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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 1  |  Page : 1-12

Efficacy of posterior sub-tenon's capsule injection compared to intravitreal injection of triamcinolone acetonide for treatment of diabetic macular edema: A systematic review and meta-analysis


1 Department of Ophthalmology, Environmental and Occupational Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Community, Environmental and Occupational Medicine, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission23-Oct-2020
Date of Acceptance14-Sep-2021
Date of Web Publication27-Jan-2022

Correspondence Address:
Dr. Mohamed Hamdy Ghazy Ibrahim
Department of Ophthalmology, Faculty of Medicine, Ain Shams University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/erj.erj_15_20

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  Abstract 


Background: Diabetic macular edema (DME) is defined as a retinal thickening in one-disc diameter of the center of the macula. It is a number of microvascular retinal changes that lead to blood-retinal barrier disruption, causing leakage of fluid and plasma components into the inner and outer plexiform layers. Aim of the Work: To conduct a systematic review and a meta-analysis estimating the efficacy and complications of posterior sub-Tenon's capsule injection of triamcinolone acetonide (STTA) compared to intravitreal injection of triamcinolone acetonide (IVTA) for management of DME. Materials and Methods: A comprehensive literature search was conducted using the databases Google Scholar, PubMed, MEDS, web of science, EMBASE, and Cochrane Library for published studies from January 01, 2000 to September 01, 2019. This meta-analysis included ten studies. They were randomized controlled clinical trials, and about 343 patients with DME (469 eyes) participated in these studies. Results: This study demonstrated a statistically significant change in the mean of best-corrected visual acuity (BCVA) improvement and central macular thickness (CMT) reduction in both groups when comparing the baseline to 1- and 3-month follow-ups after the injection, though with no statistically significant difference in the IVTA compared to the STTA group. At a 6-month follow-up, both groups showed no significant differences in the BCVA and CMT compared to the baseline. Both groups showed no statistical differences in the BCVA or CMT over the follow-up periods. Regarding intraocular pressure (IOP) changes, the present study showed that the mean IOP was elevated in both groups at 1- and 3-month follow-ups after the injection compared to their baseline. There was a statistically significant difference between both groups at 1 and 3-months. The IOP was more elevated in the IVTA compared to the STTA group. At a 6-month follow-up, both groups showed no significant difference in the IOP elevation compared to the baseline. IOP elevation was the most reported adverse effect in all included studies. Cataract formation is also reported in some studies, though no other complications, such as endophthalmitis, vitreous hemorrhage, and/or retinal detachment, are reported in any of the studies. Conclusion: STTA injection has a comparable effect to the IVTA injection and carries a lower risk of intraocular complications. It is considered an easy, safe, and valid alternative to intravitreal injection for the treatment of DME.

Keywords: intravitreal injection, posterior sub-Tenon's capsule injection, triamcinolone acetonide


How to cite this article:
Ibrahim MH, Salman AG, Said AM, Al-Feky MA, Moustafa ME. Efficacy of posterior sub-tenon's capsule injection compared to intravitreal injection of triamcinolone acetonide for treatment of diabetic macular edema: A systematic review and meta-analysis. Egypt Retina J 2021;8:1-12

How to cite this URL:
Ibrahim MH, Salman AG, Said AM, Al-Feky MA, Moustafa ME. Efficacy of posterior sub-tenon's capsule injection compared to intravitreal injection of triamcinolone acetonide for treatment of diabetic macular edema: A systematic review and meta-analysis. Egypt Retina J [serial online] 2021 [cited 2022 May 20];8:1-12. Available from: https://www.egyptretinaj.com/text.asp?2021/8/1/1/336667




  Introduction Top


Diabetes mellitus (DM) is one of the four major types of noncommunicable diseases. From 1980 to 2014, the number of individuals living with diabetes globally expanded from 108 million to 442.[1] In 2019, the evaluated figure had risen to approximately 463 million adults. By 2045, this figure will increase to 700 million worldwide. The majority of adults with diabetes were living in low -and middle-income countries.[2]

