Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Impact of Time to Anti-Vascular Endothelial Growth Factor Intervention on Visual Outcomes for Patients Diagnosed With Retinal Vein Occlusion

Jessica Hsueh, BS; Karen M. Wai, MD; Felipe F. Conti, MD; Thais F. Conti, MD; Rishi P. Singh, MD

Abstract

BACKGROUND AND OBJECTIVES:

To analyze the impact of time to treatment with anti-vascular endothelial growth factor (VEGF) for patients with macular edema (ME) secondary to retinal vein occlusions (RVO) in routine clinical practice.

PATIENTS AND METHODS:

One hundred fifty-five eyes with ME secondary to RVO were identified. Patients were divided into initiation of anti-VEGF treatment at 28 days or fewer after symptom onset (Group A), between 28 and 84 days (Group B), and 84 days or more (Group C).

RESULTS:

A significant central subfield thickness (CST) decrease at 12 months was observed in Groups A, B, and C (−184.14 µm, −204.55 µm, and −170.71 µm, respectively; P < .001). At 12 months, Groups A and B showed significant BCVA improvement (19.14 and 21.11, respectively; P ≤ .001), whereas Group C showed no significant improvement from baseline (4.01; P < .28).

CONCLUSIONS:

Anatomical response as measured by CST did not differ between groups, whereas delays in treatment resulted in smaller BCVA improvement with anti-VEGF treatment.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:832–837.]

Abstract

BACKGROUND AND OBJECTIVES:

To analyze the impact of time to treatment with anti-vascular endothelial growth factor (VEGF) for patients with macular edema (ME) secondary to retinal vein occlusions (RVO) in routine clinical practice.

PATIENTS AND METHODS:

One hundred fifty-five eyes with ME secondary to RVO were identified. Patients were divided into initiation of anti-VEGF treatment at 28 days or fewer after symptom onset (Group A), between 28 and 84 days (Group B), and 84 days or more (Group C).

RESULTS:

A significant central subfield thickness (CST) decrease at 12 months was observed in Groups A, B, and C (−184.14 µm, −204.55 µm, and −170.71 µm, respectively; P < .001). At 12 months, Groups A and B showed significant BCVA improvement (19.14 and 21.11, respectively; P ≤ .001), whereas Group C showed no significant improvement from baseline (4.01; P < .28).

CONCLUSIONS:

Anatomical response as measured by CST did not differ between groups, whereas delays in treatment resulted in smaller BCVA improvement with anti-VEGF treatment.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:832–837.]

Introduction

Retinal vein occlusion (RVO) is the second most common cause of retinal vascular disease, with an estimated incidence of 180,000 affected eyes per year in the United States.1 The pathogenesis of visual impairment in RVO is not entirely understood but may result from a multitude of factors, including retinal ischemia, hemorrhage, and macular edema (ME). ME is thought to be the predominant cause of recoverable vision loss in RVO.2 Anti-vascular endothelial growth factor (VEGF) therapy is now widely used in the management and treatment of RVO. It has been demonstrated that anti-VEGFs are effective for macular edema secondary to branch RVO (BRVO) and central RVO (CRVO).3,4,5 A number of phase 3, multicenter clinical studies have been critical in establishing anti-VEGF therapy for RVO. The COPERNICUS and GALILEO studies showed that monthly injections of aflibercept (Eylea; Regeneron, Tarrytown, NY) for patients with ME secondary to CRVO resulted in significantly improved visual acuity (VA) at 6 months.6,7 The BRAVO and CRUISE trials demonstrated that BRVO and CRVO patients who received monthly injections of ranibizumab (Lucentis; Genentech, South San Francisco, CA) experienced a higher mean improvement in letters compared to patients receiving sham injections.8,9

Further post hoc analysis of anti-VEGF clinical trials demonstrated that a 6-month treatment delay in the sham treatment group was associated with reduced VA outcomes in comparison to earlier treatment groups.3,6,7 However, the study design of the aforementioned clinical trials may have allowed for a treatment delay well beyond 6 months for the sham groups. The sham group in each trial was used to analyze the impact of time to treatment on VA compared to earlier treatment groups. In the COPERNICUS and GALILEO studies, CRVO patients diagnosed within 9 months were included, and in the BRAVO and CRUISE trails, patients with ME secondary to BRVO and CRVO who were diagnosed within 12 months were included. Additionally, there was a 28-day screening period for the BRAVO and CRUISE trails. The inclusion criteria in both BRAVO and CRUISE created a potential 13-month delay between diagnosis and treatment, not including time between symptom onset and diagnosis. Thus, it remains unclear what the impact of delayed time to treatment is on visual outcomes.

