Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Intravitreal Ziv-Aflibercept in Patients With Diabetic Macular Edema Refractory to Intravitreal Bevacizumab

Nazanin Ebrahimiadib, MD; Alireza Lashay, MD; Hamid Riazi-Esfahani, MD; Sepideh Jamali, MD; Alireza Khodabandeh, MD; Mohammad Zarei, MD; Ramak Roohipoor, MD; Hassan Khojasteh, MD; Fatemeh Bazvand, MD; Mina Ojani, MD; Mojtaba Shahabinejad, MD; Mehdi Yaseri, PhD; Bobeck S. Modjtahedi, MD; Samaneh Davoudi, MD; Mohammad Riazi-Esfahani, MD

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate the efficacy of intravitreal ziv-aflibercept (IVZ) in patients with diabetic macular edema (DME) resistant to intravitreal bevacizumab (IVB).

PATIENTS AND METHODS:

This prospective study was conducted in patients with persistent DME. Patients were switched to IVZ no longer than 6 weeks after the last three consecutive monthly IVB treatments and monitored over a course of 12 weeks. Changes in best-corrected visual acuity (BCVA), central macular thickness (CMT), and macular volume on optical coherence tomography were compared.

RESULTS:

A total of 59 eyes (38 patients) were included. Mean BCVA improved from 0.84 to 0.71 logMAR (P = .001) after first IVZ treatment and remained significant. In a subgroup analysis, this significance was observed only in the group with baseline visual acuity of less than 20/50. Mean CMT decreased from 479 μm to 364 μm (P = .004) after the first IVZ injections and remained significant.

CONCLUSION:

IVZ may be best reserved for patients with persistent DME after initial failure with bevacizumab, with less likelihood for anatomic or functional improvement in those with mild persistent DME.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:145–151.]

Abstract

BACKGROUND AND OBJECTIVE:

To evaluate the efficacy of intravitreal ziv-aflibercept (IVZ) in patients with diabetic macular edema (DME) resistant to intravitreal bevacizumab (IVB).

PATIENTS AND METHODS:

This prospective study was conducted in patients with persistent DME. Patients were switched to IVZ no longer than 6 weeks after the last three consecutive monthly IVB treatments and monitored over a course of 12 weeks. Changes in best-corrected visual acuity (BCVA), central macular thickness (CMT), and macular volume on optical coherence tomography were compared.

RESULTS:

A total of 59 eyes (38 patients) were included. Mean BCVA improved from 0.84 to 0.71 logMAR (P = .001) after first IVZ treatment and remained significant. In a subgroup analysis, this significance was observed only in the group with baseline visual acuity of less than 20/50. Mean CMT decreased from 479 μm to 364 μm (P = .004) after the first IVZ injections and remained significant.

CONCLUSION:

IVZ may be best reserved for patients with persistent DME after initial failure with bevacizumab, with less likelihood for anatomic or functional improvement in those with mild persistent DME.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:145–151.]

Introduction

Diabetic macular edema (DME) affects 20% to 40% of patients with diabetes over a 10- to 20-year period and is a leading cause of vision loss globally.1 The first-line treatment in most practices for DME is anti-vascular endothelial growth factor (VEGF) therapy. Unlike ranibizumab (Lucentis; Genentech, South San Francisco, CA) and aflibercept (Eylea; Regeneron, Tarrytown, NY), bevacizumab (Avastin; Genentech, South San Francisco, CA) is used as an off-label medication for DME and represents a more cost-effective option.2 Aflibercept is a soluble decoy receptor that binds to circulating VEGF and comprises extracellular VEGF-binding domains (second domain of human VEGF receptor 1 and the third domain of VEGF receptor 2), which is fused to the Fc (constant) domain of human immunoglobulin G1 for stability. Aflibercept is specifically purified and formulated for intraocular injection and has a higher binding affinity to VEGF-A than bevacizumab or ranibizumab.3

Many clinicians initiate treatment with bevacizumab as a first-line agent given its comparable efficacy compared to ranibizumab and aflibercept and its more favorable cost profile; however, persistent DME is more common with bevacizumab than the other two agents.4,5 The management of patients with persistent DME represents a clinical challenge with many clinicians switching to a second anti-VEGF agent.