The World Health Organization claims diabetes is the second-most common cause of death in Egypt after cardiovascular disease.[3] In 2013, Egypt was ranked eighth highest in the world for diabetes rates. In 2015, the prevalence of diabetes in Egypt was around 15.6% of all adults aged 20–79.[4] In 2017, the incidence of diabetes rose with approximately 17.3% in adults. According to the International Diabetes Federation, 8.2 million adults were affected by diabetes, which is expected to double to 16.7 million by 2045.[5]

Diabetic retinopathy (DR) is a complication seen in patients with diabetes, who have long suffered from the disease. The long duration of diabetes is one of the significant risk factors for DR.[6]

Diabetic macular edema (DME), is a very common complication of diabetes. It is the leading cause of vision loss in people with DR. It can occur at any stage of DR either nonproliferative DR or proliferative DR. It is more likely to occur later as the disease goes on.[7]

DME occurs in about 12% of type 1 diabetes mellitus and 28% of type 2 diabetes mellitus, causing more than 10,000 new blindness cases each year. Both duration and type of diabetes have a direct impact on the DME prevalence rate.[8]

Inflammation has been shown to play a crucial part in DME pathogenesis. Different inflammatory mediators are involved in the breakdown of the blood–retinal barrier (BRB) and increased vascular permeability such as vascular endothelial growth factor (VEGF), prostaglandins, cytokines, adhesion molecules, tumor necrosis factor, interleukins, and angiotensin II (ANG II).[9]

Corticosteroids have both anti-inflammatory and anti-angiogenic properties. They can suppress the production of inflammatory mediators and inhibit the phospholipase A2 pathway responsible for DME development. They also reduce vascular permeability and stabilize the BRB by promoting tight junction protein expression.[10]

The commonly used corticosteroids for DME treatment include triamcinolone acetonide (TA), dexamethasone, and fluocinolone acetonide. These three agents are potent and selective glucocorticoid receptor agonists with different binding affinity and lipophilicity.[11]

Several routes of administration have been used to deliver corticosteroids. The most commonly used ocular administration routes are intravitreal injection and posterior sub-Tenon's capsule injection.[12]

Many previous studies compared intravitreal injection of TA (IVTA) and sub-Tenon's capsule injection of TA (STTA) injections in DME patients. These studies reported that STTA for DME had a comparable effect to IVTA with a significant improvement in BCVA and central macular thickness (CMT) at 1- and 3-months postinjection. They found that STTA is associated with a lower risk of elevated IOP than IVTA.[12],[13],[14],[15],[16],[17],[18],[19]


  Materials and Methods Top


The review authors have come up with a systematic review and meta-analysis protocol in accordance with PRISMA-P or the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols.[20]

They used the PRISMA checklist to make sure that the reported items are complete and to optimize the protocol's quality. The authors then reported the results of the systematic review in alignment with the PRISMA guidelines and abstract checklist and the guidelines for reporting systematic review and meta-analysis of human studies.

Eligibility criteria

Inclusion criteria

This systematic review included randomized controlled clinical trials (RCTs) in any language between January 01, 2000, and September 01, 2019, center involving DME (newly diagnosed or refractory types), Studies comparing the two interventions for the management of DME (single IVTA [4 mg/0.1 ml] vs. single STTA [40 mg/ml]) and follow-up at least of 3-months.

Exclusion criteria

While causes of macular edema other than DR, DME with vitreoretinal traction, ischemic maculopathy, A prior cataract surgery within the past 6-months, macular laser photocoagulation within 3-months before the injection, TA as adjuvant therapy for the other modalities for DME were excluded.

Outcome measures

The outcome measures in these studies included at least a single change in BCVA, CMT, and IOP.

Search methods for identifying studies

A comprehensive literature search was conducted using the databases Google Scholar, PubMed, MEDS, WEB of Science, EMBASE, and Cochrane Library with the keywords: “posterior sub-Tenon's,” “intravitreal,” “triamcinolone acetonide,” “diabetic macular edema,” and “central macular thickness” for published studies from January 01, 2000 to September 01, 2019.

