Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Baseline Ocular Characteristics of Patients Undergoing Initiation of Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema

Waseem H. Ansari, MD; Michael M. Han, BS; Siraj Haq, BS; Felipe F. Conti, MD; Fabiana Q. Silva, MD; Rishi P. Singh, MD

Abstract

BACKGROUND AND OBJECTIVES:

Patients with diabetic macular edema (DME) have variable anatomic and visual responses to anti-vascular endothelial growth (VEGF) treatments based on their presenting visual acuity (VA). The aim of study is to report the baseline ocular and imaging characteristics of patients presenting with DME who were treatment-naïve and who initiated anti-VEGF in routine clinical practice.

PATIENTS AND METHODS:

Single-center, cross-sectional study of 638 patients. Subjects were divided into two VA groups: Early Treatment Diabetic Retinopathy Study (ETDRS) less than 70 and ETDRS greater than 70 and ocular variables were compared between groups.

RESULTS:

Average central subfield thickness (CST) was 363.5 μm, cube volume was 11.7 mm3, and cube average thickness (CAT) was 326.1 μm. Additionally, 21.5% had subretinal fluid (SRF), and 50.5% had hard exudates on presentation. Eyes with ETDRS less than 70 had greater CAT (338.5 μm3 vs. 313.2 μm3; P < .001), greater cube volume (12.2 mm3 vs. 11.3 mm3; P < .001), greater CST (383.5 μm vs. 350.0 μm; P < .001), and SRF (25.5% vs. 17.3%; P = .012). Furthermore, 7.64% had glaucoma, 1.3% had dry age-related macular degeneration, 4.5% of patients were vitrectomized, and 28.7% were pseudophakic. Regarding diabetic stage, 37% had proliferative diabetic retinopathy (PDR) and 63% presented with nonproliferative diabetic retinopathy. Patients presenting with ETDRS less than 70 were more likely to have a history of vitrectomy (7.1% vs. 1.9%, P = .002) and presence of PDR (42.3% vs. 31.4%, P = .004).

CONCLUSION:

The results describe a population of patients from a routine clinical practice not entirely represented in clinical trials, with key differences in ocular characteristics seen between VA groups.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:69–75.]

Abstract

BACKGROUND AND OBJECTIVES:

Patients with diabetic macular edema (DME) have variable anatomic and visual responses to anti-vascular endothelial growth (VEGF) treatments based on their presenting visual acuity (VA). The aim of study is to report the baseline ocular and imaging characteristics of patients presenting with DME who were treatment-naïve and who initiated anti-VEGF in routine clinical practice.

PATIENTS AND METHODS:

Single-center, cross-sectional study of 638 patients. Subjects were divided into two VA groups: Early Treatment Diabetic Retinopathy Study (ETDRS) less than 70 and ETDRS greater than 70 and ocular variables were compared between groups.

RESULTS:

Average central subfield thickness (CST) was 363.5 μm, cube volume was 11.7 mm3, and cube average thickness (CAT) was 326.1 μm. Additionally, 21.5% had subretinal fluid (SRF), and 50.5% had hard exudates on presentation. Eyes with ETDRS less than 70 had greater CAT (338.5 μm3 vs. 313.2 μm3; P < .001), greater cube volume (12.2 mm3 vs. 11.3 mm3; P < .001), greater CST (383.5 μm vs. 350.0 μm; P < .001), and SRF (25.5% vs. 17.3%; P = .012). Furthermore, 7.64% had glaucoma, 1.3% had dry age-related macular degeneration, 4.5% of patients were vitrectomized, and 28.7% were pseudophakic. Regarding diabetic stage, 37% had proliferative diabetic retinopathy (PDR) and 63% presented with nonproliferative diabetic retinopathy. Patients presenting with ETDRS less than 70 were more likely to have a history of vitrectomy (7.1% vs. 1.9%, P = .002) and presence of PDR (42.3% vs. 31.4%, P = .004).

CONCLUSION:

The results describe a population of patients from a routine clinical practice not entirely represented in clinical trials, with key differences in ocular characteristics seen between VA groups.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:69–75.]