Ziv-aflibercept is an identical isomer of aflibercept, which was approved in 2012 by the U.S. Food and Drug Administration for the treatment of metastatic colorectal cancer that is refractory to oxiplatin (Eloxatin; Sanofi-Aventis, Bridgewater, NJ) chemotherapy.6,7 The possibility of compounding ziv-aflibercept represents a means to achieve the potential benefits of aflibercept's molecular profile while significantly mitigating costs. Due to its formulation in hypertonic sucrose, it has an osmolarity of 1,000 mOsm/kg, which is three-times higher than aflibercept.8,9 Despite concerns about hyperosmolarity of this substance, safety of intraocular injection of ziv-aflibercept (IVZ) has been shown in previous studies.6,10–12 These studies suggested that dilution in the vitreous volume may mitigate the risks of hyperosmolarity of the medication. Similar to aflibercept, ziv-aflibercept has a high affinity to VEGF-A and blocks placental growth factor and VEGF-B, as well.13

The efficacy of IVZ in the treatment of choroidal neovascular membranes, macular edema secondary to retinal vein occlusion, and DME has been previously explored.2,6,14–16 Most studies have examined IVZ in the management of treatment naïve patients. This study aims to examine the safety and outcomes of IVZ in patients with DME that is refractory to intravitreal bevacizumab (IVB).

Patients and Methods

This prospective nonmasked study was conducted at the Farabi Eye Hospital (Tehran, Iran) between October 1, 2017, and August 1, 2018, on patients with visually significant DME with an incomplete response to IVB. Patients were defined as having refractory DME if they had less than 10% (or 50 μm) improvement in central macular thickness (CMT) after at least three consecutive monthly bevacizumab injections and if their CMT was still greater than 300 μm. Approval from Tehran University of Medical Science's institutional review board was obtained and the study adhered to the tenets of the Declaration of Helsinki.

Patients were excluded from this study if they had an uncontrolled glaucoma, uncontrolled diabetes (HbA1c > 10), uncontrolled blood pressure (systolic blood pressure > 160), a history of intraocular surgery in the preceding 6 months, active proliferative diabetic retinopathy, significant vitreomacular interface disorders, treatment with intravitreal or peri-bulbar corticosteroid during the prior 6 months, or retinal laser therapy during the prior 3 months. Additionally, monocular patients were excluded as were those who may require a pars plana vitrectomy in the future (such as for epiretinal membrane or tractional retinal detachment). All included patients had been received at least three consecutive monthly intravitreal injections of 1.25 mg / 0.05 cc bevacizumab before switching.

Then, three monthly intravitreal injections of 1.25 mg / 0.05 cc IVZ were given. The first IVZ injection was injected no later than 4 to 6 weeks after the last bevacizumab injection. Patients were examined 1 and 7 days after IVZ injections to assess for possible adverse reactions. A detailed baseline ophthalmic examination, including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, dilated fundus exam, and measurement of intraocular pressure, were performed for all patients at every visit. Fluorescein angiography (FA) and optical coherence tomography (OCT) were done for all patients at the baseline, and OCT was repeated before each intravitreal injection.

Anatomical and functional outcomes were evaluated based on monthly OCT and BCVA measurements, which were compared to values at the time of IVZ initiation. CMT and macular volume (MV) in ETDRS circles were compared. BCVA was recorded in Snellen and then converted to a logarithm of the minimum angle of resolution (logMAR) scale for analysis.

The primary outcome measure was the change in BCVA after 12 weeks. Additionally, patients' response to IVZ was assessed at each follow-up visit based on BCVA, MV, and CMT. To assess the possible role of baseline BCVA on final outcome, we categorized our cases into two subgroups: those with initial BCVA of less than 20/50 and those with BCVA of 20/50 or better.

Statistical Method

To evaluate the changes in the outcome measures, a linear mixed model was employed. Multiple comparisons were considered by using the Sidak method. A separate linear mixed model was used to compare outcomes between patients based on their baseline BCVA (< 20/50 versus ≥ 20/50). Using this method, another subgroup analysis was done with patients stratified based on CMT: 375 μm or less and greater than 375 µm.

