Evaluation Of The Effectiveness Of Intravitreal Anti-VEGF Injection With Intravitreal Dexamethasone Implant In Patients With Treatment-Resistant Diabetic Macular Edema

Abstract

Purpose: To assess the effectiveness of monthly anti-VEGF therapy with an intravitreal dexamethasone (DEX) implant in patients with diabetic macular edema (DME) whose macular edema persists despite anti-VEGF therapy.

Materials and methods: This study included 94 eyes of 94 patients whose diabetic macular edema (Central Macular Thickness (CMT) >300 µm) persisted despite previous injections of 3 doses of anti-VEGF. The patients were followed up at the first, second, third, and six month after intravitreal injection. Best corrected visual acuity (BCVA), central macular thickness (CMT) and intraocular pressure (IOP) change parameters were evaluated.

Results: In terms of age, proliferation, and lens status, there was no statistically significant difference between the groups. When CMT, BCVA, and IOP were assessed among the 4 groups at the end of the sixth month, no statistical difference between the groups was found. There was no need for medical intervention despite the statistically significant increase in IOP at the end of the sixth month compared to the third month in the dexamethasone implanted groups. In contrast to the decrease in CMT, which was statistically significant in all 4 groups at the end of the 6th month compared to the 3rd month, the increase in BCVA was not statistically significant in any of the 4 groups at the end of the 6th month.

Conclusion: According to the results of our study, there is no superiority between continuing with existing anti-VEGF or switching to dexamethasone implant after 3 doses of anti-VEGF.

1. Introduction

Diabetes Mellitus (DM) is a disease related to dysregulation and elevation in blood glucose values resulting from decreased insulin production or systemic resistance to the effects of insulin.¹ Diabetic retinopathy (DRP) is a specific microvascular complication of DM and is the leading cause of vision loss worldwide in middle-aged and economically active people.² Some level of diabetic retinopathy (DRP) develops in 35% of diabetic patients.³ Secondary to hyperglycemia, glucose metabolism products cause endothelium and pericyte loss in retinal arteries, resulting in deterioration of the blood-retina barrier and tissue hypoxia. As a result of tissue hypoxia, many cytokines are secreted, the most important of which being vascular endothelial growth factor (VEGF). Diabetic macular edema (DME) arises at the end of this process.⁴ Macular edema affects around 14% of people with diabetes. In people with newly diagnosed type 2 diabetes, the 10-year incidence of macular edema is 20%.⁵ In addition, its prevalence increases with the duration of the disease, and diabetic macular edema affects more than 60% of patients followed for more than 20 years.⁶ Although an increase in VEGF appears to be the primary contributing factor to the pathophysiology of DME, many inflammatory cytokines and prostaglandins also contribute to the development of DME. In addition to lowering VEGF secretion and vascular permeability, corticosteroids stabilize lysosomal membranes and the blood-retina barrier. As a result, corticosteroid medications are used to treat DME.⁷ Since corticosteroids are continuously released from slow-release intravitreal implants, fewer injections are required.⁸ Aflibercept is a fusion protein created recombinantly by joining the human immunoglobulin G1 Fc portion with the extracellular portions of VEGFR-1 and VEGFR-2. It functions as a soluble decoy receptor and contains the entire human amino acid sequence. It has a strong affinity for binding VEGF-A, VEGF-B, and PlGF.⁹ This means that a lower dose can produce an effect that lasts for a longer period of time.¹⁰ Ranibizumab is a humanized monoclonal antibody that is produced by Escherichia coli through the use of recombinant DNA technology. It is considered to be one of the anti-VEGF agents. Ranibizumab has the ability to bind to all of the VEGF-A isoforms. In the treatment of diabetic macular edema (DME), the first FDA-approved agent is intravitreal Ranibizumab (Lucentis, Genentech, California, USA). The intravitreal injection dosage of ranibizumab is either 0.5 or 0.3 milligrams.¹¹

2. Materials And Methods

Study Population

The study was done in accordance with the principles of the Declaration of Helsinki and the study was started after permission by the local ethics committee. Ninety-four eyes of 94 patients with a central macular thickness (CMT) greater than 300 microns, diagnosed with NPDR or early PDR, who had previously received 3 doses of anti-VEGF therapy due to chronic diabetic macular edema and were followed up in the Bulent Ecevit University Department of Ophthalmology, were included in the study.Only the right eye was included when both eyes met the criteria for inclusion because there was a tendency for the outcome measurements from the same subject's two eyes to be positively correlated.. Before the injection, all of the patients were told about the benefits, risks, and possible side effects of the procedure and gave their consent. Patients aged 18 and up with Type 2 DM who had previously received three monthly anti-VEGF injections but still had CMT values above 300 µm were enrolled in the study.