Introduction

Diabetic macular edema (DME) is the most common cause for visual impairment in patients with diabetes.1 Retinal microvascular ischemia stimulates the release of vascular endothelial growth factors (VEGFs), which break down the blood-retinal barrier and allow the leakage of fluid into intraretinal spaces.2 Clinical trials have attempted to characterize the presentation of DME, but their strict inclusion and exclusion criteria limit the clinical practice applicability of their findings. A recent referenced paper from the Early Treatment Diabetic Retinopathy Study (ETDRS) Research Group found that 75% of patients had 20/40 or better acuity when they presented with DME, a population that is often excluded from clinical trials.3 Other reports are limited by low patient volumes.4,5 The baseline presentation of patients with DME in routine clinical practice based on their ocular findings is lacking.

Anti-VEGF treatment results improved visual and anatomic outcomes in diabetic macular edema.6–8 Protocol T by the Diabetic Retinopathy Clinical Research Network has shown that DME responds to treatment with intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA), intravitreal aflibercept injection (Eylea; Regeneron, Tarrytown, NY) (IAI), and ranibizumab (Lucentis, Genentech, South San Francisco, CA).9 However, the mean change in visual acuity (VA) primary outcome varied based on initial presenting baseline VA. IAI demonstrated superiority in patients with 20/50 or worse vision, whereas no difference was seen across treatment groups when the initial vision was 20/40 or better.9 These findings imply that DME may be a “blanket” term that encompasses different morphological and functional entities that respond differently to similar treatments.10 Thus, we will compare the two cohorts of our patient population in an attempt to elucidate ocular and imaging differences which may account for the varied response in treatment.

Patients and Methods

Data Collection

This study was performed at Cole Eye Institute in Cleveland, Ohio, after receiving approval from the Cleveland Clinic Investigational Review Board (IRB). All study-related procedures were performed in accordance with good clinical practice (International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use E6), applicable U.S. Food and Drug Administration regulations, and the Health Insurance Portability and Accountability Act. A retrospective chart review was performed to identify patients with DME who were initiating anti-VEGF treatment at a single institution from April 2012 to December 2016 (Cleveland Clinic, Cleveland, Ohio).

Study Participants

The study enrolled patients with a required age of 18 years or older and a diagnosis of type 1 or 2 diabetes, defined by glycated hemoglobin greater than 6.5 or historical or current use of hypoglycemics, receiving their first anti-VEGF for the treatment of DME (treatment-naïve for DME on study entry). Criteria also included characteristic findings of foveal-involving retinal edema based on clinical examination and spectral-domain optical coherence tomography (SD-OCT). Patients were excluded if the macular edema was not related to diabetes or for a history of any minor intraocular surgery, such as cataract extraction within 3 months of presentation. Baseline demographics and ocular comorbidities were recorded. Best-corrected presenting VA was collected, along with both quantitative and qualitative characteristics SD-OCT and patterns on fluorescein angiography (FA). Qualitative characteristics investigated on SD-OCT were hard exudates, tractional components to the macular edema, subretinal fluid, and epiretinal membrane (ERM). In patients in whom both eyes were eligible to be enrolled, only one was chosen at random. Widefield FA photography was performed with the Panoramic 200MA (Optos PLC, Dunfermline, Scotland), whereas SD-OCT B-scans were performed with Cirrus HD-OCT 4000 and 5000 (Carl Zeiss Meditec, Dublin, CA).

Statistical Methods

Categorical variables were described using frequencies and percentages, whereas continuous variables were described using means and standard deviations, medians and quartiles, and/or ranges. Relationships between categorical variables and ETDRS groups were assessed using Pearson Chi-square tests, Fisher's exact tests, or Kruskal-Wallis tests (for ordered variables), whereas relationships between continuous variables and ETDRS group were assessed using t-tests (for normally distributed variables) or Kruskal-Wallis tests (for non-normally distributed variables). Analyses were performed using SAS Software (version 9.4; SAS, Cary, NC).

Factors of interest were evaluated with both univariate and multicollinearity using variance inflation factors and condition indices. A multivariable logistic regression model was fit with ETDRS less than 70 as the response, with the key clinical factors as potential predictors. One patient with an aphakic lens was excluded from this analysis. Glaucoma was included as present versus not present. Results of the model are presented as odds ratios with 95% confidence intervals. A significance level of .05 was assumed for all tests.