P values less than .05 were considered statistically significant. All statistical analysis performed by SPSS software (IBM SPSS Statistics for Windows, Version 24.0; IBM Corp., Armonk, NY).

Results

Eighty-two eyes from 65 patients had DME refractory to intravitreal bevacizumab and were converted to IVZ. A total of 23 eyes were excluded after initiation of IVZ from the study for the following reasons: 20 patients (19 eyes) were lost to follow-up or had switching time more than 6 weeks from the last IVB, three eyes reverted back to IVB per the patients' request, and one eye developed post-injection endophthalmitis. Ultimately, a total of 59 eyes from 38 individuals were included in the study.

Switching was done before 6 weeks of the last IVB injection, and the maximum interval time between the last IVB and switch to IVZ was 5 weeks and 3 days. All patients were initially treated with three IVZ injections and then transitioned to pro re nata dosing with injections given for CMT greater than 300 µm.

Patients' baseline demographic characteristics are presented in Table 1. Fifty percent of patients were female, and the average age was 63 years old.

Demographic and Baseline Characteristics of the Patients at Time of First Ziv-Aflibercept Injection

Table 1:

Demographic and Baseline Characteristics of the Patients at Time of First Ziv-Aflibercept Injection

Baseline visual acuity (VA) before IVB injections was 0.88 ± 0.52 logMAR (Snellen: 20/151). The mean CMT before IVB injections was 501 μm ± 165 μm. Mean number of IVB injections before switching to IVZ was 7.3 ± 2.2 (median: 8; range: 3 to 15 injections). There was not a significant correlation between number of pre-switching IVB injections, functional, and anatomical improvement after switching (P = .304 and 0.121 for BCVA and CMT improvement).

After conversion, all eyes received at least three monthly IVZ. Average follow-up time was 3.8 months ± 0.39 months. Outcomes were measured relative to the date of the first IVZ injection, which was considered as baseline.

Visual Outcomes After Switching to Ziv-Aflibercept

The VA changes were not significant after IVB injections (0.88 ± 0.52 logMAR to 0.84 ± 0.44 logMAR; P = .89). Table 2 provides a summary of visual outcomes after switching. Compared to baseline pre-switching (0.84 ± 0.44 logMAR; Snellen: 20/138), patients experienced a statistically significant improvement in VA at 4 weeks (0.71 ± 0.43 logMAR; Snellen: 20/102; P = .001), 8 weeks (0.67 ± 0.46 logMAR; Snellen: 20/93; P < .001), and 12 weeks (0.67 ± 0.4 logMAR; Snellen: 20/93; P = .003).

Changes in BCVA and CMT in Two Subgroups Based on Baseline BCVA and CMT

Table 2:

Changes in BCVA and CMT in Two Subgroups Based on Baseline BCVA and CMT

Subgroup analysis of baseline VA was performed for VA of 20/50 or greater (11 eyes) and less than 20/50 (48 eyes). Only for eyes with a baseline BCVA of less than 20/50 a significant improvement was found at each visit (P < .001). Patients with a worse baseline vision (< 20/50) gained a more vision than those with better baseline vision (≥ 20/50) at each follow-up interval, with this difference reaching statistically significant at 4 weeks and 12 weeks (P = .035 and P = .001, respectively).

Anatomic Outcomes After Switching to Ziv-Aflibercept

The CMT did not change significantly after IVB injections (501 μm ± 165 μm to 479 μm ± 131 μm; P = .741). The CMT just before switching (after at least three consecutive IVB injections) was 479 μm ± 131 μm (range: 303 μm to 899 μm), which decreased significantly at 4 weeks (364 μm ± 125 μm; P = .001), 8 weeks (341 μm ± 115 μm; P = .001), and 12 weeks (344 µm ± 115 µm; P = .001) after switching. The greatest reduction in CMT was observed in post-second IVZ injection (8 weeks from baseline; Table 2). Eyes with less than 20/50 and 20/50 or greater vision at baseline both experienced statistically significant improvements in CMT at each follow-up interval.

Thirteen eyes (22%) had a complete resolution of fluid after 3 months, whereas nine eyes (15%) remained unchanged (less than 10% CMT reduction). There was no correlation between baseline VA and CMT reduction (P = .51).

