Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Prevention of Macular Edema in Patients With Diabetic Retinopathy Undergoing Cataract Surgery: The PROMISE Trial

Weilin Song, BS; Thais F. Conti, MD; Richard Gans, MD; Felipe F. Conti, MD; Fabiana Q. Silva, MD; Namrata Saroj, OD; Rishi P. Singh, MD

Abstract

BACKGROUND AND OBJECTIVE:

To determine the safety and efficacy of intravitreal aflibercept injection (IAI) in patients with diabetic retinopathy (DR) in the prevention of macular edema (ME) following cataract surgery.

PATIENTS AND METHODS:

This phase 2, prospective, interventional, single-masked, randomized trial at a single academic center included 30 patients who were 18 years of age or older with nonproliferative DR and undergoing cataract surgery with phacoemulsification. Patients received 2 mg intravitreal aflibercept (0.05 mL) or sham injection during cataract surgery. Main outcome measures included treatment adverse events (AEs), best-corrected visual acuity (BCVA), and incidence of ME (defined as presence of cystoid abnormalities as detected by optical coherence tomography at any follow-up visit), a 30% or greater increase from preoperative baseline in central subfield macular thickness, or a BCVA decrease of more than 5 ETDRS letters from Day 7 due to retinal thickening.

RESULTS:

There were similar incidences of AEs between the two groups and no clinically serious ocular AEs in either group. The IAI group had fewer ME events at Day 14 (13% vs. 53%; P = .022), but there was no significant difference in ME events at Day 30 (27% vs. 60%; P = .057), Day 60 (27% vs. 60%; P = .057), or Day 90 (40% vs. 67%; P = .161). Compared to the study group, the control group had a significantly greater increase in central subfield thickness (CST) at Day 30 (50.05 μm vs. 7.95 μm; P = .040) and Day 60 (56.45 μm vs. 3.02 μm; P = .010). However, the difference in CST between groups was no longer significant at Day 90 (50.31 μm vs. 18.48 μm; P = .12). There were no significant differences in BCVA gains between the IAI and sham group at the end of the follow-up period (Day 90, ETDRS letters: 9.88 vs. 8.52; P = .66).

CONCLUSIONS:

Use of IAI in patients with DR for prevention of ME following cataract surgery showed no significant AEs. Although there were significant differences in ME incidence and retinal thickness at periods of time, there was no clinically meaningful benefit in terms of VA. Further larger trials are needed to validate these findings.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:170–178.]

Abstract

BACKGROUND AND OBJECTIVE:

To determine the safety and efficacy of intravitreal aflibercept injection (IAI) in patients with diabetic retinopathy (DR) in the prevention of macular edema (ME) following cataract surgery.

PATIENTS AND METHODS:

This phase 2, prospective, interventional, single-masked, randomized trial at a single academic center included 30 patients who were 18 years of age or older with nonproliferative DR and undergoing cataract surgery with phacoemulsification. Patients received 2 mg intravitreal aflibercept (0.05 mL) or sham injection during cataract surgery. Main outcome measures included treatment adverse events (AEs), best-corrected visual acuity (BCVA), and incidence of ME (defined as presence of cystoid abnormalities as detected by optical coherence tomography at any follow-up visit), a 30% or greater increase from preoperative baseline in central subfield macular thickness, or a BCVA decrease of more than 5 ETDRS letters from Day 7 due to retinal thickening.

RESULTS:

There were similar incidences of AEs between the two groups and no clinically serious ocular AEs in either group. The IAI group had fewer ME events at Day 14 (13% vs. 53%; P = .022), but there was no significant difference in ME events at Day 30 (27% vs. 60%; P = .057), Day 60 (27% vs. 60%; P = .057), or Day 90 (40% vs. 67%; P = .161). Compared to the study group, the control group had a significantly greater increase in central subfield thickness (CST) at Day 30 (50.05 μm vs. 7.95 μm; P = .040) and Day 60 (56.45 μm vs. 3.02 μm; P = .010). However, the difference in CST between groups was no longer significant at Day 90 (50.31 μm vs. 18.48 μm; P = .12). There were no significant differences in BCVA gains between the IAI and sham group at the end of the follow-up period (Day 90, ETDRS letters: 9.88 vs. 8.52; P = .66).

