Oman Journal of Ophthalmology

ORIGINAL ARTICLE
Year
: 2017  |  Volume : 10  |  Issue : 3  |  Page : 177--183

Experience of intravitreal triamcinolone acetonide for treatment of diabetic macular edema among Omani population


Ahmed Al Hinai1, Upender Krishen Wali1, Tayseer Abdul Rasool1, Syed G Rizvi2,  
1 Department of Ophthalmology, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman
2 Department of Family Medicine and Public Health, Sultan Qaboos University Hospital, Muscat, Sultanate of Oman

Correspondence Address:
Ahmed Al Hinai
Department of Ophthalmology, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat
Sultanate of Oman

Abstract

PURPOSE: The purpose of this study was to evaluate the outcome of intravitreal (IVT) triamcinolone in diabetic macular edema (DME). MATERIALS AND METHODS: A retrospective study of 42 eyes diagnosed clinically and supported with optical coherence tomography (OCT), with DME of more than 300 μm in thickness. All eyes were injected with a single IVT injection of preservative free triamcinolone acetonide (TA) with dose of 4 mg. Patients were subjected to visual acuity (VA) and OCT on each follow-up visit which was continued for 6 months. The total number of IVT injections given was 48. Six eyes had a repeat injection. None of the eyes had any other IVT injection within 6 weeks of TA. Twenty-one eyes were pseudophakic. RESULTS: Mean age of the patients was 58.8 years. The mean central subfield thickness (CST) at baseline was 504.6 μm. At 6 weeks, the mean CST dropped by 183.6 μm (P < 0.00001). At 6-month follow-up, the mean CST had increased by 74.6 μm from 6 weeks level; however, the 6-month mean CST was 109 μ less than mean baseline thickness (P < 0.0005). The mean baseline VA was 0.80 LogMAR units. At 6 weeks, the mean VA dropped by 0.01 LogMAR. At 6 months, VA improved by 0.02 LogMAR units from baseline. Overall, VA improved in 47% eyes, dropped from baseline in 35% eyes, and remained unchanged in 18% eyes. CONCLUSION: Triamcinolone acetonide is a safe, effective, and promising therapy in DME.



How to cite this article:
Al Hinai A, Wali UK, Rasool TA, Rizvi SG. Experience of intravitreal triamcinolone acetonide for treatment of diabetic macular edema among Omani population.Oman J Ophthalmol 2017;10:177-183


How to cite this URL:
Al Hinai A, Wali UK, Rasool TA, Rizvi SG. Experience of intravitreal triamcinolone acetonide for treatment of diabetic macular edema among Omani population. Oman J Ophthalmol [serial online] 2017 [cited 2019 Aug 24 ];10:177-183
Available from: http://www.ojoonline.org/text.asp?2017/10/3/177/215995


Full Text

 Introduction



Diabetic macular edema (DME) is the most common cause of disturbed central vision in diabetic retinopathy (DR). Visual acuity (VA) and macular thickness are two important parameters in the follow-up of patients with DME. We have attempted to design our study taking these two parameters into consideration in three groups: (1) overall values in terms of VA (LogMAR) and central subfield thickness (CST) in optical coherence tomography (OCT) in all patients irrespective of age or gender; (2) gender-wise; and (3) two age groups (<60 years and ≥ 60 years); age demarcation is based on mean age of all patients (58.8 years). The results are in terms of changes in macular thickness and VA before and after single injection of 4 mg intravitreal triamcinolone acetonide (IVT TA) in patients with DME [Figure 1]. This study is based on a selected population in the Arabian Peninsula.{Figure 1}

Oman has nearly 14.5% DR rate among a huge population of about 260,000 diabetics. Among Omani population of 20 years of age and above, nearly 12.2% are diagnosed with diabetes mellitus (DM).[1] Wisconsin Epidemiological Study of DR states the 10-year cumulative incidence of macular edema to be 20.1% among Type 1 diabetes and 25.4% among those with type 2 diabetes.[2] Vascular endothelial growth factor (VEGF) is an important cytokine responsible for initiation and progression of DR. Aldose reductase, vasoproliferative factors, and blood viscosity functions have been proposed in the pathogenesis of DR. Duration of diabetes, poor glycemic control, hypertension, pregnancy, nephropathy, hyperlipidemia, smoking, obesity, and anemia are known risk factors for DR.