Eyes with CMT greater than 375 μm at the time of IVZ switch had a significantly improved CMT and vision at each follow-up interval. Those with CMT 375 µm or less at the time of IVZ switch experienced non-statistically significant improvements in CMT at each follow-up interval. Vision improved after one IVZ injection in those with CMT of 375 μm or less at the time of switch; however, on subsequent follow-ups, the change in VA did not reach statistical significance.

Comparing these two subgroups, those with CMT of greater than 375 μm showed a significant anatomic improvement at every follow up interval, whereas this was not significant for VA (Table 2).

The mean macular volume at baseline was 10.6 ± 1.61 μm3 (range: 7.51 μm3 to 15.99 μm3). There was a significant reduction in macular volume at each follow-up interval (P = .004, P < .0001, and P < .0001 at 4 weeks, 8 weeks, and 12 weeks, respectively). The amount of macular volume change after switching to IVZ did not differ between groups based on baseline VA at different time points. There was no significant difference in change in macular volume between those with less than 20/50 vision and those with 20/50 vision or better (P = .801, P = .729, and P = .820, respectively).

Adverse Reactions

No cases of retinal detachment, uveitis, retinal pigment epithelium tear or sustained elevated intraocular pressure requiring pharmacologic intervention were observed. There was one case of culture positive endophthalmitis that was treated with pars plana vitrectomy with intravitreal antibiotics. The infection was controlled and the vision was returned to baseline VA, although the patient was excluded from the study. The most common side effect was subconjunctival haemorrhage at the site of injection (n = 11). No systemic adverse events, including thromboembolic events (eg, cerebrovascular accident, myocardial infarction, or transient ischemic attack) occurred.

Discussion

The management of patients with DME refractory to intravitreal bevacizumab represents a significant challenge in clinical practice. Many clinicians employ a second-line anti-VEGF agent, especially in phakic patients, with additional alternatives being focal macular laser or intraocular steroid injections.13,17 The results outlined herein demonstrate that patients with DME that is refractory to IVB have good anatomic and visual outcomes with IVZ injections. Rahimy et al.11 found that patients who were switched from bevacizumab or ranibizumab to aflibercept experienced significant anatomic improvements. Although there was a trend toward better vision after switching in their cohort, this did not reach a statistical significance. Laiginhas et al.13 found patients who were switched to aflibercept from bevacizumab for DME experienced both anatomic and functional improvements, with 24% having resolution of macular fluid. Ashraf et al.14 examined IVZ in patients who had undergone prior anti-VEGF treatment and found an improvement in VA (0.63 logMAR to 0.51 logMAR; P < .084) and macular thickness (513.79 μm to 411.79 μm; P = .006). Patients in the study by Ashraf et al. had only undergone an average of 2.03 anti-VEGF injections prior to being switched to IVZ. This represents a modest number of anti-VEGF injections before considering patients refractory to IVB, and it is possible that these patients may have continued to improve with attaching to the first-line anti-VEGF therapy.18 In comparison, the average number of bevacizumab injections before switching to IVZ was seven in the present study.

IVZ is an attractive treatment for patients who have refractory macular edema after bevacizumab because it possesses a similar molecular profile to aflibercept but can be compounded at a considerably reduced cost for intravitreal injections. In addition to patients who fail to respond to the initiation of intravitreal bevacizumab or ranibizumab, IVZ may be an option in those who develop long term tachyphylaxis.6,9,10,19

Patients may be nonresponders to either a specific anti-VEGF agent or the entire class of medication. Chen et al. found that 42% of patients who did not initially respond to bevacizumab or ranibizumab also failed to respond to aflibercept. Fifteen percent of patients in our study had unchanged macular edema after three injections of IVZ (less than 10% CMT reduction). VEGF represents only one of many pathophysiologic pathways responsible for DME, and it is possible that some patients have a greater contribution from other pathways.3,5

Patients experienced anatomic improvement in CMT and MV regardless of baseline vision. VA significantly improved at each follow-up interval in all patients. Subgroup analysis examining patient outcomes based on baseline categorization of vision found that patients with 20/50 or better vision did not experience a significant gain in vision after three injections of IVZ. Although patients with worse initial vision experienced a greater improvement in vision at 12 weeks, they did not catch the patients with better initial vision who continued to have better average VA at final follow-up.

