Comparative Efficacy of Intravitreal Triamcinolone and Dexamethasone Intravitreal Implant for Diabetic Macular Edema

Abstract

Purpose: To compare the efficacy, adverse effects, and treatment burden of two injectable corticosteroids, triamcinolone acetonide (Kenalog® or Triesence®) and the dexamethasone intravitreal implant (Ozurdex®), for treating diabetic macular edema (DME).

Methods: This was a retrospective review at a single tertiary care center. Eyes treated with either intravitreal triamcinolone two mg (IVTA) or the intravitreal dexamethasone 0.7 mg implant for center-involving DME and with follow up of at least six months were included. Main outcomes were visual acuity (VA), intraocular pressure (IOP), IOP medication use, central macular thickness (CMT), and time to next treatment of any kind.

Results: There were 24 eyes in the IVTA group and 15 eyes in the dex group. Baseline mean VA was 20/60 (range 20/30-20/800) in the IVTA group and 20/35 (range 20/20-20/100) in the dex group (p=0.0011). Only the subgroup of pseudophakic IVTA patients experienced a statistically significant increase in vision early on (+2 letters at month 1, +3 letters at month three), though not at month six. Mean IOP increased by 2.5 and 0.20 mmHg at month one in the IVTA and dex groups, respectively (p=0.27). Mean CMT decreased by 143 mm with IVTA and 39 mm with dex at month one (p=0.00025). Mean time to next treatment of any kind was 19 weeks for IVTA and 20.3 weeks for dex (p=0.41).

Conclusions: Intravitreal triamcinolone and the intravitreal dexamethasone implant both show similar efficacy at reducing DME and its treatment burden, but neither significantly affected visual acuity over six months.

Introduction

A minority of patients respond poorly to anti-VEGF and may benefit from local corticosteroids, like dexamethasone or triamcinolone, which reduce macular edema by inhibiting inflammatory mediators, improving leukostasis, and enhancing tight junctions between endothelial cells [1].

Despite being the only medium-acting, intravitreal corticosteroids, triamcinolone acetonide is a short-to-medium-acting injectable intravitreal corticosteroid lasting from one to several months. No randomized trials comparing the two agents for DME have been performed, so their comparative risk-benefit profiles are unclear. The purpose of this study was to assess and compare the efficacy of these two treatments in a real-world setting.

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Methods

This study was approved by the institutional review board of the home institution and adhered to the Health Insurance Portability and Accountability Act of 1996 and the Declaration of Helsinki. A retrospective chart review was performed on patients 18 or older who had diabetic macular edema and had been treated with either the intravitreal dexamethasone implant, Ozurdex © (Allergan PLC; Dublin, IE) or intravitreal triamcinolone acetonide, Kenalog® (Bristol-Myers Squibb Company; Princeton, NJ) or Triesence® (Alcon Laboratories, Inc; Fort Worth, TX), injections between January 2012 and July 2019 at a single academic medical center. Diabetic macular edema was diagnosed based on center-involving intraretinal cystoid spaces on spectral domain optical coherence tomography (SD-OCT) findings in combination with diabetic retinopathy on clinical exam. Patients with initial central macular thickness (CMT) values under 300 µm were removed from the data set. Patients were excluded from the study if they had retinal vein occlusions, retinal artery occlusions, age-related macular degeneration, or any other pre-existing macular conditions that would otherwise affect the retinal vasculature or macular thickness, or if they had significant media opacity precluding OCT evaluation of the macula. Patients were also excluded if they did not maintain regular follow-up for at least six months after their first corticosteroid injection or if they received centrifuged Kenalog® injections. Patients who had received prior anti-vascular endothelial growth factor (VEGF) treatments were not excluded from the study. Furthermore, some patients continued to receive anti-VEGF treatments a month or more after their first corticosteroid injection, as is consistent with a real-world clinical setting. Similarly, treatment of ocular hypertension with topical ocular hypotensive agents was at the discretion of the treating physician.

Data collected included patient demographics, diabetic diagnosis (DM1 or DM2), prior treatments, lens status, central macular thickness (CMT), best-corrected visual acuity (BCVA), intraocular pressure (IOP), use and number of IOP medications, and time to next treatment (anti-VEGF or corticosteroid). Main outcomes measures were CMT at month one, general trend of CMT change over time, BCVA, IOP and number of IOP medications, and time to next treatment. Outcomes were compared both within a given treatment group over time and between treatment groups. CMT measurements were obtained using the Spectralis (Heidelberg Engineering, Heidelberg, Germany) or the Zeiss Cirrus Angioplex 5000 (Carl Zeiss Meditec, Jena, Germany), with a given patient consistently undergoing imaging on the same machine.