  • References cited in these articles were searched to come up with additional articles
  • Titles and abstracts were screened for eligibility and the full texts for all potentially eligible publications were reviewed.


Data extraction

Data included study population characteristics (age, gender, number of patients and eyes, and location), intervention groups, outcome variables, duration of follow-up, mean duration of DM and DME, and baseline characteristics of patients in the two groups.

Data synthesis and analysis

Statistical analysis was performed using Open Meta-Analyst (Center for Evidence-based Medicine, Brown University, Rhode Island, USA),[21] and StatsDirect 2.8 (Manchester University, Manchester, England, United Kingdom).[22]

Testing for heterogeneity

The studies included in the meta-analysis were tested for heterogeneity of the estimates using the following tests:

  • Cochran Q Chi-square test: A statistically significant test (P ≤ 0.05) denoted heterogeneity among the studies
    • I-square (I2) index which is interpreted as follows:


  • I2 = 0%–40%: Unimportant heterogeneity
  • I2 = 30%–60%: Moderate heterogeneity
  • I2 = 50%–90%: Substantial heterogeneity
  • I2 = 75%–100%: Considerable heterogeneity.


Pooled estimates

With the test of heterogeneity, if it was significant random effect estimates should be considered, otherwise fixed effect estimate should be used. Estimates from included studies were pooled using the DerSimonian-Laird random-effects method (REM) and the Mantel-Haenszel fixed-effects method (FEM). In the presence of significant heterogeneity, the REM was considered a first option before the FEM where P ≤ 0.05 are considered statistically significant.

Examination of publication bias

Publication bias was assessed by examination of the funnel plots of the effect size measures. The funnel plot is a plot of the estimated effect size on the horizontal axis versus standard error (SE) or a measure of study size (precision = 1/SE) on the vertical axis. If publication bias, which results in the asymmetry of the funnel plot, is present, the smaller studies will show the larger effects. The funnel plot may not always be a reliable tool, especially if the number of studies included in the analysis is small.

Funnel plot assessment is a qualitative analysis that can be subjective as its interpretation is reviewer-dependent. Complementary statistical tests such as Begg-Mazumdar Kendall's tau and Egger bias have been developed to quantify publication bias for the included small number of studies. P ≤0.05: Was significant.


  Results Top



  Search results Top


An extensive search of electronic literature located 419 studies; 260 duplicates were removed and 144 of which were eliminated after the title and abstract were reviewed. On the other hand, fifteen studies were retrieved for more detailed assessment and five more studies were excluded based on comprehensive full-text reviews. [Figure 1], a flow diagram, provides an overview of the selection process for the study. A final total of ten studies were included in the meta-analysis. The reasons for exclusion are mentioned in [Table 1].
Figure 1: Flow diagram for systematic review

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Table 1: Excluded randomized controlled trials

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A common practical problem associated with meta-analysis of repeated measures in calculating the difference in mean change between groups.

The mean change in BCVA, CMT, and IOP for 1-, 3-, and 6-months follow-ups and baseline after the injection could not be calculated.

The mean paired difference between each time point and the baseline and the standard deviation of that difference should be obtained to examine the change between 1-, 3-, and 6-months from the baseline.

Unfortunately, these figures are not reported in most papers in all branches of medicine and not exclusively in ophthalmology. They usually report mean and standard deviation at each timepoint and make the comparisons, and be satisfied with the P value, without mentioning these two measures. The required measurements from the written ones couldn't be predicted.

Included studies characteristics

[Table 2] outlines the characteristics of the included studies; all were published between 2000 and 2019. They were RCTs – 343 participants with DME (469 eyes). The mean age ranged between 54.125 and 64.7 years. The baseline of the mean BCVA ranged between 1.077 and 0.6 logMAR. The CMT mean baseline ranged between 308.80 and 525.1 μm. m. The IOP mean baseline ranged between 13 and 16.46 mmHg. For STTA, a vial of 1 ml containing 40 mg of TA was injected in all the included studies. For IVTA, a volume of 0.1 ml containing 4 mg of TA was injected in all the included studies. The shortest duration of the studies included was 3-months, while the longest 6-months.
Table 2: Included studies characteristics

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Visual acuity

BCVA is the most important primary outcome in measuring the efficacy of both interventions on patients. In the included studies, BCVA is measured using the logMAR scale, and reported for each group as the mean difference in logMAR units at 1-, 3-, and 6-month follow-ups after the injection.