Patients whose median CMT was greater than 375 µm at the time of IVZ switch experienced significant improvements in macular thickness as well as vision, whereas those with a CMT of 375 μm or less experienced less significant anatomic and functional changes. This is likely because patients with more severe macular edema have a greater opportunity for improvement, and these patients had not suffered significant long-term vision loss from chronic macular edema.

In addition, the subgroup with a CMT of 375 μm or less did not achieve a significant reduction in CMT, which is due to the fact that there is less room for improvement in this subgroup.

VA outcomes depend on a number of factors, including the chronicity of macular edema at baseline (which influences visual potential even when dry) and the presence of other comorbid conditions. Therefore, anatomic results may be more useful in assessing drug efficacy in shorter-term studies with heterogeneous populations such as this study.8 Mixed models were used during statistical analysis to limit the possible compounded confounding from studying both eyes in this analysis.20 The visual and anatomic definitions of a nonresponder remain the subject of debate, as does the number of injections necessary before declaring treatment failure. Some success in medication switching studies can be attributed to sustained VEGF blockage, as Martin et al. demonstrated.18

Twenty-two percent achieved a dry macula in this study. In low-income countries, bevacizumab, although off-label, is the first line of treatment. The off-label use of IVZ in recalcitrant cases of DME seems to be promising and cost-effective.6,12

IVZ was generally well-tolerated in most patients, although there was one case of culture-positive endophthalmitis. Whether this represented a risk attributable to compounding, the medication specifically, or intravitreal injections in general cannot be discerned; however, there were no cases of sterile inflammation following IVZ as has been described previously with aflibercept.21–23 The prospective nature of this study represents a strength, although there are some limitations including its small size and the lack of a control group.

Overall, patients had an improvement in VA and anatomic outcomes after three IVZ injections. IVZ may represent a cost-effective treatment strategy in patients with an incomplete response to intravitreal bevacizumab for DME in lower-income countries.

References

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  22. Goldberg RA, Shah CP, Wiegand TW, Heier JS. Noninfectious inflammation after intravitreal injection of aflibercept: clinical characteristics and visual outcomes. Am J Ophthalmol. 2014;158(4):733–737.e1. doi:10.1016/j.ajo.2014.06.019 [CrossRef] PMID:24983791
  23. Hahn P, Chung MM, Flynn HW Jr, et al. Postmarketing analysis of aflibercept-related sterile intraocular inflammation. JAMA Ophthalmol. 2015;133(4):421–426. doi:10.1001/jamaophthalmol.2014.5650 [CrossRef] PMID:25590968

Demographic and Baseline Characteristics of the Patients at Time of First Ziv-Aflibercept Injection

ParameterLevelTotal (n = 59)Baseline VA

20/50 and Better (n = 11)Worse Than 20/50 (n = 48)

Age (years)Mean ± SD63 ± 661 ± 563 ± 6
Median (Range)62 (49 to 75)61 (52 to 70)63 (49 to 75)

GenderMale19 (50%)10 (71.4%)9 (37.5%)
Female19 (50%)4 (28.6%)15 (62.5%)

EyeOD8 (13.6%)1 (9.1%)7 (14.6%)
OS9 (15.3%)0 (0.0%)9 (18.8%)
OU42 (71.2%)10 (90.9%)32 (66.7%)

Number of IVB injectionsMean ± SD7.3 ± 2.27.1 ± 27.4 ± 2.3
Median (Range)8 (3 to 15)8 (4 to 9)8 (3 to 15)
<826 (44.1%)4 (36.4%)22 (45.8%)
8+33 (55.9%)7 (63.6%)26 (54.2%)

VA before switching (logMAR)Mean ± SD0.84 ± 0.440.27 ± 0.160.97 ± 0.37
Median (Range)0.8 (20/126)0.3 (20/39)1 (20/200)
(0 to 1.8)(0 to 0.4)(0.5 to 1.8)

Baseline CMT (before IVB injections; μm)Mean ± SD501 ± 165461 ± 76510 ± 96
Median (Range)509 (328 to 887)475 (328 to 552)512 (332 to 887)