There are many nonsteroidal anti-VEGF drugs currently being injected intravitreally for the treatment of DME. These include bevacizumab, ranibizumab, and aflibercept. The steroid group includes TA, dexamethasone, and fluocinolone. Not all are approved by the Food and Drug Administration (FDA) for use in DME and some are used off-label worldwide. Our endeavor to study effect of single IVT injection of 4 mg of preservative free TA is based on the severity of DME, resistance to laser or anti-VEGF therapy or effort to reduce DME before laser can be initiated and effective. TA is a company-packed drug hence quite reliable. Ranibizumab has cost-effective issue and costs 10 times more than bevacizumab or TA. At the time of diagnosis of DM, DR is present in 0%–30% of patients.[3] The incidence of DR is estimated to be 2.3/100 person per year for the overall diabetic population and 4.5 for patients on insulin therapy.[4] After fundus angiography, two major advances in the diagnosis and treatment of DR have been OCT and intravitreal anti-VEGF agents.

In Type 1 DM, there is a very low risk of retinopathy in the first 5 years. However, this jumps to 27% for those who have diabetes for 5–10 years and 71%–90% of those who have diabetes for more than 10 years, and after 20–30 years of diagnosis of DM, the incidence rises to 95%.[5] In Type 2 diabetes, the prevalence of retinopathy has been widely reported at 23% after 11–13 years and 60% after 16 or more.[6] The prevalence of DME does not vary much by type of diabetes. It stands approximately at 18%–20% in patients with Type 1 or Type 2 diabetes.[7] Pregnant diabetics with non-proliferative DR (NPDR) at the onset tends to show progression in DME. Fortunately, there is regression after delivery.

Diabetic maculopathy includes foveal edema, exudates, or ischemia. Macular edema is an important manifestation of any stage of DR and represents the leading cause of legal blindness in diabetics, particularly of Type 2. The Early Treatment Diabetic Retinopathy Study (ETDRS) research group found 3-year risk of moderate visual loss for patients with foveal or perifoveal macular edema to be 24% for the control group and 12% for the laser-treated group.[8] VEGF-A is a major contributor to the inflammatory, angiogenesis, and permeability processes. Hyperglycemia has been linked to neuronal dysfunction and subsequent vision loss. Diffuse capillary incompetence and leakage from microaneurysms lead to intercellular fluid collection. Clinically, it can be seen as a swollen, translucent retina. In chronic and severe cases, fluid leakage is associated with accumulation of lipids in the outer plexiform layer. Slit-lamp stereoscopic biomicroscopy with a contact lens, and OCT is the classic methods of examination and diagnosis in DME. Laser had been the mainstay of treatment so far, but currently anti-VEGF drugs and steroids have proved potential alternatives based on clinical evidences. Treatment of macular edema includes laser photocoagulation, anti-VEGF agents, steroids and vitrectomy. In ETDRS, although laser was shown to reduce moderate visual loss (three ETDRS lines) by 50%, VA improved by three lines in only 3% of treated patients,[8] and overall VA improvement of at least one line was observed in 40% of patients.[9] Some promising results have been shown recently for the treatment of refractory DME with TA.

Patients with DME who stand good chance for improved vision are those with circinate retinopathy of recent duration or focal, well-defined leaking areas with good capillary perfusion. Diffuse and severe macular edema, perifoveal ischemia, multiple leaking areas, and cystoid macular edema stand poor chance of response to treatment.