[Table 3] presents the mean difference of BCVA improvement comparing the results of the IVTA and STTA groups for 1-, 3-, and 6-month follow-ups and baseline evaluations.
Table 3: Mean difference of best corrected visual acuity in intravitreal injection of triamcinolone acetonide and sub-Tenon's capsule injection of triamcinolone acetonide at baseline and 1-, 3-, and 6-months

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The BCVA's results indicate that both IVTA and STTA groups were associated with significant BCVA improvement from the baseline to 1 and 3-months following the injection. However, after 6-months, no significant improvement could be seen in the BCVA either in the IVTA or STTA groups when compared to the baseline value. [Figure 2] shows logMAR BCVA improvements in the IVTA group versus those in the STTA after the injection.
Figure 2: Forest plot summary of studies comparing IVTA with STTA for BCVA at 1-, 3-, and 6-months

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At a 1-month follow-up after the injection, the Q test for heterogeneity = 44.055013, degree of freedom (df) =8, P < 0.0001, I2 (inconsistency) is 81.8%, − reflects a highly significant heterogeneity and points out to REM's competence to assess efficacy − with an overall pooled weighted mean difference (WMD) of − 0.021043 and a 95% confidence interval (CI) ranging from − 0.107621 to 0.065534, reflecting a nonsignificant difference in the BCVA efficacy in the IVTA group compared to the STTA group where P = 0.6338. Treatment with IVTA showed no significant BCVA improvement compared with STTA (pooled estimate = −0.021 logMAR; 95% CI − 0.108–0.066; P > 0.05).

At a 3-month follow-up after the injection, the Q test for heterogeneity = 48.715484, df = 8, P < 0.0001, I2 (inconsistency) =83.6% − reflects a highly significant heterogeneity and REM's competence to assess efficacy − with an overall pooled WMD of 0.01088 and a 95% CI ranging from − 0.074574 to 0.096334, reflecting a nonsignificant difference in the BCVA efficacy in the IVTA group compared to the STTA group where P = 0.8029. Treatment with IVTA showed no significant BCVA improvement compared with STTA (pooled estimate = 0.011 logMAR; 95% CI − 0.075–0.096; P > 0.05).

At a 6-month follow-up after the injection, the Q test for heterogeneity = 12.066197, df = 4, P = 0.0169, I2 (inconsistency) =66.8% − reflects a moderately significant heterogeneity and REMs competence to assess efficacy − with an overall pooled WMD of 0.022254 and a 95% CI ranging from − 0.100734 to 0.145243, reflecting nonsignificant difference in the BCVA efficacy in the IVTA group compared to the STTA group where P = 0.7229. Treatment with IVTA showed no significant BCVA improvement compared with STTA (pooled estimate = 0.022 logMAR; 95% CI − 0.101 to 0.145; P > 0.05).

Central macular thickness

CMT, which is an important secondary outcome, is considered a strong prognostic measure of the DME severity degree. It is measured in the included studies using OCT and reported to each group as the mean difference in the macular thickness (μm) m) at 1-, 3-, and 6-month follow-ups after the injection.

[Table 4] shows the mean difference of the CMT reduction in the two groups of IVTA and STTA at 1-, 3-and 6-month follow-ups compared to baseline evaluations.
Table 4: Mean difference of the central macular thickness in intravitreal injection of triamcinolone acetonide and sub-Tenon's capsule injection triamcinolone acetonide at baseline and 1-, 3-, and 6-months

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According to CMT reduction, both IVTA and STTA were associated with a significant reduction in CMT from baseline to 1- and 3-months postinjection. However, at 6-months, there was no significant reduction in CMT in both groups when compared to the baseline value. [Figure 3] shows CMT reduction in the IVTA group versus those in the STTA after the injection.
Figure 3: Forest plot summary of studies comparing IVTA with STTA for CMT at 1-, 3-, and 6-months