CONCLUSIONS:

Use of IAI in patients with DR for prevention of ME following cataract surgery showed no significant AEs. Although there were significant differences in ME incidence and retinal thickness at periods of time, there was no clinically meaningful benefit in terms of VA. Further larger trials are needed to validate these findings.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:170–178.]

Introduction

Macular edema (ME) is a common cause of poor visual outcomes following uncomplicated cataract surgery and is reported to occur in up to 2% of patients.1,2 When cataract extraction is complicated by posterior capsule rupture with vitreous loss or severe iris trauma, the incidence of ME may be as high as 20%.3 In diabetic patients, especially those with pre-existing retinopathy, macular changes are more likely to occur, with estimates of ME development in diabetic patients ranging from 31% to 81% at various time points following cataract extraction.4–6 Numerous studies have reported that macular changes in diabetic patients were accelerated by cataract surgery.7–9 Other studies attributed this acceleration to the natural course of diabetic retinopathy (DR) disease or due to the inflammation following cataract extraction.6,10 Even if the visual outcome is improved by cataract surgery, ME may ultimately limit postoperative visual acuity (VA) in diabetic patients.

Factors involved in the pathogenesis of post-cataract ME in diabetic eyes include chronic hyperglycemia, blood-retinal barrier dysfunction, and chronic subclinical inflammation.2 Post-surgical inflammation is believed to be a major factor in ME that develops subsequent to cataract extraction.11 Prostaglandins contribute substantially to the inflammatory processes that result in fluid leakage from perifoveal capillaries into the extracellular space of the macular region. Several studies have investigated the prophylactic use of topical and intravitreal corticosteroids.1,12,13 However, there are safety concerns associated with the use of steroids including ocular hypertension and increased susceptibility to endophthalmitis.14,15 Upregulated expression of vascular endothelial growth factor (VEGF), a permeability factor that has been implicated in cystoid macular edema (CME), also induces fluid leakage. In fact, patients with diabetes mellitus were found to have significantly greater increases in VEGF levels than that of control patients 1 day after cataract surgery.16 Therefore, there are theoretical data supporting administration of an anti-VEGF agent during cataract surgery to prevent the subsequent formation of ME and improve visual outcomes in diabetic patients.

Although there have been previous trials studying the safety and efficacy of different intravitreal anti-VEGF injections for the prevention of ME following cataract surgery in diabetic patients,14,17 to the best of our knowledge, this is the first prospective, randomized study to examine the use of prophylactic intravitreal aflibercept injection (IAI) (Eylea; Regeneron, Tarrytown, NY). In contrast to the antibody-based VEGF-binding strategy used by ranibizumab (Lucentis; Genentech, South San Francisco, CA) and bevacizumab (Avastin; Genentech, South San Francisco, CA), aflibercept incorporates additional binding domains of VEGF receptors, resulting in higher VEGF binding affinity and intravitreal binding activity beyond 1 month.18 Aflibercept is an anti-VEGF therapy that has been U.S. Food and Drug Administration (FDA)-approved for the treatment of exudative age-related macular degeneration (AMD), ME secondary to retinal vein occlusion (RVO), diabetic macular edema (DME), and DR in the setting of DME. IAIs have been shown to be safe and effective for the treatment of DME19 and demonstrated a significant reduction in central macular thickness and improvement in best-corrected VA (BCVA).20 This prospective, randomized study was conducted to specifically assess the safety and efficacy of a single IAI for the prevention of DME following cataract surgery in eyes with preexisting DR.

Patients and Methods

The study included 30 patients who were 18 years of age or older with diabetes (Type 1 or 2) and nonproliferative DR (NPDR) or inactive proliferative DR (PDR), without clinically significant ME, and requiring cataract extraction by phacoemulsification with planned implantation of a posterior chamber intraocular lens into the capsular bag. All patients had a central subfield macular thickness (CST) of less than 320 μm (evaluated using the Cirrus SD-OCT [Zeiss, Dublin, CA]) in the study eye prior to cataract surgery and BCVA between 20/20 and 20/200 at time of enrollment into the study. Only one eye was enrolled in the study at a time.

Patients who presented with active PDR or signs of clinically significant vitreomacular traction or epiretinal membrane in the study eye were excluded. Additionally, patients who had a history of retinal detachment, ischemic maculopathy, central or branch retinal vein occlusion, central or branch retinal artery occlusion, exudative AMD, corneal transplants, or chronic or recurrent inflammatory eye disease were excluded. Exclusion criteria based on previous treatment included those who received intraocular or periocular corticosteroids within 3 months of surgery; intravitreal anti-VEGF therapy within 6 months of preoperative baseline visit; systemic corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDS), or anti-VEGF agents within 7 days of surgery; or topical NSAIDs or corticosteroids within 7 days before surgery. (Figure 1).

