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 Table of Contents  
Year : 2021  |  Volume : 22  |  Issue : 1  |  Page : 49-55

Efficacy and safety of Ziv-aflibercept in patients with central retinal vein occlusion

Department of Ophthalmology, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission18-Feb-2020
Date of Decision31-May-2020
Date of Acceptance28-Jul-2020
Date of Web Publication24-Mar-2021

Correspondence Address:
MD, FRCS Amin E Nawar
Department of Ophthalmology, Faculty of Medicine, Tanta University, El Geish Street, Tanta 31516
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/DJO.DJO_16_20

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Background Retinal vein occlusion is one of the most common vascular disorders that can cause visual loss. It is classified into central retinal vein occlusion (CRVO) and branch retinal vein occlusion. The most common cause of visual loss in CRVO is cystoid macular edema. Intravitreal injection of many antivascular endothelial growth factor agents can treat cystoid macular edema that occur owing to CRVO.
Purpose The aim of the present study was to evaluate the efficacy of a new drug (Ziv-aflibercept) in the management of patients with CRVO.
Patients and methods This is a prospective interventional study that was conducted on 15 eyes of 15 patients of recently diagnosed nonischemic CRVO of less than 2-month duration. Three loading doses of 1.25 mg of Ziv-aflibercept were given 1 month apart for each patient and then continued as needed in a pro re nata regimen. Complete ophthalmic evaluation was done at the Ophthalmology Department of Tanta University, including best-corrected visual acuity (BCVA), fundus examination, intraocular pressure measurement, and anterior segment examination. Optical coherence tomography (TOPCON 3D optical coherence tomography machine) was done for all patients at presentation and 1 month after each injection and then monthly during the follow-up period, which persisted for 6 months.
Results The intraocular pressure did not show a statistically significant increase after intravitreal injection of Ziv-aflibercept. The BCVA improved significantly from 0.87±0.10 to 0.32±0.12 LogMAR after injection (P=0.001). The central macular thickness decreased significantly from a baseline value of 771±141.87 μm before injection to 306.67±91.51 μm after the three loading doses and to 208.07±12.97 μm after 6 months (P=0.001). There was no statistically significant correlation between the final BCVA and the final central macular thickness after 6 months (r=0.054, P=0.848). No serious complications were reported, such as endophthalmitis, vitreous hemorrhage, retinal detachment, or stroke.
Conclusion Ziv-aflibercept is a highly effective drug in cases of nonischemic CRVO with a high safety profile and a relatively low cost.

Keywords: branch retinal vein occlusion, central macular thickness, central retinal vein occlusion, cystoid macular edema, optical coherence tomography, retinal vein occlusion

How to cite this article:
Nawar AE, Shafik HM. Efficacy and safety of Ziv-aflibercept in patients with central retinal vein occlusion. Delta J Ophthalmol 2021;22:49-55

How to cite this URL:
Nawar AE, Shafik HM. Efficacy and safety of Ziv-aflibercept in patients with central retinal vein occlusion. Delta J Ophthalmol [serial online] 2021 [cited 2022 Aug 18];22:49-55. Available from: http://www.djo.eg.net/text.asp?2021/22/1/49/311887

  Introduction Top

Retinal vein occlusion (RVO) is one of the most common retinal vascular disorders that cause visual loss. Many factors are involved in RVO like hypertension, arteriosclerosis, hyperviscosity, coagulation disorders, and chronic open-angle glaucoma [1]. RVO is classified into two main types: branch RVO and central retinal vein occlusion (CRVO). The main cause of visual loss in RVO is cystoid macular edema [2].

Hypoxia and upregulation of proinflammatory mediators and vascular endothelial growth factor (VEGF) occur on top of CRVO [3]. Inhibition of VEGF by intravitreal injection of medications like ranibizumab, bevacizumab, aflibercept, and intravitreal corticosteroids is effective for the treatment of macular edema associated with CRVO [4],[5],[6],[7].

Ziv-aflibercept (Zaltrap), an anti-VEGF drug, is a recombinant fusion protein with a similar mechanism to aflibercept. It was approved in August 2012 by the FDA for the management of resistant metastatic colorectal carcinoma [8]. Few studies have also reported the clinical outcome of intravitreal injection of Zaltrap through 1 year [9],[10].