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At a 1-month follow-up after the injection, the Q test for heterogeneity = 792.410514, df = 7, P < 0.0001, I2 (inconsistency) =99.1% – reflects a highly significant heterogeneity and REM's competence to assess efficacy – with an overall pooled WMD of − 38.814566 and a 95% of the CI ranging from − 105.808339 to 28.179207, shows non-significant difference in CMT reduction in the IVTA group compared to the STTA group where P = 0. 2561. Treatment with IVTA showed no significant CMT reduction compared with STTA (pooled estimate = −38.815 μm; m; 95% CI − 105.808 to 28.179; P > 0.05).

At a 3-month follow-up after the injection, the Q test for heterogeneity = 262.078208, df = 8, P < 0.0001, I2 (inconsistency) is 96.9% – reflects a highly significant heterogeneity and points out to REM's capacity to assess efficacy – with an overall pooled WMD of − 21.081903 and a 95% CI ranging from − 63.588609 to 21.424803, reflecting a nonsignificant difference in CMT reduction in the IVTA group compared to the STTA group where P = 0. 331. Treatment with IVTA showed no significant CMT reduction compared with STTA (pooled estimate = −21.082 μm; m; 95% CI − 63.589–21.425; P > 0.05).

At a 6-month follow-up after the injection, the Q test for heterogeneity = 653.817758, df = 3, P < 0.0001, I2 (inconsistency) is 99.5% – reflects a highly significant heterogeneity and points out to REM's competence to assess efficacy – with overall pooled WMD of 47.080327 and a 95% CI ranging from − 94.707657 to 188.868311, reflecting a nonsignificant difference in CMT reduction in the IVTA group compared to the STTA group where P = 0. 5152. Treatment with IVTA showed no significant CMT reduction compared with STTA (pooled estimate = 47.080 μm; m; 95% CI − 94.708 to 188.868; P > 0.05).

Intraocular pressure

The primary adverse effect with either treatment group is increase in IOP. IOP is measured by applanation tonometry and reported for each group as the mean difference in mmHg at 1-, 3-, and 6-months follow-ups after the injection.

[Table 5] presents the mean difference of the elevation in the IOP elevation through a comparison between the results of the IVTA and STTA groups at 1-, 3-, and 6-months follow-ups and baseline evaluations.
Table 5: Mean difference of intraocular pressure for intravitreal injection of triamcinolone acetonide and sub-Tenon's capsule injection triamcinolone acetonide at baseline and 1-, 3-, and 6-months

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According to IOP measurements, both IVTA and STTA were associated with significant elevation in IOP from baseline to 1-and 3-months postinjection. However, at 6 months, there was no significant IOP elevation in both groups when compared to the baseline value. [Figure 4] shows elevations in IOP in the IVTA group versus those in the STTA after the injection.
Figure 4: Forest plot summary of studies comparing IVTA with STTA for IOP elevation at 1-, 3-, and 6-months

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At a 1-month follow-up after the injection, the Q test for heterogeneity = 61.836607, df = 9, P < 0.0001, I2 (inconsistency) is 85.4% – reflects a highly significant heterogeneity and points out to REM's competence to assess safety – with overall pooled WMD of 1.461358 and a 95% CI ranging from 0.550927 to 2.37179, reflecting a significant difference in the IOP elevation in the IVTA group compared to the STTA group where P = 0.0017. Treatment with IVTA showed significant IOP elevation compared with STTA (pooled estimate = 1.461 mmHg; 95% CI 0.551–2.372; P < 0.01).

At a 3-month follow-up after the injection, the Q test for heterogeneity = 57.220222, df = 9, P < 0.0001, I2 (inconsistency) =84.3% – reflects a highly significant heterogeneity and points out to REM's competence to assess safety – with overall pooled WMD of 1.602749 and a 95% CI ranging from 0.80512 to 2.400378, reflecting a significant difference in the IOP elevation in the IVTA group compared to the STTA group where P < 0.0001. Treatment with IVTA showed significant IOP elevation compared with STTA (pooled estimate = 1.603 mmHg; 95% CI 0.805–2.4; P < 0.01).