Study flow chart.

Figure 1.

Study flow chart.

Study Design

This was a prospective, randomized, and single-masked trial conducted at the Cole Eye Institute, Cleveland, Ohio. The principal investigator held the investigational new drug application for this study as this was an unapproved indication. Prior FDA review and approval was obtained, and the study was registered at www.clincaltrials.gov with the study identifier of NCT01988246.

The study consisted of eight visits: a screening visit (performed within 4 weeks to 2 days before the surgery visit), the cataract surgery (Day 0), and six postoperative follow-up visits (Days 1, 7, 14, 30, 60, and 90). Patients who withdrew from the study returned to the clinic for early exit study assessments. As a single-masked treatment trial, patients were unaware of their treatment assignment. Once assigned to a treatment arm by sequential entry, neither the cataract surgeon nor the treating physician could change the assignment.

The study was conducted in accordance with the Good Clinical Practice and the tenets of the Declaration of Helsinki and U.S. Code 21 of Federal Regulations. The study protocol was reviewed and approved by the Cleveland Clinic Institutional Review Board. All patients provided written informed consent before entering the study.

Treatment

Enrolled patients were randomized 1:1 to receive either 2 mg IAI (0.05 mL) or sham in the study eye at the time of surgery (Day 0) post-cataract excision. All patients received standard-of-care (SOC) medications in the study eye during the 90-day follow-up period. The SOC regimen consisted of topical ciprofloxacin hydrochloride four times per day for 1 week and topical prednisolone acetate four times per day in the study eye for 2 weeks following cataract surgery.

Study Objectives

Due to the investigational nature of this study for an unapproved indication, the principal investigator was required to hold the investigational new drug application and submit data on drug safety to the FDA. Therefore, the primary objective for this study was required to be the safety of a single injection of IAI versus sham injection by documenting the incidence and severity of ocular and nonocular adverse events (AEs) and serious AEs following cataract surgery in patients with pre-existing DR. The study also examined if IAI could prevent ME following cataract surgery based on the percentage of patients who developed ME within 90 days after cataract surgery. This was defined in multiple fashions in order to assess the various definitions reported in previous studies including: 1) the presence of cystoid abnormalities as detected by OCT, 2) 30% or greater increase from preoperative baseline in CST, or 3) a BCVA decrease of less than 5 E-ETDRS letters from Day 7 that was due to retinal thickening. A 30% increase in CST was chosen because it is well above the 10% coefficient of variation associated with OCT repeat testing variability.21,22 It also approximately corresponds to CST changes exceeding 50 μm, which was shown to reflect clinically meaningful changes in a published neovascular AMD study.23 Additional secondary endpoints evaluated were: 1) the proportion of patients with 15 letters or greater increase in BCVA from preoperative baseline; 2) the proportion of patients with more than 15 letters decrease in BCVA from preoperative baseline; 3) the proportion of patients that were 20/40 or better; 4) the proportion of patients that were 20/200 or worse.

Safety Assessments

All AEs that occurred during the study were recorded. AEs were assessed for seriousness, severity (mild, moderate, or severe), onset, duration, outcome, and relationship to study drug.

Efficacy Assessments

Retinal characteristics were evaluated by two masked investigators. The scanning protocol incorporated fast macular thickness maps and high definition 6.0 mm linear scans centered on the fovea using Cirrus SD-OCT.24 OCT scans were scored for their morphological patterns. Foveal minimum and volumetric analysis for each patient were recorded. BCVA was assessed at each visit in the study eye using the electronic Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Study eye BCVA was assessed at the screening visit and on Days 1, 7, 15, 30, 60 and 90 post-cataract surgery.

Statistical Analysis

Descriptive summaries were presented as means and standard deviations. Mean levels at specific time points were compared between the two groups using two-sample t-tests. To estimate changes at BCVA and CST from baseline at 30, 60, and 90 days within groups and compare these changes between groups, linear mixed-effect models were fitted. An autoregressive correlation structure modeled repeated measures within subject. Estimated change at each time point along with mean differences between groups on these changes were presented with 95% confidence intervals. Models were then adjusted for the baseline measure of each outcome.