The cost of one dose of intravitreal injection of ranibizumab and aflibercept is high, whereas that for the off-label bevacizumab (IVB) and Ziv-aflibercept (IVZ) is much less per dose [11],[12]. Bevacizumab and Ziv-aflibercept have a nearly similar cost, so Ziv-aflibercept could replace bevacizumab in developing countries in which treatments that are cost-effective are needed.

The purpose of this study was to evaluate the intravitreal injection of Ziv-aflibercept (Zaltrap) as a primary treatment in cases of nonischemic CRVO.

  Patients and methods Top

This is a prospective interventional case series that was conducted on 15 eyes of 15 patients with nonischemic CRVO with macular edema after approval of the Ethical Committee of the Faculty of Medicine, Tanta University, Egypt (approval code number 32970/02/19). All procedures were carried out under the tenets of the Helsinki Declaration. A written informed consent was signed by all patients to participate in the study and for publication of data after discussing the procedure, alternative treatment plans, follow-up schedules, and possible benefits and risks.

The study included treatment-naive patients of recently diagnosed nonischemic CRVO of less than 2-month duration with macular edema documented by fundus fluorescein angiography, Topcon camera (Hasunuma-cho, Itabashi-Ku, Tokyo, Japan), and optical coherence tomography (OCT) (Topcon 3D OCT, Hasunuma-cho).

Eyes with previous intraocular surgery (except previous uncomplicated cataract surgery), coincident retinal pathology such as diabetic retinopathy, myopic choroidal neovascularization, choroidal neovascularization owing to different causes like age-related macular degeneration, angioid streaks, trauma and choroiditis, prior ocular inflammation, presence of retinal degeneration, and patients who did not complete 6 months of follow-up were excluded from the study.

Thorough ophthalmic evaluation was done for all patients including best-corrected visual acuity (BCVA) using Landolt’s C chart that was converted to LogMAR for statistical analysis, intraocular pressure (IOP) measurement using applanation tonometry, anterior segment examination using the slit lamp, posterior segment examination by slit-lamp bimicroscopy using a +78 D lens, and indirect ophthalmoscopy. In addition, spectral domain optical coherence tomography (SD-OCT) (Topcon 3D OCT) was performed for all patients at presentation and after 1 month of each injection.

Surgical procedure

The patients were prepared by topical fluoroquinolone eye drops (moxifloxacin hydrochloride 0.5%; Vigamox, Alcon-Couvreur, Puurs, Belgium) four times daily for 3 days before injection, although no study supported this, but this is the usual technique done in Tanta University for medicolegal aspects.

The intravitreal injection was carried out in the operating room after taking all sterilization measures using an operating microscope. The eye was prepared in the usual technique using a drop of benoxinate hydrochloride 0.4% (Benox, E.I.P.I.CO, 10th of Ramadan City, Egypt) ophthalmic solution that was applied to the ocular surface for topical anesthesia followed by topical application of 10% povidone iodine (Betadine, El-Nile Co for Pharmaceuticals and Chemical Industries, Cairo, Egypt) to the periocular area, lids, and eye lashes and 5% povidone iodine inside the conjunctival sac for three minutes before the intravitreal injection.

Three loading doses of 0.05 ml (1.25 mg) of Ziv-aflibercept (Zaltrap; Regeneron, New York, New York, USA, a 4 ml vial containing 100 mg) were injected into the vitreous cavity 1 month apart. The injections were done in the inferotemporal quadrant of the globe using a 30-G needle, 4 mm from the limbus. Paracentesis was planned if marked rise of IOP occurred after injection. The rise in IOP following injection was assessed both digitally and clinically by asking the patient if he/she can see light perception.

Postoperatively, a drop of moxifloxacin hydrochloride 0.5% (Vigamox) was applied and the eye was patched for several hours. Then the patients were instructed to administer antibiotic eye drops four times daily for 3 days.

The patients were examined the next day and the third day after injection to exclude any complications like elevation of IOP, endophthalmitis, retinal break, retinal detachment, and vitreous hemorrhage. All patients were followed up at 4 weeks after the first injection.

At each visit, a thorough ophthalmic examination including BCVA and SD-OCT was performed.