At a 6-month follow-up after the injection, the Q test for heterogeneity = 99.193256, df = 5, P < 0.0001, I2 (inconsistency) is 95% – reflects a highly significant heterogeneity and points out to REM's competence is considered to assess safety – with an overall pooled WMD of 0.178271 and a 95% CI ranging from − 1.428108 to 1.784649, reflecting a nonsignificant difference in the IOP elevation in the IVTA group compared to the STTA group where P = 0.8278. Treatment with IVTA showed no significant IOP elevation compared with STTA (pooled estimate = 0.178 mmHg; 95% CI − 1.428–1.785; P > 0.05).

Adverse effects

Elevated IOP is the most frequent adverse event associated with either the IVTA injection group or STTA injection group as shown in [Table 6]. Cardillo et al.[28] showed that only one eye in each group (8%) with increased IOP >21 mmHg after injection. These eyes were treated with brimonidine three times daily, and IOP measurements returned to a normotensive level on subsequent evaluation.
Table 6: Number of eyes complicated with intraocular pressure elevation

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Furthermore, Choi et al.[13] reported that in the IVTA group, ten eyes (33%) experienced an IOP elevation to 21 mmHg or higher during the follow-up period, while only one eye (3.3%) in the STTA group.

As well, El-Sayed et al.[15] showed those 11 eyes (27%) suffered from increasing IOP above 21 mmHg after IVTA injection, but only five eyes (12%) after STTA injection. These patients received beta-blocker twice daily, and they returned to baseline on their next follow-ups.

Meanwhile Saleh et al.[29] mentioned that, about 4 eyes (24%) in the STTA group showed an increase in IOP by 5 mmHg from the baseline value. On the other hand, about 10 eyes (62%) in IVTA showed an increase in IOP by 5 mmHg from the baseline value. Only one eye in each group showed an increase in IOP >21 mmHg and required medical treatment. The eye in the PST group did not respond to medical treatment and was restored to normal IOP by excision of TA particles from the subconjunctival space. On the other hand, the eye in the IVT group improved on medical treatment and restore normal IOP.

Soujanya and Lodhi[30] reported that in the IVTA group, there was a pressure rise in 4 out of 20 eyes (20%). Meanwhile, about 5 out of 20 eyes (25%) showed IOP rise in the STTA group. In the IVTA group, all were well controlled with anti-glaucoma medications. In the STTA group, four patients were controlled with medical treatment while one patient developed intractable rise in IOP and had to undergo trabeculectomy.

Soliman et al.[19] showed that only the IVTA group had three eyes (20%) of glaucoma.

Some studies reported other complications besides IOP elevation such as cataract progression as shown in [Table 7]. El-Sayed et al.[15] reported posterior subcapsular cataract (PSC) development in two patients in the IVTA group (5%) 6-months after the injection.
Table 7: Number of eyes complicated with cataract development

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Saleh et al.[29] reported PSC development in two patients who received IVTA (12%) 6-months after the injection just as patients who received STTA showed PSC development in two patients (12%) also 6-months after the injection.

Soliman et al.[19] reported progression of preexisting cataracts in three patients (20%) in the IVTA group and a progression of a preexisting cataract in two patients (13%) in the STTA group. Soujanya and Lodhi, 2018 reported that 4 out of 20 patients (20%) in either group developed cataract. No other complications, such as endophthalmitis, vitreous hemorrhage (VH), and retinal detachment (RD), were reported in any of the included studies.


  Discussion Top


This study was conducted to assess the efficacy and complications of the IVTA injection, compared to the STTA injection, in the treatment of DME. BCVA is considered a highly important outcome for patients, which is the primary measure of efficacy, and the change in the CMT, which is the secondary prognostic measure.

The results of the mean difference of BCVA improvement showed that the IVTA and STTA were both associated with significant BCVA improvement from the baseline to 1 and 3 months following the injection. However, after 6 months, no BCVA improvement could be detected in either the IVTA or STTA between the baseline and a 6-month follow-up after the injection.

