studies have also shown that VEGF mediates vascular permeability, which likely contributes to macular edema (ME), prompting interest in anti-VEGF therapy for RVO.3 The advent of anti-VEGF medications has resulted in a paradigm shift in the initial management of ME secondary to RVO from laser therapy4,5 and steroids,6 to anti-VEGF therapy.7,8

Currently, three major anti-VEGF medications are used for the treatment of ME-associated RVO: ranibizumab (Lucentis; Genentech, South San Francisco, CA) is a 48 kDa humanized, affinity-matured antibody fragment against all isoforms of VEGF-A;9 bevacizumab (Avastin; Genentech, South San Francisco, CA) is a 149 kDa full-length humanized monoclonal immunoglobulin-G1 antibody that binds all isoforms of VEGF-A;10 and aflibercept (Eylea; Regeneron, Tarrytown, NY) is a decoy fusion receptor protein comprising key domains of human VEGF receptors 1 and 2 with immunoglobulin-G Fc that binds all isoforms of VEGF-A, VEGF-B, and placental growth factor.11 Both ranibizumab and aflibercept have approved U.S. Food and Drug Administration (FDA) indications, whereas bevacizumab is used off-label.

Numerous studies have shown efficacy of both bevacizumab12–14 and ranibizumab7,8,15,16 in treatment of ME secondary to RVO. Given the wide variation in cost of these existing treatments, a clinical outcome comparison following use of these agents is warranted. Recently published 6-month data from the CRAVE study17 and the MARVEL study18 have shown no anatomic or visual outcome difference following treatment with bevacizumab versus ranibizumab. However, these studies did not separate branch retinal vein occlusion (BRVO) from central retinal vein occlusion (CRVO)/hemi-retinal vein occlusion (HRVO) patients. Given that the pathogenesis of BRVO and CRVO are different and vitreous VEGF levels have been shown to be higher in patients with CRVO/HRVO compared with BRVO,19 it is reasonable to look at the two subgroups to identify differences in clinical response to the different anti-VEGF options. Also, many patients in many of these previous studies received loading doses of anti-VEGF injections instead of treatment decisions being based on anatomical state of macular edema by OCT. Therefore, in this study, we present the clinical outcomes at both 6 and 12 months following treatment of ME from CRVO/HRVO and BRVO separately with bevacizumab versus ranibizumab in routine clinical practice.

Patients and Methods

Study Design

The study was performed at the Cole Eye Institute (Cleveland, OH) and received approval from the Cleveland Clinic Investigational Review Board for a retrospective review of the medical records. All study-related procedures were performed in accordance with standard clinical practice and applicable FDA regulations.

Participants

A retrospective analysis of patients seen at the Cole Eye Institute between January 2011 and December 2014 was completed. The inclusion criteria for the study were: (1) a new diagnosis based on ICD-9 codes of CRVO, HRVO, or BRVO (362.35, 362.36, 362.37) and then confirmed by chart review, (2) completion of a spectral-domain optical coherence tomography (SD-OCT) scan at time of diagnosis with the presence of ME, (3) age of 18 years or older, (4) no previous anti-VEGF or laser treatment for macular edema, or (5) follow-up of at least 6 months after their first anti-VEGF injection. An absolute minimum central subfield thickness (CST) on OCT was not an entry criterion for the study, as the investigators in routine clinical practice treated based on the presence of ME on the OCT and not by threshold values of the central subfield measurements.

Exclusion criteria included the presence of active confounding retinal or ocular disease (eg, proliferative diabetic retinopathy, exudative macular degeneration, uncontrolled glaucoma, uveitis, macular hole, amblyopia), history of pars plana vitrectomy, or any prior intravitreal injection treatment in the study eye. Additionally, patients who switched treatment agents (to either a different anti-VEGF agent or intravitreal steroids) during the 6 months of follow-up were also excluded from the final analysis. Specifically, patients were excluded from the analysis at the point that they crossed over to a different treatment. For example, if a patient initially received ranibizumab injections and then switched over to a different treatment agent between the 6- and 12-month follow-up visits, they were included in the 6-month analysis but excluded from the 12-month analysis.

There was a total of 177 eyes identified, of which four were excluded due to lack of 6-month follow-up. Patients were treated with a specific anti-VEGF agents based on physician and patient preference. Patients were followed at 4- to 8-week intervals and retreated based on investigator determination of the presence of subretinal or intraretinal fluid as seen either by comprehensive ophthalmic examination and/or SD-OCT.