Anti-VEGFs are the first-line treatment for patients with ME in the setting of RVO. Rigid treatment regimens and inclusion and exclusion criteria used in randomized clinical trials are impracticable in real-world environments. Given that patients in routine clinical practice might manifest with different outcomes than those enrolled in clinical studies, it is worthwhile to examine if there is a relationship between time to treatment initiation on long-term visual outcomes in real-world clinical settings. This retrospective study analyzes the impact of time to treatment with anti-VEGF agents on long-term visual outcomes for patients with RVO in routine clinical practice. The purpose of this study is to capture a better understanding of when to begin anti-VEGF treatment in the management and treatment of patients with ME secondary to RVO based on symptom onset.

Patients and Methods

Study Design

This retrospective study was performed at Cole Eye Institute, Cleveland, Ohio, after receiving approval from the Cleveland Clinic Investigational Review Board. A comprehensive chart review was performed to assess ophthalmic data. All study-related procedures were performed in accordance with good clinical practice (International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use [ICH] E6), applicable U.S. Food and Drug Administration regulations, and the Health Insurance Portability and Accountability Act.

Patients were included if the following variables were present in the electronic medical record (EMR): RVO ICD codes, date of diagnosis, symptom start date, initial treatment date, and anti-VEGF treatment (bevacizumab [Avastin; Genentech, South San Francisco, CA]; ranibizumab; or aflibercept). Patients were treated with a variety of treatment regimens based on physician preference, including pro re nata (PRN) or treat and extend (TAE). Patients were excluded if the EMR contained non-discrete descriptions of symptom onset (ie, “weeks” or “years”), or if patients had previous anti-VEGF, laser treatment, or pars plana vitrectomy. Patients missing central subfield thickness (CST) or best-corrected visual acuity (BCVA) values at two or more time points were excluded. Patients were also excluded if there was evidence of active confounding retinal or ocular disease such as proliferative diabetic retinopathy, age-related macular degeneration, macular hole, or amblyopia. Patients were divided into initiation of anti-VEGF treatment groups at 28 days or fewer after symptom onset, between 28 and 84 days, and 84 days or more. CST and BCVA values were evaluated at 3 months, 6 months, and 12 months after initial treatment.

The main outcome measures were change in BCVA and change in CST at 3, 6, and 12 months of anti-VEGF treatment. BCVAs were recorded and converted from Snellen to approximate Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores for statistical analyses using the formula: ETDRS letter score = 85+50 × log (Snellen fraction).10

Data Collection and Analysis

Symptom onset; date of diagnosis; date of first treatment; and dates of 3-month, 6-month, and 12-month treatments (± 1 month) were collected from the EMR. CST and BCVA were retrieved at diagnosis and all subsequent visits. CST and BVCA values at baseline and each time point were analyzed using an unpaired two-tailed t-test with Welch's correction. CST decrease from baseline between groups was analyzed using a one-way analysis of variance with Dunn's multiple comparison test and BVCA improvement from baseline was analyzed using an unpaired two-tailed t-test with Welch's correction. All calculations were performed using GraphPad Prism software version 6.00 (GraphPad Software, San Diego, CA).

Results

Demographics and Baseline Diseases Characteristics

Two hundred thirty-five patients from January 2011 to December 2015 were identified at a single academic institution. Based on a review of previously obtained medical records, 155 eyes were identified with symptom onset recorded, 14 (9.0%) with HRVO, 67 (43.2%) with BRVO, and 74 (47.7%) with CRVO. When divided into initiation of anti-VEGF treatment groups, 72 patients (46.4%) were included in Group A (≤ 28 days), 43 patients (27.7%) in group B (between 28 to 84 days), and 40 patients (25.8%) in group C (≥ 84 days). Of group A patients, eight (11.1%) presented with HRVO, 27 (37.5%) with BRVO, and 37 with (51.4%) CRVO. Among the patients in Group B, one (2.3%) showed HRVO, 24 patients (55.8%) demonstrated BRVO, and 18 patients (41.9%) had CRVO. Five (12.5%) patients from Group C presented HRVO,16 (40.0%) BRVO, and 19 (47.5%) CRVO.