Results

The study included 638 treatment-naïve patients classified as having DME requiring anti-VEGF treatment by the investigators (Table 1). Of these patients, 7.7% presented with a previous diagnosis of glaucoma. Subtypes included 61% of patients with primary open angle glaucoma, 12.2% of neovascular glaucoma, and 23% listed as other, which included pigmentary, traumatic, and chronic angle closure glaucoma. Additionally, overall, 1.3% of patients presented with a history of non-exudative age-related macular degeneration (NEAMD). There was no significant difference in prevalence of AMD between those presenting with ETDRS less than 70 and more than 70, 1.5% versus 0.96% (P = .73). Considering lens status in the overall cohort, 69.9% of patients presented were phakic, 29.9% were pseudophakic, and 0.16% aphakic. Lens status was also found to be of insignificance in correlation with baseline presenting VA.

Prevalence of Ocular Comorbidities and History Among All Patients and the Two Different VA Cohorts

Table 1:

Prevalence of Ocular Comorbidities and History Among All Patients and the Two Different VA Cohorts

When looking at the stage of diabetes in the overall cohort, 37.0% of patients presented with proliferative diabetic retinopathy (PDR), and 63% presented with non-proliferative diabetic retinopathy (NPDR). Patients with ETDRS less than 70 were more likely to have PDR compared to those who were ETDRS greater than 70 (42.3% vs. 31.4%, respectively; P = .004). Additionally, 31.3% of patients had a history of intraocular surgery, but there was no significant difference between ETDRS less than 70 and ETDRS greater than 70 (32.8 vs. 29.8, respectively; P = .41). Among patients, 4.5% had a history of vitrectomy, and it was much more likely to be found in patients presenting with ETDRS less than 70 (7.1% ETDRS < 70 vs. 1.9% ETDRS > 70; P = .002).

OCT demonstrated the average central subfield thickness (CST) on presentation was 363.3 μm. Patients presenting with ETDRS less than 70 were found to have a higher mean CST values than those with ETDRS greater than 70 (383.5 μm vs. 350 μm, respectively; P < .001) (Figure 1). Box-and-whisker plot representation of the data found a similar trend (Figure 2). Cube volume was 11.7 ± 1.9 mm3 and cube average thickness 326.1 ± 54.0 mm3. Similar to CST, those with higher values tended to present with ETDRS less than 70 rather than ETDRS greater than 70, 12.2 mm3 versus 11.3 mm3 for cube volume and 338 mm3 versus 313 mm3 for cube average thickness (CAT) (P ≤ .001 for both). Qualitative analysis revealed 50.4% of OCTs demonstrated hard exudates, 27.7% with a tractional component to the macular edema, 21.4% with subretinal fluid, and 20.8% with an ERM (Table 2). Between the two cohorts, only subretinal fluid was associated with the ETDRS less than 70 (P ≤ .012).

Percentage of patients on each central subfield thickness bracket when split into two different cohorts of Early Treatment Diabetic Retinopathy Study (ETDRS) letters: 70 or greater and less than 70.

Figure 1:

Percentage of patients on each central subfield thickness bracket when split into two different cohorts of Early Treatment Diabetic Retinopathy Study (ETDRS) letters: 70 or greater and less than 70.

Box plot demonstrating central subfield thickness on optical coherence tomography for all patients, and when split into two different cohorts of Early Treatment Diabetic Retinopathy Study (ETDRS) letters: 70 or greater and less than 70.

Figure 2:

Box plot demonstrating central subfield thickness on optical coherence tomography for all patients, and when split into two different cohorts of Early Treatment Diabetic Retinopathy Study (ETDRS) letters: 70 or greater and less than 70.

Results of Qualitative Analysis of OCT for All Patients and the Two Separate VA Cohorts

Table 2:

Results of Qualitative Analysis of OCT for All Patients and the Two Separate VA Cohorts

FA was present for 228 patients (35.7%). Analysis revealed the presence of cystoid leakage in 69.6%, diffuse leakage in 41.7%, and capillary ischemia in 40.5% of images (Table 3). Only capillary ischemia was found to be significantly associated with ETDRS less than 70 (P ≤ .041).