Study End Points and Data Collection

The main outcomes measured in this study were the mean change in visual acuity (VA) and the mean change in CST (defined as the average thickness within the central 1 mm subfield) from baseline as measured by SD-OCT (Zeiss, Oberkochen, Germany) at 6 months and at 12 months following initiation of treatment. Secondary outcomes included mean change from baseline in macular volume and cube average thickness as measured by SD-OCT. Snellen VA was recorded and converted to approximate Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores for statistical analyses using the formula: ETDRS letter score = 85 + 50 * log (Snellen fraction).20

Statistical Analysis

Statistical analysis was performed using SAS software (version 9.3; SAS Institute, Cary, NC). Continuous measures were compared using two-sample t-tests or analysis of variance models. To evaluate patterns of change, linear mixed-effect models were used. In each model, time was treated as a categorical factor to allow for nonlinear change patterns. Visits closest to 6 and 12 months were used to determine efficacy outcomes. The correlation between observations from the same subject over time was modeled using an auto-regressive correlation structure. A significance level of 0.05 was assumed for all tests, and when three or more groups were compared, a Bonferroni corrected significance criteria was used to preserve the overall significance level.

Results

CRVO/HRVO Baseline Comparison by Treatment Type

A total of 89 patients presented with CRVO/HRVO. Baseline patient characteristics were similar between the two treatment groups (Table 1). The average age, the presenting logMAR/ETDRS VA in the groups, and the baseline CST showed no significant difference between the treatment groups.


Baseline Injection Type Comparison: HRVO/CRVO

Table 1:

Baseline Injection Type Comparison: HRVO/CRVO

Visual Acuity and Anatomic Outcomes at 6 and 12 Months

At 6-month follow-up, the mean change in vision in the intravitreal ranibizumab (IVR) group was +9.8 letters (95% CI, −3.2 to 22.8 letters) and in the intravitreal bevacizumab (IVB) group was +10.96 letters (95% CI: 4.5, 17.5 letters) with no significant differences noted between the two groups (P = .88) (Table 2). Similarly, a continued improvement from baseline in vision was noted at the 12 months follow-up (IVR: +12.9 letters, IVB: +6.9 letters; P = .53).


Comparison of Changes at by Baseline Injection Type: HRVO/CRVO

Table 2:

Comparison of Changes at by Baseline Injection Type: HRVO/CRVO

The anatomical outcomes at 6 and 12 months included the changes in CST, cube volume, and cube average thickness on SD-OCT from baseline. At 6 months, the mean decrease in CST in the IVR group was −117.8 μm (95% CI, −219.0 μm to −16.5 μm) compared to the IVB group with −155.4 μm (95% CI, −205.8 μm to −105.0 μm) (P = .51. No statistically significant difference was noted in cube volume (P = .41) or cube average thickness (P = .53) at this time point, either. The trends seen in anatomic improvement at 6 months persisted at 12 months with no differences between IVR and IVB noted with regard to: CST (P = .88), cube volume (P = .39), and cube average thickness (P = .46).

BRVO Baseline Comparison by Treatment Type

A total of 84 subjects were identified for inclusion in the study (Table 3). The baseline ETDRS vision of subjects in the IVR group was 57.8 letters ± 24.2 letters and of those in the IVB group was 58.2 letters ± 16.6 letters (P = .94). The baseline CST was significantly lower in the IVR group (327.8 μm ± 168.0 μm) when compared to the IVB group (413.9 μm ± 122.5 μm; P = .027. However, no significant differences were noted between the two treatment groups with regards to baseline cube volume (P = .81) and baseline cube average thickness (P = .12).


Baseline Injection Type Comparison: BRVO

Table 3:

Baseline Injection Type Comparison: BRVO

Visual Acuity and Anatomic Outcomes at 6 and 12 Months

At 6-month follow-up, the VA improved in both the treatment groups. The ETDRS visual acuity in the IVR group had a mean change of +10.2 letters (95% CI, 1.1 letters to 19.2 letters), compared with a change of +11.2 letters in the IVB group (95% CI, 6.9 letters to 15.5 letters; P = .84). Similar improvements in EDTRS visual acuity were also noted at the 12-month follow-up with no significant difference noted between IVR and IVB (P = .46).