Criteria for Exclusion

• High-risk PDR
• Pregnancy
• Uncontrolled hypertension
• Retinal Vascular Disease, Age-related macular degeneration, presence of epiretinal membrane in OCT
• Uveitis, Glaucoma
• History of Pars plana vitrectomy
• Severe cataracts
• History of Yag laser capsulotomy within 6 months
• Patients who underwent laser photocoagulation were not included in the study.

Study Design

The patients were divided into 4 groups. 1.group, 3 patients who received an additional 3 doses of Aflibercept after 3 doses of Aflibercept treatment (AFL+AFL), group 2, patients who received an additional 3 doses of Ranibizumab after 3 doses of Ranibizumab treatment (RAN+RAN), group 3, patients who underwent intravitreal Dexamethasone after 3 doses of Aflibercept treatment (AFL+DEX), group 4, patients who received intravitreal Dexamethasone (RAN+DEX) after 3 doses of Ranibizumab treatment were patients. Detailed ophthalmologic examinations of the patients were performed. The best corrected visual acuity (BCVA) with the Snellen chart, anterior segment examinations with a biomicroscope, intraocular pressures (IOP) with a Goldmann applanation tonometer, and posterior segment examinations using 90D non-contact lenses after pupil dilatation were performed. CMT was measured by OCT (Heidelberg Engineering, Heidelberg, Germany). All of the patients included in the study with the diagnosis of DME were evaluated with FFA and macular ischemia was ruled out.

Treatment Protocol

Before the injection, the conjunctiva was cleaned with 5% povidone iodine and the skin was cleaned with 10% povidone iodine. The sterile eye cover was covered and worn in blepharos. The injection site was chosen as the upper temporal area, and topical proparacaine was administered prior to the injection. The anti-VEGF and dexamethasone implants were injected into the vitreous via their own injector system at a distance of 4 mm from the limbus in phakic patients and 3.5 mm from the limbus in pseudophakic patients. Post-injection light detection and IOP were evaluated. After the injection, all patients were given topical moxifloxacin 0.5% prophylaxis 4 times a day for 1 week and were called for postoperative first week for infection. All patients were called for first week, first month, second month, third month, fourth month, fifth month and sixth month controls after injection. Full ophthalmologic examinations were performed at each control. BCVA, CMT and IOP values were recorded. Patients who did not come to their regular monthly follow-up were excluded from the study.

Statistical Analysis

SPSS 19.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. The Shapiro-Wilk test was used to determine whether numerical variables were suitable for the normal distribution. For categorical data, descriptive statistics were expressed as numbers and percentages, while mean, standard deviation, and median (minimum-maximum) were used for numerical variables. The Chi-square test was used to look at the categorical variable differences between the groups. A Kruskal-Wallis analysis of variance was used to compare the four groups in terms of numerical variables. The measurement values between the two dependent groups were compared using the Wilcoxon-marked sequence(s) test. p<0.05 was considered significant.

3. Results

Study Participants Between January 2014 and January 2019, 94 eyes of 94 patients with chronic macular edema were included in the study. The demographic characteristics of the patients included in the evaluation are summarized in Table 1.

Table-1. Demographic characteristics of the data

There was no statistically significant difference between the four groups in terms of age, proliferation, laterality, or lens status. (phakic, pseudophakic). (p > 0.05)

Table 2. Comparison of treatment groups in terms of evaluation parameters after three anti-VEGF doses (3rd month).

When the mean visual acuity, mean central macular thickness, and mean intraocular pressure were evaluated after three doses of anti-VEGF treatment, there was no statistically significant difference between the four groups. (p > 0.05)

İntragroup Analysis

Table-3 Comparison of intragroup mean visual acuity values after 3 anti-VEGF treatments (3rd month) and 6 anti-VEGF treatment or 3rd month (6th month) of DEX implant treatment.

When the visual acuity of the 3rd month of anti-VEGF treatment (3rd month) and 6-dose anti-VEGF treatment or the 3rd month (6th month) of DEX implant treatment was examined with intragroup analysis; there was no statistically significant difference between the mean visual acuity at the 3rd month and the mean visual acuity at the 6th month in all 4 groups. (p > 0.05)

When the mean central macular thickness values after 3 doses of anti-VEGF (3rd month) and 3rd month (6th month) of 6 doses of anti-VEGF or dexamethasone implant were examined with intragroup analysis in each of the 4 groups, the average central macular thickness of the 3rd month in all 4 groups was examined. There was a statistically significant difference between the mean central macular thickness and the 6th month post-injection (p < 0.05).