The dexamethasone 0.7 mg implant was inserted according to manufacturer’s recommendation. Triamcinolone acetonide two mg, either Kenalog or Triesence, was administered in 0.05 cc. Statistical tests used were student t-tests, hazard ratios, and Cox proportional hazards models. Student t-tests were all carried out using Microsoft Excel (Microsoft, Redmond, Washington), and proportional hazard tests were carried out using IBM SPSS Statistics (IBM, Armonk, New York).

Results

42 patients were screened, and 35 eyes of 29 patients were included after inclusion and exclusion criteria were applied (Table 1). 20 eyes (14 patients) received triamcinolone treatment (IVTA), while 15 eyes (11 patients) received dexamethasone (dex) treatment.

Both groups were well matched in most respects. Fourteen patients, six in the IVTA treatment group and eight in the dex group, had co-existing heart disease. Thirty-four patients, twenty in the IVTA group and fourteen in the dex group, had co-existing hypertension. Finally, fourteen patients, ten in the IVTA group and four in the dex group, had hyperlipidemia. A1c measures were elevated in both groups with an average overall A1c of 7.29. The IVTA group had an average A1c of 7.07 and the dex group had an average A1c of 7.56 (p = 0.11). Median age was 60 years (IQR 14 years) in the IVTA group versus 63.7 years (IQR 12 years) in the dex group. Women made up 56% of patients in IVTA group and 36.4% of the dex group, type 1 diabetics 28% of the IVTA group and 27% of the dex group, and phakic patients 20% of the IVTA group and 33% of the dex group. Mean baseline CMT was 464.5 µm in the IVTA group and 426.3 µm in the dex group (p = 0.13). Average decimal BCVA was 0.33 (Snellen equivalent 20/60) for IVTA patients and 0.57 (Snellen equivalent ~ 20/35) in the dex group (p = 0.0011), and average IOP 15.3 mmHg for IVTA patients and 16.1 mmHg for dex patients. The average number of anti-VEGF injections prior to first corticosteroid injection was 3.7 for patients in the IVTA group and 6.5 for patients in the dex group (p = 0.02).

Discussion

Presently, both triamcinolone acetonide and dexamethasone are widely used in the treatment of diabetic macular edema refractory to anti-VEGF treatment with or without focal or grid macular photocoagulation. Triamcinolone is administered as an injection approximately every three months, while dexamethasone is an implant advertised to last six months. The zero-order kinetics of dexamethasone implant theoretically improves its IOP profile in contrast to large-bolus triamcinolone injections. Both treatments have been assessed separately to measure efficacy with regard to diabetic macular edema [2, 3]. They have also been directly, prospectively compared in a comparative effectiveness trial for the treatment of uveitic macular edema and retrospectively for retinal vein occlusions [4, 5]. Data comparing the two for diabetic macular edema are surprisingly very limited. This retrospective study sought to compare the efficacy and adverse effects of triamcinolone with the dexamethasone implant for treating DME.

The main outcome measure for this study was change in central macular thickness at one month. While a large amount of additional and still informative data was collected, this outcome was chosen because it represents an important clinical outcome that was free of any confounding by combination treatments. The results clearly demonstrate a superior effect of IVTA over dexamethasone in treating DME at month one, with a change in CMT of -143 µm versus − 39.3 µm (p = 2.5 x10^− 4). This difference is not only highly statistically significant, but is clinically significant as well. CMT changes beyond month one cannot be reliably attributed to the effects of these two corticosteroids because combination treatment was allowed at the discretion of the treating physician. Thus, overall CMT trends across the six months are difficult to interpret. However, one important observation in the dexamethasone group is that there is an inflection point of mean CMT at month three. It falls for the first three months and then begins to rise thereafter. Again, one cannot definitively conclude that the dexamethasone implant’s peak effect is three months because some of these patients received anti-VEGF from month one onwards, but it suggests that the agent’s efficacy declines after month three. These results are consistent with the anatomical data in the Ozurdex PLACID Study comparing the dexamethasone implant plus macular laser photocoagulation to sham treatment plus laser [6]. Peak effect was seen at approximately month one, and there was a steady increase in CMT thereafter. To the authors’ knowledge, anatomical data between injections during the three-year Ozurdex MEAD Study were never published [3, 7]. Interestingly, the POINT Trial comparing the dexamethasone implant to IVTA or periocular triamcinolone for uveitic macular edema, a different indication for corticosteroids but similarly an exudative maculopathy, did not find greater size or duration of effect for the dexamethasone implant over triamcinolone [4].