With regard to anatomical outcome differences between drugs, at 6 months, SD-OCT showed a mean change in CST in the IVR group of +0.7 μm (95% CI, −75.2 μm to 76.7 μm) compared to −88.5 μm in the IVB group (95% CI, −124.6 μm to −52.4 μm). This difference in mean change in CST between IVR and IVB groups was statistically significant (P = .038); however, no significant differences were noted in the mean change in cube volume (P = .13) or the cube average thickness (P = .17) between the two treatment groups (Table 4). Subsequently, at 12-month follow-up, there was no difference noted between the two treatment regimens with regard to changes in CST (P = .16), cube volume (P = .27), or cube average thickness (P = .36).


Comparison of Changes by Baseline Injection Type: BRVO

Table 4:

Comparison of Changes by Baseline Injection Type: BRVO

Injection Burden

In addition to evaluating the efficacy of IVR versus IVB, we also wanted to determine the burden to the patient from repeated injections. At 6-month follow-up, patients with CRVO/HRVO required on average 3.1 injections in the IVR group and 3.7 injections in the IVB group (P = .28), whereas patients with BRVO required 3.4 injections in IVR group and 3.6 injections in the IVB group (P = .81). Similarly, at the 12-month follow-up, no significant differences were noted in the number of injections required in IVR versus IVB group for both CRVO/HRVO (P = .70) or for BRVO (P = .15) cohorts. Overall, we found there was no difference between the two medications and the average number of injections needed to treat ME from both CRVO/HRVO and BRVO.

Discussion

In this study, we compare the outcomes of patients with CRVO/HRVO or BRVO when treated with IVR versus IVB. We found no significant difference between these treatment groups with respect to functional outcome as represented by changes in VA, or anatomic outcome as represented by macular thickness/CST. VA and CST have been established by numerous studies in the field as appropriate outcome measures in gauging treatment efficacy18,21,22 for ME.

Two recently published, randomized, controlled trials comparing the efficacy of IVR versus IVB in treatment of ME from RVOs are the MARVEL study18 and the CRAVE study, which each had 6-month results.17 The MARVEL study evaluated the efficacy of IVR versus IVB in BRVO, whereas the CRAVE study evaluated the efficacy of these two treatment options in all forms of vein occlusions, treating patients with BRVO and CRVO alike. Both trials demonstrated that there were no differences in outcomes with regard to VA or CST following treatment with IVR versus IVB. Findings in this study are consistent with prior findings and also suggest that there is no difference regardless of the type of vein occlusion — CRVO/HRVO or BRVO. In contrast to CRAVE, which had treated patients based on preset treatment schedules, the data in this study were generated from multiple practitioners in clinical practice who treat ME from RVO based on OCT findings, thus reflecting the real-world utilization of these treatment modalities.

As mentioned earlier, CST has been used as a primary outcome measure in prior studies evaluating efficacy of anti-VEGF injections for ME from RVO. For example, in the phase 3 clinical trials looking at efficacy of ranibizumab for treatment of macular edema in BRVO23 and CRVO7, a CST of ≥ 250 μm had to be present to be enrolled within the study. This CST-based inclusion criteria is often not reflected in routine clinical practice. Therefore, this study did not set CST guidelines for selecting patients for inclusion in the final analysis. As follows, there was a significant difference noted in the baseline CST for the IVR versus IVB groups in the BRVO cohort. Thus, even though there was an observed statistically significant difference in the change in CST from baseline within the two treatment groups in the BRVO cohort, this difference is likely not a reflection of greater efficacy of IVB in treating ME from BRVO, but rather a consequence of discrepancy in the baseline CST between these groups. This is further corroborated by the fact that the mean final CST at 6 months for the IVR group was 328.5 μm (95% CI, 267.5 μm to 389.5 μm), which is very similar to that for the IVB group (325.4 μm [95% CI, 295.4 μm to 355.4 μm]). We acknowledge that lack of CST criteria also adds bias to our analysis in the form of a “ceiling effect”: if a group had many cases where the initial CST was less than 250 μm, there may not be much room for improvement (a ceiling effect), which may confound the results.

Some of the study limitations include the small cohort size, particularly in the IVR groups, for CRVO, HRVO, and BRVO. Also, the retrospective nature of this study introduces some inherent biases. For example, if a patient received two or three injections and had an extremely good or bad response, they would have switched or discontinued follow-up and not been included within this study. Individual patients' insurance status likely also played a role in medication selection, given IVR is significantly more expensive than IVB. Finally, since our data included patients from multiple practitioners, the follow-up intervals were at the treating clinician's discretion and ranged from 4 weeks to 8 weeks, since exact follow-up periods could not be determined, further introducing bias into our dataset but likely representing a routine clinical practice environment.