When the mean intraocular pressure values after 3 doses of anti-VEGF (3rd month) and 3rd month (6th month) of 6 doses of anti-VEGF or dexamethasone implant were examined with intra-group analysis in each of the 4 groups, there was a statistically significant statistical significance in the mean intraocular pressure in the groups switched to dexamethasone difference was observed. (p < 0.05) However, none of these patients needed medical or surgical treatment.

Intergroup Analysis

For the analysis between the groups, the values ​​obtained at the 6th month after the injection in each of the 4 groups were calculated and evaluated.

Table-4. Evaluation of mean visual acuity, mean central macular thickness and mean intraocular pressure between groups at 6 months after injection.

When the values obtained in mean visual acuity, mean central macular thickness and mean intraocular pressure were compared between the four groups; there was no statistically significant difference between the groups at 6 months (p < 0.05)

4. Discussion

Diabetic macular edema (DME) is a common complication of diabetic retinopathy (DR) and is the most important cause of vision loss in working-stage people in developed countries.^12–13 Numerous studies demonstrate a relationship between VEGF level and retinopathy activity and show that VEGF is the primary angiogenic factor responsible for the development of diabetic retinopathy and maculopathy.^14–15 With the understanding of the role of VEGF in the pathogenesis of DME, the use of anti-VEGF agents in the treatment has become widespread.

Patients who received 0,3 and 0,5 mg of ranibizumab injection were compared with the control group in the "Study of Safety and Efficacy of Ranibizumab in Diabetic Macular Edema" (RESOLVE) and "Study of Ranibizumab for Diabetic Macular Edema" (RISE and RIDE) studies. In the groups receiving intravitreal Ranibizumab, a significant improvement in visual acuity and a significant decrease in central macular thickness were seen after 12 months.¹⁶ The efficacy and safety of intravitreal The efficacy and safety of intravitreal Aflibercept was evaluated in the study ‘An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular edema’. A decrease in central macular thickness and mean letter gain in visual acuity were observed 6 weeks after the injection.¹⁷ In the study ‘Aflibercept, Bevacizumab or Ranibizumab for diabetic macular oedema: recent clinically relevant findings from DRCR.net Protocol T’, 0,3 mg Ranibizumab, 2,0 mg Aflibercept and 1,25 mg Bevacizumab were compared. When the Ranibizumab and Aflibercept groups were examined, a significant decrease in central macular thickness and a significant increase in visual acuity were observed in this group at 12 months.¹⁸ Compared to other studies, although the central macular thickness in both the AFL + AFL group and the RAN + RAN group decreased statistically significantly at the 6th month compared to the 3rd month, the increase in visual acuity was not statistically significant at the 6th month compared to the 3rd month, unlike other studies.

Corticosteroids stabilize lysosomal membranes and the blood-retina barrier while reducing VEGF secretion and vascular permeability. For this reason, corticosteroid agents are used in the treatment of DME.⁷ In a study examining the changes in the amounts of inflammatory and angiogenic cytokines in the humoral aqueous after intravitreal injection of triamcinolone and bevacizumab in patients with DME, IL6, inducible protein 10, monocyte chemoattractant protein, platelet-derived growth factor AA, and VEGF were observed to be significantly decreased in eyes injected with triamcinolone, only VEGF has been shown to be reduced in eyes injected with bevacizumab.¹⁹ In this case, it was stated that the use of corticosteroids in DME may be more meaningful than anti-VEGF therapy, which is effective only on a part of the inflammatory cascade.²⁰ Intravitreal corticosteroids in DME; It can be considered if anti-VEGFs are contraindicated, if there is poor compliance with repetitive anti-VEGF applications and if there is resistance to anti-VEGFs.²¹ In the study of Vujosevic et al. Dexamethasone has been shown to be effective in cases of increased foveal autofluorescence.²² In the study of Vural et al., it was concluded that dexamethasone implant responds better than anti-VEGF treatment in DME cases with subretinal fluid.²³ The CHAMPLAIN study evaluated 55 vitrectomized eyes with treatment-resistant DME. A single dose of 0,7 mg dexamethasone implant was applied to the patients and they were followed for 26 weeks. There was a statistically significant increase in visual acuity of these patients at the end of the 26th week. In the eighth week, visual improvement of 10 letters or more was achieved in 30.4% of the patients.²⁴ In the MEAD study, 0.7mg dexamethasone was randomized to 0.35mg dexamethasone and sham groups. It was determined that the decrease in central macular thickness and letter gain were higher in the groups receiving intravitreal dexamethasone. In addition, it was reported that approximately one third of the patients in the group receiving dexamethasone had an increase in intraocular pressure that required treatment.²⁵