Based on previous studies performed within the same patient cohort, sample size for this trial was determined with the assumption that the study would have at least 80% power. With a sample size of 30, a difference of approximately 45% to 50% in the incidence of ME events could be detected between groups with a significance level of .05.

In evaluating the changes over time, non-normality of the macular volume measurements was observed. A sensitivity analysis comparing the changes using nonparametric Wilcoxon rank sum tests was performed. All statistical analysis was performed using SAS software (version 9.4; Cary, NC). A significance level of .05 was assumed for all tests. Last observation carried forward was used for missing data.

Results

Patient Demographics and Baseline Characteristics

Data were collected for 30 patients between September 2014 and April 2018. The baseline and demographic characteristics are shown in Table 1. The mean age for both the IAI and sham groups was 66 years. The IAI group had nine males (60%), whereas the sham group had five males (33%). There were no meaningful differences in baseline HbA1C values, severity of DR (mild, moderate, severe, or inactive PDR), or initial mean BCVA, CST, or macular volume (MV). There were three (20%) and two (13%) patients in the IAI and control groups, respectively, who received anti-VEGF treatment prior to study entry. There was one patient in the sham group who dropped out voluntarily after Day 14, and no drop-outs in the IAI group.

Baseline and Demographic Characteristics

Table 1:

Baseline and Demographic Characteristics

Safety

AEs are summarized in Table 2. Ten patients (67%) in the IAI group and 11 patients (73%) in the sham group experienced at least one ocular nonserious AE likely related to surgery. There were no treatment-emergent AEs in either group that were related to IAI. At Day 90, there were no significant changes in intraocular pressure (IOP) from baseline in either group (IAI: 14.87 vs. 14.13, P = .50; sham: 14.73 vs. 15.1, P = .76).

Summary of Adverse Events

Table 2:

Summary of Adverse Events

Neither the IAI nor the sham group reported any ocular serious AEs such as retinal detachment or tear, infectious endophthalmitis, or vitreous hemorrhage. In the IAI group, three (20%) reported nonocular serious AEs that were not treatment related. Two (13%) patients had paracentesis for chronic ascites, whereas one (7%) patient was admitted to the emergency department 1 week after surgery with a sudden onset of severe cough and vomiting that subsided after antitussive medication. There were two (13%) patients in the sham group who experienced nonocular serious AEs that were also not treatment-related. One (7%) patient developed a rash on the lower leg that was treated with antibiotics, and one (7%) patient experienced inflammation and pain near a former intravenous injection site. There were no deaths during the study period in either groups.

Macular Edema

Figure 2A provides the percentage of ME occurrences by any of the three definitions used in this study. The sham injection group had significantly more ME occurrences than the IAI group at the Day 14 visit (53% vs. 13%; P = .0224), with no significant difference at Day 30 (60% vs. 27%; P = .0570), Day 60 (60% vs. 27%; P = .0570), or Day 90 (67% vs. 40%; P = .161).

Breakdown of macular edema events by definition. IAI = intravitreal aflibercept injection; OCT = optical coherence tomography; CST = central subfield macular thickness; BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; VA = visual acuity

Figure 2.

Breakdown of macular edema events by definition. IAI = intravitreal aflibercept injection; OCT = optical coherence tomography; CST = central subfield macular thickness; BCVA = best-corrected visual acuity; ETDRS = Early Treatment Diabetic Retinopathy Study; VA = visual acuity

There were six (40%) patients in the IAI group and nine (60%) patients in the sham group who developed cystoid abnormalities on OCT during the duration of the study overall (P = .27) (Figure 2B). There were no statistically significant differences between the groups at any postoperative visit.

A lower percentage of eyes in the IAI group had a 30% or greater increase in CST from baseline at only the Day 60 postoperative visit (0% vs. 33%) (P = .02; Figure 2C). There was no significant difference in the percentage of patients between the two groups at any other postoperative visits or over the duration of the study overall (13.3% vs. 33%) (P = .19).

Change in Central Subfield Thickness and Macular Volume

After adjusting for baseline levels, the sham group had a significantly greater change in CST compared to the IAI at Day 30 (50.05 μm [95% CI, 14.22–85.88] vs. 7.95 μm [95% CI, −9.66 to 25.56]; P = .040) and at Day 60 (56.45 μm [95% CI, 20.62–92.28] vs. 3.02 μm [95% CI, −14.59 to 20.62]; P = .010) (Table 3). The sham group also had a greater increase in MV (median, 0.85 mm3 [interquartile range (IQR), 0.60–1.4]) than the IAI group (0.50 mm3 [IQR, 0.30–0.70]) at Day 60 (P = .018), but MV changes were not statistically significant at any other postoperative visits (Table 3).