CMT before switching (μm)Mean ± SD479 ± 131452 ± 90485 ± 138
Median (Range)495 (333 to 899)465 (343 to 536)495 (333 to 899)

Baseline macular volume (before IVB injections; μm3)Mean ± SD10.9 ± 1.4310.21 ± 1.3211.03 ± 1.76
Median (Range)10.64 (7.21 to 16.31)10.17 (7.21 to 13.68)10.34 (8.11 to 16.31)

Macular volume before switching (μm3)Mean ± SD10.6 ± 1.6110.04 ± 1.4110.73 ± 1.64
Median (Range)10.34 (7.51 to 15.99)10.03 (7.51 to 13.43)10.34 (8.26 to 15.99)

Changes in BCVA and CMT in Two Subgroups Based on Baseline BCVA and CMT

ParameterBCVACMT
Total (logMAR)20/50 or Better (n = 11)Worse Than 20/50 (n = 48)P Value**Total (µm)20/50 or Better (n = 11)Worse Than 20/50 (n = 48)P Value **
Baseline0.84 ± 0.440.27 ± 0.160.97 ± 0.37479 ± 131452 ± 90485 ± 138
4 w0.71 ± 0.430.27 ± 0.160.8 ± 0.41364 ± 125315 ± 68375 ± 133
0–4 w0.13 ± 0.260 ± 0.080.16 ± 0.27.035115 ± 151137 ± 73110 ± 163.436
P value within*.0011.000< .001< .001< .001< .001
8 w0.67 ± 0.460.18 ± 0.160.78 ± 0.43341 ± 115297 ± 51351 ± 123
0–8 w0.17 ± 0.280.09 ± 0.140.19 ± 0.3.354138 ± 151155 ± 72134 ± 164.633
P value within*< .001.630< .001< .001< .001< .001
12 w0.67 ± 0.40.22 ± 0.360.73 ± 0.39344 ± 119304 ± 63355 ± 128
0–12 w0.19 ± 0.390.05 ± 0.390.28 ± 0.34.001144 ± 159140 ± 82145 ± 175.758
P value within*.003.254< .001< .001< .001< .001
ParameterBCVACMT
Total (logMAR)CMT ≤ 375 μm (n = 15)CMT > 375 μm (n = 44)P Value***Total (logMAR)CMT ≤ 375 μm (n = 15)CMT > 375 μm (n = 44)P Value***
Baseline0.84 ± 0.440.94 ± 0.510.8 ± 0.41479 ± 131310 ± 44536 ± 96
4 w0.71 ± 0.430.75 ± 0.610.69 ± 0.36364 ± 125302 ± 56385 ± 135
0–4 w0.13 ± 0.260.19 ± 0.280.11 ± 0.25.278115 ± 1518 ± 31151 ± 158< .001
P value within*.001.016.007< .001.630< .001
8 w0.67 ± 0.460.75 ± 0.620.64 ± 0.39341 ± 115287 ± 56359 ± 124
0–8 w0.17 ± 0.280.19 ± 0.290.16 ± 0.27.816138 ± 15124 ± 26177 ± 156< .001
P value within*< .001.124.003< .001.066< .001
12 w0.67 ± 0.40.82 ± 0.570.63 ± 0.34344 ± 119262 ± 37365 ± 124
0–12 w0.19 ± 0.390.2 ± 0.30.19 ± 0.41.992144 ± 15930 ± 37173 ± 166.002
P value within*.003.382.013< .001.124< .001
Authors

From Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran (NE, AL, HRE, SJM, AK, MZ, RR, HK, FB, MO, MS); the Department of Ophthalmology, Southern California Permanente Medical Group, Baldwin Park, California (BSM); Eye Monitoring Center, Kaiser Permanente Southern California, Baldwin Park, California (BSM); the Department of Ophthalmology, University of Florida, Gainesville, Florida (SD); and the Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, California (MRE).

The authors report no relevant financial disclosures.

Address correspondence to Hamid Riazi-Esfahani, MD, Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Qazvin Square, South Kargar Street, Tehran, Iran 1336616351; email: Hamidriazi@gmail.com.

Received: February 07, 2019
Accepted: October 25, 2019

10.3928/23258160-20200228-03

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