In the study conducted by Totan et al., after intravitreal dexamethasone administration to patients who received 3 doses of 2.5 mg intravitreal bevacizumab at 6-week intervals and whose central macular thickness was above 275 microns, there was a significant decrease in central macular thickness in the 1st, 3rd and 6th months; In addition, a significant increase in mean visual acuity and mean intraocular pressure was detected in the 1st and 3rd months.²⁶ In the study of Zhioua et al., intravitreal dexamethasone was administered to 12 patients whose central macular thickness continued to be 300 microns and above, despite 6 consecutive months of Ranibizumab, and they found that dexamethasone was effective on central macular thickness and visual acuity.²⁷ In the study by Maturi et al (Protocol U), the group that continued with 0.3 mg of Ranibizumab after 3 doses of 0.3mg Ranibizumab was compared with the group that was switched to Dexamethasone implant; Although the decrease in mean central macular thickness and increase in mean intraocular pressure were greater in the group switched to dexamethasone at the end of 24 weeks, there was no significant difference in mean visual acuity.²⁸ In a meta-analysis study by Khan et al., it was reported that the DEX implant applied to patients with refractory DME despite the use of anti-VEGF agents improves vision and may be a treatment alternative for patients with DME who have low response to anti-VEGF agents.²⁹ Ozata et al. showed that dexamethasone implantation was effective in increasing BCVA and lowering CMT in the first 3 months in DME resistant to sequential intravitreal Ranibizumab therapy. They reported that intravitreal dexamethasone implantation could be considered as an alternative method in the treatment of resistant DME.³⁰

In our study, when the groups that continued with 3 doses of anti-VEGF after 3 doses of anti-VEGF treatment and the groups that were switched to intravitreal dexamethasone implant were compared at the end of the 6th month, the decrease in mean central macular thickness, increase in mean intraocular pressure and increase in mean visual acuity were not found statistically significant. Despite the statistically significant increase in intraocular pressure at the 6th month compared to the 3rd month in the dexamethasone implanted groups, the patients did not need anti-glaucomatous drug treatment.

Strengths and Limitations

Although this study has disadvantages such as being retrospective, having a small number of patients in the groups, not being able to evaluate on inflammatory markers, and having an average follow-up period of 6 months; The absence of a similar study conducted on four different groups is also important for our study. Our study should be supported by prospective, long-term follow-up and further studies with large patient groups. New molecules with fewer side effects and longer acting are needed for better therapeutic results.

5. Conclusion

According to the results of this study, there is no superiority between continuing with the existing anti-VEGF or switching to dexamethasone implant in the choice of treatment after 3 doses of anti-VEGF, since there is no statistical difference between mean visual acuity and central macular thickness at 6 months. Considering the results of the study; After 3 doses of anti-VEGF (3rd month), to apply for a drug change (to switch to dexamethasone implant treatment) should be decided according to the patient (presence of glaucoma, compliance with treatment, etc.) and cost. Dexamethasone implant has an advantage over anti-VEGF in that it requires fewer injections and its cost is lower than 3 doses of anti-VEGF. In addition, although the increase in intraocular pressure was statistically significant in the groups switched to dexamethasone, it is also important for the transition to dexamethasone that this condition does not require medical or surgical treatment.

Declarations

ACKNOWLEDGMENTS

I would like to thank Suat Hayri Ugurbas and Atilla Alpay for their support and knowledge during the execution of this study.

CONFLICT OF INTEREST

There is no financial conflict of interest with any institution, organization, person related to our article and also there is no conflict of interest between the authors.

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Tables

Table-1 Demographic characteristics of the data

Table-2 Comparison of treatment groups after 3 doses of anti-VEGF (3rd month) in terms of evaluation parameters 

Table-3 Comparison of   intragroup mean visual acuity, mean central macular thickness and mean intraocular pressure values after 3 anti-VEGF (3 months) and 6 anti-VEGF post or DEX 3 months (6 months)

Table-4 Evaluation of mean visual acuity, mean central macular thickness and mean intraocular pressure between groups at 6 months after injection