Comparison of Changes From Baseline Between Groups, Adjusted for Baseline Levels

Table 3:

Comparison of Changes From Baseline Between Groups, Adjusted for Baseline Levels

Best-Corrected Visual Acuity

Mean BCVA were similar between the two groups throughout the duration of the study (Table 3). Additionally, no patients in the IAI group and three (20%) patients in the sham group experienced a BCVA decrease of more than 5 letters from the Day 7 postoperative visit at any subsequent visit that was due to retinal thickening (Figure 2D).

At 3 months, there was no difference in the number of patients who gained 15 letters or more from baseline between the IAI and sham injection groups (27% vs. 20%). No patients in either group experienced a loss of 15 letters or more. Similarly, there was no difference in patients who were 20/40 or better (both 14 patients [93%]) and no patients in either group who were 20/200 or worse at any point in the study.

Discussion

Results of this study demonstrate that IAI following cataract surgery is safe. Although there were significant differences in ME incidence and retinal thickness at periods of time, there was no clinically meaningful benefit in terms of VA at the end of the study. Given that the peak incidence of ME after cataract surgery occurs at 4 to 6 weeks after surgery,2 our anatomic data support prophylactic IAI following cataract surgery may be protective against the development of ME but the visual outcomes do not.

When examining the three criteria for ME separately, there were no patients in the IAI group and five patients in the sham injection group who developed a 30% or greater increase in CST at Day 60, which was statistically significant. As mentioned previously, there is significant rationale for using this as an objective measure of ME following cataract surgery. Compared to the sham injection group, the IAI group also had significantly smaller CST increases relative to baseline at the postoperative Day 30 and Day 60 visits, and smaller MV increases at the Day 60 visit. The association between treatment with IAI and reduction in CST increase suggests that IAI may have reduced the leakage of fluid from perifoveal capillaries into the extracellular space of the macular region following cataract surgery. In the VISTA and VIVID studies, patients with DME who received IAI achieved statistically significant improvements from baseline CST when dosed either monthly or at every 2 months.25 In this study, the lack of difference at Day 90 was due to a significant increase in CST in the IAI group, and may reflect the need for additional treatments in the early period following cataract surgery to maintain protective effects. The prospective trials by Chae et al. and Khodabandeh et al., which studied the use of prophylactic ranibizumab and bevacizumab, respectively, similarly observed significant changes in CST from baseline at 30 days but not at 90 days.17,26

These findings were consistent with studies that utilized prophylactic corticosteroids or NSAIDs during cataract surgery, albeit that the NSAID was given for 90 days.12,23 In two trials reported by Singh et al., patients who received prophylaxis nepafenac 0.3% for the 90-day trial duration had significantly fewer ME events and anatomic changes.12 Topical corticosteroids and NSAIDs are currently available for the treatment or prevention of postoperative inflammation and ME. However, eye drop regimens are often associated with patient nonadherence as treatment regimens are often complex, leading to patients frequently applying only half of the prescribed number of postoperative drops.28 There is the risk for corneal thinning, erosion, delayed wound healing, ulceration, and perforation with NSAID use in patients with compromised corneas, who may benefit instead from prophylactic IAI.29 Although the efficacy of steroid treatments in ME prevention have been demonstrated across multiple clinical studies, there is safety concern that intraocular pressure (IOP) increases with the use of corticosteroid drops30 or intravitreal injection of triamcinolone acetonide.15,27 No eyes had a significant increase of IOP postoperatively in this study, suggesting that prophylactic IAI may be a potential alternative for individuals who develop increased IOP with steroid use.

Although the immediate similar gain in BCVA letters between the two groups at Day 30 may be due to the cataract surgery, there was further improvement at Day 60 in the IAI group but not in the sham group. Some of the VA improvements were lost at Day 90 in the IAI group, which was consistent with the anatomical findings and further supports the need for additional treatment in the months following cataract surgery. In two of the three patients who lost more than 5 letters from the postoperative Day 7 visit, this loss was due to the development of CME, and all three patients had increased CST following cataract surgery. Notably, Chae et al. similarly found that patients who received intravitreal ranibizumab injections did not have significantly greater BCVA improvements by 3 months.17 However, they found a significant difference in VA improvement by 6 months after surgery, which they proposed could be due to long-term protective effects mediated by prevention of CME early on. This study unfortunately did not follow patients beyond 90 days.