Visual acuity showed no significant improvement within either group. Both groups contained a mix of phakic and pseudophakic patients. This result is not particularly surprising given the well documented experience with each of these agents in mixed phakic and pseudophakic populations. The Diabetic Retinopathy Clinical Research Network’s Protocol I study, comparing ranibizumab with prompt or deferred laser, triamcinolone with laser, or sham plus laser found no visual acuity benefit at two years with IVTA [8]. In a later DRCR trial, adding dexamethasone to regular anti-VEGF therapy similarly did not improve visual acuity over ranibizumab alone [9].

To assess the potential impact of lens status on visual acuity, visual acuity data was compared for phakic and pseudophakic patients, both within each treatment group and overall. From month zero to month one, there were statistically significant differences favoring improved visual acuity in both pseudophakic triamcinolone patients (p = 0.01). From month zero to month three, dexamethasone patients demonstrated the same trend (p = 0.044). Overall, pseudophakes had better visual outcomes. Although we did not specifically collect data on lens grading in the phakic group, a notoriously subjective assessment, we strongly suspect this was due to corticosteroid-induced cataract formation in these patients, effectively nullifying the expected visual gains from improved DME.

Because all efficacy data after month one are of course confounded by the use of combined anti-VEGF therapy, we sought alternate methods to assess the effect of these two corticosteroids on treatment burden for DME after month one in this real-world setting. In other words, to what extent does use of either of these drugs impact the need for future injections? To answer this question, we created a survival curve of time to next treatment of any kind (anti-VEGF or corticosteroid) and compared the two curves in general by a log-rank (Cox-Mantel) test and in particular for median time to next treatment. The mean time to next treatment was 19 weeks for IVTA and 20.3 weeks for dex. Similarly, the log-rank test showed no difference between the two curves. When only corticosteroid treatments were taken into account, there were on average 1.45 corticosteroid treatments administered within six months when patients were treated with triamcinolone, and 1.38 corticosteroid treatments administered within six months when patients were treated with dexamethasone.

With regard to corticosteroid response, both groups experienced modest increases in IOP, but with a trend towards more significant elevation in the triamcinolone group. Of course, post-injection IOPs were influenced by concurrent ocular hypotensive treatment. 16.7% of IVTA group patients were on IOP medications prior to treatment, which increased to 38.9% after one triamcinolone injection. In comparison, there were no patients in the dexamethasone treatment group receiving IOP-lowering medications prior to treatment, and only 6.6% were prescribed IOP-lowering medications after one implant. Considering the statistically and clinically significantly greater fraction of patients requiring ocular hypotensive treatments post-injection, it is possible that adverse IOP effects induced by triamcinolone may be greater than those of the slow-releasing dexamethasone implant.

This study was limited by several factors. First, it suffers from the usual weaknesses of retrospective studies. The groups were not randomized, and thus there may be imbalances between them. Indeed, the IVTA group had slightly greater CMT at baseline, which increases this group’s ability to improve CMT, the so-called ceiling or floor effect. Similarly, they differed in number of prior anti-VEGF treatments, 3.9 in the IVTA group and 6.53 in the dexamethasone group. However, the implications of this difference are unclear. On one hand, it may suggest DME that is more resistant to treatment. On the other hand, a suboptimal response to eight anti-VEGF injections should not necessarily preclude response to intravitreal corticosteroids because of their different mechanism of action, which is precisely why they remain a second-line treatment option. Moreover, physicians treated their patients per clinical judgment, and thus times to next treatment reflect the treating physicians’ degree of aggressiveness and not simply the efficacy of these different agents. Last, as already mentioned, efficacy data after month one were confounded by combination treatment with anti-VEGF in most cases, and IOP data by the use of ocular hypotensive treatments. However, analyzing several metrics like use of ocular hypotensive agents in each group and time to next treatment “survival” curves allow us to make meaningful if limited real-world conclusions about comparative IOP profiles and treatment burdens with these agents.