Results of FA for All Patients and the Two Separate VA Cohorts

Table 3:

Results of FA for All Patients and the Two Separate VA Cohorts

To eliminate the correlation among the factors associated with VA in DME eyes, a multivariate regression analysis was performed. The analysis showed that PDR, the presence of subretinal fluid, and history of vitrectomy were significant factors to having an ETDRS less than 70. The odds of someone with PDR having ETDRS less than 70 were 50% higher than the odds of a person with NPDR. Similarly, those with subretinal fluid and those with history of vitrectomy had significantly higher odds of ETDRS less than 70 than patients without these conditions, holding all other factors constant (Table 4).

Results From Multivariable Model for ETDRS < 70 (N = 637)

Table 4:

Results From Multivariable Model for ETDRS < 70 (N = 637)

Discussion

A series of recent anti-VEGF treatment trials has revolutionized the treatment of DME. This retrospective study presents a large characterization of patients with DME who received anti-VEGF in routine clinical practice. By separating patients into two cohorts by their VA as done in Protocol T, significant risk factors between the two population groups were identified that may be associated with this VA on presentation.

The prevalence of NEAMD in our patient group was 1.3%. This number is likely on par with the prevalence in the normal population. One study estimated the prevalence of AMD in the 50- through 54-year-old range at 0.20% and at 1.52% of those aged 70 through 74. The mean age of the population in this study is 63.1.11 Overall prevalence of glaucoma was 7.6%, a number much higher than the reported prevalence in the U.S. of 2.1% to 2.5%.12,13 Studies have previously identified diabetes mellitus as an independent risk factor for glaucoma.14 Further inquiry is warranted. No significant differences were identified between the two VA cohorts of NEAMD and glaucoma. Unfortunately, NEAMD was only present in eight patients, and a higher number of patients with NEAMD will likely be required to evaluate this relationship.

No significant differences were identified between the two VA cohorts regarding lens status. Diabetic patients undergoing cataract extraction have a higher risk of developing macular edema after surgery.15 Due to the inclusion criteria, these patients would not have been included within this study. No difference was found between patients with different lens statuses or patients who had any history of intraocular surgery except vitrectomy. Patients with a history of vitrectomy were more likely to present with VA ETDRS less than 70. Multiple studies have suggested the use of early vitrectomy for treatment of tractional DME and PDR.16,17 The results in this study suggest that a history of vitrectomy was associated with poorer presenting VA. This result warrants further evaluation as they may strictly represent confounding due to various other ocular conditions warranting surgery.

It has historically been difficult to draw correlations with OCT data and VA in patients with DME, or edema of any origin. A study by the Diabetic Retinopathy Clinical Research Network found modest correlation between center point retinal thickness on OCT versus VA with a correlation coefficient at 0.52 at presentation. However, they demonstrated that a wide range of acuity may be observed for a given degree of retina edema, and thus, OCT cannot act as a surrogate for VA testing.18 Other studies have supported this modest correlation between retinal thickness and VA.19 In this patient population, patients presenting with ETDRS less than 70 were all significantly more likely to have a higher CST, a higher cube volume, and a higher CAT on OCT. This study presents further evidence that increased retinal thickness on OCT is associated with a worse VA on presentation. Additionally, patients with ETDRS less than 70 were more likely to present with subretinal fluid. This finding is contrary to other studies that have found no correlation between subretinal fluid and VA; however, these were smaller studies enrolling fewer than 70 patients.20

FA demonstrated that patients with ETDRS less than 70 were more likely to have capillary ischemia on presentation. Macular ischemia has been associated with vision loss in patients with diabetes previously and is associated with damage to the foveal ganglion cell layer.21,22 This study further provides evidence that those with macular ischemia are more likely to have worse VA on presentation. On the contrary, leakage, whether diffuse or cystoid had no bearing on presenting VA. However, other studies have found that leakage on FA may affect VA.23 This study may be limited by the fact that FA was only ordered on 35.7% of the patient database and there may be a self-selection bias, due to more severe presentations or questionable presentations based on fundus examination triggering the physician to order an FA. Further investigation into a study which standardizes the use of FA is warranted.

This study has advantages in its large number of subjects and consistent and standardized imaging data with OCT. Additionally, it has a less stringent inclusion criteria reflecting routine clinical practice. The data reviewed were collected over many years, which presents a more modern viewpoint into the DME than previous studies. Weaknesses include the retrospective nature of the study, the limit to only one study center for patient data collection, and low number of patients with access to FA.