Steroids and anti-VEGF drugs are now established treatment modalities in the management of DME. Steroids stabilize the blood–retinal barrier; regulate the expression of VEGF, and inhibit pro-inflammatory factors such as tumor necrosis factor alpha and other inflammatory chemokines. Other actions of steroids include expression of anti-inflammatory pigment epithelial-derived factor, inhibiting the expression of matrix metalloproteinases and downregulating expression of intercellular adhesion molecule on vascular endothelial cells. All such actions stabilize the basement membrane and reduce permeability-related exudation.

Intravitreal delivery of steroids has facilitated the treatment of many posterior segment inflammations and exudations without serious systemic side effects, improving both morphological and functional outcomes.

 Materials and Methods



A retrospective analysis (2014–2015) of thirty patients (42 eyes) with DME was undertaken at single referral institute. Thirteen were males and 17 females. All patients had pre- and post-injection measurement of DME using Zeiss Cirrus OCT. Four milligrams of preservative-free TA was used for IVT injection. The main outcome parameters were effect on macular edema and change in best-corrected VA (BCVA). All patients were recruited from eye clinic and clearance from Ethical Committee of university was obtained. The study adheres to the tenets of the Declaration of Helsinki.

Inclusion criteria

Age more than 18 yearsDME refractory to other anti-VEGF therapyCST >300 μmNo prior IVT injection within 6 weeksNo prior ocular laser of any sort within 3 months of injectionNo prior intraocular surgery within 6 months of IVT injection.

Exclusion criteria

Subretinal fibrosisIntraocular surgery in the study eye for the last 6 monthsHistory of ocular inflammationGlaucomaSteroid responsive patientsPatients on drugs that can be associated with the risk of developing macular edema such as glitazones, prostaglandin analogs, alkylating agents, antineoplastic agents, fingolimod, or tamoxifen.

Patients were divided into two age groups; Group 1 aged <60 years and Group 2 aged ≥60 years. The cutoff level of 60 years of age was based on mean age of all patients.

VA was measured in LogMAR units from ETDRS digital charts while CST was taken as reference macular thickness as it represents the subfoveal edema which is most common factor for reduced vision in DME.

Triesence 40 (40 mg/ml Alcon Inc., Fort Worth, Texas, USA) is a preservative free brand of TA recently approved by the FDA for intraocular use. It is indicated in the treatment of sympathetic ophthalmia, noninfectious uveitis, venous occlusions, and temporal arteritis. At present, TA is used off label for DME. Preservative–free TA suspension appears to have more uniform crystal size compared to preserve one, which may affect the half-life of the drug.

Statistical analysis

IBM SPSS (Statistical Packages for the Social Sciences) 23 Statistics software for windows was used for the statistical analysis. Descriptive statistics were firstly performed and quantitative parameters were reported as means in the form of simple bars. Kolmogorov–Smirnov test was used to test the normality of the quantitative variables under study, and if the study variable was found to follow the normal pattern, then paired t-test was used to test the significance of difference between baseline and the other two measurements. In case of nonnormal pattern of the variable, Wilcoxon test was applied instead of paired t-test. P ≤ 0.05 was considered as statistically significant.

 Results



The total number of TA IVT injections given was 48 (42 eyes). Six eyes had repeat injection of TA but not within 6 months of the first injection. None of the eyes had any other IVT injection within 6 weeks of TA injection. Twenty-one eyes were pseudophakic.

There were 42 eyes of 30 patients included in this study. Mean age of the patients was 58.8 years.

Macular edema [Figure 2]{Figure 2}

The mean CST at baseline (on the day and before giving IVT TA) was 504.6 μm. At 6 weeks, the mean CST dropped by 183.6 μm. This was found to be statistically highly significant (P < 0.00001). At 6-month follow-up, the mean CST had increased by 74.6 μm from 6 weeks level; however, the 6-month mean CST was 109 μm less than mean baseline thickness. This was also found to be statistically very significant (P < 0.0005). Other result parameters of CST based on gender and ages are given in [Table 1a], [Table 1b], [Table 1c], [Table 1d].{Table 1a}{Table 1b}{Table 1c}{Table 1d}