Last, we concede on two points. We realize that the retrospective design of our study allowed for there to be less chronic cases in one group over the other. This is something that we tried to control for by following records back to the first recorded injection at our facility, assumedly documenting all anti-VEGFs used as well as the first corticosteroid administered. Many of these were 2012 or prior, so paper records were used at that time. It is possible that we did not catch the first injection for everyone, but we strived to ensure that we did.

Secondly, 29 patients (35 eyes) meeting inclusion and exclusion criteria do not constitute a large group. One example of this is that there was only one treatment-naïve patient per group, which prevented comparison of treatment-naïve to non-naïve. While certain limited conclusions can be reached, other questions can only be answered with larger numbers and in a prospective fashion. For instance, determining the comparative duration of effect of the two agents can only be determined in a randomized, head-to-head trial without the use of combination therapy.

In summary, intravitreal triamcinolone and the intravitreal dexamethasone implant both show efficacy at improving DME and reduce treatment burden similarly, but both had little effect on visual acuity. Triamcinolone had superior anatomical efficacy at one month, but possibly at the expense of a worse IOP profile. While this study could not determine which drug has the greater duration of effect, the dexamethasone implant showed waning efficacy after three months. Additionally, pseudophakic patients receiving either treatment demonstrate better outcomes with regard to visual acuity measures.

References

1. Whitcup SM, Cidlowski JA, Csaky KG, Ambati J (2018) Pharmacology of corticosteroids for diabetic macular edema. Invest Ophthalmol Vis Sci 59:1–12
2. Hong IH, Choi W, Han JR (2020) The effects of intravitreal triamcinolone acetonide in diabetic macular edema refractory to anti-VEGF treatment. Jpn J Ophthalmol 2:196–202
3. Boyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RJ, Augustin AJ et al for the Ozurdex MEAD Study Group (2014) Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular. edema Ophthalmology 121:1904–1914
4. Thorne JE, Sugar EA, Holbrook JT, Burke AE, Altaweel MM, Vitale AT et al (2019) Periocular triamcinolone vs intravitreal triamcinolone vs intravitreal dexamethasone implant for the treatment of uveitic macular edema: the periocular vs. intravitreal corticosteroids for uveitic macular edema (POINT) trial. Ophthalmology 126:283–295
5. Ozkok A, Saleh OA, Sigford DK, Heroman JW, Schaal S (2015) The OMAR study: comparison of Ozurdex and triamcinolone acetonide for refractory cystoid macular edema in retinal vein occlusion. Retina 35:1393–1400
6. Callanan DG, Gupta S, Boyer DS, for the Ozurdex PLACID Study Group (2013) Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular. edema Ophthalmology 120:1843–1851
7. Ziemssen F, Agostini H. Re: Boyer et al (2015) Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 122:20 – 1
8. Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL, Friedman SM, Glassman AR et al for the Diabetic Retinopathy Clinical Research Network (2011) Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 118:609–614
9. Maturi RK, Glassman AR, Liu D, Beck RW, Bhavsar AR, Bressler NM et al for the Diabetic Retinopathy Clinical Research Network (2018) Effect of adding dexamethasone to continued ranibizumab treatment in patients with persistent diabetic macular edema: a DRCR Network phase 2 randomized clinical trial. JAMA Ophthalmol 136:29–38

Tables

Table 1. Baseline Demographics and Clinical Values by Group at  Baseline^a

^aTwo patients were excluded from the baseline CMT calculations due to inaccurate computed CMT values 

Table 2. Clinical Outcomes of CMT, BCVA, and IOP Following Administration of Triamcinolone or Dexamethasone. In the Difference Between Groups section, the desirable result (decrease for CMT and change in IOP and increase for BCVA) is listed, along with a D or T (dexamethasone or triamcinolone) for which treatment group was comparatively better and a p value comparing the two groups. P values are in parentheses.

Table 2. CMT, BCVA, and IOP Following Intravitreal Injection of Triamcinolone or Dexamethasone

Table 3. logMAR Change in BCVA Over Time for Pseudophakic and Phakic Patients. This table compares change in BVCA over time for phakic and pseudophakic patients, both within dexamethasone and triamcinolone trials and overall. Units are reported in logMAR to allow comparison. There was no dexamethasone data for phakic patients receiving follow-up at both month 1 and moth 6 post-treatment, so only triamcinolone data is reflected in the “Month 1 to Month 6” section.

Table 3. logMAR Change in BCVA Over Time for Pseudophakic and Phakic Patients