The results of the mean difference of the CMT reduction showed that the CMT in both groups had significantly reduced from the baseline to 1 and 3-months after the injection. However, at 6-months, there was no CMT reduction in either group between the baseline and a 6-month follow-up after the injection.

The results of the mean difference of the IOP measurements showed that IOP elevation in both groups had significantly elevated from the baseline to 1 and 3-months after the injection. However, at 6-months, there was no IOP elevation in either group between the baseline and a 6-month follow-up following the injection.

The meta-analysis shows no significant difference in the BCVA (logMAR) of both groups at 1-, 3-, and 6-month follow-ups after the injection. Both the IVTA and STTA had a comparable effect and no significant difference in BCVA efficacy could be seen in both groups. It also shows no significant difference in the CMT (μm) m) of both groups at 1-, 3-, and 6-month follow-ups after the injection. Both groups also had a comparable effect and no significant difference with regard to the CMT.

These results are in agreement with Choi et al.,[13] Qamar et al.,[12] El-Sayed et al.,[15] Luo et al.,[16] Elfassi et al.,[18] Saleh et al.,[29] Soliman et al.,[19] and Soujanya and Lodhi.[30]

Choi et al.[13] reported no significant difference in the mean of BCVA and CMT in the two groups at 1-and 3-month follow-ups after the injection.

Qamar et al.[12] reported no significant difference, in terms of the BCVA improvement and CMT reduction, between the two groups in the 1 and 3-months following the injection.

El-Sayed et al.[15] reported no statistically significant difference between both groups in 1-, 3-, and 6-months in terms of their postinjection outcome for CMT. They also report a statistically significant difference between both groups at 1-month follow-up only, and no significant difference at 3- and 6-month follows-ups regarding their postinjection outcome for the BCVA.

Luo et al.[16] reported similar results after the injection for the IVTA and STTA at 1 and 3-months in terms of the mean of the BCVA and CMT. There was no significant difference in both eyes receiving different routes of the same treatment.

Elfassi et al.[18] reported a significant CMT reduction and BCVA improvement in both groups 1 and 3-months after the injection.

Saleh et al.[29] reported a nonstatistically significant difference in the mean BCVA in both groups at 1-, 3-, and 6-months after the injection. CMT reduction was significantly higher at a 1-month follow-up, though only in the IVTA group compared to the STTA group.

This is the only paper that reported the mean change in CMT from baseline in both study groups at 1-, 3-, and 6-month follow-ups and the baseline after the injection.

No direct comparison between the mean in the two groups was carried out since the CMT values were obtained using different OCT machines with different protocols for CMT calculation. However, the same OCT was used on every single patient at different study points to validate the calculation and use of the change in the CMT achieved by every eye as an outcome measure.

Soliman et al.[19] also reported no significant difference at 1 and 3-months regarding/in relation to their postinjection outcome for the mean of the BCVA and CMT.

Soujanya and Lodhi[30] reported no statistically significant difference between the two groups in the BCVA and CMT at any stage at 1-, 3-, and 6-months following the injection.

In contrast to these results, some studies show significant differences in the mean of BCVA improvement and CMT reduction between both groups. Bonini-Filho et al.[27] reported an improvement in the mean of BCVA as well as a CMT reduction at 1-, 3-, and 6-month follow-up examinations which were significantly higher in the IVTA group compared to the STTA group.

It was noted that some TA reflux of the STTA injection has occurred in three eyes after the infusion of at least 0.8 mL of the suspension, leading to suboptimal dosing. This fact may have partly contributed to a diminished effect observed in the STTA group. Only diabetic patients with satisfactory glycaemic and blood pressure control were included in this study. Additional bias could be derived from temporal variation to minimize such natural effects. OCT evaluations were performed between 1.00 and 6.00 p.m. during follow-up visits.