Strength of this study was its prospective and randomized design, which decreased confounding and selection bias. Limitations for this study included the small sample size and low incidence rates of individual ME criteria, use of only a single injection, and the relatively short duration of study, which does not evaluate long-term effects of IAI.

In conclusion, a single IAI during cataract surgery appears to be safe and can potentially decrease the development of ME in patients with DR. Further investigation with administration of multiple injections, longer follow-up and larger series of patients is needed to further validate these findings.

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Baseline and Demographic Characteristics

DemographicsBaseline

IAISham Injection

  Eyes1515
  Average age at screening6666
  Age range (years)53–8047–80
  Males95
  Females610
  Initial HbA1C (mean ± SD)8.3 ± 2.648.7 ± 1.91

ETDRS Scores: Average (Range)
  Study eye70.1 (50–81)69.2 (41–84)

Diabetic Retinopathy Severity
  Mild55
  Moderate45
  Severe11
  Inactive PDR54

OCT Values: Average (Range)
  CST262.8 (211–310)251.4 (218–309)
  Cube volume9.6 (8.3–10.6)9.9 (8.4–11.1)

Summary of Adverse Events

Aflibercept (n = 15)Sham (n = 15)

At Least One Ocular TEAE10 (67%)11 (73%)
At Least One Non-Ocular TEAE3 (20%)5 (33%)

Any Serious AE
  Paracentesis2 (13%)0 (0%)
  Cough/vomiting1 (7%)0 (0%)
  Rash/swellling on limbs0 (0%)2 (13%)

Most Frequent AEs
  Foreign body sensation in eye3 (20%)3 (20%)
  Corneal edema1 (7%)0 (0%)
  Eye irritation/pain2 (13%)2 (13%)
  Eye itching2 (13%)1 (7%)
  Lacrimation increased1 (7%)1 (7%)
  Vision blurred2 (13%)4 (27%)
  Photophobia0 (0%)3 (20%)
  Floaters2 (13%)4 (27%)

Comparison of Changes From Baseline Between Groups, Adjusted for Baseline Levels

FactorTimeIAI (95% CI)IAI Change, P ValueaSham (95% CI)Sham Change, P ValueaDifference, P Valuea

CST307.95 (−9.66,25.56).3750.05 (14.22,85.88).007.040
603.02 (−14.59,20.62).7356.45 (20.62,92.28).003.010
9018.48 (0.87,36.09).04050.32 (14.49,86.15).007.12

MV300.63 (0.30,0.95)< .0011.21 (0.55,1.87)< .001.12
600.55 (0.22,0.87).0011.21 (0.55,1.87)< .001.078*
900.51 (0.19,0.84).0021.11 (0.45,1.77).001.11

ETDRS307.68 (3.34,12.02)< .0016.12 (1.86,10.38).006.61
6011.08 (6.74,15.42)< .0016.19 (1.92,10.45).005.11
909.88 (5.54,14.22)< .0018.52 (4.26,12.78)< .001.66
Authors

From Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (WS); the Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio (TFC, FFC, FQS, RPS); Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio (TFC, RG, FFC, FQS, RPS); All Eyes Consulting, LLC, New York, New York (NS); and Case Western Reserve University School of Medicine, Cleveland, Ohio (RPS).

Supported by a research grant from Regeneron Pharmaceuticals.

Dr. Saroj has received personal fees from Aerie, Adverum, Apellis, Regeneron, and RegenxBio; personal fees and other funding from Allegro and SamaCare; and other funding from Pr3vent outside the submitted work. Dr. Singh has received personal fees from Regeneron Pharmaceuticals, Genentech/Roche, Optos, Alcon/Novartis, Zeiss, and Bausch + Lomb, as well as grants from Apellis, outside the submitted work. The remaining authors report no relevant financial disclosures.

Dr. Singh did not participate in the editorial review of this manuscript.

Address correspondence to Rishi P. Singh, MD, Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, Mail Code i-32, Cleveland, OH 44195; email: singhr@ccf.org.

Received: July 31, 2019
Accepted: December 09, 2019

10.3928/23258160-20200228-06

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