Overall, this study compares the efficacy of two commonly used therapeutics for treatment of ME resulting from RVOs in a routine clinical setting. We find no difference in the efficacy of IVR versus IVB in treatment of this condition at either the 6-month or 12-month follow-up. Our report supports the findings of prior randomized, controlled trials. Importantly, our findings are based on OCT-guided treatment, which emulates routine clinical management of patients with RVO. Long-term results from randomized, controlled trials will help us further elucidate the durability of these treatments in management of ME resulting from RVOs.

References

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  23. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: Six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1102–1112.e1. doi:10.1016/j.ophtha.2010.02.021 [CrossRef]

Baseline Injection Type Comparison: HRVO/CRVO

Ranibizumab (n = 17)Bevacizumab (n = 72)

FactornSummarySummaryP Value

Age (years)8971.3 ± 12.869.5 ± 12.6.60a

Sex89.10c
  Male5 (29.4)37 (51.4)
  Female12 (70.6)35 (48.6)

Lens status89.54c
  Phakic6 (35.3)20 (27.8)
  Psuedophakic11 (64.7)52 (72.2)

Macular edema present on initial OCT8914 (82.4)60 (83.3).92c

Baseline ETDRS (letters)8951.3 ± 20.949.9 ± 27.0.85a

Baseline LogMar890.67 ± 0.420.70 ± 0.54.85a

Baseline CST (μm)88460.5 ± 165.7486.5 ± 182.1.59a

Baseline cube volume (μm)8811.7 ± 1.911.4 ± 2.6.60a

Baseline cube average thickness (μm)88326.4 ± 53.7318.9 ± 72.9.69a

Comparison of Changes at by Baseline Injection Type: HRVO/CRVO

RanibizumabBevacizumabDifference
FactorMean Change (95% CI)P ValueMean Change (95% CI)P ValueDifference (95% CI)P Value
6 Months
ETDRS (letters)9.82 (−3.18 to 22.81).1410.96 (4.45 to 17.46).001−1.14 (−15.67 to 13.39).88
LogMar−0.20 (−0.46 to 0.06).14−0.22 (−0.35 to −0.09).0010.02 (−0.27 to 0.31).88
CST (μm)−117.75 (−218.99 to −16.51).023−155.37 (−205.77 to −104.96)< .00137.62 (−75.47 to 150.71).51
Cube volume (μm)−1.13 (−2.27 to 0.01).052−0.60 (−1.17 to −0.03).041−0.53 (−1.81 to 0.75).41
Cube average thickness (μm)−31.42 (−63.83 to 0.99).057−20.02 (−36.32 to −3.71).017−11.40 (−47.68 to 24.88).53
Number of injections3.05 (2.04 to 4.07)n/a3.68 (3.16 to 4.19)n/a−0.62 (−1.76 to 0.52).28
12 Months
ETDRS (letters)12.85 (−3.03 to 28.72).116.93 (−3.00 to 16.86).175.92 (−12.81 to 24.64).53
LogMar−0.26 (−0.57 to 0.06).11−0.14 (−0.34 to 0.06).17−0.12 (−0.49 to 0.26).53
CST (μm)−144.09 (−257.07 to −31.11).013−153.90 (−224.17 to −83.64)< .0019.81 (−123.23 to 142.86).88
Cube volume (μm)−1.53 (−2.94 to −0.13).033−0.81 (−1.69 to 0.07).072−0.73 (−2.38 to 0.93).39
Cube average thickness (μm)−42.62 (−82.34 to −2.91).036−25.20 (−50.10 to −0.30).047−17.43 (−64.31 to 29.45).46
Number of injections5.40 (4.36 to 6.44)n/a5.64 (4.98 to 6.31)n/a−0.24 (−1.47 to 0.99).70

Baseline Injection Type Comparison: BRVO

Ranibizumab (n = 14)Bevacizumab (n = 70)

FactornSummarySummaryP Value

Age (years)8465.8 ± 15.668.3 ± 13.0.52a

Sex84.85c
  Male7 (50.0)33 (47.1)
  Female7 (50.0)37 (52.9)