Additional intravitreal injection of Zaltrap was given as needed (pro re nata) after the three loading doses if SD-OCT detected intraretinal or subretinal fluid.

Statistical analysis

Statistical analysis was conducted by using the mean, SD, Student t test, χ2 test, linear correlation coefficient, and analysis of variance tests using the Statistical Package for Social Sciences (SPSS Inc., Chicago, Illinois, USA). Unpaired Student t test was used to compare between two groups in quantitative data. χ2 indicates that the row and column variables are independent, without indicating strength or direction of the relationship. Linear correlation coefficient was used for detection of correlation between two quantitative variables in one group. Analysis of variance test was used for comparison among different times in the same group in quantitative data. P value more than 0.05 was considered nonsignificant, and P value less than or equal to 0.05 was considered significant.

  Results Top

A total of 15 eyes of nonischemic CRVO were included in the study. The baseline demographic and clinical data and the number of injections in all patients, including age, sex, and prevalence of hypertension, are illustrated in [Table 1]. The number of injections ranged from three to five injections, with a mean of 3.80±0.86. Seven eyes needed three injections only as OCT was done for them at the fourth, fifth, and sixth month, and no further injections were needed. Four eyes needed four consecutive injections, and the remaining four eyes needed five consecutive injections.
Table 1 Demographic and clinical data and number of injections

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The IOP did not change significantly from the baseline value of 12.53±1.77 mmHg before injection to 13.23±1.50 mmHg and 13.47±1.60 mmHg after 3 and 6 months of injection, respectively (P=0.140). The BCVA (by LogMAR) improved significantly after 3 months, and the improvement was sustained till 6 months after injection from 0.87±0.10 before injection to 0.32±0.12 and 0.34±0.12 after 3 and 6 months of injection, respectively (P=0.001, [Table 2]).
Table 2 Intraocular pressure and best-corrected visual acuity before injection and after 3 and 6 months of injection

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The central macular thickness (CMT) decreased significantly from 771±141.87 μm before injection to 306.67±91.51 μm after the three loading doses and to 208.07±12.97 μm after 6 months of injection (P1, P2, and P3 were 0.001, 0.001, and 0.008, respectively; P1: value between before injection and after three loading doses, P2: value between before injection and after 6 months, P3: value between after three loading doses and after 6 months, [Table 3]). The macular thinning was owing to restoration of the normal macular thickness and was not associated with inner retinal atrophic changes.
Table 3 Changes in central macular thickness after three loading doses and after 6 months of injection

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There was no statistically significant correlation between the final CMT and the final BCVA after 6 months (r=0.054, P=0.848, [Figure 1]).
Figure 1 Linear correlation between the final central macular thickness (CMT) and the final best-corrected visual acuity (BCVA) after 6 months of injection (no significant correlation, P=0.848, r=0.054).

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No serious complications were reported following the injection including IOP elevation, vitreous hemorrhage, endophthalmitis, or retinal detachment. In addition, no stroke or cardiac problems were encountered. Only two cases developed subconjunctival hemorrhage after the injection.

All cases showed marked improvement of CMT after the three injections as shown by an example in [Figure 2],[Figure 3],[Figure 4],[Figure 5].
Figure 2 Fundus fluorescein angiography and optical coherence tomography (OCT) of a male patient presented with left central retinal vein occlusion (CRVO) with cystoid macular edema; the central macular thickness (CMT) is 715 μm, and the best-corrected visual acuity (BCVA) is 1 by LogMAR.

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Figure 3 Optical coherence tomography (OCT) of the previous patient after the first injection of Zaltrap; the central macular thickness (CMT) is 436 μm.

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Figure 4 Optical coherence tomography (OCT) of the previous patient after the second and third injections of Zaltrap; the central macular thickness (CMT) is 378 and 205 μm, respectively.

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Figure 5 Optical coherence tomography (OCT) of the same patient after the fourth injection of Zaltrap; the central macular thickness (CMT) is 193 μm, and the BCVA improved to 0.2 by LogMAR. BCVA, best-corrected visual acuity.