Visual acuity [Figure 3]{Figure 3}

At 6 weeks, the mean VA had dropped by a just 0.01 LogMAR units (P = 0.869). At 6 months, VA improved by 0.02 LogMAR units from baseline (P = 0.418). None of these observations were found to be statistically significant. Males consistently showed improvement at 6 weeks and 6 months follow-up but was not significant (P = 0.615, P = 0.293, respectively). However, females had a drop at 6 weeks but gain at 6 months by 0.01 LogMAR units from baseline (P = 0.384, P = 0.964, respectively). Other result parameters of VA based on gender and ages are given in [Table 1c] and [Table 1d].

Overall BCVA improved in 47% eyes (23 injections), decreased in 35% eyes (17 injections), and remained unchanged in 18% eyes (8 injections). Failure in improvement of VA could be due to the presence of macular ischemia. In an ongoing unpublished pilot study, we have found approximately one-third of our patients with DR have macular ischemia (unquoted).

IOP increased in six eyes (range 23–35 mmHg). All patients had IOP well controlled with topical beta-blockers and carbonic anhydrase inhibitors which were continued for 6–12 weeks after the injection. None of the patients required long-term therapy with drops or glaucoma surgery.

Triamcinolone acetonide-related complications

One cataract which was operated upon. There was no case of endophthalmitis or any other intraocular inflammatory reaction.

 Discussion



TA is a synthetic steroid of the glucocorticoid family. It is one of the most commonly used steroids for the treatment of ophthalmic pathologies mainly in posterior segment diseases. Four milligrams of IVT TA yields enough concentration to give therapeutic effect for approximately 3 months. Hauser et al. have found no added advantage of 4 mg dose over 1 or 2 mg dose.[10] However, Lam et al. published a report showing higher dose has more sustained effect on VA and central macular thickness.[11] All our patients have received 4 mg of preservative-free TA. IVT TA does not have a known retinotoxic effect. The treatment effect of TA wanes with time and patients may require repeated injections. None of our patients required second injection till 6 months of follow-up.

IVT triamcinolone has been tested and used (off label) in the management of diffuse or laser-refractory DME either as a naïve or after other therapies has failed. The injection needs to be repeated on a regular basis and has a high risk of cataract progression and secondary glaucoma. Strong evidence from Sutter et al. shows five or more letter improvement in BCVA in 55% eyes treated with 4 mg IVT TA at 3 months compared to 16% of placebo eyes; macular edema decreased in 75% of treated eyes compared to 16% in placebo group.[12] Our patients had an overall improvement of 0.02 LogMAR units 6 months from baseline with single injection only.

Like laser, triamcinolone may yield less vision improvement in eyes with macular ischemia. Focal and grid laser had remained the standard line of treatment in DME. However, in majority of patients, the VA remained unchanged (60.9%) or even became worst (24.6%); only 14.5% showed improvement.[13] None of our patients had received any laser therapy at least 6 weeks before IVT TA. Approximately 70% of our patients had refractory DME, as they did not respond to prior laser or other anti-VEGF injections. At present, two FDA-approved intravitreal corticosteroid implants are being used worldwide in DME. These are fluocinolone acetonide and dexamethasone intravitreal implants.[14] None of our patients had such injections before or after TA.

Ip et al. have compared 1 mg and 4 mg triamcinolone to laser photocoagulation and found greater improvement in mean BCVA with laser at 2 years compared to triamcinolone groups.[15] However, Lam et al. found no statistically significant difference between laser and triamcinolone at 6 months.[16] In a meta-analysis study from Lam, it was found that there is nonstatistically significant improvement in mean BCVA of 15 letters or more in the triamcinolone plus laser group compared to laser alone.[16] The outcome in our study, compared to above, has been a mixed one with statistically significant improvement in CST at 6 weeks and 6 months and nonsignificant improvement in BCVA at 6 months.