Patients' baseline demographics were balanced between groups. The average patient age for Groups A, B, and C was 67, 70, and 72 years, respectively (P = .08; Table 1). Average time to treatment for Groups A, B, and C was 15.4, 52.9, and 346 days, respectively (P < .001; Table 1). Baseline CST for Groups A, B, and C was 484.15 µm ± 179.26 µm, 484.21 µm ± 151.08 µm, and 490.90 µm ± 134.45 µm, respectively (P = .97; Table 1). Baseline ETDRS for Groups A, B, and C was 50.33 letters ± 23.40 letters, 46.35 letters ± 26.97 letters, and 58.37 letters ± 15.48 letters, respectively (P = .12; Table 1). Average injections during the course of 12 months for Groups A, B, and C was 6.87 ± 2.79, 6.50 ± 2.74, and 6.25 ± 2.88 injections (P = .98, Table 1). Of the 72 patients in Group A, the rate of bevacizumab, ranibizumab, and aflibercept at the very first injection was 64 eyes (88.9%), seven eyes (9.7%), and one eye (1.4%), respectively. Of the 43 patients in Group B, the rate of bevacizumab, ranibizumab, and aflibercept at the very first injection was 35 eyes (81.4%), seven eyes (16.3%), and one eye (2.3%), respectively. Of the 40 patients in group C, the rate of bevacizumab, ranibizumab, and aflibercept at the very first injection was 33 eyes (82.5%), six eyes (15.0%), and one eye (2.5%), respectively.

Baseline Characteristics of Patients Diagnosed With RVO

Table 1:

Baseline Characteristics of Patients Diagnosed With RVO

Visual Outcomes

Completeness of follow-up at 12 months was variable between groups for both CST and BVCA outcome measures. Fifty-one of 72 patients (70.8%) in Group A, 24 of 42 patients (57%) in Group B, and 31 of 40 (77.5%) patients in Group C had CST outcomes measured at 12 months of treatment. Fifty-three of 72 patients (73.6%) in Group A, 24 of 42 patients (57%) in Group B, and 30 of 40 patients (75.0%) in Group C had BVCA outcomes measured at 12 months.

There was a significant CST decrease from baseline during the course of 12 months for all groups (P < .001; Table 2). However, there was no significant difference in CST decrease between groups (−184.14 µm ± 265.01 µm, −204.55 µm ± 208.44 µm, and −170.71 µm ± 162.77 µm for groups A, B, and C; P = .85; Table 3). Groups A and B showed significant BVCA improvement from baseline during the course of 12 months (P < .001 and P = .001, respectively; Table 2). There was no significant difference in BVCA improvement between Groups A and B (19.14 letters ± 24.58 letters and 21.11 letters ± 24.04 letters; P = .39; Table 3). There was no significant BVCA improvement from baseline at 12 months in Group C (P = .28, Table 2). The mean BVCA improvement in Group C at 12 months was 4.01 letters ± 17.09 letters (Table 3).

CST and ETDRS Values at 3, 6, and 12 Months With Anti-VEGF Treatment

Table 2:

CST and ETDRS Values at 3, 6, and 12 Months With Anti-VEGF Treatment

Change in CST and ETDRS at 3, 6, and 12 Months With Anti-VEGF Treatment

Table 3:

Change in CST and ETDRS at 3, 6, and 12 Months With Anti-VEGF Treatment

Discussion

Previous clinical trials have shown that earlier treatment of RVO 6 months from diagnosis allows for significant long-term improvement in CST and BVCA.3,6,7 In this study, we retrospectively examined the impact of time between symptom to anti-VEGF treatment on VA for ME secondary to RVO. Patients in Group C (average time to treatment = 346 days) had non-significant improvement in their VA after 12 months of anti-VEGF treatment compared to significant gain of 19.14 letters and 21.11 letters in Group A (average time to treatment = 15 days) and Group B (average time to treatment = 53 days), respectively.

Patients treated for longer than 84 days after symptom onset (Group C) were initially able to show meaningful BVCA response to anti-VEGF agents at month 3 compared to baseline (P = .001) but did not have clinically meaningful or statistically significant visual gains at 12 months. It is unclear how to explain this trend, but the lack of statistically significant improvement (4.01 letters; P = .28) and relatively large standard deviation (±17.09 letters) in month 12 may be due to the wide range of RVO severity in Group C. The patients in Group C ranged from 14 weeks to 260 weeks of symptom onset to treatment. It is possible that a higher subset of these patients had ischemic RVOs due to the chronicity of their disease; however, only a minority of patients received fluorescein angiography at diagnosis to confirm ischemia and, thus, we were unable to run further analysis.