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  Discussion Top

Ziv-aflibercept and aflibercept are identical fusion proteins that have the ability to bind to circulating VEGF-A and VEGF-B and placental growth factor. Ziv-aflibercept has a molecular weight of 115 kDa. It is manufactured from the Chinese hamster ovary cells [11]. The molecular structure of Ziv-aflibercept is identical to aflibercept. However, they differ from each other in osmolarity as aflibercept is iso-osmotic (300 mOsm/kg), whereas Ziv-aflibercept is hyperosmotic (1000 mOsm/kg) because of the presence of higher concentration of sucrose [11],[13]. Multiple studies have assessed the retinal toxicity of Ziv-aflibercept due to hyperosmolarity and reported a reasonable safety of the drug with no detected toxic adverse effects [8],[9],[11],[14],[15].

Multiple studies evaluated the efficacy of aflibercept in patients with CRVO. The most important is the COPERNICUS trial, which evaluated fixed monthly regimen of aflibercept over 24 weeks and reported rapid and sustained visual and anatomic improvements that were subsequently maintained with as needed (pro re nata) dosing with monthly evaluations through year 1 [5]. Another valuable study is the NEWTON clinical trial, which switched patients with chronic CRVO (mean duration: 22 months; range: 7–90 months) who were previously treated with intravitreal injection of ranibizumab or bevacizumab to aflibercept on a treat-and-extend regimen. At month 24, patients maintained good visual and anatomical outcomes with a longer macular edema-free interval (up to 12 weeks) [16].

In the present study, no major ocular complications like endophthalmitis, retinal detachment, and vitreous hemorrhage occurred with Ziv-aflibercept supporting the safety of the new drug on the retina. Similarly, other studies confirmed the safety of Ziv-aflibercept like Malik et al. [17] who reported that the use of 1.25 and 2 mg doses of Ziv-aflibercept has no harmful effect on the human retinal pigment epithelial cells in vitro. In addition, de Oliveira Dias et al. [18] confirmed the safety of Ziv-aflibercept in rabbit eyes with higher doses up to 25 mg/ml. Chhablani et al. [8] and Mansour et al. [11] also found that intravitreal injection of 1.25 mg of Ziv-aflibercept was safe at 4 weeks in eyes with diabetic macular edema and neovascular age-related macular degeneration.

In the current study, the IOP did not change significantly after injection of Ziv-aflibercept whether immediately or after a period of injection. Thus, none of the eyes needed anterior chamber paracentesis after injection, in contrast to Chhablani et al. [19] who detected immediate IOP elevation after injection in four eyes that needed anterior chamber paracentesis.

In the present study, the BCVA was markedly improved after intravitreal injection of Ziv-aflibercept from 0.87±0.10 LogMAR to 0.34±0.12 LogMAR with a significant decrease in CMT after 6 months of injection. However, there was no significant correlation between the final BCVA and the final CMT after 6 months. This was quite similar to Paulose et al. [9] who studied persistent or recurrent ME in nine eyes because of RVO (both branch and CRVO) and detected moderate improvement in BCVA with a significant reduction in CMT (from 604±199 to 351±205 µm, P=0.02) at 4 months.

Povidone iodine antisepsis is a highly effective prophylactic measure against endophthalmitis. Reibaldi et al. [20] reported increased risk of endophthalmitis after intravitreal injection of anti-VEGF agents with the use of prophylactic antibiotics. However, in the current study, prophylactic topical antibiotics and povidone iodine antisepsis were used before intravitreal injection with no adverse effects.

The cost of the procedure of injection, in the present study, included the hospital, hospital user fees, cost of investigations like OCT and fluorescein angiography, and the cost of the anti-VEGF drug. The mean number of injections was 3.80±0.86. The approximate cost of one dose of IVB and IVZ is nearly similar ($50 and $30 per dose, respectively) [11],[21]. The cost of intravitreal injection of ranibizumab and aflibercept or intravitreal injection of ranibizumab is 20–30 times as compared with IVB or IVZ [22]. This is markedly beneficial in the developing and low-middle-income countries where insurance cannot cover all patients. In addition, the reduction of the number of hospital visits in patients who received IVZ can reduce further costs.

The small number of patients with short duration of follow-up is the main limitations of this study. So, a larger number of patients need to be further evaluated with longer follow-up period to assess the effectiveness of this new drug.

  Conclusion Top

Zaltrap is a cost-effective treatment for cases of CRVO that can achieve significant visual and anatomical improvements.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1], [Table 2], [Table 3]


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