Cardillo et al.[28] reported that the mean BCVA improvement and CMT reduction in IVTA-injected eyes were significantly better than in STTA-injected eyes at 1 and 3-months after the injection with no significant difference between both groups at 6-months. The use of symmetric paired and nonpreviously treated eyes of each patient was very restricted and was applied using two different approaches, which allowed a more reliable comparison by eliminating potential clinical, systemic, and environmental bias.

Increased IOP is the main adverse effect and the most common complication that occurred with both groups after the injection. This meta-analysis shows significant IOP elevation in the IVTA group compared to STTA at 1 and 3-months after the injection, though with no significant difference at 6-months.

This result is in agreement with other studies,[12],[15],[16],[18],[19],[29] all these studies reported a statistically significant difference in the IOP between the two groups at 1 and 3-months after the injection where the IOP elevation of the IVTA group was greater than that of the STTA group. Choi et al.[13] showed the IVTA IOP elevation at only 3-months following the injection with no significant difference between both groups at 1-month.

In contrast to this result, some studies show no significant difference in the IOP mean between the two groups after the injection, and no significant difference in IOP elevation between both. Bonini-Filho et al.,[27] Cardillo et al.[28] and Soujanya and Lodhi,[30] reported no statistically significant difference in the IOP mean between the two groups at 1-, 3-, and 6-months after the injection.

Qi et al.[31] carried out a meta-analysis with different results to this study. It showed that the IVTA led to more significant improvement in the BCVA logMAR compared to STTA from the baseline to 1 and 3-months, but at a 6-month follow-up, the difference was not significant. CMT μm rm reduction from the baseline was more significant in the IVTA group compared to the STTA group at 1 and 3-months, but at a 6-month follow-up, the difference was not significant. Comparison of IOP elevation between both interventions showed no difference in the IOP between them at a 1-month follow-up after the injection. However, at 3-months, patients with IVTA developed a more significant elevation in the IOP from the baseline compared to the STTA group. Different results are expected due to the small number of studies included in the calculation of summary estimates. Some data, regarding BCVA, CMT, and IOP, were not reported in the included studies. The BCVA data in the study of Takata et al.[24] were not reported. The CMT and IOP data in the study of Yalcinbayir et al.[25] was also not reported.

Another meta-analysis, by Yilmaz et al.[32] included only two studies. It showed that the IVTA injection demonstrated greater improvement in both the BCVA and CMT than STTA at 3-months, but not at 6-months. The IVTA demonstrated no difference in the IOP at 3 and 6-months compared to the STTA group.

Cataract progression is another adverse effect mentioned in some studies. PSC is, by far, the most common type of cataract reported in these studies. No other potential complications such as endophthalmitis, VH, and RD were reported in any study.

This meta-analysis study has several limitations such as the small size of the sample and the short follow-up period, both of which have limited the assessment of the chronic IOP changes as well as the cataract progression. The lens type of patients was also not specified in the included studies. The number of studies included in the calculation of pooled summary estimates was small.

In addition, some characteristics and outcome measures for patients are not stated in some of the studies, and no authors were contacted to complete the required data or acquire further information about the methodology. Another limitation is that only published studies and abstracts were reviewed, and even though small negative studies have been conducted, they were not potentially published in order not to expose the review to the effects of publication bias. Furthermore, few studies had measures of the patients' comorbidities, severity of diabetes, and the duration of disease and DME, which may define the heterogeneity and inconsistency found in primary studies.


  Conclusion Top


STTA achieves clinical results comparable to the IVTA regarding BCVA improvement and CMT reduction.

Elevated IOP and cataract formation are the main complications, though STTA carries a lower rate of intraocular complications than the IVTA injection in terms of elevated IOP and cataract formation.

STTA injection has a comparable effect to the IVTA injection and carries a lower risk of intraocular complication. It is considered an easy, safe, and valid alternative to intravitreal injection for the treatment of DME. Both IVTA and STTA may be equally tolerated with short-term performance.

Regarding the comparison between both treatment groups, the effects of both interventions turned out to not have reached 6-months and need to be re-injected.

Corticosteroids are preferred over anti-VEGF in patients with cerebrovascular and cardiac thromboembolic problems.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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