Lens status84.27c
  Phakic2 (14.3)20 (28.6)
  Pseudophakic12 (85.7)50 (71.4)

Macular edema present on initial OCT8413 (92.9)69 (98.6).31d

Baseline ETDRS (letters)8457.8 ± 24.258.2 ± 16.6.94a

Baseline LogMar840.54 ± 0.480.54 ± 0.33.94a

Baseline CST (μm)84327.8 ± 168.0413.9 ± 122.5.027a

Baseline cube volume (μm)8410.4 ± 1.411.3 ± 1.7.081a

Baseline cube average thickness (μm)84291.2 ± 40.1312.4 ± 47.7.12a

Comparison of Changes by Baseline Injection Type: BRVO

RanibizumabBevacizumabDifference
FactorMean Change (95% CI)P ValueMean Change (95% CI)P ValueDifference (95% CI)P Value
6 Months
ETDRS (letters)10.17 (1.10 to 19.23).02811.18 (6.86 to 15.51)< .001−1.02 (−11.06 to 9.02).84
LogMar−0.20 (−0.38 to −0.02).028−0.22 (−0.31 to −0.14)< .0010.02 (−0.18 to 0.22).84
CST (μm)0.71 (−75.24 to 76.67).99−88.52 (−124.63 to −52.40)< .00189.23 (5.13 to 173.34).038
Cube volume (μm)0.30 (−0.58 to 1.18).50−0.45 (−0.86 to −0.03).0370.75 (−0.23 to 1.72).13
Cube average thickness (μm)7.14 (−17.10 to 31.38).56−11.53 (−23.08 to 0.01).05018.68 (−8.17 to 45.52).17
Number of injections3.43 (2.47 to 4.38)n/a3.55 (3.09 to 4.02)n/a−0.13 (−1.19 to 0.94).81
12 Months
ETDRS (letters)15.21 (4.16 to 26.26).00710.55 (4.81 to 16.28)< .0014.66 (−7.79 to 17.11).46
LogMar−0.30 (−0.53 to −0.08).007−0.21 (−0.33 to −0.10)< .001−0.09 (−0.34 to 0.16).46
CST (μm)−23.14 (−107.05 to 60.76).59−91.43 (−135.55 to −47.30)< .00168.28 (−26.51 to 163.08).16
Cube volume (μm)−0.04 (−1.05 to 0.98).94−0.69 (−1.22 to −0.15).0120.65 (−0.50 to 1.80).27
Cube average thickness (μm)−1.57 (−29.92 to 26.78).91−16.35 (−31.14 to −1.56).03114.78 (−17.20 to 46.76).36
Number of injections5.93 (4.97 to 6.88)n/a5.13 (4.59 to 5.67)n/a0.80 (−0.30 to 1.90).15
Authors

From the Cole Eye Institute, Cleveland Clinic, Cleveland.

This study was presented at the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, May 1–5, 2016, in Seattle.

Dr. Wai has received grants from Prevent Blindness Ohio. Dr. Srivastava has received grants and personal fees from Allergan and Bausch + Lomb and personal fees from Zeiss, Regeneron, Optos, and Clearside outside the submitted work. Dr. Ehlers has received grants and personal fees from ThromboGenics, grants from Genentech and Regeneron, and personal fees from Alimera, Alcon, Leica, Zeiss, and Bioptigen outside the submitted work. Drs. Rachitskaya and Babiuch have received personal fees from Allergan outside the submitted work. Dr. Kaiser has received personal fees from Alcon, Allergan, Bayer, Novartis, Regeneron, Kanghong, and Ohr outside the submitted work. Dr. Schachat has received personal fees from the American Academy of Ophthalmology, Elsevier, the State of Ohio, and the Cleveland Clinic, as well as other fees from Easton Capital, outside the submitted work. Dr. Singh has received grants and personal fees from Alcon, Genentech, and Regeneron, as well as personal fees from Shire and Optos, outside the submitted work. The remaining authors report no relevant financial disclosures.

This study received support from Prevent Blindness Ohio fellowship (KW) and an unrestricted grant from Research to Prevent Blindness. The sponsors did not participate in the design, execution, data review, or publishing of this manuscript.

Address correspondence to Rishi P. Singh, MD, 9500 Euclid Avenue, Desk i32, Cleveland, OH 44195; 216-445-9497; email: singhr@ccf.org.

Received: October 27, 2016
Accepted: February 21, 2017

10.3928/23258160-20170601-04

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