In conclusion, the results here represent a population of patients from routine clinical practice not entirely represented in clinical trials due to less stringent inclusion and exclusion criteria. It also is different from DME prevalence studies by only evaluating those who are severe enough to warrant anti-VEGF initiation. In this scenario, it was found 51% of patients were ETDRS less than 70 and 49% of patients were ETDRS greater than 70 and that retinal thickness on OCT, presence of subretinal fluid, capillary ischemia on FA, history of vitrectomy, and advanced stages of diabetic retinopathy were all associated with ETDRS less than 70.

References

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Prevalence of Ocular Comorbidities and History Among All Patients and the Two Different VA Cohorts

OverallETDRS < 70ETDRS ≥ 70P Value

(N = 638)(N = 326)(N = 312)

Lens Status.51
  Aphakic1 (0.16%)1 (0.31%)0 (0.0%)
  Phakic446 (69.9%)224 (68.7%)222 (71.2%)
  Pseudophakic191 (29.9%)101 (31.0%)90 (28.8%)

Stage of Retinopathy.004
  NPDR402 (63.0%)188 (57.7%)214 (68.6%)
  PDR236 (37.0%)138 (42.3%)98 (31.4%)

Glaucoma.32
  Neovascular6 (0.94%)5 (1.5%)1 (0.32%)
  Other13 (2.0%)8 (2.5%)5 (1.6%)
  Primary open angle30 (4.7%)17 (5.2%)13 (4.2%)
NEAMD8 (1.3%)5 (1.5%)3 (0.96%).73
History of vitrectomy29 (4.5%)23 (7.1%)6 (1.9%).002

Results of Qualitative Analysis of OCT for All Patients and the Two Separate VA Cohorts

OverallETDRS < 70ETDRS ≥ 70P Value
(N = 638)(N = 326)(N = 312)
Subretinal Fluid (%)137 (21.5%)83 (25.5%)54 (17.3%).012
Tractional Component (%)102 (16.0%)46 (14.1%)56 (17.9%).19
Epiretinal Membrane (%)110 (17.2%)65 (19.9%)45 (14.4%).065
Hard Exudates (%)322 (50.5%)163 (50.0%)159 (51.0%).81

Results of FA for All Patients and the Two Separate VA Cohorts

OverallETDRS < 70ETDRS ≥ 70P Value
(N = 228)(N = 97)(N = 131)
Cystoid Leakage117 (69.6%)70 (72.2%)47 (66.2%).41
Diffuse Leakage68 (41.7%)40 (43.0%)28 (40.0%).70
Capillary Ischemia66 (40.5%)44 (47.3%)22 (31.4%).041

Results From Multivariable Model for ETDRS < 70 (N = 637)

FactorOR (95% CI)P Value
Phakic lens: Yes vs. No1.06 (0.74, 1.53).75
PDR: Yes vs. No1.50 (1.08, 2.10).017
Glaucoma: Yes vs. No1.32 (0.72, 2.40).37
Subretinal fluid: Yes vs. No1.74 (1.18, 2.57).006
Tractional macula: Yes vs. No0.83 (0.53, 1.28).39
ERM on OCT: Yes vs. No1.44 (0.93, 2.21).098
Hard exudates: Yes vs. No0.97 (0.71, 1.34).87
History of vitrectomy: Yes vs. No3.64 (1.42, 9.33).007
Authors

From Cole Eye Institute, Cleveland Clinic Foundation, Cleveland (WHA, FFC, FQS, RPS); Case Western Reserve University School of Medicine, Cleveland (MMH, SH, RPS); the Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland (FFC, RPS); and Federal University of São Paulo, São Paulo, Brazil (FFC).

Portions of the study were funded by an unrestricted research grant from Regeneron Pharmaceuticals.

Dr. Singh has received grants and personal fees from Regeneron Pharmaceuticals, Genentech / Roche, and Alcon / Novartis; grants from Apellis; and personal fees from Optos, Zeiss, and Biogen during the conduct of the study. The remaining authors report no relevant financial disclosures.

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

The authors would like to acknowledge James Bena, lead Biostatistician at Cleveland Clinic Foundation, Cleveland, Ohio, for his help with 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: May 15, 2018
Accepted: November 02, 2018

10.3928/23258160-20190129-02

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