The findings from this retrospective study complement the post hoc analysis of prior clinical trials which show a delay of treatment from diagnosis is associated with reduced visual outcomes compared to immediate treatment.3 Similar to previous studies analyzing impact of later treatment (> 6 months) from diagnosis, this study shows that later anti-VEGF treatment from symptom onset is not associated with significant increase in BCVA. In the COPERNICUS,6 GALILEO,7 and CRUISE9 studies, none of the VA parameters in the sham group ever approached the improvements seen in patients with earlier treatment.

Previous clinical studies do not account for the time between symptom onset to treatment, only time from diagnosis or enrollment to treatment. Because it is unclear what the average time between symptom onset to treatment is of patients enrolled in previous clinical studies, it is difficult to conduct a side-by-side comparison of this study's results on reduced CST and improved BVCA to previous studies. Based on our findings from routine clinical practice, it appears that patients can be treated with anti-VEGFs even a year after symptom onset and still be able to achieve significant long-term decrease in CST. Further studies with large sample sizes to compare different symptom to treatment time points are needed to confirm this. Additional data analyzing the impact of time between symptom to treatment on visual outcomes will be more relevant to clinical settings compared to impact of time between diagnosis and treatment.

This study is subject to recall bias as symptom onset recorded in the EMR was based on patient history, and it was assumed that symptom onset is directly related to the onset of RVO. Another drawback is that accuracy of BCVA measurements is subject to human error. One complication of retrospective studies is that patient retention rate may decrease over time, as seen in the current study. All subsequent calculations accounted for patients lost to follow up and only average CST and ETDRS values of the remaining patients were used for comparison purposes. Furthermore, although ranibizumab, bevacizumab, and aflibercept were used to treat a variety of patients, ranibizumab and bevacizumab were overrepresented due to the time period of this study. Small retrospective studies have shown that ranibizumab and bevacizumab produce similar anatomic and visual outcomes.11 Additionally, a multicenter, randomized clinical trial for RVO showed that there were no significant differences between aflibercept and bevacizumab.12 Lastly, individual analyses for each anti-VEGF drug were not possible due to small sample sizes.

In clinical practice, patients presenting with symptoms due to RVO may benefit from anti-VEGF injections soon after diagnosis. Though ME has thought to be the culprit of vision loss in RVO, there are few data to definitively show reduced CST is associated with improved BCVA.3 This finding is likely more relevant to patients with a delay in onset of treatment as they have significantly reduced CST but no significant improvement in BVCA at 12 months of treatment. Further studies are needed to assess whether reducing CST is directly related to BCVA in the context of RVO. Other anatomical parameters may include studying ellipsoid zone integrity to explain why patients with long-standing RVOs may not have as robust improvements in VA. Previous studies have linked baseline ellipsoid zone integrity with presenting VA in eyes in RVO,14 and perhaps mapping the ellipsoid zone can provide further information on overall visual outcomes.

Although the anatomical response as measured by CST did not differ between groups, smaller BCVA improvements were related with longer time to treatment with anti-VEGF agents for patients with macular edema and RVO in routine clinical practice. It is unclear still if patients with longstanding symptoms will be able to benefit from anti-VEGFs to the same degree as patients with more recent symptoms. The results indicate that patients who present with recent RVO symptoms and who are treated sooner were able to attain significant CST reduction and BCVA improvement.

References

  1. Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: The Beaver Dam Eye Study. Arch Ophthalmol. 2008;126(4):513–518. doi:10.1001/archopht.126.4.513 [CrossRef]
  2. Noma H, Funatsu H, Yamasaki M, et al. Pathogenesis of macular edema with branch retinal vein occlusion and intraocular levels of vascular endothelial growth factor and interleukin-6. Am J Ophthalmol. 2005;140(2):256–261. doi:10.1016/j.ajo.2005.03.003 [CrossRef]
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  14. Banaee T, Singh RP, Champ K, et al. Ellipsoid zone mapping parameters in retinal venous occlusive disease with associated macular edema. Ophthalmol Retina. 2018;2(8):836–841. doi:10.1016/j.oret.2017.11.009 [CrossRef]

Baseline Characteristics of Patients Diagnosed With RVO

GroupsHRVOBRVOCRVOTotal
  Group A: ≤ 28 days8 (11.1%)27 (37.5%)37 (51.4%)72 (100%)
  Group B: Between 28 to 84 days1 (2.3%)24 (55.8%)18 (41.9%)43 (100%)
  Group C: ≥ 84 days5 (12.5%)16 (40.0%)19 (47.5%)40 (100%)
Total146774155