The longest term data available for 4 mg IVT TA in refractory DME come from a study done by Gilles et al.[17] Gillies et al. in this paper have given a preliminary analysis at 3 months which made it clear that IVTA was effective in improving VA and reduce macular thickness. At 2 years, data of this study were available for 87% of eyes and showed 55% gain in VA and 126 μ improvement in macular thickness from baseline. Overall improvement in VA and macular thickness at 3 months and 2 years in Gillies' study can reflect, if not corroborate, our findings acknowledging the limitation that follow-up of our patients has been only 6 months.

Overall five major groups (American, European, Canadian, International Council of Ophthalmology, and the Asia Pacific) have laid down guidelines for treatment of DME and all have agreed that the mainstay of treatment of DME has shifted from laser to anti-VEGF treatment in most instances and resistant DME.[18] IVT TA does carry a list of potential risks such as high intraocular pressure, cataract, glaucoma, endophthalmitis, retinal tears or detachment, and hemorrhage. In our series, only one eye developed cataract which was extracted by phacoemulsification and seven eyes had high IOP (23–35 mmHg). All patients with high IOP were treated with anti-glaucoma drops and none required surgery. VA changes in our patients were not significant, but such findings have been observed by Ramezani et al.[19]

Vitrectomy in eyes with taut posterior hyaloids and removal of internal limiting membrane stand better chance of vision improvement compared to those with posterior vitreous separation.[20] None of our patients had vitrectomy before or during 6 months follow-up after IVT TA.

We observed that structural improvement was a more significant outcome than functional. Ramezani et al. have quoted that IVT injection of TA induced relative VA improvement at 6 weeks but slightly better at 6 months. However, a significant reduction occurred in macular thickness at 6 weeks and 6 months.[19] Our patients had maximum effect of TA at 6 weeks in terms of reduction in macular thickness which is corroborated by Ciardella et al.[9] The rise in IOP was highest between 4 and 12 weeks and anti-glaucoma medications had to be continued for 6–12 weeks which is comparable to the study by Jonas et al.[21]

The vitreous concentration of TA after 4 mg dose is 10,000 times greater than that required to occupy all corticosteroid receptors. Furthermore, the second injection is likely to have greater side effects and lower therapeutic response. Based on these facts, we did not consider reinjection in patients who did not show a good response.

In a landmark study by Diabetic Retinopathy Clinical Research (DRCR) network, it was found that 4 mg IVT TA has a good response on VA and OCT-measured retinal thickness at 4 months while laser photocoagulation had more positive response later. This raises the possibility that combined IVT TA and focal/grid laser photocoagulation may produce greater benefit compared to TA or laser alone. Since none of our patients had laser combined with IVT TA, it remains to be seen whether such approach would be feasible and possible. However, our results corroborate well with the 4 mg TA part of DRCR network. More recently, DRCR network has reported that 4 mg TA appears to reduce the risk of DR.[22] Furthermore, since PRP is a safe and successful treatment in PDR, use of TA in preventing progression from moderate to severe NPDR to PDR is questionable.[22] From our results, we agree with DRCR network in terms of reduction of risk of DR with 4 mg TA; however, our series has shown that cataract and glaucoma are not so serious and frequent complications as publicized.

Furthermore, our study is corroborated by Paccola et al. who compared effectiveness of single IVT 4 mg TA with IVT bevacizumab in terms of morphological and VA outcomes on short-term basis and concluded that single IVT injection of 4 mg TA showed better results in reducing DME and improving VA compared to bevacizumab.[23] After 6 months, rehabilitation of vision was comparable in both treatment arms, whereas at the final follow-up at month 12, BCVA was superior in the bevacizumab than in the triamcinolone sample. This may be related to cataract development following steroid treatment. Although our study is not comparative, we observed a statistically significant reduction in CST after 6 months with a single injection of TA.

 Conclusion



We have attempted to follow the DME Treatment Guideline Working Group and management paradigms for DME using intravitreal TA alone as a single injection.[25] We can conclude that TA is quite effective and safe in the treatment of DME. Macular ischemia could be a very important factor in poor visual outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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