Time to TreatmentMean (Days) ± SD, Range, Median, Mode
  Group A15.38 ± 9.07, 3 to 38, 14, 4
  Group B52.98 ± 25.61, 29 to 84,49, 35
  Group C346.03 ± 368.11, 98 to 1,825, 168, 168

Sex
N (%)
  Male75 (48.39%)
  Female80 (51.61%)
AgeBaseline CSTBaseline ETDRSTotal No. of Injections at 365 Days of TreatmentRate of Bevacizumab, Ranibizumab, Aflibercept at First Injection
Mean (Years) ± SD, RangeMean (CST) ± SDMean (ETDRS) ± SDMean (Injections) ± SD, nBevacizumab (Avastin)Ranibizumab (Lucentis)Aflibercept (Eylea)Total
Group A66.56 ± 12.65, 37–93484.15 ± 179.2650.33 ± 23.406.87 ± 2.79 (n = 52)64 (88.9%)7 (9.7%)1 (1.4%)72 (100%)
Group B70.23 ± 11.86, 41–91484.21 ± 151.0846.35 ± 26.976.50 ± 2.74 (n = 26)35 (81.4%)7 (16.3%)1 (2.3%)43 (100%)
Group C71.65±11.02, 43–89490.90±134.4558.37±15.486.25±2.88, (n=36)33 (82.5%)6 (15.0%)1 (2.5%)40 (100%)
P Value.08.97.12.98

CST and ETDRS Values at 3, 6, and 12 Months With Anti-VEGF Treatment

Length of Anti-VEGF Treatment
CST Values3 Months6 Months12 Months
Mean ± SD, n, P ValueMean ± SD, n, P ValueMean ± SD, n, P Value
  Group A391.96 ± 387.90, 68, .08316.01 ± 94.25, 72, < .001323.76 ± 161.18, 51, < .001
  Group B333.67 ± 118.59, 42, < .001283.47 ± 80.15, 41, < .001287.04 ± 154.16, 24, < .001
  Group C341.75 ± 108.37, 40, < .001350.03 ± 118.17, 39, < .001318.90 ± 128.45, 31, < .001

ETDRS Values3 Months6 Months12 Months
Mean ± SD, n, P ValueMean ± SD, n, P ValueMean ± SD, n, P Value
  Group A66.65 ± 18.23, 72, < .00166.91 ± 21.58, 72, < .00166.30 ± 18.36, 53, < .001
  Group B60.59 ± 26.62, 42, .0164.03 ± 23.54, 41, .00266.64 ± 19.77, 24, .001
  Group C68.88 ± 11.64, 40, .00164.62 ± 19.77, 40, .1263.01 ± 17.87, 30, .28

Change in CST and ETDRS at 3, 6, and 12 Months With Anti-VEGF Treatment

Length of Anti-VEGF Treatment
Negative Change in CST From Baseline3 Months6 Months12 Months
Mean ± SD, nP ValueMean ± SD, nP ValueMean ± SD, nP Value
  Group A91.66 ± 423.83, 68172.53 ± 203.55, 72184.14 ± 265.01, 51
  Group B143.84 ± 200.74, 42.58200.74 ± 173.27, 41.32204.55 ± 208.44, 24.85
  Group C143.90 ± 118.88, 40137.76 ± 158.94, 39170.71 ± 162.77, 31

Positive Change in ETDRS From Baseline3 Months6 Months12 Months
Mean ± SD, nP ValueMean ± SD, nP ValueMean ± SD, nP Value
  Group A16.10 ± 24.04, 7216.36 ± 26.49, 7219.14 ± 24.58, 53
  Group B14.23 ± 26.46, 42.3917.64 ± 31.00, 41.8221.11 ± 24.04, 24.39
  Group C10.51 ± 12.79, 406.26 ± 18.45, 404.01 ± 17.09, 30
Authors

From Case Western Reserve University School of Medicine, Cleveland (JH, KMW); Cole Eye Institute, Cleveland Clinic Foundation, Cleveland (FC, TC, RPS); and the Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland (FC, TC, RPS).

This study was presented at the 2018 Association for Research in Vision and Ophthalmology Annual Meeting in Hawaii.

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.

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

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

Received: March 14, 2018
Accepted: October 02, 2018

10.3928/23258160-20181101-03

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